hatchpak ib h120 applicant : merial final ... -...

HATCHPAK IBH120 FR/V/0171/001/E/001

Merial Repeat-use

Final assessment report of 304

AGENCE NATIONALE DU

MEDICAMENT VETERINAIRE

HATCHPAK IB H120

Applicant : MERIAL

FINAL ASSESSMENT REPORT

Repeat-Use Procedure N° FR/V/0171/001/E/001

PRODUCT DETAILS

Name of product HATCHPAK IB H120

Active ingredients Live infectious Bronchitis virus, H120 strain

Target species Chickens

APPLICATION DETAILS

Type of application Mutual recognition Procedure – repeat use

Name of applicant Merial

Date of receipt of request for assessment report 19/10/2012

Person for communication on behalf of the

applicant during the procedure

Nathalie BOURGUIGNON-GELE

[email protected]

33 4 72 72 31 11

Timetable Clock start : 24/01/2013

Day 54 : 19/03/2013

Day 78 : 12/04/2013

Day 90 : 24/04/2013

New concerned Member States AT*, BE*, BG, CY, IE*, NL*, RO, SI, UK*

Initial Concerned Member States

First round, where MA still valid

CZ, DE, EL, ES, HU, IT, LT, LV, PL, SK


First round, where MA withdrawn

AT*, BE*, FI, IE*, LU, NL*, UK*

* these countries have registered the vaccine in 2007, but MA was withdrawn thereafter; they are

now involved in the repeat-use

REFERENCE MEMBER STATE DETAILS

Assessment report prepared by France

Date of preparation 24/04/2013

Date of the first marketing authorisation in the RMS 14/09/2007

Contact Name Dr Céline Lorteau

Address ANSES - ANMV

8 rue Claude Bourgelat - Parc d'activités de la

Grande Marche - Javené - BP 90203

35302 Fougères Cedex - FRANCE

Phone 33 2 99 94 78 60 (or 33 2 99 94 78 82)

mailto:[email protected]


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E-mail [email protected]



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TABLE OF CONTENTS

INTRODUCTION ............................................................................................................................... 4

PRESENTATION OF THE PRODUCT .................................................................................................................................................. 4 PRESENTATION OF THE PROCEDURES ........................................................................................................................................... 4 SUMMARY OF THE DOSSIER.............................................................................................................................................................. 6

I.A. ADMINISTRATIVE DATA ..................................................................................................................................................... 6 II.B. SUMMARY OF PRODUCT CHARACTERISTICS .................................................................................................................. 8

INITIAL DCP .................................................................................................................................... 12

DCP INITIAL ASSESSMENT REPORT .............................................................................................................................................. 12 ASSESSMENT REPORTS OF THE APPLICANT’S ANSWERS DURING THE INITIAL DCP PROCEDURE ........................ 93

VARIATIONS REPORTS ............................................................................................................... 260

VARIATION FR/V/0171/001/II/001.................................................................................................................................................... 260 VARIATION FR/V/0171/001/II/002.................................................................................................................................................... 264 VARIATION FR/V/0171/001/II/003.................................................................................................................................................... 274 VARIATION FR/V/0171/001/IA/005/G.............................................................................................................................................. 282 VARIATION FR/V/0171/001/IA/006/G.............................................................................................................................................. 282 VARIATION FR/V/0171/001/IB/007 .................................................................................................................................................. 283

RENEWAL ...................................................................................................................................... 285

REPEAT USE .................................................................................................................................. 298


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INTRODUCTION

PRESENTATION OF THE PRODUCT

HATCHPAK IB H120 is a monovalent live vaccine intended for active immunisation of day-old chickens to reduce

infection with Massuchusetts serotype of Infectious Bronchitis virus .

This frozen vaccine is indicated for administration by coarse spray to day old chicks.

This vaccine can be mixed with HATCHPAK AVINEW prior administration.

- Analytical documentation: Controls and production process are performed in conformity with the European

regulation and allow to ensure the consistency of the production. Safety and efficacy data have been taken into

account to determine the minimal and maximal guaranteed titres. The product is stable during storage as

recommended.

- Safety documentation: Safety of the vaccine has been adequately demonstrated in day-old chickens, in

accordance with EU regulation. The vaccine complies with to the requirements of the Ph. Eur. monograph 442

(Avian infectious bronchitis live vaccine). Safety of the mixing with HATCHPAK AVINEW and of the association

with VAXXITEK HVT + IBD has been demonstrated.

- Efficacy documentation: Efficacy of the vaccine has been adequately demonstrated in day-old chickens, in

accordance with EU regulation. The vaccine complies with to the requirements of the Ph. Eur. monograph 442

(Avian infectious bronchitis live vaccine). Efficacy of the mixing with HATCHPAK AVINEW and of the association

with VAXXITEK HVT + IBD has been demonstrated.

PRESENTATION OF THE PROCEDURES

Record of particulars of the initial registration

HATCHPAK IB H120 is one of the 2 components of HATCHPAK AVINEW IB H120.

HATCHPAK AVINEW is the other component of HATCHPAK AVINEW IB H120.

For the record, HATCHPAK AVINEW IB H120 was a bivalent live vaccine, containing the Newcastle disease virus

strain VG/GA (ND component) and the Infection bronchitis strain H120 (IB component). The ND component was

filled in an ampoule and the IB component was filled in another ampoule. Both ampoules were stored frozen in

liquid nitrogen. At the time of vaccination, one ampoule of each component was thawed and diluted in mineral

water; both components were mixed and administered to day-old chicks by nebulisation. This bivalent vaccine is

no more registered as both monovalent vaccines are registered with a claim of possible mixing.

HATCHPAK IB H120 and HATCHPAK AVINEW IB H120 were registered at the same time in all the initial CMSs,

by DC procedures with FR acting as the RMS. The report of the bivalent vaccine has been the support for the 2

procedures. As a consequence, a single assessment report was the basis for the 2 procedures (with crossing out

of information/questions not applicable for the monovalent vaccine).

A few months later, HATCHPAK AVINEW was registered in the same CMSs by a MRP with HU, who had already

a national MA, acting as RMS. The CMSs were the same and the scientific information identical as for the bivalent

vaccine.

Initial Decentralised Procedure

HATCHPAK IB H120 was approved in France and in CMS of the 1st round on 25/07/2007 via decentralised

procedure FR/V0171/001/DC.

Initial CMS were AT,BE,CZ,DE,EL,ES,FI,HU,IE,IT,LT,LU,LV,NL,PL,PT,SK,UK.

Since initial registration, the MA was withdrawn in some of these CMSs (AT,BE,FI,IE,LU,NL,PT,UK) for

administrative (sunset clause) or marketing reasons, and not associated with quality, safety or efficacy issues.


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Subsequent variations :

Number of procedure timetable scope Decision

FR/V/0171/001/II/001 D90: 6/10/2008 Compatibility with VAXXITEK HVT+ IBD Approved

FR/V/0171/001/II/002 D90:

11/01/2009

Addition of a new manufacturing site for the active

ingredient

Approved

FR/V/0171/001/II/003 D90:

31/03/2009

Addition of a new manufacturing site for the final

product

Approved

FR/V/0171/001/IA/004 D30:

17/08/2011

Update of the Ph. Eur. test for bacterial and fungal

sterility

Approved

FR/V/0171/001/IA/005G D30:

16/03/2012

Change of name/address of a manufacturing site Approved

FR/V/0171/001/IA/006G D30:

03/08/2012

Deletion of a manufacturing site Approved

FR/V/0171/001/IB/007 D30:

21/11/2012

Extension of shelf-life to 36 months Approved

Renewal

Renewal of the MA of this vaccine took place between ended on 13/05/2012 and lead to unlimited MA.

Repeat-Use

The applicant proposes to start a repeat-use procedure with J0 on 24/01/2013 including:

- new CMS : BG,CY, RO & SL

- some CMS of the 1st round where MA was withdrawn: AT, BE, IE, NL, PT, UK

Data provided by the applicant for the repeat-use

Consolidated list of all the registration documentation provided on this MRP’s vaccine for its Registration,

Renewal and Variations.

REGISTRATION European dossier (volumes 1 to 10), referenced 1033/EU-01 dated January 2006, including Part I, Part II,

Part III and Part IV

And all the supporting documentation regarding the registration dossier:

• CPh-JL-GeR-EBR-07-D40 (Volumes 1 to 3)

• CPh-JL-GeR-EBR-07-D341

• CPh-GeR-EBR-07-D723


• CPh-EBR-07-D492



• CPh-EBR-07-D542

• CPh-EBR-07-D555

• CPh-EBR-07-D583

• CPh-MB-BioNP-08-E13

• RMM-CB-LCM-08-E321

• AMB-LCM-08-E0681

• RMM-LCM-10-E491

RENEWAL The technical document referenced EU11D0847 dated December 2011

The answers further to renewal document, referenced EU12D0168 dated April 2012

VARIATIONS


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FR/V/0171/001/II/001

• AMB-LBM-LCM-08-D381

FR/V/0171/001/II/002

• FD-CB-LCM-08-D240

• RMM-CB-LCM-08-D0672

• FD-SaC-LCM-08-D0704

• VG-LCM-11-D0867

FR/V/0171/001/II/003

• FD-SaC-LCM-08-D0742

• FD-CC-LCM-09-D0424

• FD-LCM-09-D0472

• VG-IP-LCM-11-D0690

FR/V/0171/001/IA/004

• SC-RMM-LD-LCM-11-D0397

FR/V/0171/001/IA/005

• IP-CB-LCM-11-D0943

FR/V/0171/001/IA/006/G

• VG-LCM-12-D0284

FR/V/0171/001/IB/007

• NBo-VSe-CB-LCM-12-d0535 • NBo-VSe-CC-LCM-12-D0750

Data provided by the RMS for the repeat-use

This assessment report includes the original assessment report of the decentralized procedure, followed by all

assessments performed on this dossier (AR on responses, AR on variations and AR during renewal) and summary

information for minor variations.

SUMMARY OF THE DOSSIER

I.A. ADMINISTRATIVE DATA

I.A.1 Product


Type of product Frozen suspension for nebuliser suspension

Active ingredient Live Infectious Bronchite virus, H120 strain, 3.7 to 4.7 log10 EID50/dose

Container Type I glass ampoules (10,000 or 15,000 doses)

Package size Ampoule carriers are stored in canisters, and within liquid nitrogen containers


Route / method of

administration

Respiratory route by coarse spray


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I.A.2 Source

Holder of the MAA Merial

Name and address of the

applicant

Merial

29, avenue Tony Garnier

69007 Lyon

France

Name and address -

batch release

Merial

Rue de l’aviation

69800 Saint-Priest

France

Name and address -

controls of the finished

product

Merial

Rue de l’aviation

69800 Saint-Priest

France

Tests in animals performed at

Merial – ZI plaine de l’Ain

Allée des cypress

01150 Lagnieu

France


manufacturers of the

active ingredient (2 sites)

Merial

Rue de l’aviation

69800 Saint-Priest

France

IZO

SS 234 per Cremona km 28.2

27013 Chignolo Po (Pavia)

Italy



vaccine and packaging

(3 sites)

Merial

254 rue Marcel Mérieux

69007 Lyon

France

Merial

Rue de l’aviation

69800 Saint-Priest

France

IZO



Italy


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II.B. SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

HATCHPAK IB H120, frozen suspension for nebuliser suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Per one reconstituted dose:

Active substances:

Live Infectious Bronchitis virus, H120 strain .......................................................... 3.7 to 4.7 log10 EID50*

Excipient(s):

For a full list of excipients, see section 6.1.

* 50 per cent egg infective doses

3. PHARMACEUTICAL FORM

Frozen suspension for nebuliser suspension. Yellow.

4. CLINICAL PARTICULARS

4.1 Target species

One day old chickens

4.2 Indications for use, specifying the target species

In one day-old chickens: active immunisation against Infectious Bronchitis in order to reduce infection with

Massuchusetts serotype of Infectious Bronchitis virus.

Onset of immunity: 21 days

Duration of immunity: 6 weeks after a single administration.

4.3 Contraindications

None

4.4 Special warnings for target species

Vaccine viruses can spread to unvaccinated birds. Infection of unvaccinated chickens with the vaccine virus from

vaccinated birds does not cause any signs of disease. Reversion to virulence trials carried out in the laboratory

have shown that the vaccine viruses do not acquire any pathogenic characteristics after at least 5 passages in

chickens.


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4.5 Special precautions for use

Special precautions for use in animals

Vaccinate healthy birds only.

Special precautions to be taken by the person administering the veterinary medicinal product to

animals

- Care should be taken when handling the vaccine preparation. The cold gas must not be breathed. The

manipulation should take place only in well ventilated place to prevent fatal suffocation .

- Wear protective gloves and spectacles during the ampoule thawing and opening operations. Skin contact

with liquid nitrogen must be prevented as it can cause tissue freezing, resulting in severe burns.

- Open ampoules holding them at arm’s length in order to prevent any risk of injury should an ampoule

break.

- Wash and disinfect hands and equipment after vaccinating.

- For more information, contact the manufacturer.

4.6 Adverse reactions (frequency and seriousness)

"Bronchial rales, not associated with respiratory distress or any general sign, may be observed between 5 and 14

days after vaccination in up to 15% of the birds.

4.7 Use during pregnancy, lactation or lay

The vaccine is only intended for use in newly hatched chicks and is not appropriate after the age of one day. The

data available on the properties of the strain are not indicative of a detrimental effect on the reproductive tract, in

particular the strain is compliant to the specifications of the Ph. Eur. with regard to the safety for the reproductive

tract.

4.8 Interaction with other medicinal products and other forms of interaction

No information is available on the safety and efficacy from the concurrent use of this vaccine with any other except

with a frozen live vaccine against Newcastle disease containing VG/GA strain and with a recombinant HVT vaccine

expressing the protective antigen of the Infectious Bursal disease virus. It is therefore recommended that no other

vaccines than these should be administered within 14 days before or after vaccination with the product.

4.9 Amounts to be administered and administration route

4.9.1 Reconstitution of the vaccine

1. Prepare a container filled with the appropriate quantity of clean non-chlorinated drinking water (7 to 30 ml

per box of 100 chicks according to the type of sprayer used in the hatchery).

2. Wear protective gloves and spectacles whilst thawing and opening the ampoules. Maximal precautions

when handling liquid nitrogen should be taken. Refer to the section 4.5. Special precautions for use.

3. Remove from the liquid nitrogen container only those ampoules carried by a yellow cane which are to be

used during the vaccination session.

4. Thaw the contents of the ampoules rapidly by agitation in water at 25-30°C. Proceed immediately to next

step.

5. As soon as they are completely thawed, open the ampoules by holding them at arm’s length in order to

minimise risk of injury should the ampoule break.

6. Once the ampoule is open, draw up the content into a 10-ml sterile syringe.


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7. Transfer the suspension into the container containing the appropriate quantity of clean non-chlorinated

water prepared at step1.

8. Draw up 5 ml of the contents of the container into the syringe.

9. Rinse the ampoule with these 5 ml, and then transfer the rinsing liquid into the container.

10. Repeat the rinsing operation once or twice.

11. Where HatchPak Avinew (carried by green cane) is to be used concurrently and presented in a second

ampoule, carry out again the steps 3 to 10 (opening the ampoule, drawing up vaccine, rinsing the ampoule) with

the second ampoule of vaccine. Then, transfer the contents of this second ampoule into the container which has

previously been used for the first vaccine.

12. The reconstituted vaccine prepared as described is ready for use. It should be used immediately after

preparation and therefore the vaccine suspension should only be prepared as and when required.

13. Discard any ampoules that have been accidentally thawed. Do not re-freeze under any circumstances.

4.9.2 Posology

One administration from day-old, via the respiratory route (spray application).

4.9.3 Method of administration

- The vaccine is intended for mass vaccination of chicks in the hatchery, the vaccine solution should be applied as

a coarse spray whilst the chicks are in their chick boxes.

- Spray the vaccine solution above the birds using a sprayer that enables produc tion of drops of 100 µm or more

that cover the chicks with the vaccine, so the vaccine is administered directly to their eye and the droplets pearls

that shine on the down will encourage them to pick them off of each other and from the surface of the box.

- For effective vaccine distribution, make sure that birds are closely confined together during spraying. During and

after vaccination ventilation should be switched off in order to avoid turbulences.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary

No side effects other than those listed in paragraph “Adverse reactions” have been observed following the

administration of more than 10 times the recommended dose of vaccine.

4.11 Withdrawal period(s)

Zero days.

5. IMMUNOLOGICAL PROPERTIES

ATCVet Code: QI01AD07.

The vaccine contains live infectious Bronchitis virus, H120 strain (Massachusetts serotype). The vaccine

stimulates active immunity against Infectious Bronchitis.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Protein hydrolysate

Mannitol


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6.2 Incompatibilities

The presence of disinfectant and/or antiseptic in water and material used for the preparation of the vaccine

solution is not compatible with effective vaccination.

Do not mix with any other medicinal product, except a live frozen vaccine against Newcastle disease containing

VG/GA strain.

6.3 Shelf life

Shelf life of the medicinal product as package for sale: 3 years

Use immediately after opening the vials and administer within 2 hours after preparation of the vaccine for use.

6.4. Special precautions for storage

Store and transport the vaccine in liquid nitrogen (-196°C) and regularly check the level of liquid nitrogen.

Store the reconstituted vaccine at a temperature lower than 25°C.

6.5 Nature and composition of immediate packaging

Type I glass ampoule, 4- yellow ampoules cane.

Ampoule canes are stored in canisters, and within liquid nitrogen containers.

- 10,000 doses ampoule

- 15,000 doses ampoule

Not all pack sizes may be marketed.

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste

materials derived from the use of such products

Dispose of waste material and any unused veterinary medicinal product by boiling, incineration or immersion in

an appropriate disinfectant in accordance with national requirements.

7. MARKETING AUTHORISATION HOLDER

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 DATE OF REVISION OF THE TEXT

PROHIBITION OF SALE, SUPPLY AND/OR USE

The import, sale, supply and/or use of HatchPak IB H120 is or may be prohibited in certain Member States on the

whole or part of their territory pursuant to national animal health policy. Any person intending to import, sell,

supply and/or use HatchPak IB H120 must consult the relevant Member State’s competent authority on the

current vaccination policies prior to the import, sale, supply and/or use of the product.


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INITIAL DCP

DCP INITIAL ASSESSMENT REPORT


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FRENCH AGENCY FOR FOOD SAFETY

(Agence Française de Sécurité Sanitaire des Aliments)

National Agency for Veterinary Drugs

(Agence Nationale du Médicament Vétérinaire)

DECENTRALISED PROCEDURE

1st STEP – ASSESSMENT REPORT and CLOQ

FR/V/0171/001/DC

PRODUCT DETAILS


Active ingredient(s) Live infectious Bronchitis virus, H120 strain


APPLICATION(S) DETAILS

Type of application Decentralised procedure

Name and address of applicant MERIAL

29 avenue Tony Garnier

69007 LYON

France

Phone number 33-(0)-4 72 72 39 72

Fax number 33-(0)-4 72 72 33 68


Person for communication on behalf of the applicant

during the procedure

Corinne Philippe-Reversat (replacing Rose-Marie

MOLINA)

[email protected]

Reference number of application FR/V/0171/001/DC


Day 70 : 08/12/2006

Day 100 : 07/01/2007

Day 105 : 12/01/2007

Concerned member states AT, BE, CZ, DE, EL, ES, FI, HU, IE, IT, LT, LU, LV,

NL, PL, PT, SK, UK

RMS DETAILS

Member state responsible for preparing the

assessment report

France


Reference number in the originating member state

(e.g. marketing authorisation number)

12418

Date product first authorised in the originating member

state

Not applicable

CONTACT WITH THE RMS

Contact name Dr Céline LORTEAU

Address ANMV - BP 90203 - 35302 Fougères CEDEX France

Phone number + 33 2 99 94 78 82

Fax number + 33 2 99 94 78 88



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e-mail address [email protected]



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I. Summary of the dossier

Introduction from the RMS

HATCHPAK IB H120 is one of the 2 components of HATCHPAK AVINEW IB H120. For the record, HATCHPAK

AVINEW IB H120 is a bivalent live vaccine, containing the Newcastle disease virus strain VG/GA (ND component)

and the Infection bronchitis strain H120 (IB component). The ND component is filled in an ampoule and the IB

component is filled in another ampoule. Both ampoules are stored frozen in liquid nitrogen. At the time of

vaccination, one ampoule of each component is thawed and diluted in mineral water; both components are mixed

and administered to day-old chicks by nebulisation.

The RMS has reviewed the dossier of HATCHPAK IB H120 and checked whether or not the information

concerning the IB component provided in the dossier HATCHPAK AVINEW IB H120 (corresponding thus to

HATCHPAK IB H120) was identical in both dossiers. It appears that this information is strictly identical. With

regard to the safety and efficacy information, the dossier of HATCHPAK IB H120 doesn’t contain any specific

information not provided in the dossier HATCHPAK AVINEW IB H120. Both products are applied for a marketi ng

authorisation in the same EU countries following the same timetable.

Thus, in order to save time at each step of the procedure and to avoid mistakes in replicating part of the

report, questions and answers, the RMS has decided to present the same report for both products. Only the

SPC (and part I information) are analysed specifically for HATCHPAK IB H120. Questions specific to the ND

component (HatchPak Avinew) and bivalent vaccine (HatchPak Avinew IB H120) are crossed out in the

report for HATCHPAK IB H120.

The Infectious Bronchitis H120 strain is already present in a monovalent live vaccine of the same applicant:

BIORAL H120. BIORAL H120 is freeze-dried and stored at +5°C and indicated in chicks from the age of 1 day.

BIORAL H120 was registered in France in 1988.

There is a Ph. Eur. monographs live Infectious Bronchitis vaccine (n°442) applicable to HATCHPAK IB H120.

Compliance to this monograph is discussed in the RMS report.

The data from the dossier are summarised in normal fount, whereas the RMS comments and questions are in

italics.

Question 1

For the information of the applicant:

Finland has a serological surveillance program for Infectious Bronchitis and no clinical disease. Therefore, the

sale, supply and use of this product will not be allowed in Finland (Council Directive 90/677/EEC, Article 4).


Pharmacovigilance system

Question 2

The outstanding issues to be considered are as follow:

- Qualified person responsible for pharmacovigilance.

- Description of the back-up procedure to apply in their absence.

The applicant should submit a brief description of the back-up system in place in the QP’s absence and the name

of the QP´s substitute person.

- Procedures in place which are documented in writing.

Continuous monitoring of the safety profile of the authorised medicinal products and notifying competent authorities

and health professionals of changes to the benefit / risk balance of products. Signal generation and Benefit / risk

assessment.

The applicant should provide information about: activities of the QPPV, the collection, processing, coding,

classification and medical review. It is also necessary incorporate follow-up of reports for missing information and


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for information on the progress and outcome of the case(s), detection of duplicate reports, expedited reporting,

electronic reporting, PSURs, continuous monitoring of the safety profile of the authorised medicinal products and

notifying competent authorities (CA) and healthcare professional of changes to the risk -benefit balance of products,

responses to request for information from regulatory authorities, meeting commitments to CA, global

pharmacovigilance activities applying to all products, management and use of databases.

- Handling of urgent safety restrictions and safety variations.

The applicant should submit a commitment to amend the procedure on the handling of urgent safety restrictions

and safety variations to deal with such restrictions and variations rather than risk management procedures only.

- Internal audit of the Pharmacovigilance system.

The applicant should provide the reference code number of the SOP (Standard Operation Procedure) for auditing

the pharmacovigilanca system.

- Staff training.

The applicant should submit a commitment to put in place a system of staff training in place.

- Provide a brief description of the agreements with co-marketing partners and contractor for

Pharmacovigilance activities: include reporting responsibilities and arrangements for literature searches.

The applicant should provide a brief but comprehensive description of the agreements with co-marketing partners

and contractors for Pharmacovigilance activities, including reporting responsibilities and arrangements for literature

searches.

- Provide a brief description of the Quality management system, making cross-reference to the elements

provided under the above sections. Particular emphasis should be placed on organisational roles and

responsibilities for the activities and documentation, and for ensuring corrective and preventive action.

The applicant should provide a brief description of the quality management system in place including description of

SOP and its reference code, audits and management oversight.

I.A.1 Product


Type of product Live viral vaccine


Pharmaceutical form Frozen suspension for suspension for nebulisation

Container Type I glass ampoule, 4-ampoule carrier. Ampoule carriers are stored in

canisters, and within liquid nitrogen containers.

Package size - 10,000 doses: 10,000-dose IB ampoule

- 15,000 doses: 15,000-dose IB ampoule

Target species Chicken

Route / method of administration Respiratory route / nebulisation

I.A.2 Source

Applicant MERIAL


69007 LYON

France

Manufacturer of the active

ingredients

MERIAL Laboratoire de Lyon Gerland


69007 LYON

France

Or MERIAL ITALIA SPA


27013 CHIGNOLO PO (PAVIA)

Italy

Manufacturer of the finished

product – primary packaging



69007 LYON

France




Italy

Labelling and second

packaging

Not applicable


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Final product testing MERIAL Laboratoire Porte des Alpes

Rue de l’Aviation

69800 SAINT PRIEST

France

And Testing using animals :

Centre de Saint-Vulbas

Z.I. Plaine de l’Ain

Allée des Cyprès

01150 Lagnieu

France

Responsible for batch release MERIAL Laboratoire Porte des Alpes

Rue de l’Aviation

69800 SAINT PRIEST

France

Question 3

EMEA/INS/GMP/3351/03/Rev 4 states that “GMP inspections should be carried out at least every 2 years. Large

companies may be inspected department by department, a full GMP inspection being completed at least every 5

years. The interval between inspections should never exceed 3 years ….”. Consequently more recent certification

should be available based on inspections conducted at Lyon (before December 2006) and Chingolo Po (before

June 2006). The Applicant should provide current GMP certification.

The Applicant should provide documentation to confirm that finished product testing at Centre de Saint -Vulbas is

covered by appropriate GMP certification.

The Applicant has provided GMP certification for Novento Padovana. The Applicant should clarify what role this

site plays during production.

I.B.1 SPC

Question 4

For the record: there may be additional changes required in light of the responses received in response to the

outstanding points.

1. Name of the Veterinary Medicinal Product

HatchPak IB H120

2. Qualitative and Quantitative composition

Live Infectious Bronchite virus, H120 strain, at least ............................................... 3.7 log10 EID50

Question 5

The maximum titre per dose at release should be included for both vaccine strains.

The epigraph “Active substance” and “per one reconstituted dose” should be indicated in this section.

The sentence “For a full list of excipients, see section 6.1”. should be included.

The meaning of EID50, should be clearly clarified with an asterisk (*), and a footnote.

3. Pharmaceutical form

Frozen suspension for suspension for nebulisation.

Question 6

The physical aspect of the suspension should be added.

Suspension for nebulisation is not a standard term of Eur. Ph., but it is Nebuliser suspension. Thus, it should be

indicated as “Frozen suspension for nebuliser suspension”.

4. Clinical particulars

4.1. Target species

Chickens.


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Question 7

This section may need to be revised to “Chickens (broiler chickens)” depending on the answer to t he questions

raised concerning the efficacy in conventional layer chickens (see part IV).

4.2. Indications for use, specifying the target species

In day-old chickens:

- active immunisation against Infectious Bronchitis in order to reduce infection with Massuchusetts serotype

of Infectious Bronchitis virus.

Immunity has been demonstrated 21 days after first administration and has been shown to persist until 6 weeks of

age.

Question 8

Instead of “In day-old chickens”, “In one day-old chickens” is considered clearer. This applies also to other points.

The applicant should also refer to the last questions in the conclusion of the efficacy section.

4.3. Contraindications

None.

Question 9

As indicated in section III.C.4., the studies to show the innocuousness of the vaccine on reproductive

performance are not acceptable and the vaccine should be contraindicated in animals destined for breeding (CMS

n°4).

4.4. Special warnings for each target species

Vaccine viruses can spread to unvaccinated birds. Infection of unvaccinated birds with the vaccine virus from

vaccinated birds does not cause any signs of disease. Moreover, reversion to virulence trials carried out in the

laboratory have shown that the vaccine viruses do not acquire any pathogenic characteristi cs after at least 5

passages in chickens. Therefore, spread to unvaccinated birds, in the present state of knowledge, can be

considered as safe.

Question 10

Tak ing into account the data available, and the fact that only the chicken was studied, it is proposed to modify the

section to:

“Vaccine viruses can spread to unvaccinated birds. Infection of unvaccinated birds chickens with the vaccine

virus from vaccinated birds does not cause any signs of disease. Moreover, reversion to virulence trials carried out

in the laboratory have shown that the vaccine viruses do not acquire any pathogenic characteristics after at least 5

passages in chickens.” Therefore, spread to unvaccinated birds, in the present state of knowledge, can be

considered as safe.

Nevertheless, the section may be revised in the light of the answers to the questions raised in part III of the report.

Specific approach of CMS n°4:

It should be recommended to vaccinate all the birds in the flock . A sentence with this recommendation should be

included in this section. “To prevent spreading of the vaccine strain to unvaccinated birds, vaccinate all the chicks

in the flock”

Position of CMS n°6:

Additional data on spread to other avian species are awaited (see question under III.E).

4.5. Special precautions for use

i) Special precautions for use in animals


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ii) Special precautions to be taken by the person administering the medicinal products to animals

- Care should be taken when handling the vaccine preparation.

- Wear protective gloves and spectacles during the ampoule thawing and opening operations.


break.

- Hands should be washed and disinfected after vaccinating.


Question 11

It is proposed to reword the section to:



- Because live Newcastle disease virus may cause a mild transient conjunctivitis in the person

administering the vaccine, contact of eyes and airways with the vaccine virus should be prevented.

Therefore it is recommended to wear respiratory and eye protection in compliance with current European

standards.


break.



In addition, some special warning concerning handling of liquid nitrogen should be added: warning of burning,

warning of opening in an open-place or not breathing, etc.

4.6. Adverses reactions (frequency and seriousness)

No general reactions or lesions were observed following the administration of one dose of vaccine except slight and

transient bronchial rales within the 2 weeks following vaccination.

Question 12

Tak ing into account the adverse reactions observed in section III of the dossier, it is propos ed to revise the

section to:

“Reduced weight gain attributable to the Newcastle Disease vaccine strain may be observed after vaccination.

Bronchial rales, not associated with respiratory distress or any general sign, may be observed between 5 and 14

days after vaccination in up to 75% of the birds, attributable to the Infectious Bronchitis vaccine strain.”

However, a CMS (n°1) requires the applicant to provide further justifications and data to support this proposal,

tak ing into account:

- that coughing was observed up to 33 days in one field study

- the results of the new overdose dose study requested by the spray route of administration (see questions in

section III); the applicant should note that this section of the SPC may need further modification depending on the

results of the required overdose study due to the use of a route other than that recommended

- that rales were observed for up to 21 days in report 04.0188.R.

4.7. Use during pregnancy, lactation or lay

Not claimed. However, the vaccine strain has been shown to be safe in pullets with regard to reproductive

performance, and absence of effect on the genital tract.

Question 13

Tak ing into account the information available in the safety part of the dossier, the RMS proposes to reword the

section to:

“The vaccine is not intended for use in breeders and layers. The data available on the properties of the strains are

not indicative of a detrimental effect on the reproductive tract, in particular the IB strain is compliant to the

specifications of the Ph. Eur. with regard to the safety for the reproductive tract.”


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However, divergent opinions from CMSs were received, (see below and also section III.C.4. examination of

reproductive performances) and should be taken into account by the applicant when proposing a new wording for

the section.

Position of CMS n°4: The sentence “not claimed. However, the vaccine strains have been shown to be safe in

pullets” should be removed, as safety on reproductive performance has not been demonstrated. Instead, the

following sentence should be stated “Do not vaccinate during pregnancy, lactation or lay”

Position of CMS n°1: see III.C.4.

4.8. Interaction with other medicinal products and other forms of interaction

No information is available on the safety and the efficacy from the concurrent use of this vaccine with any other

except with MERIAL live vaccines against Newcastle disease containing VG/GA strain and with MERIAL

recombinant HVT expressing the protective antigen of the Infectious Bursal disease virus. It i s therefore

recommended that no other vaccines than this should be administered within 14 days before or after vaccination

with the product.

Question 14

This section should be revised tak ing into account the questions raised in part III and IV of the report concerning

the interaction with VAXXITEK HVT+IBD.

4.9. Amount(s) to be administered and administration route


1. Prepare a container filled with the appropriate quantity of clean non-chlorinated water (7 to 30 ml per box of

100 chicks according to the type of sprayer used in the hatchery).

2. Wear protective gloves and spectacles whilst thawing and opening the ampoules.

3. Remove from the liquid nitrogen container only those ampoules which are to be used during the

vaccination session.

4. Thaw the contents of the ampoules.









11. Where another vaccine is to be used concurrently and presented in a second ampoule, carry out steps 3-

10 (opening the ampoule, drawing up vaccine, rinsing the ampoule) with the second ampoule of vaccine,

the contents of which are transferred into the container which has previously been used for the first

vaccine.



Question 15

It is considered that for user safety reasons Section 4.9.1 (Reconstitution of the vaccine) should be reworded. In

particular it is considered that point 11 should be revised to be more explicit to the end user. It could be helpful to

include the aspects of the instructions currently included in section 11 (in a revised form) after point 2.

The sentence concerning tak ing maximal precautions when handling liquid nitrogen should be included in bullet

point 2.

The instruction: “thaw the contents of the ampoules” should explain in more details if the ampoules can be thawed

at 37ºC or should be thawed at room temperature (bullet point 4).

All efficacy trials with spray vaccination were done with spring water diluted vaccine, and in the SPC for

reconstitution of the vaccine clean non-chlorinated water is proposed. Either the SPC wording should be changed

for spring water or the quality of the non-chlorinated water should be determined more precisely. Another CMS

proposes to change in the SPC section 4.9.1., “non-chlorinated water” to “commercial available mineral water with


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low concentration of minerals and pH 7”, because it reflects the fact that in all the tria ls presented, the vaccine

was solved in Volvic or Evian.

4.9.2 Posology

One administration of the product from day-old, via the respiratory route (spray application).

Question 16

The applicant should refer to the CMS n°6 question concerning the IB booster in section IV.E.Conclusion.




- For effective vaccine distribution, make sure that birds are closely confined together during spraying.

Question 17

The spray application should be described in more detail especially with regard to the characteristics of the

application machine. (Please compare with the SPCs of other vaccines already licensed via MRP).

4.10. Overdose (symptoms, emergency procedures, antidotes), if necessary



Question 18

This section may be revised in the light of the results of the trial requested demonstrating the safety of an

overdose of both components administered together, as claimed.

4.11. Withdrawal period(s)

Zero days.

5. Immunological properties


The vaccine contains live Infectious Bronchitis virus, H120 strain. The vaccine stimulates active immunity against

Infectious Bronchitis.

Question 19

As in the indications, it should be mentioned that the vaccine induces active immunity against Massachusetts

serotype of the IBV.

6. Pharmaceutical particulars

6.1. List of excipients

None.

Question 20

A full list of excipients should be included in this section, in particular components of the stabiliser should be

mentioned.

6.2. Incompatibilities


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The presence of disinfectant and/or antiseptic in water and material used for the preparation of the vaccine solution

is not compatible with effective vaccination.

Do not mix with any other medicinal product, except MERIAL live frozen vaccine against Newcastle disease

containing MERIAL VG/GA strain.

Question 21

It is considered that the 1st sentence proposed under Section 6.2 (Incompatibilities) should be placed under

section 4.5 (Special Precautions for use).

6.3. Shelf-life

18 months.

Use immediately after opening.

Use within 2 hours after reconstitution.

Question 22

It is considered that the following wording could be more informative to the end user: “Use immediately after

opening the vials and administer within 2 hours after preparation of the vaccine for use”.


Store the vaccine in liquid nitrogen (-196°C) and regularly check the level of liquid nitrogen.


Question 23

It is considered that the word reconstituted is not appropriate for a wet frozen preparation and therefore the word

“reconstituted” should be replaced by the word “prepared”.

6.5. Nature and composition of immediate packaging

Type I glass ampoule, 4-ampoule carrier.

Ampoule carriers are stored in canisters, and within liquid nitrogen containers.

- 10,000-dose ampoule

- 15,000-dose ampoule

Question 24

A brief explanation of the nature of the carriers and canister should be included.

6.6. Special precautions for the disposal of unused veterinary medicinal product or waste materials

derived from the use of such products, if appropriate

Discard any ampoules that have been accidentally thawed. Do not re-freeze under any circumstances.

Dispose of waste material by boiling, incineration or immersion in an appropriate disinfectant in accordance with

national requirements.

Question 25

The sentence “”Discard any ampoules that have been accidentally thawed” and “do not re-freeze under any

circumstances” should be indicated in section 4.9 (Amounts to be administered and administration route).

The sentence “Dispose of waste material by boiling…” should be reworded to “Dispose of waste material and any

unused veterinary medicinal product by boiling…”

7. Marketing authorisation holder

MERIAL


69007 LYON

France


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8. Marketing authorisation number(s)


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I.B.2 LABELLING / LEAFLET

Question 26


In addition to any changes following from amendments to the SPC, PT national requirements must also be

fulfilled.

IE national issues concerning leaflet: include the VPA number and Indicate the method of sale and supply as

POM – Prescription only medicine.

Labelling

Vol. 1/12, p.101-102

Hatchpak IB H120 is composed of ampoules of 5 ml, clipped on metallic carriers (4 ampoules per carrier). Carriers

are stored and sold in liquid nitrogen containers (-196°C).

The applicant explains that the primary packaging is very small (5-ml ampoule) and there is no possibility to

perform any labelling operation after freezing (the operation of filling, sealing and freezing are carried out

consecutively in closed circuit).

Therefore, the applicant plans to label the ampoules before filling, with the following minimum information:

- name of the product : “Hatchpack IB H120”

- number of dose: “10 000 doses” or “15 000 doses”

- the wordings “lot” and “exp.”

- The national translation of the sentence “for animal treatment only”; when CMS can agree, the wording “ad

us. vet.” is used instead of the national translation

- “Merial”

RMS comment

The applicant should indicate on the ampoules the route of administration, as it is requested by the EC directive

2004/28, article 59.

The applicant should provide the RMS with a sample (ampoules and carrier) of the final product.

Else, the labelling of the ampoules as indicated is acceptable.

Question 27


Concerning the immediate packaging, it is acknowledged that the storage conditions impose some restrictions on

the amount of information placed on the label. However, it is considered that the Applicant should justify this by

discussion of these limitations and clarification of how the information is applied (to the vial or cane).

In addition, the applicant should indicate on the ampoules the route of administration, as it is requested by the EC

directive 2004/28, article 59.

The applicant is informed of specific approaches of CMSs and should take them into account when revising the

proposal:

A CMS has the following position: the quantity of the active substance, route of administration and withdrawal

period must be included on the label. Besides, the nitrogen container should have a label with all the leaflet

information.

Another CMS has the following position: The mandatory items (quantity of the active substance, route of

administration and withdrawal period) should be stated. A multilingual labelling cannot be accepted i f it is not

possible to include the minimum information and the minimum letter size for readability.

A 3rd CMS has the following position: We’d like to propose a label (particulars to appear on the outer package)

using for the liquid nitrogen container. It should be attached to the liquid nitrogen container or if there are different

vaccines or batches of vaccines in the container, different labels should be attached to different metallic carrier.

A 4th CMS considers that the immediate label is acceptable.


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Leaflet

Vol.1/12, p.109


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II. Analytical part

Vol. 4/12, p.001

The applicant reminds that active ingredients (ND and IB components) are considered as starting materials. Thus,

the production and control of these active ingredients are described in section II.C.2.1.

Section II.B. describes the preparation of the final product and section II.D. describes the controls performed during

production of the final product.

Note from the RMS

The part II of the dossier doesn’t follow the numbering of the sections according to the directive 2004/28/EC (no

part II.D for TSE risk). In this report, the RMS has modified the numbering to be in accordance with the directive.

Question 28


Some CMSs don’t agree to consider the active component as the starting material, mak ing for them difficult to

perform the assessment of the dossier. One of them (DE) informs the applicant that in future, dossiers in this

format may not be validated.

II.A. QUALITATIVE AND QUANTITATIVE PARTICULARS

II.A.1. Table of qualitative and quantitative particulars

Vol. 4/12, p.003

Hatchpack Avinew

Name of ingredients Quantity per dose function

Active ingredient Live Newcastle Disease Virus (VG/GA)

component

5.5 to 6.7 log10 EID50 Supply of antigen

Adjuvant(s) Not applicable Not applicable Not applicable

Excipient(s) Not applicable Not applicable Not applicable

Hatchpack IB H120

Name of ingredients Quantity per dose function

Active ingredient Live Infectious Bronchitis (H120) component 3.7 to 4.7 log10 EID50 Supply of antigen

Adjuvant(s) Not applicable Not applicable Not applicable

Excipient(s) Not applicable Not applicable Not applicable

RMS comment

The preparation of the final product (see section II.B.) consists of filling and freezing the active ingredients in

ampoules; thus, there are no excipients in the final product, which is constituted only of active ingredient. However,

this approach is not well understood by a number of CMS and the applicant should provide a clarification.

Question 29




Question 30


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There is conflicting and confusing information regarding the stabiliser used. At various points in the dossier the

Applicant refers to Stabilser 26, 44, 54 and 56. It is considered that a clear explanation should be provided to

clarify the specific differences in these stabilisers, which stabiliser is used for which component and at which point

the stabiliser is added.

In addition, the ingredients of the stabiliser constitute excipients. Therefore, the Applicant should amend the table

of qualitative and quantitative particulars accordingly. Furthermore, Section 6.1 of the SPC will also need to be

revised accordingly as currently the section states “none”.

The final composition of antibiotics and stabilizer should be clearly stated.

II.A.2. Containers

Vol. 4/12, p.003

Sealed glass ampoule

Type I glass, complying with the current Ph. Eur. edition.

The vaccine is filled into ampoules, which are sealed using a flame.

The ampoule is open by breaking its neck; the content of the vaccine is diluted in water just after thawing.

RMS comment

The certificate of analysis is provided in section II.C.1.12, vol. 4/12 p.081. The results comply with the

requirements of Ph. Eur. monograph 3.2.1. for hydrolytic resistance (test A) and arsenic.

Concerning the identification of the ampoules, please refer to section I.B.2. Labelling and leaflet.

II.A.3. Development of the product

Vol. 4/12, p.004

The vaccine consists of 2 ampoules, one containing a frozen live suspension of the VG/GA strain of ND virus

(Hatchpack Avinew) and the other a frozen live suspension of the H120 strain of IB virus, to be reconstituted

simultaneously together with mineral quality water for simultaneous administration by nebulisation to chickens.

Summarised data

The justifications are summarised below; studies cited are described thereafter.

choice of the strains:

Newcastle disease: VG/GA strain naturally apathogenic and viscerotropic; genetic identificat ion available

(annex p.397). This strain induces no or minimal respiratory reaction after vaccination (annex p.531), a

protection similar to B1B1 or Hitchner B1 strain (annex p.533), has no negative effect on growth

performances and mortality, is lentogenic (IPIC < 0.5, report 99.0676.R p.334 & report

SG/VA.DEB.95/D254 p.355), has an amino acid sequence around the cleavage site identical to the Ulster

strain (annex p.397).

Infectious bronchitis strain H120: attenuated by serial passages in embryonated chick en eggs, widely

used, has a respiratory tropism and is suitable for respiratory administration.

Starting materials: those of biological origin are used only if absolutely necessary and are gamma irradiated

(validation provided in annex p.404)

BSE/TSE assessment: see details in relevant section II.D.

Pharmaceutical form: frozen form suitable for hatchery (stability, quick reconstitution, high dose presentation)

Antigen concentration: minimal and maximal amounts per dose determined from respectively the effic acy and

safety trials

No preservative because the vaccine is to be used immediately after reconstitution

Container compliant to Ph. Eur. and of a size adapted to the reduced volume of the vaccine (approx. 5

ml/container)


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Overage: no loss of titre is observed during storage, therefore, the release titre is the minimum titre claimed

(no overage)

Reproducibility of production:

Reproducibility/repeatability of the quantification of the antigens (report 00.0874.R in annex p.424 for ND

component and report 00.0838.R in annex p.435 for IB component)

Manufacturing process ensuring the consistency of production

Batch to batch consistency supported by the results obtained for 6 batches of active ingredient and 6

batches of finished product for both components

Diluent: mineral quality water, due to the route of administration (respiratory by spray); no diluent provided with

the vaccine

Question 31

The applicant partially justifies the use of IB H120 strain as follows “initial isolates from main countries are of that

serotype”. The applicant should further justify if these “main countries” include European countries and the

relevance of this strain in Spain.

Detailed reports

Report (vol.5/12, p.397): VG/GA strain – amino-acid sequence

The amino-acid sequence around the protein F clivage site was determined for the VG/GA strain:

F2 Cleavage site F1

Site 111 112 113 114 115 116 117 118 119

Gly Gly Lys Gln Gly Arg Leu Ile Gly

RMS comment

This result is compliant to the requirements of the Ph. Eur. 450 (section 2.4.2).

Report 99.0676.R (vol.5/12, p.334) : VG/GA strain – measurement of the ICPI

MSV+1 (Master Seed Virus + 1 passage) was inoculated to embryonated eggs, allantoic fluids collected after 48

hours and the resultant viral suspension titrated on embryonated eggs (10.1 log10 EID50/ml). 4 groups of 12 SPF

chicks aged 26-35 hours were inoculated with a volume of 0.05ml by intracerebral route:

- group G1: 8.8 log10 EID50/chick



- group G4: chick inoculated with virus-free allantoic fluid

The chicks were monitored from day 1 to day 8. The IPIC was determined according to the Ph. Eur. monograph

450 (live vaccine against Newcastle disease). The IPIC were:

Group 1 Group 2 Group 3 Group 4

Dose received 8.8 log10 EID50/chick 8.5 log10 EID50/chick 8.2 log10 EID50/chick -

ICPI 0.32 0.18 0 0

RMS comment

This report is compliant to the requirements of the Ph. Eur. 450 (section 2.4.1.), in term of both protocol and

results.

Report SG/VA.DEB.95/D254 (vol.5/12, p.355) : VG/GA strain – reversion to virulence

The vaccine Avinew (same strain as in Hatchpak Avinew, MSV+2) was administered to 10 one-day-old SPF chicks

by the oculo-nasal route (1st passage); 8 serial passages were conducted thereafter in groups of ten SPF chicks

aged 1 to 3 days by natural route; 20 birds were used for the 10 th passage.

Persistence of the virus throughout the passages was checked.

The ICPI of the vaccine strain VG/GA passaged 10 times was calculated. At the same time, the ICPI of the

unpassaged strain was also calculated. The IPIC were:

Unpassaged virus Virus from the 10th passage


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Dose received 8.8 log10 EID50/chick 8.5 log10 EID50/chick 8.0 log10 EID50/chick 7.7 log10 EID50/chick

ICPI 0.36 0.31 0.13 0.28

RMS comment


results. See also part III of the dossier for further information on the biological properties of the vaccine strain.

Report 00.0874.R (vol.5/12, p.424) : validation of the titration of ND virus strain VG/GA on eggs

4 independent titration sessions were carried out involving 2 operators; in each session the operators made 3 or 4

titrations. 18 results were obtained and analysed.

standard deviation of repeatability: 0.25 log10

standard deviation of reproducibility: 0.30 log10

RMS comment

For the record, this result corresponds to a coefficient of variation of reproducibility of 3% (std/mean), the mean

titre being 9.187 log10 EID50/bottle.

Report 00.0838.R (vol.5/12, p.436) : validation of the titration of IB virus strain Mass41 on eggs

3 independent titration sessions were carried out involving 2 operators; in each session the operators made 3

titrations. 12 results were obtained and analysed.

standard deviation of repeatability: 0.28 log10

standard deviation of reproducibility: 0.36 log10

RMS comment

The validation was performed for the Mass 41 strain whereas the vaccine contains the H120 strain. The applicant

should thus explain the relevance of these results for the vaccine strain IB H120.

For the record, this result corresponds to a coefficient of variation of reproducibility of 5% (std/mean), the mean

titre being 7.88 log10 EID50/bottle.

Question 32

Report 00.0838.R (p.436) : validation of the titration of IB virus strain Mass41 on eggs



Only reproducibility and repeatability have been evaluated, however the linearity, sensitivity and specificity of the

technique have not been demonstrated. Further data should be provided.

II.B. METHOD OF PREPARATION

Vol.4/12, p.11-16

The same process applies to Hatchpak Avinew and Hatchpak IB H120.

If the active ingredient is frozen, thawing of the active ingredient; stirring; storage at +5°C; filling; sealing of the

ampoule; freezing at < -120°C; storage in liquid nitrogen.

For both Hatchpak Avinew and Hatchpak IB H120, tables of the characteristics of 3 batches produced at Chignolo-

Pô (Italy) and Lyon laboratories (France) are provided p.17-18.

RMS comment

It is indicated that the blended product may be stored at +5°C. The applicant should indicate how long this storage

may last and analyse the impact on stability; however, this is not a major issue as far as it is a live vaccine titrated

at release.

Question 33


may last and analyse the impact on stability.


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In the production flow chart for the IB H120 component, the applicant indicates that this component can be used

extemporaneous or thawed. It should be clarified whether this can affect the quality and propert ies of the product.

Moreover, the maximum storage period for this component under these conditions should be clearly indicated. A

similar question is raised for stage 2 to 3 of the production process for the IB component. The maximum storage

period for the blended product should be stated.

Validation studies

A table summarises the validation studies available vol. 4/12, p.18.

II.C. PRODUCTION AND CONTROL OF STARTING MATERIALS

II.C.1. Starting materials listed in a pharmacopoeia

ingredient Pharmacopoeia reference Certificate of analysis Page

Dipotassium phosphate 1003 Compliant 21

Disodium phosphate dihydrate 602 Compliant 26

Gentamicin sulphate 331 Compliant 31

Mannitol 559 Compliant 36

Polymyxin B sulphate 203 Compliant 42

Povidone 685 Viscosity test missing 48

Potassium dihydrogen phosphate 920 Compliant 54

Water for injection in bulk 169 Compliant 58

Sodium chloride 193 Compliant 64

SPF embryonated hen eggs 5.2.2. See comment below 69

Sucrose 204 Compliant 75

Glass container for parenteral use (type

I)

3.2.1. See report section II.A.2. 81

RMS comment

Mannitol: the monograph published in the addendum 5.3. and provided by the applicant in the dossier has

been corrected in the addendum 5.4.; indeed, identification is either made by Infrared absorption

spectrophotometry (test C) or by tests A, B and D. The certificate of analysis of the applicant is thus

compliant to the current monograph.

Povidone: the applicant should provide a complete certificate of analysis for povidone, including the test for

viscosity expressed as K-value.

SPF eggs:

Charles River: the IBDV serotype 2 virus is controlled in the flock by means of an AGP instead of VN

prescribed by the Ph. Eur. 5.2.2. Charles River Laboratories have provided a validation (vol.5/12 p.445) to

demonstrate the suitability of the AGP test.

Couvoir de Cerveloup: avian nephritis virus (ANV) is tested by ELISA instead of an immuno-staining

method as prescribed by the Ph. Eur. 5.2.2.; no validation to demonstrate the suitability of the ELISA test

for ANV is available. This validation is requested; else, the method prescribed by the Ph. Eur. 5.2.2.

should be used.

Question 34

The applicant should provide a complete certificate of analysis for povidone, including the test for viscosity

expressed as K-value.

SPF eggs: the Applicant should confirm that 100% of SPF birds are initially tested (by both suppliers) in

compliance with the requirements of the Ph.Eur. In addition it is noted (from the table on Page 069 of the

dossier) that it is not made clear that the Ph. Eur. requires Avian Leucosis virus testing by by EIA and Avian

Leucosis antibody testing by virus neutralisation (VN).

SPF eggs from Couvoir de Cerveloup: avian nephritis virus (ANV) is tested by ELISA instead of an immuno-

staining method as prescribed by the Ph. Eur. 5.2.2.; no validation to demonstrate the suitability of the ELISA

test for ANV is available. This validation is requested; else, the method prescribed by the Ph. Eur. 5.2.2.


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should be used. It is also noted that the test for avian leucosis antibodies at Couvoir de Cerveloup site is being

done by ELISA when the Ph.Eur. states this should be done by VN. Validation data should be supplied to

confirm that the EIA test for antibodies is at least as sensitive as the recommended Ph.Eur. tes t or the Ph.Eur.

recommended tests should be performed.

II.C.2. Starting materials not listed in a pharmacopoeia

II.C.2 1. Starting materials of biological origin

Newcastle disease virus component, strain VG/GA – vol. 4/12 p.90

Origin and history: initial strain isolated in turkeys in Georgia, USA (annex p.531) – 5 passages in SPF

embryonated hen eggs prior transmission to Merial in 1988-89

Master Seed Virus (MSV)

Obtaining: on 25/10/1989, by 1 passage in SPF hen eggs from the strain received in Merial

Identification: VG/GA (X+1) 102589

Storage : -70°C

Controls (certificate of analysis vol. 4/12 p.100):

bacterial and fungal sterility: according to Ph. Eur. 2.6.1.

mycoplasmic sterility: according to Ph. Eur. 2.6.7. (by culture and epifluorescence)

identity: by neutralisation with a monospecific antiserum

ICPI = 0.37

Control of the neutralising serum: according to Ph. Eur. 2.6.24, section 7

Titration

Viral purity: tests performed according to the Ph. Eur. in force at the time of testing (3 rd edition,

1997)

in kidney cell culture

in embryonated eggs using neutralised MSV

in chicks (performed twice); in addition to the viruses to be checked according to the current

Ph. Eur., antibodies to the following agents were tested and found negative: haemorrhagic

turkey enteritis virus, rotavirus, PMV type 2 and 3, Mycoplasma gallisepticum and

Mycoplasma synoviae.

in turkeys for Chlamydia testing

test for lymphoproliferative disease virus according to current Ph. Eur.

test for leucosis virus

Working Seed Virus (WSV)

Obtaining: by not more than 4 passage in SPF hen eggs from the MSV

Storage : -70°C



mycoplasmic sterility: according to Ph. Eur. 2.6.7. (by culture)

identity: by IF using a specific monoclonal antibody to VG/GA strain

titre

Active ingredient (AI)

Obtaining : by passage(s) in SPF eggs from the WS ; the AI is not more than 5 passages from the

MSV

Culturing in SPF hen eggs: all the passages between the MSV and the active ingredient are carried

out by inoculation of 10-12 day-old SPF embryonated eggs; the eggs are incubated for 65 hours,

harvested; gentamycin sulphate and polymyxin B sulphate are added to the harvested allantoic fluid;

clarification; addition of stabiliser 54 (optional); 0.45 µm filtration; storage at 5 + 3°C or < -40°C until

formulation

Controls (certificates of analysis for 3 batches produced in Chignolo-Pô and 3 batches produced in

Lyon):

Titration (validation of titration in eggs: report 00.0874.R described in section II.A.3. and report

05.0287.R in vol. 5/12 p.468 described below)

Bacterial and fungal sterility


Merial Repeat-use


Report 05.0287.R (vol. 5/12 p.468) : transfer of control method 15001 from Lyon, France to Noventa, Italy

(ND strain Ulster)

Step 1: Noventa operator training in Lyon (3 titrations in parallel by an operator from Lyon and one from Noventa)

Step 2: Running of the control method in Noventa Laboratory (2 different operators, 3 sessions, 2 vials of control

reagent, 2 titrations)

Step 3: Validation study in both laboratories (Noventa and Lyon laboratories, 2 sessions, 1 titration of control

reagent and 3 titrations of ND active ingredient – strain Ulster)

Statistical analysis were conducted on the results obtained at each step. Overall the results in the 2 sites are not

significantly different.

RMS comments



Controls

The tests described in the dossier were performed according to the Ph. Eur. in force at the time of testing (1998);

the extraneous agent testing in avian master seeds has be reviewed by the Ph. Eur. and the new monograph was

published in 2005. However, this Master Seed is well known now, as far as it is also used for the production of

another live ND vaccine (AVINEW) on the market in at least 11 European countries since May 2001. Bearing this

in mind, it will not be asked to the applicant to performed again tests already done but slightly modified in the Ph.

Eur. 2005. Only clarifications and request of testing of new extraneous agents listed in the Ph. Eur. are relevant.

Viral purity in k idney cell cultures: the applicant should indicate whether or not the MSV is neutralised prior to

inoculation of cell cultures.

The NDV strain VG/GA was isolated from turkey; according to Ph. Eur. 2.6.24. section 6.B. (if material of turkey

origin is used) a specific test for Infectious bursal disease type 2 by seroneutralisation should be performed. The

applicant should provide the result of this test.

In the test for Leukosis virus, no subgroup J control was included; the specific tests for reticuloendotheliosis and

CAA were not performed. These deviations should at least be justified.


The applicant should clarify the steps described in section 2.1.5.a.iv (vol. 4/12, p.97) : some steps appear to be

optional (clarification, addition of stabiliser; 0.45µm filtration; storage at –40°C). Maximum duration of storage at

+5°C and –40°C should be indicated and supported by appropriate stability data.

It is indicated in section 2.1.5.a.iv that the stabiliser used is stabiliser 54, whereas for batches produced at Lyon

Laboratories, the stabiliser used is stabiliser 44. The applicant should justify this difference, describe the

differences between the 2 stabilisers and analyse the consequences for the equivalence of the final products

derived from the 2 different types of active ingredient. As a consequence, the relevance of the batches of

vaccines used to perform the analytical, safety and efficacy studies has also to be analysed.

Concerning the equivalence of production of both manufacturing sites, it should be noted that the results of

Chignolo-Pô are from pilot batches (8 litres of active ingredient, when data for 71 to 126 litres batches are provided

for Lyon Laboratories). However, the vaccine is produced in eggs and not in bottles or fermenters, therefore the

scale of production should have no impact on the results obtained. For the record, the mean titre of the 3 batches

produced at Chignolo-Pô is 9.8 log10 EID50/ml and 9.6 log10 EID50/ml for batches produced in Lyon.

Question 35



Controls

Mycoplasmic sterility: it is not clear from the information provided whether appropriate control

strains of mycoplasma as required by the Ph.Eur. were used during mycoplasma testing.

Sufficient information to enable confirmation that the requirements of the current Ph. Eur. have

been met are required

Control of the neutralising antiserum: the neutralising antiserum used for the purposes of

identification and neutralisation for extraneous agents had not been tested for antibodies to

Haemorrhagic turkey enteritis, PMV 1 and 4-9 (only 2 and 3 tested) nor Herpesvirus of turkeys. In

addition an absence of PMV 2 and 3 cannot be excluded because of a cross -reactivity of the anti-

NDV (Paramyxovirus Type 1) antiserum. The Applicant should justify the use of this serum and

provide data to confirm the absence of these potential extraneous agents.

Viral purity in cell cultures (k idney): the applicant should indicate whether or not the MSV is

neutralised prior to inoculation of cell cultures


Merial Repeat-use


The NDV strain VG/GA was isolated from turkey; according to Ph. Eur. 2.6.24. section 6.B. (if

material of turkey origin is used) a specific test for Infectious bursal disease type 2 by

seroneutralisation should be performed. The applicant should provide the result of this test.

The applicant should justify why specific tests for reticuloendotheliosis virus and chicken anemia

virus were not performed, as requested by Ph. Eur. 2.6.24. Unless an acceptable justification is

available, these tests should be done.

The applicant should justify why in the test for Leukosis virus no subgroup J cont rol was included,

why only the supernatant and not the cells was tested, and why only the last passage was tested

and not the intermediate passages. Unless an acceptable justification is available, the test for

Leukosis virus should be performed again according to the current Ph. Eur.


The applicant should declare, if the same WSV is used in both production sites.


Production steps: the applicant should clarify the steps described in section 2.1.5.a.iv (vol. 4/12,

p.97) : some steps appears to be optional (clarification, addition of stabiliser; 0.45µm filtration;

storage at –40°C). Maximum duration of storage at +5°C and –40°C should be indicated and

supported by appropriate stability data.

Stabilisers: It is indicated in section 2.1.5.a.iv that the stabiliser used is stabiliser 54, whereas for

batches produced at Lyon Laboratories, the stabiliser used is stabiliser 44. The applicant should

justify this difference, describe the differences between the 2 stabil isers and analyse the

consequences for the equivalence of the final products derived from the 2 different types of active

ingredient. As a consequence, the relevance of the batches of vaccines used to perform the

analytical, safety and efficacy studies has also to be analysed. In addition, it is a requirement of the

TSE guidelines that the lowest risk material should be used during production. Consequently the

Applicant should use the stabiliser with the lowest TSE risk .

For the information of the applicant concerning the controls performed on the VG/GA Master Seed Virus, to be

taken into consideration when providing further information on the extraneous agents testing – 1st point:

Position of the RMS: The tests described in the dossier were performed according to the Ph. Eur. in force at

the time of testing (1998); the extraneous agent testing in avian master seeds has be reviewed by the Ph. Eur.

and the new monograph was published in 2005. However, this Master Seed is well known now, as far as it is

also used for the production of another live ND vaccine (AVINEW) on the market in at least 11 European

countries since May 2001. Bearing this in mind, it will not be asked to the applicant to performed again tests

already done but slightly modified in the Ph. Eur. 2005. Only clarifications and request of testing of new

extraneous agents listed in the Ph. Eur. are relevant.

A CMS doesn’t follow this approach and asked the following questions:

The extraneous agents test in eggs did not use the yolk sac route as required by the Ph.Eur. The

Applicant should confirm how it is ensured that the testing for extraneous agents was not compromised by

the omission of this route of inoculation. In the absence of a robust justification the Applicant should

provide these data to fulfil the requirements of the Ph.Eur.

Insufficient detail has been provided to confirm that the Ph.Eur. requirements for testing in avian cell

cultures have been met. It is also noted that the adsorption time used is less than that recommended by

the Ph.Eur. (20 minutes not 1 hour). In view of this the Applicant should provide data to confirm how the

requirements of the Ph.Eur. have been met.

It is noted that extraneous agents testing in chicks is not in full compliance with the Ph. Eur. monograph

because the tests for Haemorrhagic Turkey Enteritis (EIA not AGP) and Avian infectious bursitis type 2

(EIA not SN) do not use the recommended Ph. Eur. test. Either the recommended tests should be done

or validation data provided to confirm that the methods used are at least as sensitive as the

recommended tests.

It is noted that the inoculum used for the eggs for production of antigen is given as approximately 0.2 ml

per egg. The Applicant should provide details of the quantity of seed virus inoculated. It should be made

clear if this is a fixed quantity or, if a range of titre may be used, the details should be provided.

For the information of the applicant concerning the controls performed on the Master Seed Virus, to be taken into

consideration when providing further information on the extraneous agents testing – 2nd point:


Merial Repeat-use


Position of the RMS: If Mycoplasma testing was done on the Master Seed Virus by the culture method and the

epifluorescence test, it is not required to perform it again by both methods on the Work ing Seed Virus. Ph.

Eur. monograph 2.6.7. says “where the test for mycoplasmas is prescribed for […] a virus seed lot, both […]

methods are used” and the guidelines says “the Master Seed Virus shall pass the tests for sterility and

freedom from mycoplasma” without any indication concerning the Work ing Seed.

A CMS doesn’t follow this approach and asked the following question:

It is noted that Mycoplasma testing of the Work ing seed virus was done by the culture method only (no

epifluorescence test). It is a requirement of Ph. Eur. monograph 2.6.7 that both tests are done on all

seedlots, therefore compliance should be demonstrated.

Question 36

Validation for titration of NDV; Transfer of control material 15001:

With respect to Lyon control charts, the applicant should give an explanation as to how limits were determined. As

stated by the applicant the criteria for titrations status is validated if the titre of the control standard virus is within

the confidence limits of the control chart. In the case of ND there are two values outside of control limits (ref chart

3), give a justification for these out of specification results. Are %CV limits of acceptability determined for

repeatability and reproducibility data? Will control limits specific for the Noventa laboratory be generated?

Infectious bronchitis virus component, strain H120 – vol. 4/12 p.119

Origin and history: initial strain isolated in the Netherlands and passaged 120 th times in embryonated eggs


Obtaining: in 1975, by 2 passages in embryonated hen eggs from the strain received in Merial; freeze

drying

Identification: H120/LF2/754-15

Storage: freeze-dried at –70°C

Controls:



identity: by neutralisation of infectivity with a monospecific antiserum

Control of the neutralising sera: according to Ph. Eur. 2.6.24, section 7. (the serum used for

identification – see doc CG/DCQ 189.99 p.134 - was positive for CAA antibodies, but it doesn’t

impair the identification; the serum used for neutralising prior to extraneous agent testing – see

doc CG/DCQ 176.99 p.139 - is negative to all the agents listed in the Ph. Eur. 2.6.24 section 7)

Viral purity: tests performed according to the Ph. Eur. in force at the time of testing (3 rd edition,

1997)

in kidney cell cultures using neutralised MSV

in embryonated eggs using neutralised MSV

in chicks; in addition to the viruses to be checked according to the current Ph. Eur.,

antibodies to the following agents were tested and found negative: haemorrhagic turkey

enteritis virus, rotavirus, PMV type 2 and 3.

test for leucosis virus using neutralised MSV


Obtaining: by not more than 4 passage in SPF hen eggs from the MSV

Storage : -70°C




identity: by neutralisation of infectivity with a monospecific antiserum




Obtaining : by passage(s) in SPF eggs from the WS ; the AI is not more than 5 passages from the

MSV

Culturing in SPF hen eggs: all the passages between the MSV and the active ingredient are carried

out by inoculation of 11-12 day-old SPF embryonated eggs; the eggs are incubated for 18-24 hours,

harvested; gentamycin sulphate and polymyxin B sulphate are added to the harvested allantoic fluid;

clarification; addition of stabiliser 56 (optional); 0.45 µm filtration; storage at 5 + 3°C or < -40°C until

formulation


Merial Repeat-use


Controls (certificates of analysis for 3 batches produced in Chignolo-Pô and 3 batches produced in

Lyon p.142-147):



Bacterial and fungal sterility

Report 05.0310.R (vol. 5/12 p.502) : transfer of control method 15003 from Lyon, France to Noventa, Italy

(IB strain)

Step 1: Noventa operator training in Lyon (3 titrations in parallel by an operator from Lyon and one from Noventa)

Step 2: Running of the control method in Noventa Laboratory (2 different operators, 3 sessions, 2 vials of control

reagent, 2 titrations)

Step 3: Validation study in both laboratories (Noventa and Lyon laboratories, 2 sessions, 1 titration of control

reagent and 3 titrations of IB active ingredient)

Statistical analysis were conducted on the results obtained at each step. Overall the results in the 2 sites are not

significantly different.

RMS comments



Controls:

The tests describes in the dossier were performed according to the Ph. Eur. in force at the time of testing (1997-

1999); the extraneous agent testing in avian master seeds has be reviewed by the Ph. Eur. and the new

monograph was published in 2005. The applicant should justify the non compliance to the current Ph. Eur.

monograph 2.6.24. The differences noted between the tests performed and the current requirements of the Ph.

Eur. 2.6.24. are:

1. Test in cell cultures Giemsa coloration and test for hemagglutination agents were not performed; else, the

protocol (duration of passage, cell type, duration of the test) is not modified

2. Test in embryonated eggs: group inoculated in yolk sac not performed

3. Test for Leukosis virus: no subgroup J control

4. Specific test for reticuloendotheliosis not performed

5. Specific test for CAA not performed

6. Mycoplasmic sterility: the test by epifluorescence as requested by the Ph. Eur. 2.6.7. has not been performed

(requirement of the Ph. Eur. since at least 2001). The applicant should perform this test.


The applicant should clarify the steps described in section 2.1.5.a.iv (vol. 4/12, p.125) : some steps appears to be

optional (clarification, addition of stabiliser; 0.45µm filtration; storage at –40°C). Maximum duration of storage at

+5°C and –40°C should be indicated and supported by appropriate stability data.

It is indicated in section 2.1.5.a.iv that the stabiliser used is stabiliser 56 in Chignolo-Pô Laboratories and

stabiliser 26 in Lyon Laboratories. The applicant should justify this difference, describe the differences between

the 2 stabilisers and analyse the consequences for the equivalence of the final products derives from the 2

different types of active ingredient. As a consequence, the relevance of the batches of vaccines used to perform

the analytical, safety and efficacy studies has also to be analysed.

Concerning the equivalence of production of both manufacturing sites, as for the ND component, it should be

noted that the results of Chignolo-Pô are from pilot batches. However, the same remarks as for the ND

component apply (production in egg and equivalent concentration of the active ingredient of both sites).

Question 37



Controls:

The tests for extraneous agents should comply to the current Ph. Eur. monograph 2.6.24. The differences noted

between the tests performed and the current requirements of the Ph. Eur. 2.6.24. are:

1. Test in cell cultures: Giemsa coloration and test for hemagglutination agents were not performed


3. Test for Leukosis virus: no subgroup J control, only the supernatant and not the cells was tested, only the

last and not the intermediate passages was tested



Merial Repeat-use



6. Mycoplasmic sterility: the test by epifluorescence as requested by the Ph. Eur. 2.6.7. has not been

performed (requirement of the Ph. Eur. since at least 2001). It is not clear from the information provided

whether appropriate control strains of mycoplasma as required by the Ph.Eur. were used during

mycoplasma testing. Sufficient information to enable confirmation that the requirements of the current

Ph. Eur. have been met are required

The applicant should perform the tests for reticuloendotheliosis, CAA and mycoplasmic sterility by

epifluorescence.

For the tests in cell cultures, in embryonated eggs and test for leucosis viruses, either these tests should be

performed again according to the current Ph. Eur. monograph 2.6.24, or the applicant should demonstrate that the

tests already done give the same level of confidence in detecting extraneous agents as the tes ts prescribed in

monograph 2.6.24. In particular:

- Insufficient detail has been provided to confirm that the Ph.Eur. requirements for testing in avian cell

cultures have been met. It is also noted that the adsorption time used is less than that recommended by

the Ph.Eur. (20 minutes not 1 hour). In view of this the Applicant should provide data to confirm how the

requirements of the Ph.Eur. have been met.

- It is noted that the inoculum used for the eggs for production of antigen is given as approximately 0.2 ml

per egg. The Applicant should provide details of the quantity of seed virus inoculated. It should be made

clear if this is a fixed quantity or, if a range of titre may be used, the details should be provided.

H120 component – viral purity. The applicant should be informed that a CMS (n°3) requires the submission of the

data of compliance with the methods of section 2.6.24. of Ph. Eur:5 (availability of these data supposed to be in

Dec 2006).

H120 component – sterility testing. The applicant should be informed that a CMS (n°4) has the following request:

the applicant states that it complies with several Eur. Ph, but these pharmacopoeias are from 1970 to 1998; the

test should comply with the current Eur.Ph.

H120 component - viral purity, request from CMS n°4: regarding the test for extraneous agents, the method

followed are from Ph Eur 1997.and Ph Eur 1989 The test should be performed according to the actual Ph Eur.

and results should be shown.




The applicant should clarify the steps described in section 2.1.5.a.iv (vol. 4/12, p.125) : some steps

appears to be optional (clarification, addition of stabiliser; 0.45µm filtration; storage at –40°C).

Maximum duration of storage at +5°C and –40°C should be indicated and supported by appropriate

stability data. The consequences that this 2 different ways of storage would have on the final product

should be analysed.

It is indicated in section 2.1.5.a.iv that the stabiliser used is stabiliser 56 in Chignolo-Pô Laboratories

and stabiliser 26 in Lyon Laboratories. The applicant should justify this difference, describe the

differences between the 2 stabilisers and analyse the consequences for the equivalence of the final

products derives from the 2 different types of active ingredient. As a consequence, the relevance of

the batches of vaccines used to perform the analytical, safety and efficacy studies has also to be

analysed. In addition, it is a requirement of the TSE guidelines that the lowest risk material should be

used during production. Consequently the Applicant should use the stabiliser with the lowest TSE

risk .

For the information of the applicant concerning the controls performed on the Master Seed Virus, to be taken into

consideration when providing further information on the extraneous agents testing:

Position of the RMS: If Mycoplasma testing was done on the Master Seed Virus by the culture method and the

epifluorescence test, it is not required to perform it again by both methods on the Work ing Seed Virus. Ph.

Eur. monograph 2.6.7. says “where the test for mycoplasmas is prescribed for […] a virus seed lot, both […]

methods are used” and the guidelines says “the Master Seed Virus shall pass the tests for sterility and

freedom from mycoplasma” without any indication concerning the Work ing Seed.



Merial Repeat-use





Bovine albumin fraction V (vol. 4/12 p.148)

Origin : bovine plasma from USA, Canada, New-Zealand and Australia

Use: constituent of the stabiliser 54 for the ND active ingredient

Controls (performed after 0.22µm filtration but prior to the irradiation): general characteristics; activity and

toxicity; bacterial, fungal and mycoplasmic sterility; viral purity in bovine and monkey cell lines; specific

test for pestiviruses the material must be sterile and free from extraneous agents

Sterilisation treatment: gamma irradiation at 35 kGy (also a 0.22µm filtration is carried out upstream on

the stabiliser)

Question 38

It is noted that the gamma-irradiation validation report provided is in support of 25kGy and not 35 kGy as indicated

in the RMS report, therefore clarification is required to confirm what level of irradiation is applied.

Casein hydrolysate (vol. 4/12 p.154)

Origin: bovine milk (fit for human consumption) from USA, Canada, New-Zealand and Australia and porcine

enzyme

Use: constituent of the stabilisers 54 and 56 for both active ingredients

Controls (performed after 0.22µm filtration but prior to the irradiation): general characteristics; endotoxins

content; bacterial and fungal sterility; viral purity in bovine, porcine and monkey cell lines; specific tests for

pestiviruses and porcine parvovirus the material must be sterile and free from extraneous agents

Sterilisation treatment: gamma irradiation at 35 kGy (also a 0.22µm filtration is carried out upstream on

the stabiliser)

Question 39

The Applicant should provide information on the source of the pigs from which the porcine enzyme is derived.

RMS comments

For the record, the validation of the gamma irradiation is provided vol.5/12 p.404 and TSE risk is assessed in

section II.D of the report (II.C.3 in the dossier).

II.C.2.2. Starting materials of non-biological origin

Potassium glutamate monohydrate (vol. 4/12 p.164, in-house monograph)

This is a component of stabiliser 54. A certificate of analysis compliant to the specifications is provided.

In house prepared media and solution:

Buffered physiological saline pH 7.1 (vol. 4/12 p.161)

Composition: NaCl, disodium hydrogen orthophosphate, potassium dihydrogen phosphate anhydrous,

water for injection

Sterilisation treatment: 0.22µm filtration

Tests: pH, osmolarity

Stabiliser 54 (vol. 4/12 p.167) for the ND active ingredient

Composition: casein hydrolysate, mannitol, povidone, sucrose, monopotassium phosphate,

dipotassium phosphate, potassium glutamate, bovine albumin, water for injection

Sterilisation treatment : 0.22µm filtration

Tests : pH, bacterial and fungal sterility

Stabiliser 56 (vol. 4/12 p.170) for the IB active ingredient

Composition: casein hydrolysate, mannitol, sodium hydroxyde, water for injection

Sterilisation treatment : 0.22µm filtration


Merial Repeat-use


Tests : pH, bacterial and fungal sterility

RMS comments

Stabiliser 44 and stabiliser 26 is used in Lyon Laboratories. The applicant should provide the information relevant

to this stabilisers (composition, sterilisation treatment, tests).

The applicant should also select one of the stabiliser for each active ingredient and justify this selection, so that in

the future, there is only one method of production whatever the site of production.

Question 40

Stabiliser 44 and stabiliser 26 are used in Lyon Laboratories.

The applicant should provide the information relevant to this stabilisers (composition, sterilisation

treatment, tests).

The applicant should also select one of the stabiliser for each active ingredient and justify this selection,

so that in the future, there is only one method of production whatever the site of production. In addition, it

is a requirement of the TSE guidelines that the lowest risk material should be used during production.

Consequently the Applicant should use the stabiliser with the lowest TSE risk .

Buffered physiological saline pH 7.1: this physiological saline is sterilised by filtration and not by autoclaving.

It is an Ph.Eur. requirement that autoclaving should be used unless justified. There does not appear to be a

justification. An adequate justification should be provided or the saline should be sterilised by autoclaving.

II.D. SPECIFIC MEASURES TO PREVENT TSE RISK

Vol.4/12, p.175

ND strain VG/GA

Origin: turkey, virus passaged in SPF eggs

Evaluation of TSE risk: avian origin (species not known to be sensitive to TSEs), passaged on avian

material, high dilution during the manufacturing process, vaccine administered by respiratory route

IB strain H120

Origin: chicken, virus passaged in SPF eggs

Evaluation of TSE risk: avian origin, passaged on avian material (species not known to be sensitive to

TSEs), high dilution during the manufacturing process, vaccine administered by respiratory route

Casein hydolysate:

Origin: porcine enzyme and bovine milk fit for human consumption; a declaration of the supplier is

provided.

Bovine albumin fraction V

Origin: bovine plasma, from USA, New Zealand or Canada. The 3 suppliers have provided an EDQM

certificate of suitability

Question 41

It is noted that the Certificates of Suitability R0-CEP-2000-166-Rev 03 and R0-CEP-2001-053-Rev 00 are not

current (should be R1-CEP-2000-166-Rev 00 and R1-CEP-2001-053-Rev 01). These should be supplied and an

updated format table and revised declaration provided.

The Applicant should clarify whether stabiliser has been used for storage of both master seed viruses and if so

whether any materials of ruminant origin have been used in the stabiliser. If appropriate a risk assessment and

certificates of suitability should be provided.

II.E. CONTROL TESTS DURING PRODUCTION

(Vol. 4/12 p.190)


Merial Repeat-use


Record of time, temperature, monitoring of the sterilisation cycle, filling volume, appearance of sealing, control of

the freezing cycle.

RMS comment

For the record, the applicant has provided the details of the controls performed up to the active ingredient in

section II.C.2.1. The controls described above are performed from the step of formulation up to the final product.

Question 42

SOPs should be provided for sterilization and filling.

The limits of acceptance for time recording, temperature recording, and freezing cycle are missing and should be

clearly stated.

The batch protocols need revision. CMSs n°6 & 8 require to have them updated and completed according to the

templates published by EDQM (see: www.pheur.org)

II.F. CONTROL TESTS ON THE FINISHED PRODUCT

Vol.4/12 p.196

It is reminded that ND component is filled in an ampoule (Hatchpak Avinew) and IB component in another one

(Hatchpak IB H120). Thus 2 sets of controls are provided.

Question 43

The Applicant appears to have provided test procedures that are relatively old (some last updated 1990) that refer

to previous versions of the Ph.Eur. and which relate to the procedures used for both seedlot testing and current

product testing. Whilst it is expected that test procedures used to test the seedlots are likely to be older the

Applicant should confirm whether these test procedures reflect the current test procedures used for in process and

finished product testing. Updated test procedures should be supplied. If no updates have taken place (in some

instances during the past 17 years) this should be justified.

II.F.1. General characteristics of the finished product

Hatchpak Avinew

Appearance: yellow suspension

6.8 < pH < 7.8

filling volume > 4.5 ml

Hatchpak IB H120

Appearance: yellow suspension

7.0 < pH < 8.0

filling volume > 5.0 ml

II.F.2. Identification and assay of active ingredient(s)

Hatchpak Avinew

Identification: by IF using a monoclonal antibody (see below report 00.0815.R: validation of identity test by

IF)

Assay: 5.5 to 6.7 log10 EID50/dose (validation report 00.0874.R described in section II.A.3. and in dossier

vol. 5/12 p.424)

Hatchpak IB H120

Identification: by neutralisation

Assay: 3.7 to 4.7 log10 EID50/dose (validation report 00.0838.R described in section II.A.3. and in dossier

vol. 5/12 p.436)


Merial Repeat-use


Report 00.0815.R: validation of identity test for Avinew Vaccine by IF (vol. 5/12 p.450)

Cell cultures were infected with AVINEW vaccine (strain VG/GA), SOTASEC vaccine (strain LaSota) or PESTOS

vaccine (strain HB1). Positive and negative controls were performed. 4 types of monoclonal antibodies were tested:

- U11: monoclonal antibody against VG/GA strain

- monoclonal antibody against VNJO strain

- monoclonal antibody against VCO3 strain

- U85: group specific monoclonal antibody

The results were as expected:

- The U11 antibody reacts with AVINEW vaccine but not with SOTASEC and PESTOS vaccines

- The group-specific antibody reacts with the 3 vaccines

- The non-specific antibodies do not react with any vaccine

RMS comments

Identification of both strains:

The applicant should list all the Infectious Bronchitis strains and Newcastle Disease strains handled in the

manufacturing premises (Lyon and Chignolo-Pô) and demonstrate that the identification methods used are able to

discrimate between the vaccine strains and other IB and/or ND strains handled in the same premises.

Question 44



manufacturing premises (Lyon and Chignolo-Pô) and demonstrate that the identification methods used are

able to discrimate between the vaccine strains and other IB and/or ND strains handled in the same premises.

CMS n°2 also considers that based on the immunofluorescence pictures provided in report 00.0815.R:

validation of identity test for Avinew Vaccine by IF (vol 5/12, p.450), a reliable identification of both the

Newcastle disease virus and the ND virus strain VG/GA is highly questionable. The use of the monoclonal

anti-VG/VA antibody U11 should be re-evaluated and properly justified by the company. Identification of the

virus should be done according to Ph Eur 0450.

CMS n°4 also requires a 2nd identification of the ND component: the applicant has performed the identification

of vaccine virus using monoclonal antibodies however the identification of the vaccine strain by the inhibition

of the agglutination assay should also be performed according to the Ph Eur monograph.

II.F.3. Identification and assay of adjuvants

Not applicable.

II.F.4. Identification and assay of excipient constituents

Not applicable.

II.F.5. Safety tests

(SOP in vol. 5/12 p.320)

10 SPF chicks aged 1 to 5 days are administered 10 doses of vaccine under a volume of 0.05 ml via the ocular

route and observed daily for 21 days: none of the chicks shows any serious respiratory or nervous sign.

RMS comments

The vaccine is indicated from the age of 1 day. According to the Ph. Eur. monographs 442 and 450, the batch

safety should be tested in chicks of the minimum recommended age of vaccination. Thus the applicant should

use for this test only day-old birds.


Merial Repeat-use


According to the Ph. Eur. monograph 62, in the case of a combined vaccine, birds of the safety test should

receive the combined product. As far as a batch protocol is provided for Hatchpak Avinew and another one for

Hatchpak IB H120, the RMS understands that the birds don’t receive the combined product. The applicant should

confirm that the safety test will be performed according to the Ph. Eur. monograph 62, that is by administration of

both components to the same birds.

Question 45


safety should be tested in chicks of the minimum recommended age of vaccination. Thus the applicant should

use for this test only day-old birds.

The Applicant should more closely define what are considered acceptable/unacceptable reactions in the batch

safety test. These criteria should be justified.

According to the Ph. Eur. monograph 62, in the case of a combined vaccine, birds of the safety test should

receive the combined product. As far as a batch protocol is provided for Hatchpak Avinew and another one for

Hatchpak IB H120, the RMS understands that the birds don’t receive the combined product. The app licant should

confirm that the safety test will be performed according to the Ph. Eur. monograph 62, that is by administration of

both components to the same birds.

II.F.6. Sterility and purity test

Bacterial and fungal sterility test according to Ph. Eur.

Mycoplasmic sterility according to Ph. Eur.

Viral purity:

In chicks according to Ph. Eur. monograph 2.6.24. test 6.A.

In embryonated hen eggs according to Ph. Eur. 2.6.25. (allantoic cavity and chorio-allantic membrane

routes only)

In cell cultures (kidney or embryo liver cells)

Test for avian leucosis virus

RMS comments

Viral purity:

The extraneous agent testing in avian live vaccines has be reviewed by the Ph. Eur. and the new monograph

2.6.25. was published in 2005. The applicant should implement the new protocol of viral purity testing for avian live

viral vaccines prescribed by the Ph. Eur.; else, a detailed justification for this non compliance to the current Ph.

Eur. should be provided. Furthermore, for each possible extraneous agent, the appl icant should demonstrate that

his testing methods are at least as sensitive as the test of the current Ph. Eur. and of an appropriate specificity.

Question 46

Viral purity:


2.6.25. was published in 2005. The applicant should implement the new protocol of viral purity testing for avian live

viral vaccines prescribed by the Ph. Eur.; else, a detailed justification for this non compliance to the current P h.

Eur. should be provided. Furthermore, for each possible extraneous agent, the applicant should demonstrate that

his testing methods are at least as sensitive as the test of the current Ph. Eur. and of an appropriate specificity.

The following specific points needs in particular to be considered:

- For the ND component: The neutralising antiserum used for the purposes of identification and

neutralisation for extraneous agents had not been tested for antibodies to Haemorrhagic turkey enteritis,

PMV 1 and 4-9 (only 2 and 3 tested) nor Herpesvirus of turkeys. In addition an absence of PMV 2 and 3

cannot be excluded because of a cross-reactivity of the anti-NDV (Paramyxovirus Type 1) antiserum. The

Applicant should justify the use of this serum and provide data to confirm the absence of these potential

extraneous agents.

- For the ND component: The extraneous agents test in eggs does not use the yolk sac route. The

Applicant should justify the omission of this route of inoculation and provide data to confirm how the

requirements of the Ph.Eur. have been fully met.


Merial Repeat-use


- For ND and IB components: It is not clear from the information provided whether appropriate control

strains of mycoplasma as required by the Ph.Eur. were used during mycoplasma testing. Sufficient

information to enable confirmation that the requirements of the current Ph. Eur. have been met are

required.

- For ND and IB components: Insufficient detail has been provided to confirm that the Ph.Eur. requirements

for testing in avian cell cultures have been met. It is also noted that the adsorption time used is less than

that recommended by the Ph.Eur. (20 minutes not 1 hour). In view of this the Applicant should provide

data to confirm how the requirements of the Ph.Eur. have been met.

The applicant should be informed that a CMS (n°3) requires the submission of the data of compliance with the

methods of section 2.6.25. of Ph. Eur:5 (availability of these data supposed to be in Dec 2006).

II.F.7. Inactivation

Not applicable.

II.F.8. Residual humidity

Not applicable.

II.F.9. Batch-to-batch consistency

The applicant has provided the results of the tests performed on 3 batches of Hatchpak Avinew produced in

Chignolo-Pô (using for each batch a different batch of active ingredient) and on 3 batches Hatchpak Avinew

produced in Lyon (using for each batch a different batch of active ingredient). The results are conform to the

specifications, consistent between batches and consistent between manufacturing sites.

The applicant has provided the results of the tests performed on 3 batches of Hatchpak IBH120 produced in

Chignolo-Pô (using for each batch a different batch of active ingredient) and on 3 batches Hatchpak IB H120

produced in Lyon (using for each batch a different batch of active ingredient). The results are conform to the

specifications, consistent between batches and consistent between manufacturing sites.

RMS comments

For the record, the specification for filling volume was increased from 4.7 ml to 5.0 ml/ampoule after the date of

manufacture of the batches in Lyon; however, this is a vaccine to be diluted and the volume of filled product has

no incidence on potency, the titre being established by ampoule and not by unit of volume.

Question 47

It is noted that there is a range in fill volume allowed during production. It is also noted that the presentations are

very high dose and therefore minor differences in filling volume will have greater implications for the number of

doses filled. In addition to this there is variability in the titration assay. The specification is reported as the quantity

of virus per dose, which is based on the nominal target number of doses. Because the presentation is wet frozen

there is no standardisation by way of reconstitution volume as would be the case with freeze-dried presentations.

The combination of these factors raises concerns relating to the consistency of product with respect to the final

numbers of doses contained within a vial of product. The Applicant should comment on this and provide data or a

justification to confirm how the consistency of the finished product is ensured.


Merial Repeat-use


II.G. STABILITY TESTS

II.G.1. Stability of the finished product

Hatchpak Avinew (vol. 4/12 p.255)

27-month stability study using 3 batches produced at Lyon Laboratories and containing stabili ser 44 :

report 03.0549.R (vol. 5/12 p.485)

On 3 batches stored in liquid nitrogen for 27 months, record every 3 to 6 months of the appearance, pH,

volume, titre; at release and after 27/28 months of storage, sterility and safety tests performed;

the appearance, pH, and volume remain stable over the 27 months of storage

the estimated slope of the linear model applied to assess the detitration over time is not significantly

different from 0

the batches remains sterile (bacteria, fungi and mycoplasma) and safe until 27 months of storage

On-going stability study using 3 batches produced at Chignolo-Pô Laboratories and containing stabiliser

54

The same protocol as described above is planed. The results are available for the first 6 months of storage and

are satisfactory.

Hatchpak IB H120 (vol. 4/12 p.259)

21-month stability study using 3 batches produced at Lyon Laboratories and containing stabiliser 26 :

report 04.0641.R (vol. 5/12 p.516)


volume, titre



different from 0


56

The same protocol as described above is planed. The results are available for the first 6 months of storage and

are satisfactory.

RMS comment

Hatchpak Avinew

The results obtained from batches produced in Lyon demonstrate a satisfactory stability of Hatchpak Avinew

stored in liquid nitrogen.

However, the stabiliser used in Chignolo-Pô (n°54) and in Lyon (n°44) laboratories is different, which justifies to

have a complete stability study on 3 batches produced at Chignolo-Pô to grant a duration of storage of 24 months,

whatever the manufacturing site. Results of the on-going stability study in Chignolo-Pô are thus awaited and the

duration of storage that will be accepted will correspond to the duration established for both sites; a complete

report is awaited for the Chignolo-Pô results. A CMS (n°4) points out that it will not bee possible for the applicant

to claim a shelf life of 18 months during this procedure, and will not accept the results with one stabilizer to cover

the stability of the vaccine produced with another stabilizer.

For the record, the duration of stability currently claimed is 18 months due to a shorter stability study of the

Hatchpak IB H120.

Hatchpak IB H120

The results obtained from batches produced in Lyon demonstrate a satisfactory stability of Hatchpak IB H120

stored in liquid nitrogen.

However, the stabiliser used in Chignolo-Pô (n°56) and in Lyon (n°26) laboratories is different, which justifies to

have a complete stability study on 3 batches produced at Chignolo-Pô to grant a duration of storage of 18 months,


duration of storage that will be accepted will correspond to the duration established for both sites; a complete

report is awaited for the Chignolo-Pô results.


Merial Repeat-use


Currently, the sterility at the end of the shelf-life is not available. The applicant should provide the result of this

test; however, it’s not a major issue as far the ampoules are sealed and controlled for sterility at release; thus,

there is no reason for a bacterial contamination to occur during storage.

Question 48

Hatchpak Avinew

The stabiliser used in Chignolo-Pô (n°54) and in Lyon (n°44) laboratories is different, which justifies to have a

complete stability study on 3 batches produced at Chignolo-Pô to grant a duration of storage of 24 months,


duration of storage that will be accepted will correspond to the duration established for both sites. A CMS (n°4)

points out that it will not bee possible for the applicant to claim a shelf life of 18 months during this procedure, and

will not accept the results with one stabilizer to cover the stability of the vaccine produced with another stabilizer.

CMSs n°6 & 8 remind that only stability data performed with batches, which contain the finally identified stabiliser

will be acceptable.

Hatchpak IB H120







CMSs n°6 & 8 remind that only stability data performed with batches which contain the finally identified stabiliser

will be acceptable.


test.

A CMS (n°4) also requires to provide the safety data at the end of the shelf-life.

The applicant should clarify the stability data as 2 CMSs have observed discrepancies:

A CMS (n°4) requires the applicant to clarify the following inconsistency: “In pages 152 and 269 of the part II, the

vaccine titre is stated as 8.1-8-5 log10 EID50/ampoule. However, the titre of the ampoules supposes to be 3.7-4.7

log 10.”

CMS n°7 states:

- The average stability titration result for infectious titre for ND over three batches is ~10.1 log10 EID50/ampoule

(ref 03.0549.R, 5.2, table V) however the min and max titres for ND vaccine is 5.5 and 6.7 log10 EID50. Clarify

why a higher titre was used for stability purposes as compared to standard batches.

- The average titration result for stability studies for IB was ~ 8.4 log10 EID50/ampoule however the min and max

titres for IB are 3.7 and 4.7 log10 EID50. Clarify why a higher titre was acceptable for stability purposes as

compared to standard batches.

CMS n°7 has the following requests:

- Study (ref 03.0549.R, 3.1.3) states animals used from 1-5 days of age however requirement states minimum age

chicks i.e. one day old. A justification is required.

- Two week old chicks were used during technique 000768. A justification is required.

II.G.2. In-use stability

Avinew (vol. 4/12 p.263)

The vaccine Avinew was reconstituted in different buffered physiological saline solutions, of different pH and

different loads in chlorine. Titrations were carried out immediately and 3 hours after reconstitution:

no significant detitration observed in chlorine-free diluent

clear reduction of the titre dependant of the load of chlorine in the diluent

Hatchpak Avinew IB H120 (vol. 4/12 p.265)


Merial Repeat-use


1 ampoule of Hatchpak Avinew and 1 ampoule of Hatchpak IB H120 were reconstituted together in chlorine-free

drinking water. The titration of the IB component was performed immediately and 2 hours after reconstitution

(temperature 21°C), and after neutralisation of the ND component:

the IB titre remains stable during 2 hours after reconstitution

RMS comments

Avinew

The data provided are indicative but don’t correspond to the current product and claim; indeed, the vaccine used is

Avinew, a freeze-dried vaccine containing a stabiliser and the diluent used is a buffered physiological solution

whereas the diluent claim for Hatchpak Avinew is non-chlorinated tap water. The applicant should provide the

results of titrations performed prior to and after 3 hours of storage of the vaccine Hatchpak Avinew reconstituted in

non-chlorinated tap water as claimed.

Hatchpak IB H120 (vol. 4/12 p.265)

The data provided are satisfactory to support the claim of 2 hours of in-use stability for the IB component.

Question 49

Hatchpak Avinew







Merial Repeat-use


III. Safety

Summary table of the safety trials

Component

tested

Trial Titre per dose animals included in the

trial

Age at

vaccination VG/GA * H120 *

one dose ND 04.0571.R 7.0 - 120 SPF chickens Day-old

IB 04.0581.R - 4.7 95 SPF chickens Day-old

ND/IB 05.0367.R 6.7 4.7 85 conventional chickens Day-old




one overdose ND 04.0571.R 8.0 - 120 SPF chickens Day-old




repeated

administration

ND/IB 04.0188.R 6.7 4.7 65 SPF chickens Day-old,

14 days

reproductive

performances

ND 99.0339.R 7.0 - 420 SPF chickens Day-old


IB 97.43.R - Commerc

ial dose

120 pullets, 20 male

breeders and 140 SPF

chicks

Day-old,

8 weeks

Spread and

dissemination of

the vaccine

strains

ND ND-06-88 6.8 - 100 SPF chickens Day-old,

14 days




Reversion to

virulence


ND SG/VA.DEB.

95/D254

7.0 - 150 SPF chickens Day-old,

3 days





Biological

properties of the

vaccine strain

ND SG/VA.DEB.

95/D254

7.0 - 150 SPF chickens Day-old,

3 days

ND 99.0676.R 8.2

8.5

8.8

- 49 SPF chickens Day-old,

2 days

Interactions ND/IB/IBD/M

D

04.1064.R 6.7 4.7 65 SPF chickens Day-old


Merial Repeat-use


FIELD STUDIES ND/IB 03.0916.R Commerc

ial dose

Commerc

ial dose

44,064 conventional

chickens

Day-old

IB 97-54 - Commerc

ial dose

6,144 table-egg layer

chickens, 3,031 female

and 990 male broiler

breeder chickens, 126

SPF chickens

4 days

(layers)

Day-old

(broiler

breeders)

ECOTOXICITY ND ND-15-89 NA - 500 conventional

chickens

Day-old

ND 99.0676.R 8.2

8.5

8.8

- 49 SPF chickens Day-old,

2 days

* In log10 EID50

ND: Newcastle disease

IB: Infectious Bronchitis

IBD: Infectious Bursal disease

MD: Marek’s disease

-: not applicable

NA: Not available

RMS preliminary note

Hatchpak Avinew is called M713 (ND), and Hatchpak IB H120 is called M713 (IB) in the studies provided in this

section.

The applicant has summarised in vol. 7/12, p.1-3 the pathogenicity and epidemiology of Newcastle disease and

Infectious Bronchitis and has briefly justified the choice of the vaccine strains. Supportive literature is provided.

This section recalls that the ND vaccine strain VG/GA is already the active ingredient of the live freeze-dried

vaccine AVINEW placed on the market in 1992 (in France in 1999, and in 11 other European countries in 2001

and 2002 via a mutual recognition procedure).

The IB H120 vaccine strain is also the strain contained in the live freeze-dried vaccine BIORAL H120 (MA in

France in 1988).

In most of the laboratory trials, the vaccine was inoculated by oculo-nasal route: the birds receive a dose of 0.1 ml

(0.05 ml by ocular route and 0.05 ml nasally). The route of administration claimed is nebulisation/spray; however,

according to the applicant, the administration by ocular and nasal route guarantees that all the birds receive the

maximum amount of vaccine, and therefore it is considered an appropriate route of vaccination under laboratory

conditions. This point is further discussed in conclusion of the safety part.

In all the laboratory safety trials (except 02.0674.R), the applicant has used the following scoring system for

respiratory signs:

Score Respiratory signs Comments

0 No respiratory sign -

1 Very slight bronchial rales Audible when the chick is nearby the ear of the operator

2 Slight bronchial rales Audible without any contact of the bird with the ear of the operator

3 Severe respiratory signs Respiratory distress (dyspnoea, polypnoea), prostration

For the record, the maximum titre at release are:

- 6.7 log10 EID50/dose for the ND component

- 4.7 log10 EID50/dose for the IB component

Question 50

The applicant should identify the stabilisers used in the vaccine batches/preparation which were used in the safety

tests.

DE question: the summary reports in Vol. 6 are very short and do not contain sufficient detail on the results of the

various trial. Therefore, the summaries alone do not allow assessment of the trials provided. For future

applications, these short summaries cannot be accepted/validated.


Merial Repeat-use


III.C. LABORATORY TRIALS

III.C.1. Safety of the administration of one dose

III.C.1.1. General safety

Report 04.0571.R.: safety of 1 dose and of an overdose in day-old SPF chicks, ND component

Vol.7/12, p.7 (summary) & p.61 (detailed report)

Animals 120 1-day-old SPF chickens randomised in 3 groups of 40 birds

Vaccine Hatchpak Avinew (RMB713 - ND component) - batch 3AWF7P15A

Diluent: “Volvic” spring water, also used as placebo for control group

Administration route Oculo-nasal route

Vaccine scheme Group 1: 1 dose of 7.0 log10 DIO50/bird at the age of 1 day

Group 2: 1 overdose of 8.0 log10 DIO50/bird at the age of 1 day

Group 3: control

Follow-up Daily observation for 21 days; birds found dead are necropsied

Examination of respiratory reaction on 20 birds/group: on day 5, 7 and 10

Weight record of all the birds: on day 0, 7 and 21

On day 21, blood sampling for ND serology by IH (10 birds/group), sex

determination, euthanasia and post-mortem examination

Statistical analysis On weight gain (multifactor ANOVA taking account of factors sex and group)

Results Non specific mortality: 2 birds in group 1 and 1 bird in group 2; only non-specific

lesions at final necropsy (persistent vitellus, umbilical abscesses)

Examination of respiratory reaction: no sign recorded

Body weight gain: both groups of vaccinates have a significantly reduced weight on

day 21 compared to controls

Serology: seroconversion of the vaccinates, the controls remaining negative

RMS comments

It is indicated in the certificate of analysis p.76 that the batch of vaccine is stored at +5°C; this discrepancy

should be explained.

Question 51




Report 04.0581.R.: safety of 1 dose and of an overdose in day-old SPF chicks, IB component


Animals 95 1-day-old SPF chickens randomised in 3 groups of 30 birds + 1 group of 5 birds

Vaccine Hatchpak IB H120 (RMB713 - IB component) - batch 3BIF7A01A

Diluent: “Volvic” spring water


Vaccine scheme Group 0: 5 serological controls on day 0

Group 1: 1 dose of 4.7 log10 DIO50/bird at the age of 1 day

Group 2: 1 overdose of 5.7 log10 DIO50/bird at the age of 1 day

Group 3: control


Individual examination of respiratory reaction on 20 birds/group: on day 5, 7, 10, 12

& 14; scoring of the signs


On day 28, blood sampling for IB serology by IH (10 birds/group), sex



On respiratory score


Merial Repeat-use


Results Non specific mortality: 1 bird in group 1

Examination of respiratory reaction:

in 75 % of the vaccinates, score of 1 or 2, no birds showing a score of 3

the rales appear between 5 and 7 days after vaccination, pick at 10 days and

disappear around 14 days after vaccination

no difference of score between the single and overdose group

no signs in controls

At necropsy: inflammation of the trachea in 1 vaccinate of group 1; non-specific

lesions (gut, liver, unresorbed vitellus…)

Body weight gain: no statistical difference between groups

Serology: seroconversion of the vaccinates, the controls remaining negative

RMS comments

The applicant should indicate whether or not the control were sham vaccinated with spring water (as in report

04.0571.R).

Concerning the serological titre: the applicant considers that the HI titres of the controls (4 or 5) correspond to the

non specific background of the test and that a serological conversion occurred in vaccinates. However, when

considering individual values, all the controls had a titre of 4 or 5, whereas 2 out of 10 birds of group 1 had a titre

above 5. Thus, it is not considered appropriate to conclude that a conversion occurred in vaccinates of group 1.

Nevertheless, serology is just an indicative parameter to check the absence of intercurrent IB infection, which is

confirmed in this trial by the low titre of the controls.

Concerning the inflammation of the trachea in one vaccinate at necropsy, contrary to the statement of the

applicant, it is not possible to conclude that it is a non-specific lesion; the bird showing the lesion was not

examined until the age of 14 days for the record of bronchial rales; thus this bird might have persistent rales. The

applicant should justify his statement.



Question 52

Report 04.0581.R.: safety of 1 dose and of an overdose in day-old SPF chicks, IB component:


04.0571.R).







Four birds in the group inoculated with an overdose of the vaccine showed diarrhoea on day 28. Three of these four

birds showed also lesions at necropsy. The applicant should comment on this, and justify why this is not

considered to be related with the vaccination since this symptom has been only observed in the vaccinated

animals and in none of the controls.


Merial Repeat-use


Report 05.0367.R.: safety of 1 dose in day-old conventional chicks


Animals 85 1-day-old conventional broiler chickens, randomised in 2 groups of 40 birds + 1

group of 5 birds for serological control on day 0

Vaccine Hatchpak Avinew IB H120 (M713 ND - batch 3AWF7P15A & M713 IB batch

3BIF7A01A)



Vaccine scheme Group 2: 1 dose of 4.7 log10 DIO50/bird (IB) and 6.7 log10 DIO50/bird (ND) at the age of

1 day

Group 1: control

Group 0: 5 birds for serological control on day 0





On day 28, blood sampling for IB and ND serology by IH (10 birds/group), sex



Results Non specific morbidity/mortality: 2 birds died in control group; diarrhoea in both

groups


in 7 to 27 % of the vaccinates, score of 1 or 2, no birds showing a score of 3

the rales appear 3 days after vaccination, pick at 10 days and nearly

disappear around 14 days after vaccination


At necropsy: no specific lesion


Serology:

ND:

initial titre before vaccination: between 6.0 and 8.0 log2 (mean 6.8)

at day 28 in controls: between < 1.0 and 3.0 log2 (mean < 2.1)

at day 28 in vaccinates: between 2.0 and 6.0 log2 (mean 3.6)

IB:

initial titre before vaccination: 8.0 or 9.0 log2 (mean 8.8)

at day 28 in controls: 4.0 or 5.0 log2 (mean < 4.2)

at day 28 in vaccinates: between 4.0 and 6.0 log2 (mean 4.9)

RMS comments


04.0571.R).

Question 53

Report 05.0367.R.: safety of 1 dose in day-old conventional chicks:


04.0571.R).

III.C.1.2. Safety for the respiratory tract (IB component)

Report 04.0474.R.: ciliary activity after vaccination with the vaccine strain and passaged strain

Vol.7/12, p.10 (summary) & vol. 7/12 p.159 (detailed report)

RMS comments


Merial Repeat-use


This report deals with the biological properties of the IB H120 strain and not with the vaccine; indeed, the material

tested is the vaccine strain at passage level MSV+1 and the same strain passaged 6 times in birds. Thus, the

RMS has decided to move this report into section III.C.6.3. Reversion to virulence.

III.C.1.3. Safety for kidney (IB component)

Report 04.0856.R.: safety for kidney after vaccination with the vaccine strain and passaged strain


RMS comments




III.C.1.4. Safety for the reproductive tract (IB component)

Report 04.0060.R.: safety for the genital tract after vaccination with the vaccine strain and passaged

strain


RMS comments




RMS OVERALL COMMENT OF THE SECTION

The applicant has not provided a trial demonstrating the safety of the administration of one dose of the vaccine

Hatchpak Avinew IB H120 in birds with no maternally derived antibodies. Indeed, the safety of one dose in this

category of birds is studied separately for each component.

However, the safety of the repeated administration of one dose was performed in SPF birds (see section III.C.3.),

providing relevant information to cover this section.

Question 54

For the information of the applicant concerning this section:


Hatchpak Avinew IB H120 in birds with no maternally derived antibodies. Indeed, the safety of one dose in this


The RMS considers however, that the safety of the repeated administration of one dose was performed in SPF

birds (see section III.C.3.), providing relevant information to cover this sec tion.

A CMS (n°1) notes that single dose safety for the product is addressed in the repeat dose study and considers

this acceptable providing the safety data is supplemented by data with administration of the vaccine by the

recommended route (spray) in an overdose safety test.

III.C.2. Safety of the administration of an overdose




RMS comments

See section III.C.1. of this report for the summary of this trial. The same comments and questions apply.


Merial Repeat-use


Question 55

Report 04.0571.R.: safety of 1 dose and of an overdose in day-old SPF chicks, ND component:



Report 04.0581.R.: safety of 1 dose and of an overdose in day-old SPF chicks, IB component


RMS comments

See section III.C.1. of this report for the summary of this trial. The same comments and questions apply.

Question 56



04.0571.R).



III.C.2.2. Safety for the respiratory tract (IB component)



RMS comments

This report deals with the biological properties of the IB H120 st rain and not with the vaccine; indeed, the material



III.C.2.3. Safety for kidney (IB component)



RMS comments





The applicant has not provided a trial demonstrating the safety of the administration of an overdose of the vaccine

Hatchpak Avinew IB H120. Indeed, the safety of an overdose is studied separately for each component.

This is not conform to the regulation (EC directive 2004/28). The applicant shall provide a trial demonstrating the

safety of an overdose of the vaccine (both component administered at the same time).

Question 57


Hatchpak Avinew IB H120. Indeed, the safety of an overdose is studied separately for each component. This is

not conform to the regulation (EC directive 2004/28). The applicant shall provide a trial demonstrating the safety of

an overdose of the vaccine (both component administered at the same time).

In addition, a CMS (n°1) considers that an overdose safety study by the spray route (nebulisation) of

administration is required before the product could be accepted. The study required for the bivalent product would

be sufficient to support this.


Merial Repeat-use


In addition, CMS n°4 considers that for live vaccines, the overdose study is very important to assess the safety

profile of the product and therefore, the trial should be provided.

III.C.3. Safety of the repeated administration of one dose

Report 04.0188.R.: safety of the repeated administration of 1 dose in day-old SPF chicks


Animals 65 1-day-old SPF chickens, randomised in 2 groups of 30 birds + 1 group of 5 birds


3BIF7A01A)



Vaccine scheme Group 0 (5 birds): for serology on day 0

Group 1: 1 dose of 4.7 log10 DIO50/bird (IB) and 6.7 log10 DIO50/bird (ND) at the age of

1 day, and again at the age of 14 days

Group 2: unvaccinated controls


Individual examination of respiratory reaction on 20 birds/group: on day 5, 7, 10,

12, 14, 19, 21 & 24; scoring of the signs


On day 28, blood sampling for IB and ND serology by IH (10 birds/group), sex


Statistical analysis On weight gain (multifactor ANOVA taking account of factors sex, isolator and group)

Results Non specific morbidity/mortality: 1 dead bird in each group


in up to 60 % of the vaccinates, score of 1 or 2, no birds showing a score of 3;

pic of bronchial rales on day 10 and resolution by day 21



Body weight gain: significant reduction of weight in vaccinates compared to

controls on day 14 and day 28

Serology:

ND:

initial titre before vaccination < 2.0 log2

at day 28 in controls < 2.0 log2

at day 28 in vaccinates: between 5.0 and 9.0 log2 (mean 6.3, std 1.57)

IB:

initial titre before vaccination: 4.0 or 5.0 log2 (mean 4.2, std 0.45)

at day 28 in controls: 4.0 or 5.0 log2 (mean 4.3, std 0.48)

at day 28 in vaccinates: between 4.0 and 6.0 log2 (mean 4.7, std 0.67)

RMS comments

The results obtained are consistent with those obtained after the administration of the IB component alone (report

04.0581.R) and ND component alone (report 04.0571.R) in SPF birds: growth retardation which can be attributed

to the ND component and bronchial rales which can be attributed to the IB component. The level of the signs is

similar in the different studies.

These results are acceptable, but the signs observed (growth retardation and bronchial rales) should be reported

in the SPC (see the RMS questioning section 4.6 of the SPC).

Question 58

Report 04.0188.R.: safety of the repeated administration of 1 dose in day-old SPF chicks:

The signs observed (growth retardation and bronchial rales) after administration of one dose should be reported in

the SPC. For the record, as far as the safety of one dose of Hatchpak Avinew IB H120 (both components

administered together) was not studied in SPF birds, the signs observed after the repeated administration of one

dose can be used to document the SPC.


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A CMS (n°1) notes that rales were observed for up to 21 days not just the 14 days proposed by the RMS for

inclusion on the SPC. The applicant should address this, in particular considering this data and the fact that

coughing was observed up to 33 days in one field study. The applicant should also note the SPC may need further

modification depending on the results of the required overdose study due to the use of a route other than that

recommended.

III.C.4. Examination of reproductive performance

Report 99.0339.R.: safety of AVINEW in pullets – monitoring of the onset of lay


Animals 4 week-old SPF female chickens, randomised in 4 groups of 50 to 71 birds

Vaccine AVINEW (7.0 log10 EID50/dose)

Administration route Ocular or oral route

Vaccine scheme Group 1 (G1 - 71 birds): 1 dose (7.0 log10 EID50/dose) of AVINEW at 4 and 10 weeks

of age by ocular route

Group 2 (G2 - 67 birds): 1 dose (7.0 log10 EID50/dose) of AVINEW at 4 and 10 weeks

of age by oral route

Group 3 (G3 - 60 birds): not vaccinated with AVINEW

Group 4 (G4 - 51 birds): not vaccinated with any vaccine

Other vaccines Groups 1, 2:

- live vaccines: MD at day-old, IBD at 6 weeks, IB CR88 at 8 weeks,

encephalomyelitis at 12 weeks, ART at 14 weeks

Groups 1, 2 & 3:

- inactivated vaccine: against ND, IB, EDS, ART at 18 weeks

Follow-up weight record: every 2 weeks from 4 until 22 weeks of age (groups 1 & 2)

weekly viability (G1, G2, G3, G4)

laying performances (number of eggs, downgraded eggs, laying percentage) until

the age of 38 weeks

serology: 10 birds per group, at interval during the study (IB by SN, ND by HI, ART

by ELISA)

Results Satisfactory growth, viability (> 97%) and laying results in groups 1 and 2,

comparable to the controls

Serology:

G4 remained seronegative to the 3 components throughout the study

Seroconversion was observed for the 3 components after the administration of

the inactivated in group 3

Seroconversion was observed for the 3 components after the administration of

the live vaccine, with a booster effect of the inactivated vaccine at 18 weeks in

groups G1 and G2

The serological titres in G1 and G2 are closed to each other, but markedly

higher than in unprimed (G3) birds

RMS comments

This trial is only considered as supportive, because:

- the vaccine used is not the right one (monovalent ND lyophilised whereas Hatchpak Avinew IB H120 is a

bivalent frozen vaccine)

- the birds are not vaccinated according to the claim (at the age of 4 weeks instead of 1 day-old)

Furthermore, the growth was not recorded in controls (growth in vaccinates only compared to a standard growth

curve), thus the relevance of the conclusion for this parameter is poor.

For the record, the relevance of the serological response in term of efficacy is also poor, because the vaccine

AVINEW was used at a dose higher than normal dose.

Question 59

Report 99.0339.R.: safety of AVINEW in pullets – monitoring of the onset of lay:




Merial Repeat-use


- the vaccine used is not the right one (monovalent ND lyophilised whereas Hatchpak Avinew IB H120 is a

bivalent frozen vaccine)





strain


RMS comments



RMS has decided to move this report into section III.C.6.3. reversion to virulence.

Document 97-43: evaluation of the DOI of an hexavalent inactivated vaccine – CNEVA Ploufragan


RMS comments

The report is not summarised by the RMS, because it is of poor interest for the following reasons:

1. the vaccine used was BIORAL H120 and not the bivalent vaccine Hatchpak Avinew IBH120

2. no detail is provided concerning the batch used and in particular the titre of IB component/dose

3. there was no control group (birds not receiving BIORAL H120), so that it’s not possible to assess the

potential detrimental effect of the vaccine

4. the birds were not the most susceptible ones: there were conventional breeders with antibodies to IB and

not SPF birds

5. It is clearly stated in the report that the protocol was not written to assess the effect on lay, and in

particular, the harvest on the eggs was not conducted correctly (indeed it’s a trial to assess the potency of

the IBD component of an hexavalent inactivated vaccine)

In conclusion, the RMS doesn’t consider that this trial can support the safety for the reproductive performance of

the vaccine Hatchpak Avinew IBH120.

Question 60

Document 97-43: evaluation of the DOI of an hexavalent inactivated vaccine – CNEVA Ploufragan:


The report is of poor interest for the following reasons:





4. the birds were not the most susceptible ones: there were conventional breeders with antibodies to IB and

not SPF birds


particular, the harvest on the eggs was not conducted correctly (indeed it’s a trial to assess the potency of

the IBD component of an hexavalent inactivated vaccine)

In conclusion, the RMS doesn’t consider that this trial can support the safety for the reproductive performance of

the vaccine Hatchpak Avinew IBH120.


This vaccine is intended for use in newly hatched birds, thus this section is not mandatory. No further information

is required.

However, concerning the wording of section 4.7 of the SPC:

- the data provided are not sufficient to conclude that the use of Hatchpak Avinew IB H120 is safe in pullets

because no specific study was conducted with this vaccine (no data concerning simultaneous


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administration of both strains, data provided concern AVINEW and BIORAL H120 used separately, in

older birds than claimed, etc.),

- concerning the effect of the IB component on the reproductive tract, the trial of the Ph. Eur. monograph

442 was performed by the applicant (see report 04.0060.R in section III.C.6.3 Reversion to virulence) with

satisfactory results

- concerning the effect of the ND component, no impairment of the onset of lay was observed after

vaccination with AVINEW.

Thus, the RMS proposes the reword the section 4.7. of the SPC to:

“The vaccine is not intended for use in breeders and layers. The data available on the properties of the strain are



Question 61

This vaccine is intended for use in newly hatched birds, thus this section is not mandatory. No further information

is required.


- the data provided are not sufficient to conclude that the use of Hatchpak Avinew IB H120 is safe in pullets

because no specific study was conducted with this vaccine (no data concerning simultaneous



- concerning the effect of the IB component on the reproductive tract, the trial of the Ph. Eur. monograph

442 was performed by the applicant (see report 04.0060.R in section III.C.6.3 Reversion to virulence) with

satisfactory results




“The vaccine is not intended for use in breeders and layers. The data available on the properties of the strain are



CMS n°1 supports the RMS comments but does not support the RMS’s proposed SPC wording. The CMS n°1

considers that the vaccine should be contra-indicated in layers and breeders but that sufficient data to meet

requirements is provided on reproductive safety for use in any category of 1 day old chicks. If an additional warning

is required it must refer to the fact that no detrimental effect on the development of the reproductive tract has

been observed.

CMS n°4 position: The studies provided to demonstrate the innocuousness of the vaccine on reproductive

performance are not acceptable as the vaccine used, the posology, and the age of the animals are not the ones of

this application. More studies should be provided, or the vaccine should be contraindicated not only during

pregnancy and reproduction period, but also in animals intended for breeding.

CMS n°5 position: No data are available to support the use of the Hatchpak Avinew IB H120 vaccine in breeders

and layers, so the vaccine should not be used in these categories of chickens. SPC should be changed

accordingly.

CMS n°6 position: Doc. 04.0856.R and 0.4.0006.R and Doc. 97-54

These trials are only performed with the IB-component. The laboratory trials are performed with MSV+1, the field

trial with Bioral H 120. No trials are available with the combined vaccine Hatchpak Avinew IB H 120. These trials

can only be considered, when supporting data from a field trial with Hatchpak Avinew IB H 120 performed in layers

will be provided.

III.C.5. Examination of immunological functions

The applicant reminds that both for the Newcastle disease virus strain VG/GA (cf. publication in vol. 9/12 p.919)

and the IB component, no pathogenic effect induced by these naturally attenuated strains which could suggest a

possible adverse effect on immunological function could be found in publications. Therefore, no specific study was

carried out.


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RMS comments

This is acceptable.

III.C.6. Special requirements for live vaccines

III.C.6.1. Spread of the vaccine strain

III.C.6.1.1. ND component

Document ND-06-88: contact passage of TNDV EP5 virus


Animals 25 SPF day-old chickens + 25 hatchmate control birds

25 SPF 2-week-old chickens+ 25 hatchmate control birds

Vaccine VG/GA Master Seed Virus identified as strain TNDV EP5, 6.8 log10 EID50/dose

Administration route Eye drop

Vaccine scheme 25 SPF day-old chickens receive 6.8 log10 EID50/bird of strain TNDV EP5, and are

thereafter placed in contact with 25 hatchmate control birds

25 SPF 2-week-old chickens receive 6.8 log10 EID50/bird of strain TNDV EP5, and

are thereafter placed in contact with 25 hatchmate control birds

Follow-up at day 5, day 6, day 7 and day 8 post vaccination, 5 vaccinates and 5 contacts are

cloacal swabbed for virus recovery

Results Virus recovery in contact birds at each sampling date (number of positive/number

tested):

Day 5 Day 6 Day 7 Day 8

1-day-old contact 0/5 1/5 1/5 2/5

2-week-old contact 0/5 1/5 1/5 3/5

Conclusion The ND vaccine strain spreads from vaccinated to contact birds.

RMS comments

There are discrepancies (in bold) between the results in the report vol. 8/12 pp.439-440 and the summary in

vol.7/12 p.24 (see tables below). However, both sets of results lead to the conclusion that the ND vac cine strain

VG/GA spreads from vaccinated to contact birds.

Data from report vol. 8/12 pp.439-440 Day 5 Day 6 Day 7 Day 8

1-day-old vaccinates 3/5 1/5 4/5 2/5

1-day-old contact 0/5 1/5 1/5 3/5

2-week-old vaccinates 3/5 2/5 5/5 3/5


Data from summary vol.7/12 p.24 Day 5 Day 6 Day 7 Day 8

1-day-old contact 0/5 1/5 1/5 2/5


Nevertheless, despite this would not change the conclusion but in order to clarify the dossier, the applicant is

asked to solve this discrepancy.

Question 62

Document ND-06-88: contact passage of TNDV EP5 virus:


vol.7/12 p.24 (see tables below). The applicant is asked to solve them.


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1-day-old contact 0/5 1/5 1/5 3/5




1-day-old contact 0/5 1/5 1/5 2/5


Document 05.0061.R: ND strain VG/GA reversion to virulence study by 5 successive passages


Animals 4 groups of 12 and 1 group of 24 SPF chickens, aged 1 day at their group setting up

Vaccine VG/GA Working Seed Virus identified 3VG1A01, 7.0 log10 EID50/bird

Administration route Eye drop (1st passage)

Contact with vaccinates (next passages)

Protocol 1st passage - day 0: inoculation of 12 birds (group 1) with 7.0 log10 EID50/bird of

WSV

2nd passage: 12 birds (group 2) placed in contact with group 1 from day 3 to day 7

after the inoculation of group 1

3rd passage: 12 birds (group 3) placed in contact with group 2 from day 7 to day 14

4th passage: 12 birds (group 4) placed in contact with group 3 from day 14 to day

21

5th passage: 24 birds (group 5) placed in contact with group 4 from day 21 to day

28

A new isolator is used at each passage.

Follow-up tracheal sampling between 4 and 6 days after the beginning of each passage for

virus isolation

confirmation of final recovered virus as NDV by specific haemagglutination

inhibition test (HIT)

follow up of the clinical signs during the trial

Result virus evidenced at all the passages, confirmed to be NDV at 5 th passage (HIT)

no clinical signs observed

Conclusion The ND vaccine strain spreads from vaccinated to contact birds.

RMS comments

This trial confirms results of Document ND-06-88, which is that the ND vaccine strains spreads from vaccinated to

contact birds.

III.C.6.1.2. IB component

Document 02.0673.R: IB strain H120 - reversion to virulence study by 5 successive passages


Animals 5 groups of 15 SPF chickens, aged 1 day at their group setting up

Vaccine IB H120 Working Seed Virus (batch BI H120/01/oeuf-L546/090797), 5.0 log10

EID50/bird

Administration route Oculo-nasal route (1st passage)

Contact with vaccinates (next passages)

Protocol 1st passage - day 0: inoculation of group 1 with 5.0 log10 EID50/bird of WSV

2nd passage: group 2 placed in contact with group 1 from day 3 to day 7 after the

inoculation of group 1

3rd passage: group 3 placed in contact with group 2 from day 7 to day 14

4th passage: group 4 placed in contact with group 3 from day 14 to day 21

5th passage: group 5 placed in contact with group 4 from day 21 to day 28


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Follow-up trachea sampled on day 3 (3 birds) and day 5 (3 birds) after the beginning of each

passage for virus isolation in eggs (passages 1 to 4) ; same sampling protocol, but

on all the birds of group 5

serology HIT on birds of each group (except group 5) 35 days after the beginning of

the passage to confirm infection by the passaged strain

Result virus evidenced at all the passages

seroconversion on most of the birds at each passage

Conclusion The IB H120 vaccine strain spreads from vaccinated to contact birds.

Document 04.0022.R: IB strain H120 - reversion to virulence – passages 6 and 7


Animals 30 SPF day-old chickens

Vaccine IB H120 5th in vivo passage (obtaining described in report 02.0673.R)

Administration route Oculo-nasal route (6th passage)

Contact with vaccinates (next passage)

Protocol 6th passage - day 0: inoculation of group 1 (10 birds) with 7.3 log10 EID50/bird of

the 5th passage strain (0.1 mL per bird of a 8.3 log10 EID50/ml suspension)

7th passage – day 2: group 2 (20 birds) placed in contact with group 1 from day 2

after the inoculation of group 1


Follow-up trachea sampled on half of the birds of each group on day 4 and day 5 after the

beginning of each passage for virus isolation in eggs; titration

daily observation of the birds during the 7 days of the trial

Result virus evidenced at each passage; passage 6 virus titrated 3.32 log10 EID50/ml and

passage 7 titrated 2.84 log10 EID50/ml

no clinical signs in birds

Conclusion The IB H120 vaccine strain spreads from vaccinated to contact birds.

RMS comments

These trials are satisfactory to document the spreading of the IB H120 strain. For the record, the applicant has not

provided the certificate of analysis of the strain used for the 1st passage, which corresponds in fact to the Work ing

Seed (certificate of analysis provided in part II, vol.4/12, p.141).

III.C.6.2. Dissemination in the vaccinated animal


Document ND-06-88: contact passage of TNDV EP5 virus


RMS comments

See section III.C.6.1.1. of this report for the summary of this trial. The same comments apply.

This trial demonstrates the intestinal tropism of the VG/GA strain, which was isolated from the cloacae of

vaccinated birds and birds in contact with these vaccinates.



RMS comments

See section III.C.6.1.1. of this report for the summary of this trial.

This trial demonstrates that the VG/GA strain can disseminate in the respiratory tract.


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Document 04.0022.R: IB strain H120 - reversion to virulence – passages 6 and 7


RMS comments


This trial demonstrates that the IB H120 strain can disseminate in the respiratory tract.

Question 63

For IB component, it is well known that the virus can be disseminated to the bird cloaca (Cavanagh.D. severe

acute respiratory syndrome vaccine development: experiences of vaccination against avian infectious brobchitis

coronavirus. Avian pathol. 2003. Dec: 32(6): 567-82). The applicant should justify why the virus isolation on faeces

were not performed.

III.C.6.3. Reversion to virulence of attenuated vaccines




RMS comments


This trial demonstrates that 5 in vivo passages can be carried out with the VG/GA strain.

Concerning the follow-up of the clinical signs, the information in the report is very limited. The applicant should

provide further information concerning the clinical follow-up of the birds (duration and frequency of observation,

parameters recorded…).

Question 64

Document 05.0061.R: ND strain VG/GA reversion to virulence study by 5 successive passages:

The applicant should provide further information concerning the clinical follow-up of the birds (duration and

frequency of observation, parameters recorded…).

Document SG/VA.DEB.95/D254: ND strain VG/GA - reversion to virulence study after 10 successive

passages


The vaccine AVINEW (same strain as in HATCHPAK AVINEW, level MSV+2) was administered to 10 one-day-old

SPF chicks by the oculo-nasal route (1st passage) at the dose of 7.0 log10 EID50/bird; 8 serial passages were

conducted thereafter in groups of ten SPF chicks aged 1 to 3 days by natural route; 20 birds were used for the 10 th

passage.

Persistence of the virus throughout the passages was checked (trachea sampling).





ICPI 0.36 0.31 0.13 0.28

RMS comment

This report (also presented in part II.A.3.) is compliant to the requirements of the Ph. Eur. 450 (section 2.4.4.A), in

term of both protocol and results.


Merial Repeat-use


Document FXLG/PM/130206 VG/GA strain – amino-acid sequence of the 5th passage strain

Vol.7/12, p.39 (summary) & vol.9/12 p.632 (detailed report)

Viruses isolated from samples collected from birds of the 5th passage (study 05.0061.P described under

III.C.6.1.1.) were tested for amino-acid sequence. The sequence in the 9 different clones tested was the same one

as the in document from CNEVA, 1996.

RMS comment

This result is compliant to the requirements of the Ph. Eur. 450 (section 2.4.4.B).


The applicant has only provided part of the information required by the Ph. Eur. monograph 450 test 2.4.4.

Reversion to virulence.

Indeed, the clinical follow-up for 21 days of birds inoculated with the passaged strain (test 2.4.4.C) is not available.

The applicant is asked to provide these tests.

Question 65

The applicant should provide the clinical follow-up for 21 days of birds inoculated with the passaged strain (test

2.4.4.C), as required by the Ph. Eur. monograph 450.


Document 02.0674.R: BIORAL H120 - reversion to virulence study – safety in SPF chicks


Animals 3 groups of 25 SPF day-old chickens

Vaccine BIORAL IB H120 Working seed Virus (batch BI H120/01/oeuf-L546/090797), 5.0

log10 EID50/bird

IB H120 Working Seed Virus (batch BI H120/01/oeuf-L546/090797) passaged 5

times in chickens (see report 02.0673.R for the obtaining of the 5th passage strain)


Vaccination scheme Group 0: unvaccinated controls

Group 1: vaccinated with the 5th passage strain

Group 2: vaccinated with 5.0 log10 EID50/bird of BIORAL H120 Working Seed

Follow-up Daily clinical examination for 21 days

Examination of respiratory signs on the 3rd, 5th, 7th and 14th day after vaccination

On day 3, 5, 7 and 14, removal and euthanasia of 3 birds per group for post -

mortem and histopathology (macroscopic observation of upper and lower

respiratory tract, kidneys and reproductive tract; microscopic examination of the

trachea)

Weight record on day 0 and day 21 (remaining birds)

Statistical analysis Of weight gain (ANOVA)

Result In group 2, slight bronchial rales in 2 birds 7 days after vaccination; no other

respiratory signs recorded

No post-mortem findings

Acute to sub-acute catarrhal tracheitis of modest gravity, more pronounced in

group 2 than group 1

No difference of weight gain between groups

Conclusion No increase in virulence of 5 passages in SPF birds

RMS comments

Concerning report 02.0673.R: the passages were conducted in day-old birds, whereas the Ph. Eur. monograph

requires to use 2 week -old birds; however, the passages were successful, allowing the obtaining of a 5th passaged

strain. Therefore, the protocol for passages in acceptable.


Merial Repeat-use




Animals 85 1-day-old SPF chickens randomised in 4 groups of 20 birds + 1 group of 5 birds

“Vaccine” IB Vaccine strain at passage MSV+1 (1 passage from the Master Seed Virus)

IB Vaccine strain after 6 passages in SPF chickens

Diluent: physiological saline

Administration

route

Oculo-nasal route

Vaccine

scheme

Group 0: serological controls on day 0 (5 birds)

Group 1: 1 dose of 4.7 log10 DIO50/bird at the age of 1 day (level MSV+1)

Group 2: 1 overdose of 5.7 log10 DIO50/bird at the age of 1 day (level MSV+1)

Group 3: strain obtained after 6 in vivo passages in SPF chickens (description of the obtaining

of this 6th passage in report 02.0673.R and 04.0022.R)

Group 4: non-inoculated controls

Follow-up On day 5, 7 and 10: 5 birds in each group are euthanised, their trachea collected and treated

to obtain 10 tracheal rings per bird; examination of ciliary activity and scoring according to Ph.

Eur. monograph 442 (0 = 100% ciliary activity; 1 = 25% ciliostasis; 2 = 50% ciliostasis; 3 =

75% ciliostasis; 4 = complete ciliostasis)

Analysis of

ciliostasis

To take account of background ciliostasis observed in controls, the correct mean score/ring =

mean score/ring in vaccinates - mean score/ring in controls

Results Corrected scores per ring per observation day, and as a mean of the 3 days for each group:

G1 (MSV+1, 4.7 log10) G2 (MSV+1, 5.7 log10) G3 (passaged strain)

Day 5 Day 7 Day 10 Day 5 Day 7 Day 10 Day 5 Day 7 Day 10

Per day 2.25 3.01 1.72 2.43 1.87 2.74 0.15 1.29 0.01

Mean 2.33 2.35 0.48

Conclusion The vaccine strain comply to the Ph. Eur. 442 with regard to safety for the respiratory tract.

The vaccine strain passaged 6 times in SPF birds doesn’t show increase in virulence with

regard to the ciliostatis test.

RMS comments

Concerning the biological properties of the vaccine strain at the least attenuated passage:

The vaccine strain at passage level MSV+1 corresponds to the Work ing Seed presented in the analytical part of

the dossier (same certificate of analysis in part II, vol.4/12, p.141 and in p.173 of the present report). Thus, this

material is appropriate for this test (least attenuated passage).

The protocol of this trial complies with the Ph. Eur. monograh 442, section 2.4.1.1. The group 2 corresponds to

the group of relevance with regard to the requirements of the Ph. Eur. (birds receiving 10 times the maximum titre

of virus contained in a dose of vaccine). The applicant has included in the trial a control group, to take account of

background ciliostasis and thus correct the values observed in vaccinates.

The applicant has not expressed the score in the same way as the Ph. Eur. He has added all the scores of the 10

rings of the 5 birds of each group at each day of record and divided by the number of rings observed (50). Thus

the applicant gives the mean score/ring whereas the Ph. Eur. gives the limit for a score/trachea (which

corresponds to 10 times the value indicated by the applicant).

However, the conclusion is that the average ciliostatis score for each group is below the limit set by the

monograph (25 per trachea, corresponding to 2.5 per ring). The strain complies with the requirements of the Ph.

Eur.

Concerning the reversion to virulence:

This is compliant to the Ph. Eur. monograph 442, test 2-4-2. Increase in virulence.


Merial Repeat-use




Protocol Same protocol as report 04.0474.R described above

Follow-up Serology IB on day 0 and 28

Daily observation for 28 days; birds found dead are necropsied

On day 5, 7 and 10: 5 chicks euthanised per group and kidney tissue sampled for histo-

pathological examination

Results Serological response observed in vaccinates but not in controls

Neither mortality nor morbidity attributable to the vaccination

No lesions of the kidney attributable to the vaccination

Conclusion The vaccine strain comply to the Ph. Eur. 442 with regard to safety for the kidney

RMS comments


These results comply to the test 2.4.1.1. of the Ph. Eur. monograph 442 (safety for k idney).


The vaccine strain passaged 6 times in SPF birds doesn’t show increase in virulence with regard t o the k idney

lesions. This is compliant to the Ph. Eur. monograph 442, test 2-4-2. Increase in virulence.


strain


Animals 1-day-old SPF female chickens

“Vaccine” IB Vaccine strain at passage MSV+1 (1 passage from the Master Seed Virus)

IB Vaccine strain after 6 passages in SPF chickens

Diluent: physiological saline


Vaccination scheme Group 0 (5 birds): serological controls on day 0

Group 1 (55 birds): 1 dose of 4.7 log10 DIO50/bird at the age of 1 day (level MSV+1)

Group 2 (51 birds): strain obtained after 6 in vivo passages in SPF chickens

Group 3 (14 birds): non-inoculated controls

Follow-up Serology: day 0 (group 0), 28 (10 birds/group) and 70 (10 birds of group 3)

Record of death and necropsy between day 0 and day 70

On day 70: record of weight, euthanasia and sampling of the oviduct for weight

record and macroscopical examination (for macroscopic cysts in the lumen,

obliteration of the lumen, hypoplasia)

Statistical analysis On oviduct weight

Intercurrent event Poor condition or mortality in 10% of the birds of group 1 between day 7 and day 27

Results Examination of oviduct :

No lesions in groups 1 and 3 (1 dose and controls)

Anhydrous cyst adhesive to the oviduct (1 bird) and caseous substance within

the lumen of the oviduct (1 bird) without obliteration in group 2 4% of birds

affected

No difference in the weight of the oviduct in the 3 groups

Serology: the controls remain negative during the study and the vaccinates show a

trend to seroconversion at day 28.

Conclusion The vaccine strain comply to the Ph. Eur. 442 with regard to safety for the reproduct ive

tract

RMS comments


Concerning the clinical follow-up of group 1, repeated records of birds in poor condition and deaths were made; in

order to clarify this clinical situation specific to the group 1 (general signs and deaths were clearly lower in the 2

other groups), the applicant is asked to provide the raw data of the clinical follow-up and further analyze and

explain the results.


Merial Repeat-use


Else, both the protocol and the results comply to the Ph. Eur. 442, test 2.4.1.2.


The vaccine strain passaged 6 times in SPF birds doesn’t show increase in virulence with regard to the genital

tract. This is compliant to the Ph. Eur. monograph 442, test 2-4-2. Increase in virulence.

Question 66

Report 04.0060.R.: safety for the genital tract after vaccination with the vaccine strain and passaged strain






The absence of increase of virulence of the IB H120 strain is clearly established, and the demonstration is in

particular compliant to the Ph. Eur. monograph 442, test 2.4.2.

III.C.6.4. Biological properties of the vaccine strain

6.4.1. Newcastle disease component

Intracerebral Pathogenicity Index (ICPI)

Report SG/VA.DEB.95/D254 : VG/GA strain – reversion to virulence


The vaccine Avinew (same strain as in Hatchpak Avinew, MSV+2) was administered to 10 one-day-old SPF chicks

by the oculo-nasal route (1st passage); 8 serial passages were conducted thereafter in groups of ten SPF chicks

aged 1 to 3 days by natural route; 20 birds were used for the 10th passage.

Persistence of the virus throughout the passages was checked.





ICPI 0.36 0.31 0.13 0.28

RMS comment

This report is compliant to the requirements of the Ph. Eur. 450 (sections 2.4.1. and 2.4.4.A), in term of both

protocol and results.

Report 99.0676.R: VG/GA strain – measurement of the ICPI


MSV+1 (Master Seed Virus + 1 passage) was inoculated to embryonated eggs, allantoic fluids collected after 48

hours and the resultant viral suspension titrated on embryonated eggs (10.1 log10 EID50/ml). 4 groups of 12 SPF

chicks aged 26-35 hours were inoculated with a volume of 0.05ml by intracerebral route:




- group G4: chick inoculated with virus-free allantoic fluid

The chicks were monitored from day 1 to day 8. The IPIC was determined according to the Ph. Eur. monograph

450 (live vaccine against Newcastle disease). The IPIC were:


Merial Repeat-use


Group 1 Group 2 Group 3 Group 4

Dose received 8.8 log10 EID50/chick 8.5 log10 EID50/chick 8.2 log10 EID50/chick -

ICPI 0.32 0.18 0 0

RMS comment


results.

Amino-acid sequence

Document CNEVA, 1996: VG/GA strain – amino-acid sequence


The amino-acid sequence around the protein F clivage site was determined for the VG/GA strain:

F2 Cleavage site F1

Site 111 112 113 114 115 116 117 118 119

Gly Gly Lys Gln Gly Arg Leu Ile Gly

RMS comment

This result is compliant to the requirements of the Ph. Eur. 450 (section 2.4.2).

Document FXLG/PM/130206 VG/GA strain – amino-acid sequence of the 5th passage strain


Viruses isolated from samples collected from birds of the 5 th passage (study 05.0061.P described under

III.C.6.1.1.) were tested for amino-acid sequence. The sequence in the 9 different clones tested was the same one

as the in document from CNEVA, 1996.

RMS comment

This result is compliant to the requirements of the Ph. Eur. 450 (section 2.4.4.B).

6.4.2. Infectious bronchitis component

The H120 strain is attenuated by passages in embryonated eggs.

RMS comments

The applicant has not developed this section. However, the RMS reminds the trials demonstrating the particulars

of the strain:



The report and RMS comments are presented in section III.C.6.3.2. reversion to virulence for the IB component.





strain




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III.C.6.5. Recombination or genomic reassortment of strains

Vol.7/12, p.40

The applicant provides a rational for not conducting specific studies:

- ND component: single-stranded non-segmented RNA of negative sense not in favour of genomic

reassortment

- IB component: possibility of recombination with a wild strain. However, IBV has a single genome; there is

little risk of recombination. This virus is not integrated to the cellular genome. The risk of genomic

reassortment during a normal viral cycle is that of RNA viruses and is therefore low. The strain is derived

from an EU-origin isolate and has been used without any problem over years. No harmful consequence is

expected.

RMS comments

The applicant statement is acceptable.

III.C.7. Study of residues

Vol.7/12, p.41

The applicant reminds that this vaccine contains neither adjuvant nor preservative.

The maximum amount of gentamicin and polymyxin (used at the time of harvest of the allantoic fluid) calculated in

the finished product is respectively 0.0475 and 0.09455 µg/dose. At these concentrations, they are not considered

as pharmacologically active.

RMS comments

For antibiotics which are residue of manufacturing process present at very low concentration in the final product,

no specific study of residue is expected.


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III.C.8. Interactions

Report 04.1064.R.: safety of the simultaneous administration with RMB 533 (VAXXITEK HVT+IBD)

Vol.7/12, p.42 (summary) & vol.9, p.634 (detailed report)

Animals 65 1-day-old SPF chickens, randomised in 2 groups of 30 birds + 1 group of 5 birds


3BIF7A01A)


VAXXITEK HVT+IBD: 1 dose of 4.9 log10 pfu/bird under a volume of 0.2 ml

Administration route Oculo-nasal route for HATCHPAK

SC of 0.2 ml for VAXXITEK

Vaccine scheme Group 0 (5 birds): for serology on day 0

Group 1: unvaccinated controls

Group 2: 1 dose of 4.7 log10 DIO50/bird (IB) and 6.7 log10 DIO50/bird (ND) + 1 DOSE

OF VAXXITEK at the age of 1 day

Follow-up Daily observation for 28 days




On day 28, blood sampling for IB and ND serology by IH and IBD by ELISA (10

birds/group), sex determination, euthanasia and post-mortem examination (in

particular trachea, lung, air sacs, kidneys, bursa of Fabricius)

Statistical analysis On weight gain (multifactor ANOVA taking account of factors sex, group and isolator)

Results Non specific morbidity: diarrhoea in a few birds


in up to 35 % of the vaccinates, score of 1 or 2, no birds showing a score of 3;

pic of bronchial rales on day 7, nearly resolved by day 14



Body weight gain: significant reduction of weight in males vaccinated compared to

males of control group on day 28, no significant difference at day 7 and at day 28

in females

Serology: vaccine take confirmed in group 2, whereas no contamination occurred

in group 1 unvaccinated

RMS comments

For the record concerning VAXXITEK HVT+IBD:

VAXXITEK HVT+IBD is a frozen live recombinant vaccine against containing a HVT vector expressing the VP2

gene of the IBD virus, to be administered to chicks from the age of 1 day (and also embryonated eggs aged 18

days) by SC route under a volume of 0.2 ml in day-old chicks. The applicant states that 4.9 log10 pfu/dose is

closed to the maximum titre of 1 dose of VAXXITEK HVT+IBD, which should be confirmed by the applicant by

providing the highest release dose for VAXXITEK HVT+IBD.

According to the SPC of VAXXITEK HVT+IBD, there are no adverse reaction after the administration of 1 dose

and of an overdose of this vaccine.

The applicant states that diarrhoea was observed in both groups and thus can be considered as an unspecific

clinical sign not related to vaccination. By examination of the raw, it seems however that clinical sign of diarrhoea

was only observed in the vaccinates. The applicant should clarify this result and revise the conclusion of the trial

and of the safety of the administration of both vaccines.

Concerning the respiratory score, the effect observed in this trial is quite similar to data from report 04.0188.R

(see section III.C.3.). The protocol of both trials was comparable (vaccination of day-old SPF chickens with 1

dose of HATCHPAK AVINEW IB H120 of maximum titre, record of the score using the same scoring system at

the same timepoints. Results (mean respiratory score of vaccinates at X day after vaccination) are summarised

below:


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Report 04.0188.R Report 04.1064.R

IB: titre of the dose administrated 4.7 log10 DIO50/bird 4.7 log10 DIO50/bird

ND: titre of the dose administrated 6.7 log10 DIO50/bird 6.7 log10 DIO50/bird

HVT: titre of the dose administrated - 4.9 log10 pfu/bird

Mean score at Day 5 0.05 0.20





Mean score at Day 19 0.05 Not done

Mean score at Day 21 0 Not done

Mean score at Day 24 0 Not done

Concerning the growth retardation, this was observed in both trials (04.0188.R and 04.1064.R).

As a conclusion, provided the problem concerning the diarrhoea can be solved, the safety of the simultaneous

administration of VAXXITEK HVT+IBD and HATCHPAK AVINEW is established.

Question 67

Report 04.1064.R.: safety of the simultaneous administration with RMB 533 (VAXXITEK HVT+IBD):

The applicant states that 4.9 log10 pfu/dose is closed to the maximum titre of 1 dose of VAXXITEK HVT+IBD,

which should be confirmed by the applicant by providing the highest release dose for VAXXITEK HVT+IBD.






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III.D. FIELD STUDIES

Report 03.0916.R.: field safety of HATCHPAK AVINEW IB H120, compared to AVINEW and BIORAL H120


Animals 2 groups of 22,032 newly-hatched conventional broiler chickens

Vaccines HATCHPAK AVINEW IB H120: batch 3AWF7P15A (ND) & 3BIF7A01A (IB)

AVINEW

BIORAL H120

Diluent for the 3 vaccines: “volvic” spring water

Administration route Nebulisation

Vaccine scheme Group P1: 1 dose of HATCHPAK AVINEW IB H120

Group P2: 1 dose of AVINEW and 1 dose of BIORAL H120

Other vaccines At the hatchery, birds were vaccinated against Marek Disease (LYOMAREX-live) and

coccidiosis (PARACOX-5- live)

During rearing, birds were vaccinated at the age of 20 days against IBD (GALLIVAC

IBD-live) and against ND (AVINEW)

Follow-up General health status during the 58 days of breeding

Record of coughing every 3 days until the age of 33 days (number of coughs

recorded during 3 minutes by an operator staying in the middle of the building)

Individual examination of 50 birds/group every 3 days until the age of 33 days

Zootechnical performances: body weight (in 100 birds/group every 5 days),

consumption index, and at slaughter house: number of birds slaughtered, total

weight of bird, condemnation rate

Serology on day 0, 20, 40, 55: ND by IH and ELISA, IB by SN and ELISA on 15

birds/group

Statistical analysis None

Results Neither particular clinical event nor need of specific treatment during rearing

the kinetic of coughing is similar in both groups, with a maximum of coughing at

12-14 days after vaccination and resolution by day 28

Clinical sign after individual examination

Bronchial rales in up to 20% of the birds, with a pick between 12 and 16 days

after vaccination; neither respiratory distress nor dyspnoea recorded

Seldom record of frothy lacrimation or serous nasal discharge in 1 or 2 birds

out of 50

No difference in kinetic or frequency of the observations between groups

Zootechnical performances:

Overlaying of the growth curves of both groups

Mean daily weight gain similar in both groups

Condemnation rate, consumption index, viability, weight at slaughter very

closed for both groups.

Serology: serological response similar in both groups, the birds showing high IB

and ND maternally derived antibodies on day 0

RMS comments

There was no statistical analysis of the results; the applicant should discuss why it was not planed in the protocol.

Despite results of both groups appear very similar at first sight, the applicant should provide a stat istical analysis

supporting the equivalence of both groups.

Concerning the titre received per bird, the applicant has indicated that the birds received a commercial dose.

According to the certificates of analysis provided, the calculated titre received are:


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Titre of the container Nb doses/container Titre/dose

HATCHPAK AVINEW 9.87 LOG10 EID50/ampoule 15,000 5.7 LOG10 EID50

HATCHPAK IB H120 8.45 LOG10 EID50/ampoule 15,000 4.3 LOG10 EID50

AVINEW - 1,000 6.5 LOG10 EID50

BIORAL H120 - 5,000 4.1 LOG10 EID50

These values are within the specifications; however, it is noted that the titre of AVINEW was quite higher

compared to HATCHPAK AVINEW (thus birds of group 2 received approx. 6 times the amount of ND virus of

those of group 1). The applicant should discuss the consequences of this bias on the results of the trial.

The serological response is not discussed further in this safety section, as far as no unvaccinated control group is

included to assess the effect of the vaccines with regard to a negative reference, and to assess any potential field

virus circulation.

Question 68

Report 03.0916.R.: field safety of HATCHPAK AVINEW IB H120, compared to AVINEW and BIORAL H120:

There was no statistical analysis of the results; the applicant should discuss why it was not planed in the protocol

and provide a statistical analysis supporting the equivalence of both groups.




HATCHPAK AVINEW 9.87 LOG10 EID50/ampoule 15,000 5.7 LOG10 EID50



BIORAL H120 - 5,000 4.1 LOG10 EID50




Document 97-54: safety and serological studies for RMB 539 hexavalent inactivated vaccine


The animals included in both studies (72-94 and 73-94) were vaccinated according to the “classical” vaccination

schedule (i.e. against Marek’s disease, Newcastle disease, Infectious bursal disease, avian encephalomyelitis and

infectious bronchitis). For IB vaccination, BIORAL H120 was administered by spray at 4-day old in 6,000 table-egg

layers and on the day of birth in 4,000 broiler breeders; a 2nd administration of BIORAL H120 was performed at the

age of 4 weeks. The hexavalent inactivated vaccine RMB 539 (oily adjuvanted vaccine containing the IB strains

Mass41 and CR88, the ND strain Ulster 2C, the EDS strain V127, the Swollen Head Syndrom strain VC03 and the

IBD strain VNJO) was administered at the age of 17 weeks (table-egg layers) or 20 weeks (broiler breeders).

Any abnormal behaviour of the groups and any mortality were recorded during the daily care and maintenance of

the animals. The eggs were collected daily and the number of eggs laid was recorded weekly.

Results:

- mortality

Table-egg layers Mortality between 0 and 17 weeks of age: 0.5% Mortality during the laying season: 7.3%

Broiler breeders Mortality between 0 and 24 weeks of age: 2.7% Mortality during the breeding period: 6.2%

- laying performances: laying curves of table-egg layers and broiler breeders appear satisfactory

- hatchability (see amendment on p.787): the results of the broiler breeders between the age of 25 and 65

weeks are comparable (even slightly better) than reference values for 2 broiler breeder strains

RMS comments

This report may only support field safety of the monovalent vaccine HATCHPAK IB H120, as far as the birds didn’t

receive either AVINEW or HATCHPAK AVINEW.

The vaccine used was BIORAL H120 and not HATCHPAK IBH120; however, both vaccines contain the same

strain at nearly the same dosage (a dose of BIORAL H120 contains 3.5 to 5.0 log10 EID50 of virus), and it is not

expected that other components (excipient) may modify the safety profile of the product.

As it was done for the hatchability results, the applicant should provide a comparison of the results of mortality

and laying curves (for both table-egg layers and broiler breeders) with reference breeds of layers and breeders.

Question 69


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Document 97-54: safety and serological studies for RMB 539 hexavalent inactivated vaccine:

The applicant is informed that this report may only support field safety of the monovalent vaccine HATCHPAK IB

H120, as far as the birds didn’t receive either AVINEW or HATCHPAK AVINEW.



Coughing was observed till day 33. The applicant should comment on this in the context of the safety warnings,

(see comment under repeat dose safety).

Divergent opinion:

A CMS (n°1) considers the request for laying curves is not relevant as safety of the IB component for the

development of the reproductive tract has been demonstrated and the vaccine will be contraindicated for use in

breeders and layers.


For Hatchpak Avinew IB H120, the only field study of interest is 03.0916.R. There was no unvaccinated control

group, the control group being vaccinated with commercial IB and ND vaccines; however, this is an acceptable

approach because it’s not realistic under field conditions to include birds not vaccinated against IB and ND.

Further information is needed to validate the field safety of the product (see RMS questions concerning this trial).

Question 70

No field trial with Hatchpak Avinew IB H 120 performed in layers is provided. The lack of these date should be

justified.

III.E. ECOTOXICITY

Vol.7/12, p.47

An extensive analysis is provided in accordance with Note for Guidance EMEA/CVMP/074/95. Only major points

are reminded below.

Following chapters are documented:

1. hazard identification

1.1 capacity of live organisms to transmit to non-target species

1.1.1 ND: numerous avian species sensitive

1.1.2 IB: chicken is the only naturally infected species

1.2 shedding of live product organisms (route, number, duration)

1.2.1 ND: VG/GA strain of a predominant enteric tropism, dissemination and spread

documented in documents ND-06-88 and 05.0061.R (section III.C.6.)

1.2.2 IB: bibliographic reference to document dissemination, dissemination and spread

documented in documents 04.002.R and 02.0673.R (section III.C.6.)

1.3 capacity to survive, establish and disseminate

1.3.1 ND: bibliographic reference to document resistance of ND virus in the environment and

document ND-15-89 reisolation of ND virus in birds exposed to VG/GA

contaminated litter: (vol.9/12, p.790) briefly, chickens were placed on a litter

contaminated with the VG/GA strain; every 3 days for 4 weeks, attempts were made to

isolate ND virus from cloacal swabs and spleens; ND antibodies were tested 15 and 33

days after the placement; 1, 2, 3 and 4 weeks after placement, a group of 20 chicks was

challenged by a virulent ND strain. All these tests show the limited capability to survive in

litter or to infect chickens

1.3.2 IB: bibliographic reference to document the limited resistance of IB virus

1.4 pathogenicity to other organisms

1.4.1 ND: sensitive species reminded, as well as the characters of attenuation of the strain

VG/GA (ICPI and amino-acid sequence)

1.4.2 IB: limited host range

1.5 potential for other effects of live product organisms (refers to data exposed in section III.C.6.5.)


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1.6 toxic effect of the product components (analysis of antibiotics residue, no effect expected for the

other excipients)

1.7 toxic effects of excreted metabolites

2. assessment of likelihood

2.1 local chicken and avian species: the likelihood of exposure to the strains is moderate, the

likelihood of exposure to other components is negligible

2.2 wider avian species: the likelihood of exposure to the strains is negligible to low, the likelihood of

exposure to other components is negligible

2.3 other species: the likelihood of exposure of other species to the strains is negligible; concerning

human beings, taking into account the cooking of meat and the claimed precautions for vaccine

administration, likelihood of exposure is low.

3. assessment of consequence of a hazard occurring

3.1 local chickens and avian species: consequences low to negligible

3.2 wider avian species and other species consequences negligible

4. assessment of the level of risk

4.1 local chickens and avian species

As a result, the overall level of risk (using the matrix approach) is “low” for local chickens and “effectively

zero” for other avian species

4.2 wider avian species and other species

As a result, the overall level of risk (using the matrix approach) is “effectively zero” for wider avian species,

mammals and humans

Conclusion: the overall risk is not significant.

RMS comments

Satisfactory. It is also reminded that the 2 strains (VG/GA and H120) have been used for years in the field with no

problem identified.

For the record, with regard to the potential zoonotic effects of the Newcastle Disease virus, the applicant has

included a warning in the SPC, section 4.5.:


- Because Newcastle disease virus can cause a transitory conjunctivitis in man, it is recommended to wear

respiratory and eye protection in compliance with current European standards.

Question 71

The applicant should take account of CMS n°6 position:

No data are provided for spread to other susceptible species like turkeys, pigeons, ducks and geese. The

applicants states that vaccinated chickens are mostly held in close stables with high biosecurity standards and

contact with other birds can be excluded. The CMS is of the opinion, that this statement is not correct for the

whole of the EU. Moreover, this would exclude open air holdings and backyard holdings from vaccination with

Hatchpak Avinew IB H 120. In order to avoid a corresponding restriction in the SPC (e.g. vaccine for use in closed

stables only) data on spread to other species should be provided.

III.F. CONCLUSIONS ON SAFETY

RMS comments

A major trial is missing according to the EC directive 2004/28: safety of an overdose of Hatchpak Avinew IB H120.

The question is raised in section III.C.2.

No safety trial except the field trial was conducted by nebulisation, which is the recommended route of

administration; however, this field trial is not sufficient to confirm the safety of the vaccine administered by the

nebulisation route because the conventional birds are not the most sensitive birds and this field trial compared 2

groups both vaccinated by nebulisation. It is agreed that using the oculo-nasal route is appropriate to control as

much as possible the dose received by each bird. However, by nebulisation, the vaccine may penetrate more

deeply in the respiratory tract and may cause a different safety profile. The applicant should thus justify why t he

safety of the nebulisation was not confirmed in laboratory trials.

There is no major problem concerning the properties of the vaccine strain which have been used in the field for

years and which have been correctly documented in the dossier.


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Clarifications are needed to confirm the relevance of a number of trials provided. The questions are raised in the

relevant sections.

Updates of the SPC are also needed to reflect more adequately the safety profile of the product. The questions

are raised in the SPC.

Question 72



nebulisation route because the conventional birds are not the most sensitive birds and this field trial compared 2

groups both vaccinated by nebulisation. It is agreed that using the oculo-nasal route is appropriate to control as

much as possible the dose received by each bird. However, by nebulisation, the vaccine may penetrate more

deeply in the respiratory tract and may cause a different safety profile. The applicant should thus justify why the

safety of the nebulisation was not confirmed in laboratory trials.

The applicant should be informed that several CMSs have requested a specific trial with regard to nebulisation

route:

- The CMS n°1 requests that an overdose safety study using the spray (nebulisation) route is provided with

bivalent product to meet Ph.Eur. requirements and to support the other safety data provided where

vaccination was not carried out by the recommended route.

- CMS n°4 position: For laboratory safety studies the animals were vaccinated by ocular and nasal route

although, for field studies, animals were vaccinated by nebulization. Even though it is considered

acceptable the ocular and nasal route to assure the amount of vaccine virus given to each animal, taken

into consideration that nebulization allows the virus to get to the animal by more routes and deeper, it

would be advisable to perform at least one laboratory safety study using the nebulization route.

- CMS n°5 position: The safety of the nebulisation application of the vaccine should be confirmed by

laboratory trials.


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IV. Efficacy

Summary table of the efficacy trials

Component

tested

Trial Titre per dose animals included in the

trial

Age at

vaccination VG/GA * H120 *

Potency/

Efficacy against

challenge


IB 03.0775.R 6.5 3.7/4.1 118 SPF chickens Day-old


Duration of

immunity

ND/IB/IBD/M

D


ND 04.0508.R 5.5 3.7 30 convention. chickens

10 SPF chickens

Day-old

IB 04.0512.R 5.5 3.7 30 convention. chickens

12 SPF chickens

Day-old

Influence of

maternally

derived

antibodies

ND/IB/IBD/M

D



10 SPF chickens

Day-old


10 SPF chickens

Day-old


12 SPF chickens

Day-old


10 SPF chickens

Day-old

Compatibility ND/IB/IBD/M

D


FIELD STUDIES ND/IB 03.0913.R Commerc

ial dose

Commerc

ial dose

85,680 conventional

chickens

Day-old

ND/IB 04.0939.R Commerc

ial dose

Commerc

ial dose

44,164 conventional

chickens

Day-old

ND 03.0914.R Commerc

ial dose

Commerc

ial dose

100 convention. chickens

20 SPF chickens

Day-old

ND 04.0940.R Commerc

ial dose

Commerc

ial dose


40 SPF chickens

Day-old

IB 03.0915.R Commerc

ial dose

Commerc

ial dose


24 SPF chickens

Day-old

* In log10 EID50

ND: Newcastle disease

IB: Infectious Bronchitis

IBD: Infectious Bursal disease

MD: Marek’s disease

-: not applicable

RMS preliminary note

Hatchpak Avinew is called M713 (ND), and Hatchpak IB H120 is called M713 (IB) in the studies provided in this

section.

The applicant has summarised in vol11/12, p.1-3 the pathogenicity and epidemiology of Newcastle disease and

Infectious Bronchitis and has briefly justified the choice of the vaccine strains. Supportive literature is provided.

This section recalls that the ND vaccine strain VG/GA is already the active ingredient of a live freeze-dried vaccine

placed on the market in 1992 (in France in 1999, and in 11 other European countries in 2001 and 2002 via a

mutual recognition procedure). The vaccination scheme claimed is a first administration of HATCHPAK AVINEW


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(IB H120) from the age of 1 day by spray vaccination and a second administration using AVINEW by oral route at

the age of 2 to 3 weeks; the minimum interval between the 2 vaccinations should be of 2 weeks.

The IB H120 vaccine strain is also the strain contained in a live freeze-dried vaccine BIORAL H120 (MA in France

in 1988).

For the record, the minimum titre guaranteed for HATCHPAK AVINEW IB H120 are:

- 5.5 log10 EID50/dose for the ND component

- 3.7 log10 EID50/dose for the IB component

Question 73

The applicant should identify the stabilisers used in the vaccine batches/preparation which were used in the

efficacy tests.

DE question: the summary reports in Vol. 11 are very short and do not contain sufficient detail on the results of

the various trial. Therefore, the summaries alone do not allow assessment of the trials provided. For future


IV.C. LABORATORY TRIALS

1. Potency tests / efficacy against challenge

1.1 ND component

Report 03.0641.R.: Efficacy of Hatchpak Avinew against a virulent ND challenge (strain Herts)


Animals 38 1-day-old SPF chickens randomised in 3 groups of 5, 23 and 10 birds

Vaccine Hatchpak Avinew (RMB713 - ND component) - batch 3AWF7P15A


Administration route Respiratory (spray vaccination)

Vaccine scheme Group 0: 5 birds for serological control at day 0

Group 1: 23 birds vaccinated with 1 dose of 5.5 log10 DIO50/bird at the age of 1 day

Group 2: 10 unvaccinated controls

Challenge 21 days after vaccination, challenge with ND strain Herts by IM route (5 log10 LD50/bird)

of 20 vaccinates and 10 controls

Follow-up Serology: on day 0 for group 0 and on day 21 prior to the challenge for the other

birds for ND antibodies by HIT

Daily observation for 14 days after challenge

Results Mortality Delay Morbidity ND titre day 21

Group 1 (vaccinates) 0/20 Not applicable 0/20 6.2 log2

Group 2 (controls) 10/10 Within 3 days Not applicable < 2 log2

Group 0: On day 0, the 5 birds were confirmed as sero-negative to ND.

Conclusion HATCHPAK AVINEW is compliant to the potency test of the Ph. Eur. monograph 450

RMS comments

Only the monovalent vaccine (HATCHPAK AVINEW) was administrated to the chickens. Thus , this trial is not

sufficient to establish the efficacy of HATCHPAK AVINEW IB H120. The subsequent question is raised in the

overall RMS comments concerning the laboratory trials (at the end of the section IV.C.).


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1.2 IB component

Preliminary study to assess the minimum protective IB titre

Report 03.0775.R.: efficacy of IB H120 associated to VG/GA by means of an IBV 91-1 challenge


Animals 118 1-day-old SPF chickens randomised in 4 groups

Vaccine AVINEW

BIORAL H120



Vaccine scheme Group 1: 50 birds receiving 3.7 log10 EID50 of H120 and 6.5 log10 EID50 of VG/GA

Group 2: 50 birds receiving 4.1 log10 EID50 of H120 and 6.5 log10 EID50 of VG/GA

Group 3: 12 birds unvaccinated

Group 4: 6 birds unvaccinated

Challenge 28 days after vaccination, challenge with IBV 91-1 strain by intratracheal route on 12

birds of group 1, group 2 and group 3

Follow-up Serology: on day 28 prior to challenge, by HIT (IB and ND) and SN (IB)

5 days post challenge, euthanasia of all the challenged birds and of group 4, and

trachea sampling for virus re-isolation in eggs

Results Serology: confirmation of correct vaccination by a clear seroconversion to ND and

trend to seroconversion to IB in vaccinates; controls remain seronegative

Challenge results:

group Number of positive re-isolation / number of chicks % protection

G1 2/12 83.3%

G2 0/12 100%

G3 12/12 0%

G4 0/6 Not applicable

RMS comments

The freeze-dried vaccines AVINEW and BIORAL H120 were used instead of HATCHPAK AVINEW IB H120.

This trial is conducted in the spirit of the potency test 2.4.3.2. of the Ph. Eur. monograph 442 (infectious

bronchitis virus – live), but with reduced number of vaccinates and a longer delay between vaccination and

challenge (28 instead of 21 days). The results are compliant to the requirements of the monograph, however, the

delay between vaccination and challenge being longer in this trial than prescribed by the monograph, it is difficult

to conclude whether the vaccine would comply if the correct protocol was applied.

As indicated by the applicant, this is considered as a preliminary study to determine the minimum IB titre of a

dose of vaccine but it doesn’t formally demonstrate the efficacy of HATCHPAK AVINEW IB H120 to an IB

challenge according to the Ph. Eur. monograph 442.


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Report 04.0989.R.: efficacy of HATCHPAK IB H120 by means of an IBV 91-1 challenge


Animals 1-day-old SPF chickens randomised in 3 groups

Vaccine HATCHPAK IB H120 batch 3BIF7A01A – 3.7 log10 EID50 of H120/bird



Vaccine scheme Group 1E: 20 birds vaccinated and challenged

Group 2: 10 birds unvaccinated and challenged

Group 3: 2 birds unvaccinated and unchallenged

Challenge 21 days after vaccination, challenge with IBV 91-1 strain by intratracheal route of the

birds of groups 1E and 2

Follow-up Serology: on day 21 prior to challenge on 10 birds/group, by HIT and SN

5 days post challenge, euthanasia of all the birds, and trachea sampling for virus

re-isolation in eggs

Results Serology: detection of IB seroconversion in 6 out of 10 vaccinates by SN; controls

remain seronegative

Challenge results:

group Number of positive re-isolation / number of chicks % protection

G1 2/20 90%

G2 10/10 0%

G3 0/2 Not applicable

Conclusion HATCHPAK IB H120 is compliant to the potency test of the Ph. Eur. monograph 442.

RMS comments

Only the monovalent vaccine (HATCHPAK IB H120) was administrated to the chickens. Thus, this trial is not

sufficient to establish the efficacy of HATCHPAK AVINEW IB H120. The subsequent question is raised in the

overall RMS comments concerning the laboratory trials (at the end of the section IV.C.)

For the record: the Ph. Eur. monograph 442 indicates to perform the challenge by eye-drop whereas the applicant

has performed the challenge by intra-tracheal route; this is considered acceptable by the RMS because the

challenge was established to be severe (100% of controls infected) when the Ph. Eur. requires to obtain at least

80% of infection is controls.


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2. Duration of immunity

Report 04.1011.R.: DOI of HATCHPAK AVINEW IB H120 and compatibity with VAXXITEK HVT+IBD


Animals 1-day-old conventional broiler chickens randomised in 3 groups

Vaccine HATCHPAK AVINEW IB H120 batches 3BIF7A01A & 3AWF7P15A – 3.7 log10

EID50 of H120/bird and 5.5 log10 EID50 of VG/GA/bird - Diluent: “Volvic” spring water

VAXXITEK HVT+IBD – commercial batch – 1 dose of 0.2 ml titrating 4

log10PFU/bird

Administration route Respiratory (spray vaccination) for HATCHPAK and SC for VAXXITEK

Vaccine scheme Group 0: 10 birds for serological control on day 0

Group 1: 200 birds vaccinated with HATCHPAK AVINEW IB H120 and VAXXITEK

Group 2: 107 unvaccinated birds

Challenge Not applicable

Follow-up Serology: on 10 birds/group at 3, 4, 5, 6 and 8 weeks after vaccination to monitor

antibody response to ND virus by HIT, IB virus by SN and IBD virus by SN; on day

0 on the birds of group 0

Clinical follow-up

Results No record of specific lesion or death associated with vaccination

Serology:

In vaccinates: decline of maternally dervived antibodies (MDA) between day 0

until day 21, followed by a seroconversion to ND and IB from day 21 and

between day 21 and day 42 for the IBD

ND titre from day 21: increase until day 42 followed by a plateau

IB titre from day 21: increase until day 42 followed by a decline

IBD titre from day 21: increase until day 56

In controls: similar decline of MDA going on after day 21 until reaching the

level of detection of the test for the 3 antigens

RMS comments

This study only documents the serological response after vaccination of conventional broilers with maternally

derived antibodies for the duration of rearing of broiler chickens. It’s however difficult to conclude, as the applicant

does, that there is no incompatibility between VAXXITEK and HATCHPAK AVINEW IB H120, as far as there

were no groups of birds receiving only 1 of the 2 vaccines, in order to compare the serological response of birds

receiving the 2 vaccines with birds receiving only 1 of them. Also, it’s not possible to conclude from this trial on

the duration of immunity as far as no protective serological titre is defined.

Question 74 (1st part)

For the record:

Report 04.1011.R only documents the serological response after vaccination of conventional broilers with

maternally derived antibodies for the duration of rearing of broiler chickens. It’s however difficult to conclude, that

there is no incompatibility between VAXXITEK and HATCHPAK AVINEW IB H120, as far as there were no groups

of birds receiving only 1 of the 2 vaccines, in order to compare the serological response of birds receiving the 2

vaccines with birds receiving only 1 of them. Also, it’s not possible to conclude from this trial on the duration of

immunity as far as no protective serological titre is defined.


Merial Repeat-use


Report 04.0508.R.: efficacy against a virulent ND challenge (strain Herts) in conventional broilers 6 weeks

after vaccination


Animals day-old SPF chickens and day-old conventional broilers


EID50 of H120/bird and 5.5 log10 EID50 of VG/GA/bird - Diluent: spring water


log10PFU/bird


Vaccine scheme Group 1: 20 conventional broilers vaccinated with HATCHPAK and VAXXITEK

Group 2: 10 conventional broilers not vaccinated

Group 3: 10 SPF birds not vaccinated

Challenge Challenge of the 3 groups 42 days after vaccination, with ND strain Herts by IM route

(5 log10 LD50/bird)

Follow-up Daily observation for 14 days after challenge

Results Mortality Delay % protection

Group 1 (conventional vaccinated) 0/20 Not applicable 100 %

Group 2 (conventional unvaccinated) 9/10 Within 7 days 10 %

Group 3 (SPF birds not vaccinated) 10/10 Within 3 days 0 %

For the record, the conventional broilers included in this study were birds vaccinated during the trial presented in

report 04.1011.R.

RMS comments

This trial is satisfactory to demonstrate the efficacy against ND of HATCHPAK AVINEW IB H120 in conventional

broilers. The applicant claims a duration of immunity of 6 weeks, which is established by this trial for the ND

component.

Concerning the use of conventional birds to study DOI, the maternally derived antibodies are responsible of a very

limited protection at the age of 6 weeks, as demonstrated by the death of 9 out 10 unvaccinated conventional

birds. The severity of the challenge was also confirmed by the death of all the SPF chickens challenged at the

same age.

Concerning the interaction with VAXXITEK HVT+IBD: no group vaccinated with HATCHPAK AVINEW IB H120

and not vaccinated with VAXXITEK HVT+IBD was included to assess the effect of VAXXITEK on the efficacy of

HATCHPAK. However, if VAXXITEK had a detrimental effect on the efficacy of HATCHPAK, the protection is still

high and thus the conclusion of the possible association of the 2 vaccines is acceptable with regard to the

efficacy against an ND challenge of HATCHPAK AVINEW IB H120.

On the other hand, this trial doesn’t allow to conclude that HATCHPAK AVINEW IB H120 has no detrimental

effect on the efficacy of VAXXITEK HVT+IBD, which is another point to demonstrate to allow the association of

the 2 vaccines.

Question 74 (2nd part)

For the record:

The report 04.0508.R doesn’t allow to conclude that HATCHPAK AVINEW IB H120 has no detrimental effect on

the efficacy of VAXXITEK HVT+IBD, which is another point to demonstrate to allow the association of the 2

vaccines.


Merial Repeat-use


Report 04.0512.R.: efficacy against a virulent IBV 91-1 challenge in conventional broilers 6 weeks after

vaccination


Animals day-old conventional broiler chickens and day-old SPF chickens


EID50 of H120/bird and 5.5 log10 EID50 of VG/GA/bird - Diluent: spring water


log10PFU/bird


Vaccine scheme Group 1: 20 conventional broilers vaccinated with HATCHPAK and VAXXITEK and

challenged

Group 2: 10 conventional broilers not vaccinated, challenged

Group 3: 10 SPF birds unvaccinated, challenged

Group 4: 2 SPF birds unvaccinated and unchallenged

Challenge 42 days after vaccination, with 3.3 log10 EID50/bird of IBV 91-1 strain by intratracheal

route of group 1, group 2 and group 3

Follow-up 5 days post challenge, euthanasia of all the birds and trachea sampling for virus re-

isolation in eggs

Results Challenge results per group Number of positive re-

isolation / number of chicks

% re-isolation

of IBV

G1 (convent. vaccinated challenged) 1/20 5%

G2 (convent. unvaccinat. challenged) 10/10 100%

G3 (SPF unvaccinated challenged) 10/10 100%

G4 (SPF unchallenged) 0/2 0%


report 04.1011.R.

RMS comments

This trial is satisfactory to demonstrate the efficacy against IB of HATCHPAK AVINEW H120 in conventional

broilers. The applicant claims a duration of immunity of 6 weeks, which is established by this trial for the IB

component.

Concerning the use of conventional birds to study DOI and maternally derived antibodies, the same comments

has for report 04.0508.R apply.

Concerning the association with VAXXITEK HVT+IBD, the same comments has for report 04.0508.R apply, but

this time with regard to the IB challenge.

Question 74 (end)

For the record:



vaccines.

3. Influence of Maternally derived antibodies



RMS comments

This report and the RMS comments are already presented in section 2. durat ion of immunity.


Merial Repeat-use



after vaccination




EID50 of H120/bird and 5.5 log10 EID50 of VG/GA/bird - Diluent: “Volvic” spring water


log10PFU/bird


Vaccine scheme Group 1: 20 conventional broilers vaccinated with HATCHPAK and VAXXITEK

Group 2: 10 conventional broilers not vaccinated

Group 3: 10 SPF birds not vaccinated

Challenge 21 days after vaccination with ND strain Herts by IM route (5 log10 LD50/bird) of all the

birds

Follow-up Daily observation for 14 days after challenge; necropsy on day 14

Statistical analysis Comparison of group 1 and 2 by means of a Chi-square

Results Mortality Delay Morbidity % protection

Group 1 2/20 Within 11 days 0/20 90%

Group 2 5/10 Within 10 days 1/10 40%

Group 3 10/10 Within 3 days Not applicable 0%

Significant reduction of the mortality/morbidity in group 1 (vaccinates) compared to

group 2 (conventional broilers unvaccinated)


report 04.1011.R.

RMS comments

The partial protection observed in unvaccinated broiler chickens is attributed to their residual maternally derived

antibodies; indeed, all the SPF birds challenged died within 3 days, validating the challenge. The efficacy of the

vaccine is statistically established by a significant reduction of clinical signs and mortality associated to the ND

challenge in vaccinated broilers compared to unvaccinated broilers.


after vaccination


RMS comments

This report is described in section 2. duration of immunity.

Report 04.0509.R.: efficacy against a virulent IBV 91-1 challenge in conventional broilers 3 weeks after

vaccination



Vaccine HATCHPAK AVINEW IB H120 batches 3BIF7A01A & 3AWF7P15A – 3.7 log10 EID50

of H120/bird and 5.5 log10 EID50 of VG/GA/bird - Diluent: spring water

VAXXITEK HVT+IBD – commercial batch – 1 dose of 0.2 ml titrating 4 log10PFU/bird


Vaccine scheme Group 1: 20 conventional broilers vaccinated with HATCHPAK and VAXXITEK and

challenged

Group 2: 10 conventional broilers not vaccinated, challenged

Group 3: 10 SPF birds unvaccinated, challenged

Group 4: 2 SPF birds unvaccinated and unchallenged

Challenge 22 days after vaccination, with 3.3 log10 EID50/bird of IBV 91-1 strain by intratracheal

route of group 1, group 2 and group 3

Follow-up 5 days post challenge, euthanasia of all the birds and trachea sampling for virus re-

isolation in eggs


Merial Repeat-use


Results Challenge results per group: Number of positive re-


% re-isolation

of IBV

G1 (convent. vaccinated challenged) 2/20 10%

G2 (convent. unvaccinated challenged) 10/10 100%

G3 (SPF unvaccinated challenged) 10/10 100%

G4 (SPF unchallenged) 0/2 0%


report 04.1011.R.

Question 75

The applicant should confirm that the levels of MDA observed in the trial birds is reflective of the range observed

in the field.

4. Compatibility



RMS comments

This report and the RMS comments are already presented in section 2. duration of immunity.

5. Type of immune response

Vol.11/12, p.31, bibliographic references vol.12/12, p.450 & 477

The applicant refers to literature to summarise the known type of immune response to Newcastle Disease infection

and Infectious bronchitis infection.


Merial Repeat-use


OVERALL RMS CONCLUSION ON THE LABORATORY TRIALS

The trials are summarised in a table. In all the cases, the birds were day-old at vaccination and received the

minimum titre of ND and/or IB component using spray vaccination, thus this is not indicated again in the table.

Report Vaccines used Delay vaccination-

challenge

Type of birds

vaccinated

Demonstration provided by the

trial:

ND

challenge

IB

challenge

03.0641.

R

HATCHPAK AVINEW

(ND alone)

21 days - SPF For HATCHPAK AVINEW

Compliance to Ph. Eur.

OOI in SPF

04.0989.

R

HATCHPAK IB H120

(IB alone)

- 21 days SPF For HATCHPAK IB H120

Compliance to Ph. Eur.

OOI in SPF

03.0775.

R

AVINEW + BIORAL - 28 days SPF Supportive data (the vaccines

used are not the one under

registration)

04.1012.

R

HATCHPAK AVINEW

IB H120

VAXXITEK HVT+IBD

21 days - conventional

broilers

For HATCHPAK AVINEW IB120:

OOI for ND in convent. birds

Compatibility with VAXXITEK

(partly demonstrated)

04.0509.

R

HATCHPAK AVINEW

IB H120

VAXXITEK HVT+IBD

- 21 days conventional

broilers


OOI for IB in convent. birds



04.0508.

R

HATCHPAK AVINEW

IB H120

VAXXITEK HVT+IBD

42 days - conventional

broilers


DOI for ND in convent. birds



04.0512.

R

HATCHPAK AVINEW

IB H120

VAXXITEK HVT+IBD

- 42 days conventional

broilers


DOI for IB in convent. birds



04.1011.

R

HATCHPAK AVINEW

IB H120 + VAXXITEK

- - conventional

broilers


Supportive serological data

- : not applicable

Compliance to the Ph. Eur. monographs 442 and 450:

It appears that the compliance to the Ph. Eur. monographs 450 and 442 of the bivalent vaccine HATCHPAK

AVINEW IB H120 is not established.

Efficacy claim:

The applicant claims a reduction of clinical signs and mortality due to the Newcastle disease virus, which is

established by following mortality and clinical signs after a controlled challenge under laboratory conditions.

The applicant claims a reduction of infection with Massachusetts serotype of IBV, which is established by re-

isolation of IBV in trachea after a controlled IBV challenge.

Onset and duration of Immunity:

Onset of Immunity is established in SPF birds (using a monovalent HATCHPAK vaccine) and in conventional

birds with maternally derived antibodies, as demonstrated by a challenge performed 3 weeks after vaccination.

Duration of Immunity is established in conventional birds using HATCHPAK AVINEW IB H120, as demonstrated

by a challenge performed 6 weeks after vaccination.

Compatibility with VAXXITEK HVT+IBD:

Concerning the compatibility of HATCHPAK AVINEW IB H120 with VAXXITEK HVT+IBD:

- despite no group receiving only HATCHPAK AVINEW IB H120 was compared to the group receiving both

vaccines to establish whether VAXXITEK HVT+IBD has a detrimental effect on the efficacy of

HATCHPAK AVINEW IB H120, birds receiving both products show an acceptable level of protection to IB


Merial Repeat-use


and ND challenges. Thus, it is acceptable to state that both products can be administrated on the same

day, with regard to the efficacy of HATCHPAK AVINEW IB H120.

- However, there is no demonstration that birds receiving both products are correctly protected against

Avian Infectious Bursal Disease and Marek ’s Disease. Thus, it should be indicated in the SPC that no

information is available regarding the efficacy of VAXXITEK HVT+IBD, when both products are used on

the same day.

Efficacy of the vaccination scheme including a booster with AVINEW:

The efficacy of the booster vaccination with AVINEW is not established in laboratory trials.

Question 76


The applicant should justify why the compliance of the combined vaccine HATCHPAK AVINEW IB H120 to the

Potency test of the Ph. Eur. monographs 442 and 450 was not demonstrated; currently, this is established only for

the monovalent vaccines HATCHPAK AVINEW and HATCHPAK IB H120. CMS n°6 states that this Potency test

is necessary.

Question 77


Concerning the compatibility claim with VAXXITEK HVT+IBD: , there is no demonstration that birds receiving

both products are correctly protected against Avian Infectious Bursal Disease and Marek ’s Disease. Thus, it

should be indicated in the SPC that no information is available regarding the efficacy of VAXXITEK HVT+IBD,

when both products are used on the same day. Else, the compatibility of these products cannot be claimed.

As CMSs have divergent approaches to the compatibility problem, the applicant should take into account the

following specific approaches when dealing with this problem:

Divergent opinion from CMS n°1:

The CMS n°1 considers that compatibility in terms of efficacy can be accepted for use of VAXXITEK with

Hatchpak, the reciprocal compatibility is not shown but is not relevant to this product.


Based on the currently provided data, the concurrent use of Vaxxitek HVT+IBD is not acceptable.

Moreover, no controlled trials with Hatchpak Avinew IB H 120 alone are provided. Therefore the assessment of the

efficacy of Hatchpak Avinew IB H 120 itself is not possible.

The following question was raised by CMS n°7:

Comment as to whether it is considered that the recombinant vaccine VAXXITEK HVT+IBD caused an increase

in efficacy for Hatchpak Avinew IB H120.

Question 78

Method of vaccination





low concentration of minerals and pH 7”, because it reflects the fact that in all the trials presented, the vaccine


It should be clarified what particular size can be used in the coarse spray. SPC should be changed accordingly.

Question 79

Onset of immunity

Request from CMS n°1:

The CMS considers that onset of immunity has not been established for the ND component of the vaccine when

administered as per the vaccination schedule. Study 04.1012.R using conventional birds provides some additional

information but the difference in the level of protection between vaccinates and un-vaccinated birds means it is

not sufficient to support a claim for an onset of immunity of 3 week for the ND component. The applicant should

address this lack of onset data for the ND component.


Merial Repeat-use


IV.D. FIELD TRIALS

Report 03.0913.R.: Field efficacy of HATCHPAK AVINEW IB H120 and AVINEW in conventional broiler


Animals 85,000 newly-hatched conventional broiler chickens, divided in 2 groups of 22,000 birds

in one farm 1 and 2 groups of 20,000 birds in farm 2

Vaccines HATCHPAK AVINEW: batches 3AWF7P15A (5.7 log10 EID50/dose) & 3AWF7P17A

(5.6 log10 EID50/dose)

HATCHPAK IB H120: batches 3BIF7A01A (4.0 log10 EID50/dose) & 3AWF7P17A


AVINEW commercial batch

Diluent for HATCHPAK: “volvic” spring water

Administration route Nebulisation for HATCHPAK AVINEW IB H120 in day-old birds

Oral route (drinking water) for AVINEW at the age of 3 weeks

Vaccine scheme 1 dose of HATCHPAK AVINEW IB H120 at the age of 1 day

1 dose of AVINEW at the age of 22 days (farm 1) or 20 days (farm 2)



During rearing, birds were vaccinated at the age of 3 weeks against IBD (GALLIVAC

IBD-live or Nobilis Gumboro D78)


Zootechnical performances: body weight (in 100 birds/farm every 5 days),




birds/group

Intercurrent event 1 group in farm 2 experienced enteric disorder between 15 and 20 days of age,

associated with increased mortality and was treated by antibiotics (tylan) for 3 days

(21 to 23 day of age) – not attributable to vaccination according to the applicant


Results Zootechnical performances: Condemnation rate, consumption index, daily weight

gain, viability, weight at slaughter closed for each group and within expectations.

Serology: similar pattern in the 4 groups

High level of maternally-derived antibodies against NDV and IBV on day 1

Decrease of maternally derived antibodies until the age of 3 weeks

stable ND antibody titre from day 20/22 onwards

Increase of IB antibodies after day 20/22

RMS comments

This trial is regarded as a confirmation of vaccine intake under field condition of vaccination, tak ing into account

the serological response. No further conclusion on efficacy can be drawn because no correlation is established

between the IB and ND serological titres and efficacy towards a challenge.

From a safety point of view, it is also a confirmation of the safety under field conditions (this trial was not provided

in the safety section of the dossier). According to the age of appearance of the enteric disorder (between 15 and

20 days, at least 2 weeks after HATCHPAK vaccination) and because it is observed only in 1 or the 4 vaccinated

groups, the conclusion that it is not related to the vaccination is acceptable.


Merial Repeat-use


Report 04.0939.R.: Field efficacy of HATCHPAK AVINEW IB H120 and AVINEW in conventional broiler

Vol.11/12, p.35 (summary) & vol.12/12, p.281 (detailed report)

Animals 44,000 newly-hatched conventional broiler chickens, divided in 2 groups of 22,000 birds

in 2 farms

Vaccines HATCHPAK AVINEW: batches 3AWF7P15A (5.7 log10 EID50/dose) & 3AWF7P17A


HATCHPAK IB H120: batches 3BIF7A01A (4.0 log10 EID50/dose) & 3AWF7P17A


AVINEW commercial batch (6.9 log10 EID50/dose)

Diluent for HATCHPAK: “volvic” spring water

Administration route Nebulisation for HATCHPAK AVINEW IB H120 in day-old birds

Oral route (drinking water) for AVINEW at the age of 3 weeks

Vaccine scheme 1 dose of HATCHPAK AVINEW IB H120 at the age of 1 day

1 dose of AVINEW at the age of 20 days (farm 1) or 19 days (farm 2)



During rearing, birds were vaccinated at the age of 3 weeks against IBD (GALLIVAC

IBD-live)


Zootechnical performances: body weight (in 100 birds/farm every 5 days),




birds/group


Results Zootechnical performances: Condemnation rate, consumption index, daily weight

gain, viability, weight at slaughter closed for each group and within expectations.

Serology: similar pattern in the 4 groups

High level of maternally-derived antibodies against NDV and IBV on day 1

Decrease of maternally derived antibodies until the age of 3 weeks

stable ND antibody titre from day 20/22 onwards, with an increase between

day 40 and 56 in farm 2, attributed to a wild lentogenic NDV infection

Increase of IB antibodies after day 20/22

RMS comments

Same comments as for report 03.0913.R.


Merial Repeat-use


Report 03.0914.R.: Field efficacy of HATCHPAK AVINEW IB H120 in conventional broiler, establ ished by a

controlled ND challenge


This study was conducted using the birds involved in study 03.0913.R. Prior to day -old vaccination with

HATCHPAK AVINEW IB H120, birds of groups 0.1 and 0.2 were removed to be reared in Merial facilities.

Immediately after day-old vaccination, birds of groups 1.1 and 1.2. were moved and reared in Merial facilities. Birds

from groups 2.1 and 2.2 were reared under field conditions after day-old vaccination, and moved to Merial facilities

around the age of 3 weeks, prior vaccination with AVINEW.

SPF birds reared in Merial facilities were also included to validate the challenge.

Animals - Vaccines -

Administration route

– vaccination

scheme

G 0.1 : 10 conventional not vaccinated broilers from farm 1 reared at Merial facilities

G 0.2 : 10 conventional not vaccinated broilers from farm 2 reared at Merial facilities

G 1.1: 20 conventional vaccinated in farm 1 and thereafter reared at Merial facilities

G 1.2: 20 conventional vaccinated in farm 2 and thereafter reared at Merial facilities

G 2.1: 20 conventional vaccinated in farm 1 and thereafter reared in farm 1

G 2.2: 20 conventional vaccinated in farm 2 and thereafter reared in farm 2

G 3.1: 10 unvaccinated SPF controls

G 3.2: 10 unvaccinated SPF controls

Controlled challenge ND strain Herts by IM route (5 log10 LD50/bird) of all the birds:

At the age of 23 days for subgroups 0.1, 1.1, 2.1 and 3.1

At the age of 28 days for subgroups 0.2, 1.2, 2.2 and 3.2

Follow-up Daily record of clinical signs and deaths for 14 days after challenge

Serology prior to challenge

Statistical analysis Chi-square test on the number of protected birds

Serological results Birds from farm 1:

Persistence of MDA ND antibodies in conventional unvaccinated birds (G 0.1)

Trend toward seroconversion in vaccinates reared in Merial (G 1.1) but not in

the field (G 2.1)

Birds from farm 2:

Near disappearance of MDA ND antibodies in conventional unvaccinated birds

(G 0.2)

Clear seroconversion in vaccinates whatever rearing conditions (G 1.2, G 2.2)

SPF birds confirmed seronegative at challenge

Results in term of %

of protection to ND

challenge

Farm 1 (challenge at 23 days) Farm 2 (challenge at 28 days)

G 0.1 G 1.1 G 2.1 G 3.1 G 0.2 G 1.2 G 2.2 G 3.2

% protection 60 100 65 0 40 100 85 0

Statistical analysis

(in bold significant)

Farm 1 Farm 2

G0 (unvaccinated) vs G1 (vaccinated reared in Merial) p=0.01 p=0.00

G0 (unvaccinated) vs G2 (vaccinated reared in the field) p=1.00 p=0.03

G0 (vaccinated reared in Merial) vs G2 (vaccinated reared in field) p=0.01 p=0.23

Conclusion The death of all the SPF birds validates the challenge

Birds from farm 2 vaccinated under field conditions were significantly protected to

the ND challenge, whatever the rearing conditions the vaccine is efficacious

under field conditions

In farm 1, the efficacy was not established in birds vaccinated and reared under field

conditions; this is attributed to stress or concurrent immuno-suppressive infection;

however, birds vaccinated under field conditions and reared in Merial facilities were

significantly protected, which confirms the intake of the vaccine under field use

RMS comments

The explanation of the applicant concerning the results (in particular group G2.1) of farm 1 are accepted. The

significant protection of birds from the 3 other groups vaccinated under field conditions confirms the efficacy of

the vaccination under field conditions.

The applicant should confirmed that the vaccinates received a dose of vaccine close to the minimum titre claimed

(the values indicated in the table summarising the trial were extrapolated by the assessor from the batch

specifications, ie. titre / ampoule and number of dose in the ampoule). This would allow to consider that this field

trial is performed under stringent conditions.


Merial Repeat-use


Question 80

Report 03.0914.R.: Field efficacy of HATCHPAK AVINEW IB H120 in conventional broiler, established by a

controlled ND challenge:

The applicant should confirm that the vaccinates received a dose of vaccine close to the minimum titre claimed,

with regard to the ND component.

In study ref 03.0914.R ND challenge was given at 23 and 28 days; of the birds reared in the field only 65%

conferred protection at 23 days challenge and 85% at 28 days. This would not be supportive of 21 days onset of

immunity in the field, based on this study the onset of immunity should be 28 days in the field. The applicant is

asked to provide a comment.


Merial Repeat-use


Report 04.0940.R.: Field efficacy of HATCHPAK AVINEW IB H120 and AVINEW in conventional broiler,

established by a controlled ND challenge


This study was conducted using the birds involved in study 04.0939.R. The birds were conventional broilers

vaccinated under field conditions (2 different farms involved, each group being halved of birds from each farm).

Birds were either conventional broilers or SPF, reared in Merial facilities or under field conditions, either spray

vaccinated at day old with HATCHPAK AVINEW IB H120 or not, either booster vaccinated by drinking water with

AVINEW at the age of 3 weeks or not, challenged either at the age of 3 weeks or at the age of 4 weeks. The

treatment of each group is summarised in the table below.

Vaccine batches specifications:

HATCHPAK AVINEW: batches 3AWF7P15A (5.7 log10 EID50/dose) & 3AWF7P17A (5.6 log10 EID50/dose)

HATCHPAK IB H120: batches 3BIF7A01A (4.0 log10 EID50/dose) & 3AWF7P17A (4.2 log10 EID50/dose)

AVINEW commercial batch (6.9 log10 EID50/dose)

Animals -

Vaccines -

Administration

route – vaccination

scheme

Group Strength Hatchpak day 0 Avinew day 21 Rearing Age at Challenge

G 0.1 20 conv. birds + - Merial 3 weeks




G 2.1 40 conv. birds + - Field 3 weeks

G 2.2 40 conv. birds + - Field 4 weeks

G 3.2 40 conv. birds + + Field 4 weeks

G T.1 20 SPF birds - - Merial 3 weeks

G T.2 20 SPF birds - - Merial 4 to 5 weeks

Controlled

challenge

ND strain Herts by IM route (5 log10 LD50/bird) of all the birds

Follow-up Daily record of clinical signs and deaths for 14 days after challenge

Serology prior to challenge

Statistical analysis Chi-square test on the number of protected birds

Results in term of

% of protection to

ND challenge

Challenge at the age of 3 weeks Challenge at the age of 4 weeks

G 0.1 G 1.1 G 2.1 G T.1 G 0.2 G 1.2 G 2.2 G 3.2 G T.2

% protect 40 80 83 0 20 80 43 90 0

Statistical analysis

(in bold significant)

3 weeks 4 weeks

G0 (unvaccinated) vs G1 (vaccinated reared in Merial) p=0.00 p=0.00

G0 (unvaccinated) vs G2 (vaccinated reared in the field) p=0.00 p=0.09

G0 (vaccinated reared in Merial) vs G2 (vaccinated reared in field) p=0.77 p=0.00

G3 (booster vaccinated) vs G0 (unvaccinated) - p=0.00

G3.2 (booster vaccinated) vs G1.2 (vaccinated reared in Merial) - p=0.21

G3.2 (booster vaccinated) vs G2.2 (vaccinated reared in the field) - p=0.00

Conclusion The death of all the SPF birds validates the challenge

3 weeks after HATCHPAK AVINEW IB H120 vaccination, vaccinates reared in Merial

and in the field are significantly protected compared to the unvaccinated birds

At the age of 4 weeks, birds vaccinated with HATCHPAK AVINEW IB H120 reared in

Merial and birds booster vaccinated with AVINEW reared in the field are significantly

protected compared to the unvaccinated birds; the birds vaccinated with HATCHPAK

AVINEW IB H120 reared in the field are not significantly protected compared to the

unvaccinated birds.

RMS comments

This is the only trial for the demonstration of the efficacy of AVINEW used as a booster 3 weeks after initial

vaccination with HATCHPAK AVINEW IB H120. The ND titre of HATCHPAK AVINEW IB H120 is closed to the

minimum titre, but according to the certificate of analysis of the AVINEW, the ND titre corresponds to the

maximum batch specifications (according to the AVINEW MA, the maximum titre is 7.0 log10EID50/dose). The

applicant should explain this and analyse the consequences in term of relevance of the data to demonstrate the

efficacy of AVINEW used as booster 3 weeks after initial vaccination with HATCHPAK AVINEW IB H120.


Merial Repeat-use


Question 81


established by a controlled ND challenge








controlled IB challenge


This study was conducted using the birds involved in study 04.0913.R. The birds were conventional broilers

vaccinated under field conditions (2 different farms involved).

Birds were either conventional broilers or SPF, reared in Merial facilities or under field conditions, either spray

vaccinated at day old with HATCHPAK AVINEW IB H120 or not, either challenged or not, either at the age of 29 or

at the age of 31 days. The treatment of each group is summarised in the table below.

Vaccine batches specifications:

HATCHPAK AVINEW: batches 3AWF7P15A (5.7 log10 EID50/dose) & 3AWF7P17A (5.6 log10 EID50/dose)

HATCHPAK IB H120: batches 3BIF7A02A (4.0 log10 EID50/dose) & 3BIF7C03A (4.2 log10 EID50/dose)

Animals -

Vaccines -

Administration

route – vaccination

scheme

Group Strength Hatchpak Rearing in Challenge Age at Challenge

G 0T.1 5 conventional birds - Merial - 31 days

G 0E.1 10 conventional birds - Merial + 31 days

G 0T.2 5 conventional birds - Merial - 29 days

G 0E.2 10 conventional birds - Merial + 29 days

G 1T.1 5 conventional birds + Merial - 31 days

G 1E.1 20 conventional birds + Merial + 31 days

G 1T.2 5 conventional birds + Merial - 29 days

G 1E.2 20 conventional birds + Merial + 29 days

G 2T.1 5 conventional birds + Farm 1 - 31 days

G 2E.1 14 conventional birds + Farm 1 + 31 days

G 2T.2 5 conventional birds + Farm 2 - 29 days

G 2E.2 20 conventional birds + Farm 2 + 29 days

G 3T.1 2 SPF birds - Merial - 31 days

G 3E.1 10 SPF birds - Merial + 31 days

G 3T.2 2 SPF birds - Merial - 29 days

G 3E.2 10 SPF birds - Merial + 29 days

Controlled

challenge

3.3 log10 EID50/bird of IBV 91-1 strain by intratracheal route

Follow-up IB virus research by RT-PCR on the trachea sampled on the day of performance of

challenge (for unchallenged sub-groups T) and 5 days after challenge (sub-groups E)

Serology in 10 birds of each group prior to challenge (IB antibodies by ELISA and SN)

Statistical

analysis

Chi-square test on the number of positive birds

Unexpected event Group G2T.1 (control birds from farm 1) were contaminated prior to the challenge; Groups

G2T.1. and G2E.1. were thus excluded from the analysis


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Results Challenge results per group Number of positive re-


% re-isolation

of IBV

G 0T.1 & 2 (convent. unvaccin. unchalleng.) 0/10 0 %

G 0E.1 & 2 (convent. unvaccin. challenged) 17/20 85 %

G 1T.1 & 2 (convent. vaccinat. unchalleng.) 0/10 0 %

G 1E.1 & 2 (convent. vaccinat. challenged) 4/40 10 %

G 2T.2 (convent. vaccinated unchallenged) 0/5 0 %

G 2E.2 (convent. vaccinated challenged) 2/20 10 %

G 3T.1 & 2 (SPF unvaccinated unchalleng.) 0/4 0 %

G 3E.1 & 2 (SPF unvaccinated challenged) 19/20 95 %

Statistical

analysis (in bold

significant)

G0 (unvaccinated) vs G1 (vaccinated reared in Merial) p=0.00

G0 (unvaccinated) vs G2 (vaccinated reared in the field) p=0.00

G0 (vaccinated reared in Merial) vs G2 (vaccinated reared in field) p=1.00

Serology Persistence of MDA detected by ELISA in conventional birds on day 29 (G0E.2)

Vaccine take confirmed in both farms (Sub-groups G1E and G2E)

Absence of contamination of SPF control birds (G3E.1 and G3E.2)

Conclusion Efficacy against IB confirmed after field vaccination

OVERALL RMS CONCLUSION ON THE FIELD TRIALS

The field trials confirm the efficacy demonstrated in the laboratory trials.

These field trials also demonstrate that despite the efficacy, including onset and duration of immunity, of the ND

component are clearly established under laboratory conditions after one administration of HATCHPAK AVINEW

IB H120 in day-old birds, a booster vaccination with AVINEW is necessary to obtain a satisfactory level of

protection under field conditions. The RMS agrees with the protocol of vaccination proposed by the applicant

including the booster vaccination with AVINEW 2 to 3 weeks after initial vaccination with HATCHPAK AVINEW IB

H120.

IV.E. CONCLUSIONS ON EFFICACY

RMS comments

Please refer to overall conclusions of laboratory and field trials.

Question 82

Efficacy trials on conventional chickens were performed on broiler chickens. No efficacy trial was done on

conventional layer type chicken. As the level of maternally derived antibodies decrease slower in the layer than the

broiler type chickens this may cause a delay in the onset of immunity.

Efficacy of the vaccine is not proved in layer type conventional chickens.

Use should be retricted to broiler chickens, unless additional trials in layers is provided.

Question 83

The various trials are difficult to compare. Concerning the serological results for both antigens, there is a

significant decline in titres from potency tests to laboratory tests to field trials. As antibody titres do not correlate

directly with the protection level against ND and IB the assessment of the overall protection is not easy.

Nevertheless, the applicant should explain the possible reasons for this decline.

Question 84

Concerning the duration of immunity and booster vaccination, the applicant should take the following comments

into account:

Position from CMS n°6: The CMS supports the opinion of the RMS that a booster vaccination with Avinew is

necessary to obtain a satisfactory level of protection under condition. For common vaccination schedules a

booster against IB is normally performed at the 3rd or 4th week of live. This should be discussed and probably

mentioned in the SPC.

Position of CMS n°9: Duration of immunity stated in the SPC is 6 weeks (for both Newcastle Disease Virus and

Infectious Bronchitis virus). Although this duration of immunity (rather duration of protection) has been

demonstrated by challenge in laboratory conditions following the administration of a single dose in day-old

chickens, it is well known, and again demonstrated in the Applicant’s field study , that a single vaccination may


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not be sufficient in some cases (as described for Group G2.2. in report 04.0490.R). The Applicant rightly

recommends a second vaccination using Avinew. However, we are of the opinion that the SP C text is quite

misleading. We propose the following modifications in the SPC (section 4.2.):

Onset of protection: 21 days after the first administration.

Duration of protection:

-IBV: 6 weeks after a single dose

-Newcastle Disease Virus: a duration of immunity of 6 weeks has been demonstrated after a single dose in

laboratory conditions. However, to maintain an adequate level of immunity in field conditions, a 2nd vaccination

using Avinew is recommended.


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ASSESSMENT REPORTS OF THE APPLICANT’S ANSWERS DURING THE INITIAL DCP

PROCEDURE


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2nd STEP - ASSESSMENT REPORT OF 1st LOQ & 2nd LOQ

FR/V/0171/001/DC

PRODUCT DETAILS








69007 LYON

France

Phone number (33) 472 72 39 72

Fax number (33) 472 72 33 68





MOLINA)

[email protected]


Timetable Day 0 : 29/09/2006

Day 120 (0): 26/04/2007

Day 145 (25): 21/05/2007

Day 198 (78): 13/07/2007

Day 210 (90): 25/07/2007


NL, PL, PT, SK, UK

RMS DETAILS


assessment report

France




12418


state

Not applicable




Phone number (33) 299 94 78 82



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Fax number (33) 299 94 78 88




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POSITION OF THE MS AT DAY 145

AT

No comments received on day 145.

BE (N°9)


CZ (N°8)

The Czech National Agency agrees with the overall conclusion of the RMS and is prepared to grant a marketing

authorisation for the above DC product.

DE (N°6)

The Paul-Ehrlich-Institut is of the opinion that there are potentially serious animal health concerns related to the

use of this product and is, at present, not prepared to grant a marketing authorisation for Hatchpak Avinew IB

H120.

The PEI fully supports the questions posed by the RMS and expects that these question will be part of the

consolidated LOQs. The questions mentioned below are additive to the RMS’s questions.

EL


ES (N°4)

The AEMPS agrees with most of the points/questions addressed by the RMS but considers the following

outstanding points should be additionally addressed (see questions in the report below).

FI (N°2)


FR

The "ANMV" (French National Agency for Veterinary Medicinal Product) is of the opinion that there are potentially

serious public health concerns related to the use of this product (see below) and is, at present, not prepared to

grant a marketing authorisation.

HU (N°5)

The Directorate of Veterinary Medicinal Products (DVMP) agrees with the comments and conclusions of the RMS

in the D120 Assessment Report and has given acceptance to the applicant’s responses to Hungarian questions

raised at Day 100.

IE (N°7)

The Irish Medicines Board (IMB) agrees with the comments and conclusions of the RMS in the D120 Assessment

Report and has given acceptance to the applicant’s responses to IE questions raised at Day 100 (see below).

The IMB notes the applicant’s commitment to address all national Product Labelling and package leaflet issues on

completion of the decentralised procedure.

The IMB would like to remind the applicant that in Ireland, the Product Literature must comply with the requirements

of Directive 2001/82/EC as amended by Directive 2004/28/EC using the same template outlined by the EMEA and

the Quality Review of Documents group and tak ing into account national labelling requirements as outlined in Notice

to Applicants: Volume 6A - Chapter 7: General Information.

Please note that, should the application be successful, full colour mock -ups of the Product Literature will be

required before the licence can be issued. Mock -ups are to be supplied within 30 days after day 210 (90) of the

procedure. Please indicate prior to Day 210 (90) if joint packaging with the UK is to be implemented.

IT



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LT


LU


LV

State Agency of Medicines agrees with the overall conclusion of the RMS and is prepared to grant a marketing

authorisation for the above mentioned veterinary medicinal product.

NL


PL


PT (N°3)

Although the Direcção Geral de Veterinária agrees with the overall conclusions of the RMS and a satisfactory

response to the questions raised by the RMS is required, is also of the opinion that the hereafter comments have

to be addressed (see below in the report).

SK

Institute for State Control of Veterinary Biologicals and Medicaments agrees with the overall conclusion of the

RMS and is prepared to grant a marketing authorisation for the above DC product.

UK (N°1)

The Veterinary Medicines Directorate agrees with the comments and conclusions of the RMS in the D120

Assessment Report but considers that the following outstanding points should also be addressed (see below in

the report).


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Introduction from the RMS

The initial question is boxed, the answer of the applicant is in normal fount, and the RMS comments and

questions are in italics.

Question 1 (FI)


Finland has a disease-free status for Newcastle Disease, no clinical Infectious Bronchitis, and a serological

surveillance program for both diseases. Therefore, the sale, supply and use of this product will not be allowed in

Finland (Council Directive 90/677/EEC, Article 4).

Answer of the applicant

The applicant takes note of this comment. The registration of this product is sought in case of outbreak: the

vaccine would be available immediately for use.

RMS comment

This is a national issue not concerning the RMS.

CMS position

No comments received from FI on day 145.



Question 2 (ES)

. The outstanding issues to be considered are as follow:

- Qualified person responsible for pharmacovigilance.

- Description of the back-up procedure to apply in their absence.

The applicant should submit a brief description of the back-up system in place in the QP’s absence and the

name of the QP´s substitute person.

- Procedures in place which are documented in writing.

Continuous monitoring of the safety profile of the authorised medicinal products and notifying competent

authorities and health professionals of changes to the benefit / risk balance of products. Signal generation and

Benefit / risk assessment.

The applicant should provide information about: activities of the QPPV, the collection, processing, coding,

classification and medical review. It is also necessary incorporate follow-up of reports for missing information

and for information on the progress and outcome of the case(s), detection of duplicate reports, expedited

reporting, electronic reporting, PSURs, continuous monitoring of the safety profile of the authorised medicinal

products and notifying competent authorities (CA) and healthcare professional of changes to the risk-benefit

balance of products, responses to request for information from regulatory authorities, meeting commitments to

CA, global pharmacovigilance activities applying to all products, management and use of databases.

- Handling of urgent safety restrictions and safety variations.

The applicant should submit a commitment to amend the procedure on the handling of urgent safety restrictions

and safety variations to deal with such restrict ions and variations rather than risk management procedures only.

- Internal audit of the Pharmacovigilance system.

The applicant should provide the reference code number of the SOP (Standard Operation Procedure) for auditing

the pharmacovigilanca system.

- Staff training.

The applicant should submit a commitment to put in place a system of staff training in place.

- Provide a brief description of the agreements with co-marketing partners and contractor for

Pharmacovigilance activities: include reporting responsibilities and arrangements for literature


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searches.

The applicant should provide a brief but comprehensive description of the agreements with co-marketing

partners and contractors for Pharmacovigilance activities, including reporting responsibilities and arrangements

for literature searches.

- Provide a brief description of the Quality management system, making cross-reference to the elements

provided under the above sections. Particular emphasis should be placed on organisational roles and

responsibilities for the activities and documentation, and for ensuring corrective and preventive action.

The applicant should provide a brief description of the quality management system in place including

description of SOP and its reference code, audits and management oversight.


Since the submission of the dossier, the document BT/EPV.05/001 dated April 2006 describing the

Pharmacovigilance system included in the Annex 5.20 of the Part I.A has been updated in a consequent way.

Therefore, please find enclosed in Annex p.103 the updated version dated April 2007 that will provide the

information raised below.

RMS comment

An updated version of he document BT/EPV.05/001, dated April 2007, presents a complete description of the

pharmacovigilance system. All The outstanding issues have been considered and satisfactory answers provided. A

list of 25 procedures (3 of them being as drafts) is provided. RMS thins that it is not necessary to request a copy

of all these SOP.

CMS comment

ES: No further comment.

Conclusion

Solved.

I.A.2 SOURCE

Question 3 (UK)

EMEA/INS/GMP/3351/03/Rev 4 states that “GMP inspections should be carried out at least every 2 years. Large

companies may be inspected department by department, a full GMP inspection being completed at least every 5

years. The interval between inspections should never exceed 3 years ….”. Consequently more recent certification

should be available based on inspections conducted at Lyon (before December 2006) and Chingolo Po (before

June 2006). The Applicant should provide current GMP certification.

The Applicant should provide documentation to confirm that finished product testing at Centre de Saint -Vulbas is

covered by appropriate GMP certification.

The Applicant has provided GMP certification for Novento Padovana. The Applicant should clarify what role this site

plays during production.


A new a GMP certificate dated October 13, 2006 (see in Annex p. 120) has been issued for ‘Lyon Porte des Alpes’

site.

Chignolo site was inspected lastly in 2003 as mentioned in the dossier. The GMP certificate is enclosed in Annex

p.120. A new inspection is awaited this year and the updated GMP certificate will be sent as soon as available.

The ‘Centre de Saint Vulbas’ is indeed appropriately covered by a GMP certification (see certificate dated October

13, 2006 in Annex p.120).

Noventa site is concerned by the quality control testing of the active ingredient produced in Italy. As this activity is

a pharmaceuticals activity, the corresponding GMP documentation was included in the dossier.

RMS comment

The sites involved in the manufacturing process and in controls are updated in the RMS assessment report (data in

bold added in the table below). This information is provided in the initial dossier vol. 1/12, pp. 58-59.

I.A.2 Source

Applicant MERIAL


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69007 LYON

France

Manufacturer of the active

ingredients



69007 LYON

France




Italy

Active ingredients testing MERIAL Laboratoire Porte des Alpes

Rue de l’Aviation

69800 SAINT PRIEST

France


Via Baveria 9, ZI Camin

35027 NOVENTA PADOVANA

Italy

Manufacturer of the finished

product – primary packaging



69007 LYON

France




Italy

Labelling and second

packaging

Not applicable

Final product testing MERIAL Laboratoire Porte des Alpes

Rue de l’Aviation

69800 SAINT PRIEST

France

And Testing using animals :

Centre de Saint-Vulbas

Z.I. Plaine de l’Ain

Allée des Cyprès

01150 Lagnieu

France

Responsible for batch release MERIAL Laboratoire Porte des Alpes

Rue de l’Aviation

69800 SAINT PRIEST

France

CMS comment

None

Conclusion

Solved

I.B.1 SPC

Question 4


outstanding points.


For readability improvement, Merial proposes in Annex p. 131 and 149 a Product Literature document including an

updated SmPC compiling all the proposals detailed hereafter. This document has been updated from the one

provided in the dossier. It is proposed in two versions: track mode (p. 131) compared to the dossier and final

proposal (p. 149).

RMS comment

No further comment. If any new question appears from the assessment of the applicant’s answers, it will be raised

in the relevant question of the SPC below.

CMS Comment

None.


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1. Name of the Veterinary Medicinal Product

HATCHPAK IB H120


Live Infectious Bronchite virus, H120 strain, at least ............................................... 3.7 log10 EID50

Question 5 (ES – DE – PT – CZ)

The maximum titre per dose at release should be included for both vaccine strains. CZ - ES

The epigraph “Active substance” should be indicated in this section. ES

The sentence “For a full list of excipients, see section 6.1”. should be included. ES

The meaning of EID50, should be clearly clarified with an asterisk (*), and a footnote. ES


An updated composition according to the current QRD template is proposed hereafter:


Active substances:

Live Infectious Bronchitis virus, H120 strain, at least .............................................................. 3.7 log10 EID50*

Adjuvant(s):

Not applicable

Excipient(s):



RMS comment

The proposal is acceptable, except concerning the maximum titre which is stil l not mentioned; the initial question

is raised again.

CMS comment

CZ: no further comment.

RMS question

The maximum titre per dose at release should be included for both vaccine strains.

CMS question

ES: Maximum titre should also be indicated.

DE: Replace at least by min. Moreover the max titre must be mentioned. Cave: do not mix max titre with release

titre.

PT: supports the RMS question

Day 145 question

FR: The maximum titre per dose at release should be included for both vaccine strains.



titre.



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Frozen suspensions for suspension for nebulisation.

Question 6 (ES)





Agreed.

RMS comment

The new wording for the section is “Frozen suspension for nebuliser suspension” as requested.

However, the applicant should justify why no other indication, such as expected color, is added.

RMS question

The applicant should justify why no other indication, such as yellow color, is added.

CMS question

ES and PT: A description of the visual appearance of the pharmaceutical form should be included.

Day 145 question

FR: The applicant should justify why no other indication, such as yellow color, is added.



4.1. Target species

Chickens.

Question 7 (DE -

This section may need to be revised to “Chickens (broiler chickens)” depending on the answer to the questions

raised concerning the efficacy in conventional layer chickens (see part IV).


As discussed in the questions 70 and 82, there are no reasons to differentiate this kind of chickens. Therefore, in

accordance with the item 4.2, the applicant proposed to specify:


RMS comment

Satisfactory (see questions 70 and 82).

CMS comment

DE: no further comment.

Conclusion

Solved


In day-old chickens:




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Immunity has been demonstrated 21 days after first administration and has been shown to persist until 6 weeks of

age.

Question 8 (ES – BE - DE)


ES

The applicant should also refer to the last questions in the conclusion of the efficacy section. BE


Merial agrees to use the wording "In one day-old chickens”.

In addition, as explained in question 84, Merial accept the proposal of the CMS n° 9.

Therefore, the full text of this section would be:

In one day-old chickens:




Duration of protection: 6 weeks after a single administration

RMS comment

The classical wording is “duration of immunity” and not “duration of protection”, therefore, the RMS proposes to

keep “duration of immunity”.

The RMS can agree on the rest of the proposal.

CMS comment

ES : No further comment.

Day 145 question




None.

Question 9 (ES)

As indicated in section III.C.4., the studies to show the innocuousness of the vaccine on reproductive performance

are not acceptable and the vaccine should be contraindicated in animals destined for breeding (CMS n°4).


As explained in questions 59, 60 and 61, the vaccine cannot be cons idered as being contra-indicated for animals

intended to breeding.

Specific mentions on reproductive performance are proposed in the section 4.7 (Use during pregnancy, lactation or

lay) of the SmPC.

RMS comment

Acceptable (see comments to questions 59, 60 & 61).

CMS comment

No further comment.

Conclusion

Solved.


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Vaccine viruses can spread to unvaccinated birds. Infection of unvaccinated birds with the vaccine virus from

vaccinated birds does not cause any signs of disease. Moreover, reversion to virulence trials carried out in the

laboratory have shown that the vaccine viruses do not acquire any pathogenic characteristics after at least 5

passages in chickens. Therefore, spread to unvaccinated birds, in the present state of knowledge, can be

considered as safe.

Question 10 (ES – DE)

Taking into account the data available, and the fact that only the chicken was studied, it is proposed to modify the

section to:

“Vaccine viruses can spread to unvaccinated birds. Infection of unvaccinated birds chickens with the vaccine virus

from vaccinated birds does not cause any signs of disease. Moreover, reversion to virulence trials carried out in the



considered as safe.

Nevertheless, the section may be revised in the light of the answers to the questions rais ed in part III of the report.




in the flock” (ES)




As detailed in question 71, this restriction is not considered as useful, regarding the age of vaccination, the risk of

exposure of the other species, the wide knowledge and use of these strains.

Therefore, the applicant accepts the following wording:

"Vaccine viruses can spread to unvaccinated birds. Infection of unvaccinated chickens with the vaccine virus from



chickens."

RMS comment

The proposal of the applicant is acceptable for the RMS. See also question 71 with regard for the safety for other

birds. However, it should be corrected to:

"The Vvaccine viruses can spread to unvaccinated birds. Infection of unvaccinated chickens with the vaccine

virus from vaccinated birds does not cause any signs of disease. Moreover, reversion to virulence trials carried out

in the laboratory have shown that the vaccine viruses does not acquire any pathogenic characteristics after at

least 5 passages in chickens"

CMS comment


DE: The PEI agreed with the proposal from the RMS, provided “birds” will be changed to “chickens” and additional

data on spread to other avian species will be provided.

Day 145 question




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i) Special precautions for use in animals






break.

- Hands should be washed and disinfected after vaccinating.


Question 11 (ES – PT)

It is proposed to reword the section to:



- Because live Newcastle disease virus may cause a mild transient conjunctivitis in the person

administering the vaccine, contact of eyes and airways with the vaccine virus should be prevented.

Therefore it is recommended to wear respiratory and eye protection in compliance with current

European standards.


break.



In addition, some special warning concerning handling of liquid nitrogen should be added: warning of burning,

warning of opening in an open-place or not breathing, etc.


Merial agrees with the proposed rewording. As required, please find below a proposed text regarding the liquid

nitrogen manipulation, to be added after the first sentence of the proposed list, as follows:


manipulation should take place only in well ventilated place to prevent fatal suffocation.



RMS comment

The proposal is acceptable.

CMS comment


PT: No further comment.

Conclusion

Solved.


No general reactions or lesions were observed following the administration of one dose of vaccine except slight and

transient bronchial rales within the 2 weeks following vaccination.

Question 12

Taking into account the adverse reactions observed in section III of the dossier, it is proposed to revise the section

to:


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“Bronchial rales, not associated with respiratory distress or any general sign, may be observed between 5 and 14

days after vaccination in up to 75% of the birds.”


taking into account:







The comments of the applicant regarding the rales are provided in the answers 58.

Taking into account the arguments raised in this answer, the applicant proposes to keep the initial wording:

No general reactions or lesions were observed following the administration of one dose of vaccine except slight

and transient bronchial rales within the 2 weeks following vaccination.

RMS comment

Concerning the bronchial rales, the RMS is willing to keep the proposed sentence (see question 58): “Bronchial

rales, not associated with respiratory distress or any general sign, may be observed between 5 and 14 days after

vaccination in up to 75% of the birds.”

RMS question

Concerning the bronchial rales, the RMS is willing to keep the proposed sentence (see question 58): “Bronchial

rales, not associated with respiratory distress or any general sign, may be observed between 5 and 14 days after

vaccination in up to 75% of the birds.”

CMS comment

None.

Day 145 question

FR: Concerning the bronchial rales, the RMS is willing to keep the proposed sentence (see question 58):




Not claimed. However, the vaccine strain has been shown to be safe in pullets with regard to reproductive

performance, and absence of effect on the genital tract.

Question 13 (ES-UK)

Taking into account the information available in the safety part of the dossier, the RMS proposes to reword the

section to:

“The vaccine is not intended for use in breeders and layers. The data available on the properties of the strains are

not indicative of a detrimental effect on the reproductive tract, in particular the IB strain is compliant t o the


However, divergent opinions from CMSs were received, (see below and also section III.C.4. examination of

reproductive performances) and should be taken into account by the applicant when proposing a new wording for

the section.

Position of CMS n°4: The sentence “not claimed. However, the vaccine strains have been shown to be safe in

pullets” should be removed, as safety on reproductive performance has not been demonstrated. Instead, the

following sentence should be stated “Do not vaccinate during pregnancy, lactation or lay” ES

Position of CMS n°1: see III.C.4.


Based on the answer of the question 61, please find enclosed the applicant proposal:


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"The vaccine is only intended for use in newly hatched chicks and is not appropriate after the age of one day. The

data available on the properties of the strains are not indicative of a detrimental effect on the reproductive tract, in

particular the IB strain is compliant to the specifications of the Ph.Eur. with regard to the safety for the

reproductive tract."

RMS comment

The proposal is acceptable for the RMS.

CMS comment


UK: No further comment.

Conclusion

Solved.


No information is available on the safety and the efficacy from the concurrent use of this vaccine with any other

except with MERIAL live vaccines against Newcastle disease containing VG/GA strain and with MERIAL

recombinant HVT expressing the protective antigen of the Infectious Bursal disease virus. It is therefore

recommended that no other vaccines than this should be administered within 14 days before or after vaccination

with the product.

Question 14

This section should be revised taking into account the questions raised in part III and IV of the report.


As explained in the answers 74 and 77, the compatibility with the Vaxxitek HVT+IBD has been demonst rated.

Therefore, the section 4.8 should be kept as proposed initially.

RMS comment

Acceptable with regard to the new data provided (see questions 74 and 77)

CMS Comment

None.

Conclusion

Solved.



13. Prepare a container filled with the appropriate quantity of clean non-chlorinated water (7 to 30 ml per box of

100 chicks according to the type of sprayer used in the hatchery).

14. Wear protective gloves and spectacles whilst thawing and opening the ampoules.


vaccination session.

16. Thaw the contents of the ampoules.








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23. Where another vaccine is to be used concurrently and presented in a second ampoule, carry out steps 3-

10 (opening the ampoule, drawing up vaccine, rinsing the ampoule) with the second ampoule of vaccine,

the contents of which are transferred into the container which has previously been used for the first

vaccine.




Point 11 is not acceptable. As it is written, it encourages the user to mix HATCHPAK IB H120 with any vaccine.

Either the applicant deletes the point 11, or it should be clearly indicated that the vaccine which can be mixed is

HATCHPAK AVINEW.

It is considered that for user safety reasons Section 4.9.1 (Reconstitution of the vaccine) should be reworded. In

particular it is considered that point 11 should be revised to be more explicit to the end user. It could be helpful to

include the aspects of the instructions currently included in section 11 (in a revised form) after point 2.

The sentence concerning taking maximal precautions when handling liquid nitrogen should be included in bullet

point 2.

The instruction: “thaw the contents of the ampoules” should explain in more details if the ampoules can be thawed

at 37ºC or should be thawed at room temperature (bullet point 4).








A reworded item 11 is proposed:

11. Where HatchPak Avinew is to be used concurrently, carry out again the steps 3 to 10 (opening the

ampoule, drawing up vaccine, rinsing the ampoule) with the second ampoule of vaccine. Then, transfer the

contents of this second ampoule into the container which has previously been used for the first vaccine.

As proposed in question 11 the item 2 could include the following sentence:


when handling liquid nitrogen should be taken. Refer to the section 4.5. Special precautions for use

Regarding the thawing, the following wording is proposed for the item 4:


step.

Regarding the water, it is likely that the wording "commercial available mineral water with low concentration of

minerals and pH 7" could lead to some questions on the exact meaning of "low" and acceptable variability around

pH 7. In addition, it is not economically sustainable to vaccinate the chickens with commercial water, when

appropriate drinking water can be used.

Therefore, as explained in the question 78, and to remain consistent with other approved SmPC for Merial

Newcastle vaccines, the applicant proposes to use the expression "non-chlorinated drink ing water"

In addition, as required in the question 25, the following sentence will be added to the end of this section:

"Discard any ampoules that have been accidentally thawed. Do not re-freeze under any circumstances."

RMS comment

The RMS has reviewed the information on the quality of the water used for spray vaccination of avian live vaccines,

including AVINEW. Spring or mineral water is never requested. It is only mentioned to use dechlorinated ant iseptic

free water.

It was wise for the applicant to use a mineral quality water for the clinical trials; however, this should not be a

reason to request higher water quality than always requested for avian live vaccines. Thus, it is acceptable to

indicate "non-chlorinated drink ing water".

The other points are correctly solved.


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CMS comment


DE: No further comment.

Conclusion

Solved.

4.9.2 Posology

One administration of the product from day-old, via the respiratory route (spray application.

Question 16

This section should be revised taking into account the questions raised in IV of the report.


According to the answer to the question 84, this section should not be reworded.

RMS comment

Acceptable.

CMS comment

None.

Conclusion

Solved.





Question 17 (DE)




For the reasons detailed in the answer 78, the Applicant considers that the expression of "coarse spray" is precise

enough.

RMS comment

Acceptable.

CMS comment

DE:


application machine. (Please compare with the SPCs of other vaccines already licensed via MRP)

Example

The amount of water for spray application depends on local and husbandry conditions.

After removing the stopper under water 1000 doses of vaccine are diluted as follows:

500 ml for 1000 chickens up to the 4th week of life

750 – 1000 ml for 1000 chickens after the 4th week of life.

The birds are sprayed uniformly with a distance of 30 – 40 cm.

During and after vaccination ventilation should be switched of in order to avoid turbulences.


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For primary vaccination during the 1st weeks of life a coarse spray having a droplet size of 100 µm an more should

be used to avoid penetration into the lower parts of the respiratory tract and increased vaccination reactions.

For revaccinations in older birds an improved immunity is achieved by application of the vaccine as a fine spray or

aerosol with a droplet size lower than 50 µm which causes a penetration to the lower segments of the respiratory

tract.

Only reliable and recommended spraying devices and aerosol generators should be used.

RMS comment on DE request

The vaccine is intended to be used only in day-old birds (see point 4.7.). The example provided is thus not

appropriate, but the applicant should make a proposal in the spirit of this example.

Day 145 question

DE:



Example











tract.


Additional point from the RMS:



However the applicant is reminded that the section is pending because of the awaited overdose safety trial

performed by spray vaccination.




Question 18

This section may be revised in the light of the results of the trial requested demonstrating the safety of an overdose

of both components administered together, as claimed.


As committed in the questions 54 and 57, a new safety study will be performed safety of an overdose of t he

combined product administrated by spray. The Applicant agrees to let this section as it is and to reconsider it

once the results will be available, that is to say on D170 (15 th of June).

RMS comment

Pending with regard to the awaited overdose safety trial.

CMS comment

None.

Day 145 question

For information:


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Pending with regard to the awaited overdose safety trial.

4.11. Withdrawal period(s)

Zero days.



The vaccine contains live Infectious Bronchitis virus, H120 strain. The vaccine stimulates active immunity against

Infectious Bronchitis.

Question 19

As in the indications, it should be mentioned that the vaccine induces active immunity against Massachusetts

serotype of the IBV.


Agreed.

RMS comment

Question solved.

CMS comment

None

Conclusion

Solved.



None.

Question 20 (ES – DE – PT – UK)


mentioned.


As explained in the question 30, no excipients shall be written in this section.

RMS comment

The RMS agrees with the applicant (see question 30 – 2nd part).

CMS comment

PT: no further comment.

CMS question

ES: A full list of excipients should be included in this section. We totally disagree with the arguments given by the

applicant in treating /naming as “starting material” what is really the bulk of each of the active components to be

used for filling. Therefore, excipients included should be mentioned here.

DE and UK : same position.

Day 145 question


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The presence of disinfectant and/or antiseptic in water and material used for the preparation of the vaccine solution

is not compatible with effective vaccination.

Do not mix with any other medicinal product, except MERIAL live frozen vaccine against Newcastle disease

containing MERIAL VG/GA strain.

Question 21

It is considered that the 1st sentence proposed under Section 6.2 (Incompatibilities) should be placed under

section 4.5 (Special Precautions for use).


As mentioned in the Notice to Applicants, Vol 6C, on Summary of the Product Characteristics SPC –

Immunologicals dated July 2006, in the paragraph 6.2 Incompatibilities:

"In this section information should be given about physical or chemical incompatibilities of the product with other

products with which it is likely to be diluted, mixed or co-administered…."

Therefore, Merial believes that this sentence should be kept in this item.

RMS comment

Acceptable.

CMS comment

None

Conclusion

Solved

6.3. Shelf-life

18 months.

Use immediately after opening.

Use within 2 hours after reconstitution.

Question 22




Agreed.

RMS comment

Question solved.

For the record, the applicant has not updated its proposal but now a shelf -life of 24 months is claimed, which is

considered acceptable for the RMS, provided the applicant makes the commitment to provide the results on the

on-going stability study with the new stabilisers as soon as available (see question 48). However, UK is only ready

to accept a shelf-life of 12 months currently (see question 48).

Day 145 question


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on-going stability study with the new stabilisers as soon as available (see question 48).

However, UK is only ready to accept a shelf-life of 12 months currently (see question 48).


Store the vaccine in liquid nitrogen (-196°C) and regularly check the level of liquid nitrogen.


Question 23

It is considered that the word reconstituted is not appropriate for a wet frozen preparation and therefore the word

“reconstituted” should be replaced by the word “prepared”.


The expression "reconstituted vaccine" is used throughout the SmPC. The preparation of the vaccine does not

consist only in thawing the vaccines at ambient temperature but also to mix one part with the other. Therefore,

there is a real reconstitution and for the bivalent vaccine, Merial proposes to keep this expression.

RMS comment

Acceptable.

CMS question

None.

Conclusion

Solved


Type I glass ampoule, 4-ampoule carrier.

Ampoule carriers are stored in canisters, and within liquid nitrogen containers.

- 10,000-dose IB ampoule

- 15,000-dose IB ampoule

Question 24 (ES)



As mentioned in the Notice to Applicants, Vol 6C, on Summary of the Product Characteristics

SPC – Immunologicals dated July 2006, for the paragraph 6.5 Nature and composition of immediate packaging " A

short but complete description of the immediate packaging used for (and the contents of) the final sales

presentation should be provided"

Therefore, the description of the outer packaging is out of the scope of this item and no further description of the

carriers and canisters should be provided.

RMS comment

Acceptable.

CMS question

ES : If, as the applicant states, there will be a colour code for the vials, this colour code should be described

here, and in the corresponding section of the package leaflet.

PT: The vial colors should be stated here.


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Day 145 question




6.6. Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the

use of such products, if appropriate

Discard any ampoules that have been accidentally thawed. Do not re-freeze under any circumstances.

Dispose of waste material by boiling, incineration or immersion in an appropriate disinfectant in accordance with

national requirements.

Question 25 (ES)

The sentence “”Discard any ampoules that have been accidentally thawed” and “do not re-freeze under any

circumstances” should be indicated in section 4.9 (Amounts to be administered and administration route).

The sentence “Dispose of waste material by boiling…” should be reworded to “Dispose of waste material and any

unused veterinary medicinal product by boiling…”


Agreed.

RMS comment

Solved.

CMS comment


Conclusion

Solved

7. Marketing authorisation holder

MERIAL


69007 LYON

France

8. Marketing authorisation number(s)


Question 26


In addition to any changes following from amendments to the SPC, PT national requirements must also be fulfilled.

IE national issues concerning leaflet: include the VPA number and Indicate the method of sale and supply as POM

– Prescription only medicine.


The applicant takes notes of these comments. However, national particularities regarding the labelling and leaflet

will be discussed during the national step of the procedure, provided there are compatible with the liquid nitrogen

storage constraints.

RMS comment


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These are a national issues not concerning the RMS.

Day 145 CMS question

IE: Acceptable response, inclusion of the marketing authorisation number and the route of sale and supply can be

further discussed at the end of the procedure however it is worth pointing out that these are IE national labelling

requirements and should not be omitted.

PT: no further comment on that point on day 145.

Question 27 - 1st part



The requested samples of the ampoules and carrier have been sent to the Reference Member States on the 29th

March 2007 and receipt was confirmed.

For the information of the other Concerned Member States, please find in Annex p. 165 some photos of the final

product.

RMS comment

The RMS is in receipt of the samples which are identical to the pictures provided in annex. It doesn’t raise any

other question.

CMS comment

None

Conclusion

Solved

Question 27 - 2nd part







Regarding the limitations of the labelling on the primary packaging, the justification is discussed in the Part IB of

the dossier, and some important parts are recalled hereafter for your convenience:

… Ampoules are clipped on metallic carriers (4 ampoules per carrier). Carriers are stored and sold in liquid

nitrogen containers (-196°C). This system is already implemented in the field with other marketed frozen vaccines

of MERIAL Marek’s range (e.g. VAXXITEK HVT+IBD, CRYOMAREX HVT, CRYOMAREX RISPENS or

CRYOMAREX RISPENS+HVT).

The conditions of production have direct consequences on labels, since the primary packaging of the vaccine

suspension is very small (5 ml-ampoule), and there is no possibility to perform any labelling operation after freezing

(product is very sensitive to thawing).

In addition, the conditions of supply have direct consequences on packaging elements for the following reasons:

- there is no possibility to have an outer package for this kind of frozen product. The vaccine suspension is

stored directly in the liquid nitrogen container,

- depending on the order from a given hatchery, the same liquid nitrogen container may include several

frozen vaccines (with different strains).

Therefore, the following solutions are proposed:


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due to the size of the ampoule, only crucial information should be included in the labels, the

section of the template: "Minimum particulars to appear on small immediate packaging units" was

therefore used. In addition, the ampoule labelling must be performed before filling, sealing and freezing,

since these operations are carried out consecutively in closed circuit. Moreover, the final geographical

destination of the product in the European market is unknown at production stage. In order to be able to

supply “big” and “small” markets altogether, this implies that only a unique “harmonised” label is stuck on

ampoules with the same information provided throughout Europe. …

…We are confident that the amount of information is sufficient for a safe use of the product. Indeed the product is

used in very specialized area (hatcheries) where:

the choice of the vaccine is determined before its use (not at the time of vaccination, using

supplied leaflet),

the vaccine is administered by a professional that underwent special training before acting.

As no package leaflet nor secondary packaging can be immersed in the liquid nitrogen, we propose, in the

same way as what has already been in place for the other marketed frozen vaccines of MERIAL, to have a

package leaflet slipped within a plastic transparent wallet which is stuck on the container. The wallet

stuck on the container contains as many relevant package leaflets as vaccine types present in the container,

In order to easily distinguish the different vaccines stored in the container, MERIAL has implemented a system

of tabs stuck on the top of the carriers. The tab has its own colour coding depending on the nature of the

vaccine strain. …

So the information on the direct packaging will be stickered or engraved on each ampoule before freezing.

RMS comment

The applicant hasn’t answered the question concerning the addition of the route of administration on the ampoule.

The question is raised again.

Day 145 question

FR and PT: The applicant should indicate on the ampoules the route of administration, as it is requested by the

EC directive 2004/28, article 59.

Question 27 – 3rd part (ES -


proposal:



information.


administration and withdrawal period) should be stated. A multilingual labelling cannot be accepted if it is not

possible to include the minimum information and the minimum letter size for readability. (ES)






Regarding the two first mentioned positions of the CMS, as explained above, the space does not allow adding the

withdrawal period. Given that it is nil and that the required age of vaccination does not allow consumption of the

treated animals or their production before some months, there is really no concern regarding the safety of the

product for the public health and in addition, this is written in the leaflet stuck on the liquid nitrogen container.

Regarding the comment on the multilingual packaging and the size of the font, the leaflet does not raise any

problem.


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However, regarding the ampoules, three proposals have been done to ensure providing the minimum information

while respecting the readability:

EXP and LOT are all accepted by the Members States according to the Appendix IV: Terms for Batch

Number & Expiry Date to be used on Outer and/or Inner Labelling, Version 12/2006 published on the

EMEA website.

Ad use vet: according to the answers to enquiries done at the national level, this would be used in

replacement of the translations in the national languages as often as possible. This acceptance has been

recently confirmed in a survey organised by the CMDv and QRD at national level, following the workshop

on packaging help in April 2006 in Prague. Therefore, for those countries which accepted it, the mention

will be used and for the others, they will have their national translation written on the ampoules. Merial

hopes that this way forward will be endorsed by all members eventually at the end of the procedure to

ensure the largest access to this product. It must be also underlined that due to the very specific

presentation (nitrogen tank sent to hatcheries) the veterinary use is obvious and ad us vet may be enough

information.

Regarding the last comment made by a third CMS, it is more practical for a user to be able to take the leaflet in

hand to correctly read it instead of having it stuck on the heavy liquid nitrogen container that requires careful

manipulation. That is the reason why it is not attached but slipped within a plastic transparent wallet which is

stuck on the container.

Indeed, due to the conditions of supply, there is no possibility to have an outer package or leaflet attached to the

metallic carrier for this kind of frozen product as it is stored directly in the liquid nitrogen container,

If different vaccines are provided in the same container, the wallet stuck on the container can contain as many

relevant package leaflets as vaccine types present in the container. In order to easily distinguish the different

vaccines stored in the container, there is a system of tabs stuck on the top of the carriers. The tab has its own

colour coding depending on the nature of the vaccine strain.

RMS comment

The RMS can accept the arguments of the applicant, except concerning the route of administration to be indicated

on the ampoule.

Concerning the information to put on the ampoule, the RMS refers to the labelling of the ampoule of VAXXITEK

HVT+IBD, MERIAL frozen vaccine stored in ampoules and registered under the centralised procedure. The

quantity of active ingredients and the withdrawal period are not indicated on the ampoules, but the route of

administration is.

Tak ing into consideration that HATCHPAK may be delivered in hatcheries in the same liquid nitrogen container as

VAXXITEK (because both can be used in day-old chicks), and tak ing into consideration that VAXXITEK is used

by the SC route whereas HATCHPAK is used by nebulisation, the RMS considers it is wise to have the

administration route recalled on the ampoule (as it is for VAXXITEK).

CMS question

ES:

Labelling:

A label with all the required information for labelling, particulars to appear on the outer package, according to QRD

template, should be provided. Tak ing into account the specific elements of the product applied for, we consider

that there are two possibilities to complete the required information:

1. A secondary label should be provided, which could be included in the plastic wallet, together with the

package leaflet.

2. Alternatively a combined label-package leaflet, with all the information required (including package size,

expiry date, “for animal treatment only” and manufacturer´s batch number), would also be acceptable.

Package leaflet

3. Statement of the active substance(s) and other ingredient(s):

Maximum titre should also be indicated.

A description of the visual appearance of the pharmaceutical form should be included.

6. Adverse reactions:


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Please, close this section with: “If you notice any serious effects or other effects not mentioned in this

leaflet, please inform your veterinary surgeon”.

8. Dosage for each specie(s), route(s) and method of administration:

If, as the applicant states, there will be a colour code for the vials, this colour code should be described

here.

11. Special storage precautions:

Please, reword the sentences: “Use immediately after opening. Use within 2 hours after reconstitution.” to

the new sentences used for the SPC (section 6.3), which are more clear.

12. Special warning(s):

The phrase “Do not mix with any other medicinal product” should be reworded to include the information stated in

the SPC: “Do not mix with any other medicinal product, except Merial live frozen vaccine against Newcastle

disease containing Merial VG/VA strain”.

SPC and Package leaflet

We agree with the comment raised by another CMS that the term “reconstitution” is not appropriate for a

wet frozen preparation, and that the term “preparation” is more accurate.

The arguments given by the applicant for Hatchpak Avinew IB H120 vaccine:

“The expression "reconstituted vaccine" is used throughout the SmPC. The preparation of the vaccine does not


there is a real reconstitution and for the bivalent vaccine, Merial proposes to keep this expression.”

are not valid for the vaccine Hatchpak IB H120 vaccine (they could be valid for the combined vaccine Hatchpak

Avinew IB H120 vaccine, although even in this case we consider the term is not appropriate, as a mixing of two

parts does not mean “reconstitution”).

ences used for the SPC (section 6.3), which are more clear.

PT:

As there won’t be a label on the outer package, a combined label-package leaflet, with all the information

foreseen by the QRD template for leaflet and label must be used. Thus the QRD template for the leaflet should

apply and all label information, namely, package size, expiry date, “for animal treatment only”, batch number,

colour code for the vials plus all PT national requirements should be added.

RMS question

Taking into consideration that HATCHPAK may be delivered in hatcheries in the same liquid nitrogen container as




Day 145 question

ES:

Labelling:





package leaflet.



Package leaflet





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here.



















PT





FR





II. Analytical part

Question 28 (ES - DE)


Some CMSs don’t agree to consider the active component as the starting material, mak ing for them difficul t to




The applicant takes note of the remark. The current situation was defined years ago taking into account the

directive 92/18/EC (now 2001/82/EC) stating under paragraph C for ‘active substance’ a separate submission of

documentation and the structure for pharmaceutical products where the ‘active substance’ per se is descried in full

in part II.C.


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Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code

relating to veterinary medicinal products Annex titre II, part 6, C. PRODUCTION AND CONTROL OF STARTING

MATERIALS.../…

In the case of:

- an active substance not described in the European Pharmacopoeia or in the pharmacopoeia of a Member

State,../… which is manufactured by a person different from the applicant, the latter may arrange for the

detailed description of the manufacturing method, quality control during manufacture and process

validation to be supplied directly to the competent authorities by the manufacturer of the active

substance. ../..

This construction was/is accurately matching the internal organisation of any biological company as the skills to

‘produce’ active ingredients (based on organism cultures) is different from the one required for formulation (blending

of available starting materials). It is also the unique possibility (when antigens are sold to other manufacturers) to

keep some confidentiality in the process: culture parameters for active ingredient production being very sensitive

information.

This is even more accurate nowadays where production of active ingredients is shared between different sites (with

sometimes different from the formulation site).

In addition, in agreement with this thinking, the draft of the Annex of the Commission Directive 2004/28/EC

modifying Directive 2001/82/EC does propose the introduction of a Veterinary Antigen Master File in the Part II C

Draft: COMMISSION DIRECTIVE ../…/EC of […] modifying Directive 2001/82/EC of the European Parliament and

of the Council of 6 November 2001 on the Community code relating to veterinary medic inal products TITLE IV A.

VACCINE ANTIGEN MASTER FILE.

For particular immunological veterinary medicinal products and by derogation from the provisions of TITLE II, PART

2 Section C on active substances, the principle of a Vaccine Antigen Master File is introduced.

Nevertheless, as soon as the new Annex of the said direct ive will be published Merial will align the format.

RMS comment

The question raised by some CMSs is not a concern for the RMS. No further comment.

CMS comment

ES: We can not agree with the response given by the applicant as the structure of the dossier s hould be followed

as included in NTA, in order to make a proper assessment of the dossiers. Each Company can not decide

independently on the structure to be used.


Day 145 question

ES: We can not agree with the response given by the applicant as the structure of the dossier should be followed





Question 29 (ES- DE - UK)






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According to the description of the active ingredient (i.e. the product that is used by person to formulate/blend the

final vaccine bulk) this step is indeed only a filling process. The substances that may play a role of excipients in

this vaccine are indeed used at early stage during production of the active ingredient (harvest).

Quality of substances used for the purpose is fully and accurately described in the part II.C of the dossier.

RMS comment

The clarification requested is provided, which is satisfactory.

CMS comment

ES: We totally disagree with the arguments given by the applicant in treating /naming as “starting material” what is

really the bulk of each of the active components to be used for filling. Therefore, the final composition of all

excipients should be clearly stated.

DE: cf. question 30

UK: cf. question 30

Day 145 question




Question 30 (ES-DE)










Stabilizers

It is true that two different stabilizers are quoted in the dossier and were used for production of different batches.

One replaces the other: 56 replaces 26.

The change was done during development of this vaccine and this explains why 26 (used in 2003 in Lyon) is

quoted sometimes. Since 2004 in Chignolo-Pô as this is a new production site for these strains, only stabilizer 56

has been used. Eventually only stabilizer 56 will be used in the production of Hatchpak IB H120 (explaining why

only this one is described under chapter II.C.2.2, page 105 of part II and in the active ingredient production

paragraph 2.1.5.a.iv, page 072).

Reason of the change and its validation are described in part II.A.3 development pharmaceutics and is copied here

below for convenience.

In order to minimise the BSE/TSE risk, one starting material used in the initial stabiliser 26 (added to the allantoic

fluid) containing meat and casein derivatives was replaced during the developmental phase by an analogous

starting material containing only casein derivatives (in the newly codified stabiliser 56). Both stabilisers are

described in the Table below:

OLD: Stabiliser 26 NEW: Stabiliser 56

Meat and casein

peptone

80 mg/ml /

Casein hydrolysate / 80 mg/ml

Mannitol 80 mg/ml 80 mg/ml


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Two series of 3 consecutive productions of active ingredient and finished product manufactured with stabiliser 26

and stabiliser 56 were assessed against specifications (see Parts II.B and II.E) to confirm that the change was

validated.

Content in antibiotics.

For IB-containing ampoule: during production, polymyxin B and gentimicin are used at low quantities. Theoretical

content in one dose may be derived from the concentration in each stabilizer, taking into account dilution rate (1:1

V/V) and filled volume (5.1 ml/ampoule).

For 1 liter

Name of ingredients Quantity

Active ingredient Infectious bronchitis H120 component 0.5 L

Stabilizer S56 0.5 L

Content in antibiotics POLYMIXINE B SULPHATE (98,2 µg)

GENTAMICIN SULPHATE (49,6 µg)

--------------------------------------------------------------------------------------------------------------------------

Total volume 1 L

The worst case is using presentation with the lowest number of doses (i.e. 10 000 doses).

Therefore the final theoretical contents in antibiotics are:

polymyxin B: (98.2)*(5.1/1000)/10000 = 0.000050 µg

gentimicin: (49.6)*(5.1/1000)/10000 = 0.000025 µg

The antibiotic amount is negligible and should not be mentioned in the documentation.

As explained in answer to question 29, as these materials are not actually ‘excipients’, there is no need to update

the SPC.

RMS comment

The situation is clarified. It is important to note that from now on, only the new stabiliser (54 for ND component

and 56 for IB component) will be used. The reason for the move to the new stabilisers is acceptable.

The question concerning the relevance of the trials conducted with vaccines formulated with the old sabilisers is

dealt within part III and IV of the report.

As demonstrated, the residual antibiotics are so low in the final product that there is no reason to include them as

excipients.

The stabilisers 54 and 56 are not excipients of the vaccine (excipients are products added to the active ingredient

during formulation), because there is no step of formulation of a final product; indeed, the final product is the

active ingredient directly filled in the ampoules. Stabilisers 54 and 56 are is a stabilisers of the active ingredients,

thus included in the active ingredient. For veterinary vaccines, these materials which are constituents of the active

ingredient are not listed as excipients.

The RMS is in agreement with the applicant.

CMS comment




DE: The PEI does not agree with the table of particulars. The ingredients of the stabilisers are part of the final

product and should be mentioned here and in the SPC, where relevant. The active ingredient is defined as the

virus harvest before addition of excipients, buffers and stabilisers etc. All other applicants define active

ingredients in this way and therefore substances added to the harvested viruses are regarded as excipients, which

must be mentioned in the SPC. We cannot accept that applicants are treated differently, especially as only one

applicant (Merial) differs in the definition of the active ingredient.

UK: The UK does not accept the Applicants argument that stabiliser is not an excipient. The stabiliser forms a

significant part of the final filled product and is added at the formulation stage of the bulk which is then filled. So

far as the UK is concerned the stabiliser is clearly an excipient in the finished product. The Applicant should

clearly state the composition of the stabilisers and modify the Table of Qualitative and Quantitative Particulars

accordingly.


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Day 145 question














accordingly.


Question 31

The applicant partially justifies the use of IB H120 strain as follows “initial isolates from main countries are of that

serotype”. The applicant should further justify if these “main countries” include European countries and the

relevance of this strain in Spain.


IB H120 belongs to the Massachusetts serotype. A recent communication, enclosed in Annex p. 168 from

University of Liverpool (Worthington K. J. and Jones R.C.) at the "V. International Symposium on Avian Corona-

and Pneumoviruses, Rauichholzhausen, Germany 2006" organized by the World veterinary Poultry Association

and the Justus Liebig University (Giessen-Germany) on 14-16 May 2006, allows precising the current prevalence of

this serotype in western Europe. The study involved 1901 isolates from UK, France, Germany, Holland, Belgium

and Spain obtained since 2002 to nowadays (see table 1 page 182).

As mentioned in the Summary of this reference, "The predominant genotypes detected were 793B and

Massachusetts, both of which are used extensively in commercial ly available vaccines". In the various tested

countries, the prevalence of the Massachusetts serotype is varying within 19 to 29%, 19% being achieved in

Spain. We underline that the Massachusetts serotype remains the most pathogenic one, it is therefore im portant

to maintain an immunity level against it, although other variants are also present.

As detailed in the figure 2 page 184, the prevalence of this serotype is more or less constant over the years. The

distribution of this serotype is however classically described as "world wide" since at least 50 years (but

Australia), and therefore also involve Eastern Europe.

In addition, in 2004, in the same congress International Symposium on Avian Corona- and Pneumoviruses, a

communication, enclosed in Annex p. 182, on a study performed in Hungary confirmed that two major serotypes

are predominant, including Massachusetts serotype.

Therefore, the relevance of the IB H120 serotype is demonstrated in various countries of the enlarged Europe,

included Spain.

RMS comment

Concerning the 1st reference cited, the article is provided in the annexes vol.2/3 p.168, the table cited is on page

175 of the annex (corresponding to page 182 of the publication).

The literature cited is a satisfactory justification for the choice of the Massachussets serotype.

CMS question

No further comment.

Conclusion

Solved.


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Question 32 (ES)







Both viruses, mass41 and H120 belong to the same genus (coronavirus group 3) and serotype Massachusett.

Their behaviour on egg culture is largely similar.

During titration test, a reference virus is used (either Mass41 or H120 depending on vaccine under test). The

reference virus titer is followed in a control chart. The similarity between both virus behaviours is demonstrated by

the descriptive parameters of this control chart:

same slope values (0.897 versus 0.909)

same standard deviation values for those slopes (0.084 versus 0.083)

the standard deviation of the reference titre is equivalent (0.226 versus 0.246) even if titres are different

(7.647 versus 5.500)

Viruses having same behaviour, all characteristics demonstrated with one virus in titration technique are applicable

to the other. Therefore the report 00.0838.R validates IB Massachusett virus.

Concerning the linearity, using historical data for various IB H120 virus contents, a statistical analysis shows that

the technique is linear (see report 07.0144.R, in Annex p.191) with a line equation:

Mean titer (log10 EID50) = 4.95 + 0.74 doses (log10)

Concerning sensitivity, using historical data from the reference H120 virus, the minimum virus content giving an

effect (egg mortality) was defined at a level of 0.97 log EID50, using a Gompertz’ model (see report 07.0145.R, in

Annex p. 201)

Concerning specificity: embryo lethality is not specific but typical signs are observed on the embryos that are only

produced by egg adapted Infectious bronchitis viruses: curled and dwarfed embryo, curly feathers. The titration of

the virus is carried out at release of filled product and must take into account other information.

The purity test demonstrates that the virus is a coronavirus. This information with the observation of typical signs

ensures the specificity of this titration test.

RMS comment

The applicant has provided satisfactory answers to the questions. However, the raw data on which were made the

comparison of the behaviours of the 2 reference viruses (IB H120 and Mass41) are not provided and should be

made available. Below are detailed the data of the 2 new reports provided.

Report 07.0144.R : validation of technique 15003 – titration of IB virus on eggs – linearity study

Answer of April 2007 - Vol. 2/3 – p.191

The titration was performed on finished freeze-dried product BIORAL H120 (same vaccine strain as HATCHPAK

IB H120). 10 batches of 1000-dose vials, 10 batches of 5000-dose vials and 10 batches of 15000-dose vials were

titrated on eggs. Statistical analysis for linearity was performed (check for homogeneity of variance and linear

regression):

the titre observed is proportional to the viral doses contained by vial

Mean titer (log10 EID50) = 4.95 + 0.74 doses (log10).

Report 07.0145.R : validation of technique 15003 – titration of IB virus on eggs – sensibility study

Answer of April 2007 - Vol. 2/3 – p.201

A positive control of H120 virus is diluted to obtain the equivalent of 2.3, 1.3, 0.5 and 0.3 log10 EID50/vial. Each

dilution is injected to 4 eggs. This is repeated in 15 different sessions. The number of dead embryo is recorded

and analysed using a Gompertz model:

the detection threshold is equal to 0.97 log10 EID50/vial, with a 95% confident interval [0.88; 1.06] and a

probaibility of detection of 1 dead embryo/2injected eggs


Merial Repeat-use


RMS question


The raw data on which were made the comparison of the behaviours of the 2 reference viruses (IB H120 and

Mass41) are not provided and should be made available.

CMS comment

No further comment.

Day 145 question





Question 33 – 1st part


may last and analyse the impact on stability.


The time between blending and actual filling is very short, les than 2 days. Therefore the impact on the viral titre is

very limited. In any case should such a slight impact exists, this will be detected by the titration at QC testing

level, and the product will be released fully within its specification, the impact of storage is not existing i n such a

case.

RMS comment

As far as the titration is performed on the finished product (that is after filling), any detitration which could occur

during the 2 days of storage prior to the filling is an industrial risk , and in any case doesn’t modify the

specifications of the product (titre per dose). The answer is thus acceptable.

CMS question

None.

Conclusion

Solved.

Question 33 – 2nd part (ES)

In the production flow chart for the IB H120 component, the applicant indicates that this component can be used

extemporaneous or thawed. It should be clarified whether this can affect the quality and properties of the product.

Moreover, the maximum storage period for this component under these conditions should be clearly indicated. A

similar question is raised for stage 2 to 3 of the production process for the IB component. The maximum storage

period for the blended product should be stated.


The time between final step of active ingredient production or thawing and use for blending is, less than 2 days for

the IB active ingredient. Therefore the impact on the viral titre is very limited.

The time between final step of active ingredient production and use for blending is, at most 7 days for the ND active

ingredient. Such a time was validated with batch 3AWF7S17A, time between production and blending was 7 days

and the titre eventually was satisfactory. If the active ingredient is used after thawing, the waiting time should be

less than 2 days.


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In any case and for both cases, should such a slight impact exists, this will be detected by the titration at QC

testing level, and the product will be released fully within its specification, the impact of storage is not existing in

such a case.

RMS comment

As previously, the detitration which could occur between blending and filling is an industrial risk ; in any case, the

titration for release is performed after this storage and therefore, this storage should not result on impairment of

the specifications of the product.

However, it was also ask ed to the applicant to indicate the duration of storage under freezing conditions, which

was not answered here. See questions 35 (6th part) and 37 (9th part) where the answer is provided.

CMS comment

No further comment.

Conclusion

Solved.




The applicant should provide a complete certificate of analysis for povidone, including the test for viscosity

expressed as K-value.


A new certificate (Vse/MP/DCQ/Version 1.07/02/062) fully compliant with the current Ph. Eur edition is attached in

Annex p. 211.

RMS comment

The certificate is provided and conform to the Ph. Eur. The answer is satisfactory.

CMS question

None

Conclusion

Solved.

Question 34 – 2nd part










confirm that the EIA test for antibodies is at least as sensitive as the recommended Ph.Eur. test or the Ph.Eur.



Cerveloup: this supplier is only running ‘designated SPF flocks’ (i.e. 3 rd generation coming from a established from

Lohman SPF flock) and the routine testing as required for this generation is carried out (see certificate "Control

certificate SPF Chicken Flock" dated February 2007 in Annex p. 217).


Merial Repeat-use


Charles Rivers is a well know supplier. Merial received eggs from third or subsequent generation tested as required

by Ph. Eur using routine testing (as shown on certificate "SPF Premium Plus" dated February 2007 in Annex p.

216).

Indeed in the dossier the page 069 was confusing. A new set of texts (description in document 9V/RMM/CG/046-

002106 and certificates detailed in this question are attached in Annex, p. 214). Both tests were indeed done

(page 073, Charles Rivers tested antibodies using ELISA and Leucosis viruses using MNT (microneutralisation);

and page 074, Cerveloup tested antibodies and virus using ELISA method (validated as equivalent to VN, see

Validation report Comparison-003 from Lohman Tierzuch –LTZ), in Annex p. 218).

Cerveloup: avian nephritis virus (ANV) is tested by ELISA and the equivalence with an immuno-staining method as

prescribed by the Ph.Eur. 5.2.2. has been demonstrated (see validation report from Freie Universität Berlin in

Annex p. 225).

RMS comment

The table of the tests conducted on the SPF flocks (initial dossier vol. 4/12 p.69) is now clarified (answer of April

2007, vol.2/3 p.215): the specifications for the avian leucosis viruses are: antigen tested by EIA and antibodies by

VN, as requested by the Ph. Eur.

With regard to the request made to the applicant to confirm that 100% of SPF birds are initially tested, Lohmann

(provider of Couvoir de Cerveloup birds) and Charles Rivers SPF flocks are well established SPF flocks. Thus, the

RMS doesn’t support futher request of information concerning these suppliers.

The applicant has provided the validations requested when different methods than those indicated by the Ph. Eur.

chapter 5.2.2. are used (see below for details). With regard to the equivalence of ELISA and VN for the detection

of the ANV, the report provided is satisfactory. With regard to the detection of the Avian Leucosis Viruses, it is

noted that systematically the vironeutralisation test is more sensitive; thus the equivalence of both methods with

regard to the sensitivity is questionable. Furthermore, this validation is provided by Lohmann, whereas , if correctly

understood, it is another laboratory (Laboratoire de biologie animale et alimentaire) which performs the test for the

benefit of Couvoir de Cerveloup. The applicant needs to solve these points.

Report: Validation of the ELISA vs VNT for the detection of antibodies to Avian Leucosis viruses

Answer of April 2007 – vol.2/3, p.218

Lohmann has compared the ability of both methods to detect antibodies to avian leucosis viruses subtypes A, B

and J, based on the analysis of different commercial ant isera; a reticuloendotheliosis antiserum (REV) was

included to investigate possible cross-reactions with an unrelated retrovirus. The sera of SPF birds was also used

as negative control. The titres obtained by the different tests are:

Test used Antisera under test

RSV A RSV B ALV J (batch K0324) ALV J (batch K 1577/04) REV and SPF

IDEXX ALV A&B ELISA 1:100 1:10 Negative Negative Negative

IDEXX ALV J ELISA Negative Negative 1:2 1:8 Negative

VNT ALV A 1:320 Negative Negative Negative Negative

VNT ALV B 1:40 1:160 Negative Negative Negative

VNT ALV J Negative Negative 1:4 1:16 Negative

Report: validation of an ELISA for the detection of antibodies to ANV

Answer of April 2007, vol.2/3, p.225

This study was conducted by the University of Berlin.

All the sera used had been previously tested by the Indirect Immuno-Fluorescence Test (IIFT), and classified by

this method as positive or negative. These sera were:

- 252 negative sera obtained from SPF birds

- 9 sera negative to ANV, but from birds infected with either of the following agents: Avian Adenovirus,

Infectious Bronchitis Virus, Infectious Bursitis Virus, Newcastle disease Virus, Avian Encephalomyelitis

virus, Avian Reovirus, Reticuloendotheliosis Virus, Avian rotavirus, Chicken Anaemia Agent

- 15 hyperimmune sera against Avian Nephritis Virus (ANV)

- 11 positive sera obtained from the field

Results:


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- The cut off of the test was established from the 252 negative sera 0 to 0.19 is negative, 0.20 to 0.24 is

suspect, above 0.24 is positive (4,4 % of the 252 sera tested as false positive). The specificity of the test

is thus 95.6%

- None of the 9 sera negative to ANV but positive to another avian virus reacted positive

- Sensitivity (established from the 15+11 positive sera): 96.2% (25 out of the 26 sera tested posi tive in the

ELISA, 1 sera tested suspect)

- Comparison of ELISA and IIFT results on dilutions of 4 positive sera: on 3 out of the 4 samples, the results

were positive by the ELISA test at higher dilutions than by the IIFT

- Repeatability:

46 replications of 1 positive serum and 1 negative serum were done on the same plate (intra-

assay variation): CV was 11,5% for negative sample and 22,8% for positive sample

15 repetitions on different plates were done for 1 positive serum and 1 negative serum (inter-assay

variation): CV was 18,7% for negative sample and 17.8% for positive sample

RMS question

With regard to the detection of the Avian Leucosis Viruses by ELISA and vironeutralisation (VN), it is noted that

systematically the test VN test is more sensitive; thus the equivalence of both methods with regard to the

sensitivity is questionable. Furthermore, this validation is provided by Lohmann, whereas, if correctly understood, it

is another laboratory (Laboratoire de biologie animale et alimentaire) which performs the test for the benefit of

Couvoir de Cerveloup. The applicant is asked to solve these points.

CMS comments

None.

Day 145 question











Controls

Mycoplasmic sterility: it is not clear from the information provided whether appropriate control

strains of mycoplasma as required by the Ph.Eur. were used during mycoplasma testing.

Sufficient information to enable confirmation that the requirements of the current Ph. Eur. have

been met are required


We do not have on our record the exact nature of the reference used for the run of Mycoplama test of MSV.

Nevertheless this test is using a specific media (96B) and any batch before its use is validated for its nutritive

properties using all appropriate micro-organisms:

- Acholeplasma laidlawii;

- Mycoplasma gallisepticum;

- Mycoplasma hyorhinis

- Mycoplasma orale

- Mycoplasma pneumoniae

- Mycoplasma synoviae.

During the test run, two references were used (including one avian strain; either M synoviae or M gallisepticum) and

found satisfactorily. This confirmed the growth ability of the 96B medium to detect any mycoplasma. Therefore

even if the avian reference nature is not completely known, the test is validated and results could be accepted.


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In addition, during production, MSV+1 and MSV+2 passages were tested for Mycosplama using during the run

avian references (M gallisepticum and M synoviae), see updated certificate SV/SV.DCQ 154/98 suite n°2 in Annex

p. 242

RMS comment

Satisfactory.

CMS comment

None

Conclusion

Solved




Controls

Control of the neutralising antiserum: the neutralising antiserum used for the purposes of

identification and neutralisation for extraneous agents had not been tested for antibodies to

Haemorrhagic turkey enteritis, PMV 1 and 4-9 (only 2 and 3 tested) nor Herpesvirus of turkeys.

In addition an absence of PMV 2 and 3 cannot be excluded because of a cross -reactivity of

the anti-NDV (Paramyxovirus Type 1) antiserum. The Applicant should justify the use of this

serum and provide data to confirm the absence of these potential extraneous agents.


The Haemorragic turkey enteritis virus does not multiply on cells or eggs used for test. Therefore absence of

antibody titration is not changing the in vitro purity result. The absence of Haemorragic turkey contamination of

MSV has been confirmed by serology (ELISA) in turkey (see MSV certificate in part II).

The Newcastle disease virus is a Paramyxovirus Type 1, neutralising antiserum is necessarily positive.

The Ph Eur monograph 2.6.24§7 list the antibodies to be tested for neutralizing antisera, with the following

restriction: “Monospecific antisera for virus neutralisation can be assumed to be free of the antibodies against any

of these viruses if it can be shown that the immunising antigen could not have been contaminated with antigens

derived from that virus and if the virus is known not to infect the species of origin of the serum”

The anti serum is from chicken origin (SPF chickens) species on which only PMV1 and PMV2 are described.

Therefore PMV3-9 need not to tested. The applicant added to the list the PMV3 as this agent is specifically

investigated in the extraneous agent test on seeds issued from turkey origin (2.6.4 §6B).

“B. Additional tests for turkey extraneous agents

If the seed virus is of turkey origin or w as propagated in turkey substrates, tests for antibodies against the follow ing agents are also

carried out.

Agent Type of test

Chlamydia spp. EIA

Avian infectious haemorrhagic enteritis virus AGP

Avian paramyxovirus 3 HI

Avian infectious bursal disease virus type 2 SN

A test for freedom from turkey lympho-proliferative disease virus is carried out by intraperitoneal inoculation of tw enty 4-w eek-old turkey

poults. Observe the poults for 40 days. The test is not valid if more than 20 per cent of the poults die from non-specif ic causes. The seed

lot complies w ith the test if sections of spleen and thymus taken from 10 poults 2 w eeks after inoculation show no macroscopic or

microscopic lesions (other than those attributable to the seed lot virus) and no poult dies from causes attributable to the s eed lot.”


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Herpesvirus of Turkeys and Marek’s virus shares common antigens detectable by Agar Gel Precipitation test.

Therefore the satisfactory purity result of test focusing on MDV (Marek, test AGP) also applied to Herpesvirus of

turkeys, MSV is free of this specific virus.

Light cross reactivity between PMV2-3 and PMV1 may exist. Nevertheless in the chicken test with no

preliminary neutralization with antisera, no antibodies were found against both types (PMV 2-3) confirming

absence of such contaminants.

RMS comment

Concerning the Haemorrhagic Turkey Enteritis virus, this virus is not known to multiply in hen eggs, which is the

support for the multiplication of the initial isolate and then the vaccine strain (see Diseases of Poultry, Ed. by

B.W. Calnek, p.625). The answer is satisfactory.

Concerning the different PMVs, the answer is satisfactory. The RMS also refers to Diseases of Poultry, Ed. by

B.W. Calnek, p.544 to support that chicken is not the host of PMV3-9.

Concerning the Herpesvirus of Turkey, the applicant should provide the reference in literature supporting the

statement that “Herpesvirus of Turkeys and Marek ’s virus shares common antigens detectable by Agar Gel

Precipitation test. Therefore the satisfactory purity result of test focusing on MDV (Marek, test AGP) also applied

to Herpesvirus of turkeys, MSV is free of this specific virus ”.

Concerning the cross-reaction between PMV2-3 and PMV1, the answer is acceptable.

RMS question

Initial question 35, point relating to the control of the neutralising antiserum:




to Herpesvirus of turkeys, MSV is free of this specific virus”.

CMS comment

None.

Day 145 question






Question 35 – 3rd part



Controls

Viral purity in cell cultures (k idney): the applicant should indicate whether or not the MSV is

neutralised prior to inoculation of cell cultures


We confirm that MSV was neutralised with the anti-serum described in the part II (ref 961003).

RMS comment

Point clarified. No further question.

CMS comment

None

Conclusion

Solved.


Merial Repeat-use


Question 35 – 4th part



Controls

The NDV strain VG/GA was isolated from turkey; according to Ph. Eur. 2.6.24. section 6.B. (if

material of turkey origin is used) a specific test for Infectious bursal disease type 2 by

seroneutralisation should be performed. The applicant should provide the result of this test.

The applicant should justify why specific tests for reticuloendotheliosis virus and chicken

anemia virus were not performed, as requested by Ph. Eur. 2.6.24. Unless an acceptable

justification is available, these tests should be done.

The applicant should justify why in the test for Leukosis virus no subgroup J control was

included, why only the supernatant and not the cells was tested, and why only the last passage

was tested and not the intermediate passages. Unless an acceptable justification is available,

the test for Leukosis virus should be performed again according to the current Ph. Eur.


These requirements are linked with the new text of Ph.Eur. 2.6.24. As explained by various manufacturers ‘through

IFAH Europe channel’, implementation of these tests (2.6.24 and 2.6.25, see letter in Annex p. 245) required

heavy validation work (for at least 2 years). This work was performed within Merial in this timeframe and only now

some information is available for the new finished product testing (2.6.25). To further reduce use of animals

(replacing not only chickens but also fertilized eggs) Merial worked on PCR tests (see answer to questions 35 a).

Concerning seed lot testing, final validation work is not yet fully completed. Nevertheless we have already

information on the purity of this strain. The test for reticuloendotheliosis and chicken anemia virus has been

performed according to Ph.Eur. 2.6.24 test (see updated certificate SV/SV.DCQ 154/98 suite n°2 in Annex p.

242).

In addition, already available information on the purity of this seed used for years in other products.

The ELISA test used for the IBDV test in chicken is not group-specific. A complete virus (Lukert strain) is used for

this test. The absence of type specificity of this test is known (see Lukert and Saif, on p 732 in Annex p. 250).

Therefore, absence of antibodies against IBDV is equivalent to absence of antibodies against both IBDV1 and

IBDV2.

Concerning the detection of leucosis subgroup J antigen, the validation of this new test was not yet done but

during the test on supernatant (technique No.13002) the used ELISA is based on the p27 antigen. The latter is

present in subgroup J, therefore the satisfactory result already gives assurance of absence of Leukemia virus

subgroup J in the master seed.

As the development for Leucosis test is not yet finished, Merial commits itself to test, as soon as the validation is

finalized and before end 2007, the next working seed virus batch (to save existing master seed virus stock).

RMS comment

There is an inconsistency within the certificate of analysis of the ND virus VG/GA Master Seed (answer of April

2007, vol.2/3, pp.243-244) : on page 243, the product under test is the ND virus VG/GA Master Seed, but on page

244, the conclusion refers to Infectious Bronchitis strain H120. This should be clarified before the RMS can

accept the answer of the applicant concerning the new tests conducted on the ND virus VG/GA Master Seed.

Concerning the specific test for Infectious bursal disease type 2, the answer is supported by literature and

acceptable.

Concerning the specific tests for reticuloendotheliosis virus and chicken anemia virus, provided the applicant gives

a satisfactory answer with regard to the inconsistency of the certificate of analysis (see above), the answer is

satisfactory.

Concerning the detection of leucosis subgroup J antigen, the proposal of a commitment is acceptable, taking into

account the timetable proposed and the information the p27 antigen present in subgroup J and detectable by the

ELISA.

RMS question




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For the information of the applicant: concerning the detection of leucosis subgroup J antigen, the proposal of a

commitment is acceptable.

CMS comment

None.

Day 145 question







Question 35 – 5th part (DE)





WSVs are starting materials as others (even is more valuable) and are managed as any other starting materials as

soon specifications are met. WSVs are not unique and the production planning may require more than one WSV

batch to be use at a time. This is even truer when two sites are used to produce active ingredient. There is no

requirement to have the same WSV batch.

For the active ingredient batches already produced (reported in the dossier), WSV batches No.

VG/01/ŒUF/L538/280696 and VG/02/ŒUF/R95/110302 were used in Lyon whereas WSV batch No. 5VG3B02

was used in Chignolo-Pô.

Active ingredient batch Used WSV batch

Lyon

3VG5P41 VG/01/ŒUF/L538/280696

3VG5R43

3VG5D54 VG/02/ŒUF/R95/110302

Chignolo-Pô

C0556

5VG3B02 C0557

C0558

RMS comment

The RMS agrees with the applicant’s approach.

CMS question

DE: It is accepted that both production sites use different WSV, but the condition is, that for batch protocols, the

EDQM Template is used, with indication of the production site and the WSV.

Day 145 question

DE: It is accepted that both production sites use different WSV, but the condition is, that for batch protocols, the

EDQM Template is used, with indication of the production site and the WSV.




Production steps: the applicant should clarify the steps described in section 2.1.5.a.iv (vol. 4/12,

p.97) : some steps appears to be optional (clarification, addition of stabiliser; 0.45µm filtration;


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storage at –40°C). Maximum duration of storage at +5°C and –40°C should be indicated and

supported by appropriate stability data.


For better understanding and as no steps are optional, the description should be read:

The allantoic fluid is added with stabiliser 54 (one volume of stabiliser for one volume of viral suspension).

The mixture is clarified and treated by filtration 0,45 µm.

The suspension obtained constitutes the active ingredient (AI).

The active ingredient is kept at 5°C ± 3°C (maximum period of 7 days) or stored frozen at a target temperature

lower than or equal to -40°C (maximum period of 21 months) until use for formulation.

The ND active ingredient stability under frozen form was validated through repeated titrations over time (see table

below). Both old and current stabilisers were used.

Titers of ND AI after storage at –40°C in old (S44) and current (S54) stabilizers

Time S44 S54

838 46 2VG5 L12 5VG5 F26 5VG5 G27 5VG5 H28

0 9.77 9.3 9.4 9.44 9.56 9.47

1 9.18

3 8.58

4 9.41 8.71

5 9.56

6 9.7 9.44 9.47

7 9.28 9.38

9 9.81 9.39 9.51 9.6

10 9.59

11 9.34

12 9.58

13 9.44

15 9.19 9.7 9.47 9.51

17 9.83

18 9.33

19 9.41

21 9.45 9.56 9.04 9.21

These results demonstrate that the active ingredient is stable over 21 months and that both stabilisers have

equivalent properties.

This confirms the data obtained with the finished product. The 21-month storage period was already validated (see

report 03.0549.R in application dossier part II, page 485; key data reported in the table below) using the old

stabilizer. As the stabilizer S54 has the same properties the stability is the same. This was confirmed in recent

study including the new data (see Annex JL/GeR/EBR.07.D197 p. 253):


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Time (months) Titres (S44) Titres (S54)

0

9.9

10.4

9.8

10.3

10.5

10.3

6 Nt

10.3/10.3

10.6/10.3

10.3/10.4

9

Nt

Nt

10.5

10.0

10.2

10.2

12

10.1

10.1

9.9

10.2

10.3

10.3

15

10.0

9.9

10.3

10.2

10.4

10.1

Nt: not tested.

As a conclusion, the possible impact on the viral titre due to storage condition is extremely limited. It must also be

underlined that at final testing level, the titration will reflect the actual viral content of the ampoule. Should such a

slight impact exists, this will be detected by the titration at QC testing level, and the product will be released fully

within its specification, the impact of storage is not existing in such a case.

RMS comment

The production process is clarified. The stability data concerning the storage of the active ingredient at –40°C (1st

table) are satisfactory. The impact of the storage of the active ingredient at +5°C was already discussed in

question 33. The overall is satisfactory.

The other information concerning the new stability study (with stabilizer 54) is not assessed here, because not

related to the question (see question 48).

CMS comment

None.

Conclusion

Solved




Stabilisers: It is indicated in section 2.1.5.a.iv that the stabiliser used is stabiliser 54, whereas for

batches produced at Lyon Laboratories, the stabiliser used is stabiliser 44. The applicant should

justify this difference, describe the differences between the 2 stabilisers and analyse the

consequences for the equivalence of the final products derived from the 2 different types of active

ingredient. As a consequence, the relevance of the batches of vaccines used to perform the

analytical, safety and efficacy studies has also to be analysed. In addition, it is a requirement of

the TSE guidelines that the lowest risk material should be used during production. Consequently

the Applicant should use the stabiliser with the lowest TSE risk .


As stated in answer to question 30, the change of stabiliser (from 44 to 54) was indeed put into place to satisfy the

TSE guidelines and Ph.Eur requirements. This change replaces meat derivative by milk derivatives minimising

therefore the BSE risk.

HatchPak range is a live vaccine range. The safety and efficacy being mainly linked with the content of live virus

(inoculated titers). The development study results are therefore fully relevant. It must be noted that in both case it

is protein hydrolysate (peptone from ‘meat and casein’ or ‘casein’ alone) and put in the exact same quantity (to

minimise differences) and will be processed after inject ion through the same metabolic pathway. The behaviour of


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product produced with the new stabiliser has been demonstrated through comparative analysis (result described in

part II.A.3 development pharmaceutics). Quality (see table below) and stability (see answer above) are similar

demonstrating absence of impact (it may be noted that this change was approved through recent mutual

recognition procedure for Avinew, freeze-dried product, No. FR/V/0123/001/II/03 ended on July 4th, 2006)

Equivalence is demonstrated as both production sites, using different stabiliser at development time, obtained

product of similar quality (similar titres) and above minimum requirements (R ≥ 8.0 log10 EID50/ml):

AI Batch Titre (LPA)

(S44)

Titre (Chignolo Pô)

(S54)

1 9.3 9.91

2 9.7 9.6

3 9.7 9.8

RMS comment

THE JUSTIFICATION FOR THE CHANGE OF STABILISER IS ACCEPTED BY THE RMS

(SEE QUESTION 30). Concerning the impact on the safety and efficacy of the vaccine, the arguments of the applicant are accepted by

the RMS (see questions 50 & 73).

Concerning the data to support the equivalence of quality of the final product, the data provided are satisfactory.

However, the on-going stability study with batches of vaccines containing the new stabilisers should be run until

27 months of storage to confirm the stability observed with batches containing the “old” stabilisers. A commitment

to provide the data as soon as available is acceptable. Meanwhile, a stability of 24 months can be granted (see

also question 48).

RMS question

The on-going stability study with batches of vaccines containing the new stabilisers should be run until 27 months

of storage to confirm the stability observed with batches containing the “old” stabilisers. A commitment to provide

the data as soon as available is acceptable. Meanwhile, a stability of 24 months can be granted (see also

question 48).

CMS comment

See UK comment in question 48.

Day 145 question




question 48).

Question 35 – 8thpart


For the information of the applicant concerning the controls performed on the VG/GA Master Seed Virus, to be

taken into consideration when providing further information on the extraneous agents testing – 1st point:

Position of the RMS: The tests described in the dossier were performed according to the Ph. Eur. in force

at the time of testing (1998); the extraneous agent testing in avian master seeds has be reviewed by the

Ph. Eur. and the new monograph was published in 2005. However, this Master Seed is well known now, as

far as it is also used for the production of another live ND vaccine (AVINEW) on the market in at least 11

European countries since May 2001. Bearing this in mind, it will not be asked to the applicant to performed

again tests already done but slightly modified in the Ph. Eur. 2005. Only clarifications and request of

testing of new extraneous agents listed in the Ph. Eur. are relevant.

A CMS doesn’t follow this approach and asked the following questions:

The extraneous agents test in eggs did not use the yolk sac route as required by the Ph.Eur. The

Applicant should confirm how it is ensured that the testing for extraneous agents was not compromised

by the omission of this route of inoculation. In the absence of a robust justification the Applicant

should provide these data to fulfil the requirements of the Ph.Eur.


Merial Repeat-use


Insufficient detail has been provided to confirm that the Ph.Eur. requirements for testing in avian cel l

cultures have been met. It is also noted that the adsorption time used is less than that recommended

by the Ph.Eur. (20 minutes not 1 hour). In view of this the Applicant should provide data to confirm how

the requirements of the Ph.Eur. have been met.

It is noted that extraneous agents testing in chicks is not in full compliance with the Ph. Eur.

monograph because the tests for Haemorrhagic Turkey Enteritis (EIA not AGP) and Avian infectious

bursitis type 2 (EIA not SN) do not use the recommended Ph. Eur. test. Either the recommended tests

should be done or validation data provided to confirm that the methods used are at least as sensitive

as the recommended tests.


As partially explained in answer to question 35a, the new requirements of Ph.Eur. 2.6.24 required heavy validation

work (for at least 2 years), as explained by various manufacturers ‘through IFAH Europe channel’(see letter in

Annex p. 245) This work was performed within Merial in this timeframe and only now some information is available

for the new finished product testing (2.6.25). To further reduce use of animals (replacing not only chickens but also

fertilized eggs) Merial worked on PCR tests (see answer to question 46d).

Concerning seed lot testing, final validation work is not yet fully completed. As underlined by the RMS this strain is

not unknown from European authorities, is registered and largely used in Europe (Avinew vaccine). Nevertheless

we have already information on the purity of this strain. The test using chicken kidney cells, test for

reticuloendotheliosis and chicken anemia virus have been performed according to Ph.Eur. 2.6.24 test (see updated

certificate in Annex p. 242).







The neutralization of the VG/GA strain was not possible, and the test in embryonated hen’s eggs using the yolk

sac route cannot be implemented. According to assessment done during the ECVAM workshop 41(see in report

table III, in Annex p. 259) this intra-vitelline (IV) route is mainly for the infectious avian encephalomyelitis (IAE) virus

and chlamydia. It must be noted that this IV route may also reveal the avian nephritis virus, the avian adenovirus

and avian reovirus. According to the table of agent to specifically test for, a concern may exist mainly for the IAE

virus.

When neutralisation is not possible, the in vivo test (as already carried out as required by the previous viral purity

tests, Ph Eur 2.5.6) give valuable information; indeed absence of IAE was demonstrated by absence of specific

antibody in the test using chickens.

It is underlined that the monograph 2.6.24 section 6 allows in general EIA (ELISA) and AGP when both are

described, without validation work (Adenovirus type1, avian encephalomyelitis, reticuloendotheliosis, Influenza) this

indicates that EIA in its principle is perceived as at least as sensitive than AGP, and is in fact generally more

sensitive. We stress out as well that the EIA test is accepted for IBD type 1 serology as well as AGP or SN. The

ELISA test used for the IBDV test in chicken is not group-specific. A complete virus (Lukert strain) is used for this

test. The absence of type specificity of this test is known (see Lukert and Saif, on p 732 in Annex p. 250).

Therefore, absence of antibodies against IBDV is equivalent to absence of antibodies against both IBDV1 and

IBDV2.

The applicant would like the RMS to reconsider the request for validation of both tests according to these

observations.

RMS comment

Bearing in mind that the ND Master Seed of Hatchpak Avinew IB H120 is already used for a product on the market

recently registered (AVINEW), the RMS gives its position on the points raised by other CMSs:

Concerning the extraneous agents test in eggs via the yolk sac route, the RMS accepts the applicant’s

explanation


Merial Repeat-use


Concerning the equivalence of EIA with the reference method for the testing of Avian infectious bursitis type

2, the answer was accepted (see question 35, 4th part)

Concerning the equivalence of EIA with the reference method for the testing of Haemorrhagic Turkey Enteritis,

the applicant has not specifically answered. The question is raised again.

RMS question

It is noted that extraneous agents testing in chicks is not in full compliance with the Ph. Eur. monograph because

the test for Haemorrhagic Turkey Enteritis (EIA not AGP) does not use the recommended Ph. Eur. test. Either the

recommended test should be done or validation data provided to confirm that the method used is at least as

sensitive as the recommended test.

CMS comment

None

Day 145 question

It is noted that extraneous agents testing in chicks is not in full compliance with the Ph. Eur. monograph because

the test for Haemorrhagic Turkey Enteritis (EIA not AGP) does not use the recommended Ph. Eur. test. Either the

recommended test should be done or validation data provided to confirm that the method used is at least as

sensitive as the recommended test.

Question 35 – 9thpart


It is noted that the inoculum used for the eggs for production of antigen is given as approximately 0.2

ml per egg. The Applicant should provide details of the quantity of seed virus inoculated. It should be

made clear if this is a fixed quantity or, if a range of titre may be used, the details should be provided.


The virus is inoculated under a volume of 0.2 ml per egg (approximately is linked with inoculation device, difference

of 0.05ml is accepted).

The virus titre at inoculation varies form 4.8 to 6.8 log10 DIO per egg.

RMS comment

The applicant has clarified the point.

CMS comment

None.

Conclusion

Solved.



For the information of the applicant concerning the controls performed on the Master Seed Virus, to be taken

into consideration when providing further information on the extraneous agents testing – 2nd point:

Position of the RMS: If Mycoplasma testing was done on the Master Seed Virus by the culture method and

the epifluorescence test, it is not required to perform it again by both methods on the Work ing Seed Virus.

Ph. Eur. monograph 2.6.7. says “where the test for mycoplasmas is prescribed for […] a virus seed lot,

both […] methods are used” and the guidelines says “the Master Seed Virus shall pass the tests for

sterility and freedom from mycoplasma” without any indication concerning the Work ing Seed.







Merial Repeat-use


Both culture method and epifluorescence tests for the MSV were carried out satisfactorily. We agree on the

assessment of the RMS and this question was forwarded to the Ph.Eur. (see attached IFAH Europe’s letter in

Annex p. 245) as European vaccine manufacturers share this understanding. Until now, Ph.Eur has not yet replied.

RMS comment

The RMS has no further comment, because the applicant’s approach is accepted.

CMS comment

None.

Conclusion

Solved.

Question 36

Validation for titration of NDV; Transfer of control material 15001:

With respect to Lyon control charts, the applicant should give an explanation as to how limits were determined. As

stated by the applicant the criteria for titrations status is validated if the titre of the control s tandard virus is within

the confidence limits of the control chart. In the case of ND there are two values outside of control limits (ref chart

3), give a justification for these out of specification results. Are %CV limits of acceptability determined fo r

repeatability and reproducibility data? Will control limits specific for the Noventa laboratory be generated?


Limits of control chart of the control standard virus are based on known titre of the reference and on statistical

analysis of results of four replicates coming from three sessions with two operators.

There are:

Control standard virus titer is: 9.39

Standard deviation of 0.22 (11 ddl).

So limits of the control chart are [8.906; 9.874].

The aim of the study was to confirm that Noventa operators were able to satisfactorily titrate Newcastle Disease

Virus.

During this study, two values were out of limits in the second run. As a consequence an action similar to re-test

procedure was decided (i.e. if for a test, one out of specification result is observed, we need to carry out again this

test twice). Indeed out of specification results may occur even with fully skilled and qualified operators. In such a

case the re-test procedure is the rule and allows concluding with better confidence on results.

Therefore an additional session was carried out and found satisfactory. This was further confirmed by an additional

comparative titration (two sessions). With four satisfactory sessions, enough information was available to qualify

this Italian site.

As the Italian site is qualified, the results from titration must be in the Lyon’s limits, the existing control chart must

be used as such in Italy (no definition of new control chart limits).

RMS comment

Acceptable answer to this initial question from IE.

CMS comment

IE: The applicant’s response is acceptable.

Conclusion

Solved.




Controls:

The tests for extraneous agents should comply to the current Ph. Eur. monograph 2.6.24. The differences

noted between the tests performed and the current requirements of the Ph. Eur. 2.6.24. are:



Merial Repeat-use



9. Test for Leukosis virus: no subgroup J control, only the supernatant and not the cells was tested, only

the last and not the intermediate passages was tested




As rightly listed, these requirements are linked with the new text of Ph.Eur. 2.6.24. As explained by various

manufacturers ‘through IFAH Europe channel’, implementation of these tests (2.6.24 and 2.6.25, see letter in

Annex p. 245) required heavy validation work (for at least 2 years). This work was performed within Merial in this

timeframe and only now some information is available for the new finished product testing (2.6.25). To further

reduce use of animals (replacing not only chickens but also fertilized eggs) Merial worked on PCR tests (see

answer to questions 46d). Concerning seed lot testing, final validation work is not yet fully completed. Nevertheless

we have already information on the purity of this strain. The test using embryonated hen’s eggs (technique

No.200012, intra-vitelline route), test in chicken kidney cells (technique No.200011), test for reticuloendotheliosis

and chicken anemia virus has been performed according to Ph.Eur. 2.6.24 test (see updated certificate in Annex

CG/GC.DCQ.188.99 suite n°2 p. 278).

In addition, already available information on the purity of this seed used for years in other products.







RMS comment

The applicant has retested the MSV (at MSV+1 or MSV+2 level due to reduced stock of the MSV, which is

acceptable with regard to the provisions given in the Ph. Eur. monograph 62, under section general requirements

for Virus Seed Lot) in accordance with the new chapter 2.6.24. for the missing data:

Test in chicken k idney cell cultures,

test in eggs by the intra-vitelline route,

test for reticuloendotheliosis virus

test for CAA

Concerning the detection of leucosis subgroup J antigen, the proposal of a commitment is acceptable, taking into

account the timetable proposed and the information the p27 antigen present in subgroup J and detectable by the

ELISA.

The overall is acceptable.

RMS question



CMS comment

None.

Day 145 question






Controls:

Mycoplasmic sterility: the test by epifluorescence as requested by the Ph. Eur. 2.6.7. has not

been performed (requirement of the Ph. Eur. since at least 2001). It is not clear from the


Merial Repeat-use


information provided whether appropriate control strains of mycoplasma as required by the

Ph.Eur. were used during mycoplasma testing. Sufficient information to enable confirmation

that the requirements of the current Ph. Eur. have been met are required


Mycoplasma test using epifluoresence technique was carried out in September 2006 (see certificate

CG/CG.DCQ.188.99 suite n°1 in Annex p. 281).

We do not have on our record the exact nature of the reference used for the run of Mycoplama test of MSV.

Nevertheless this test is using a specific media (96B) and any batch before its use is validated for its nutritive

properties using all appropriate micro-organisms:


- Mycoplasma gallisepticum;


- Mycoplasma orale

- Mycoplasma pneumoniae


During the test run, two references were used (including one avian strain; either M synoviae or M gallisepticum) and

found satisfactorily. This confirmed the growth ability of the 96B medium to detect any mycoplasma. Therefore

even if the avian reference nature is not completely known, the test is validated and results could be accepted.

In addition, during production, MSV +1 and MSV+2 passages were tested for Mycosplama using during the run

avian references (M gallisepticum and M synoviae),.(see updated certificate CG/CG.DCQ.188.99 suite n°2 in

Annex p. 278).

RMS comment

Satisfactory.

CMS Comment

None.

Conclusion

Solved.




Controls:

The applicant should perform the tests for reticuloendotheliosis, CAA and mycoplasmic sterility by

epifluorescence.

For the tests in cell cultures, in embryonated eggs and test for leucosis viruses, either these tests should be

performed again according to the current Ph. Eur. monograph 2.6.24, or the applicant should demonstrate that

the tests already done give the same level of confidence in detecting extraneous agents as the tests

prescribed in monograph 2.6.24. In particular:

- Insufficient detail has been provided to confirm that the Ph.Eur. requirements for testing in avian cell

cultures have been met. It is also noted that the adsorption time used is less than that recommended

by the Ph.Eur. (20 minutes not 1 hour). In view of this the Applicant should provide data to confirm how

the requirements of the Ph.Eur. have been met.


The mycoplamsic sterility test by epifluorescence has been satisfactorily performed (see certificate

CG/CG.DCQ.188.99 suite n°1 in Annex p. 281)


Merial Repeat-use


Technique No. 13 001 is indeed not detailed as referring to Ph.Eur. 2.6.5, 1997. Full compliant implementation of

the Ph.Eur. test (of the version valid at that time) was performed and adsorption time was indeed 20 minutes.

See answer above concerning validation work and results for the new Ph.Eur. 2.6.24 requirements.

RMS comment

The overall is satisfactory (see also question 37 – 1st part).

CMS Comment

None.

Conclusion

Solved.




Controls:

- It is noted that the inoculum used for the eggs for production of antigen is given as approximately 0.2

ml per egg. The Applicant should provide details of the quantity of seed virus inoculated. It should be

made clear if this is a fixed quantity or, if a range of titre may be used, the details should be provided.


The virus is inoculated under a volume of 0.2 ml per egg (approximately is linked with inoculation device, difference

of 0.05ml is accepted).

The virus titre at inoculation varies form 3.0 to 5.0 log10 DIO per egg.

RMS comment

The applicant has clarified the point.

CMS Comment

None.

Conclusion

Solved.

Question 37 – 5th part (PT)



Controls:

H120 component – viral purity. The applicant should be informed that a CMS (n°3) requires the submission of

the data of compliance with the methods of section 2.6.24. of Ph. Eur:5 (availability of these data supposed to

be in Dec 2006).


As explained at the beginning of this answer, various manufacturers ‘through IFAH Europe channel’,

implementation of these tests (2.6.24 and 2.6.25) required additional time (end of 2006) due to technical difficulties

(mainly neutralization of strain) and heavy validation work. This work was performed within Merial in this timeframe

and only now some information is available for the new finished product testing (2.6.25). To further reduce use of

animals (replacing not only chickens but also fertilized eggs) Merial worked on PCR tests.

Concerning seed lot testing, final validation work is not yet fully completed. This strain is not unknown from

European authorities, is registered and used in Europe (Bioral H120 vaccine), so less emphasis was put on master

seed testing. Nevertheless we have already information on the purity of this strain. The test in embryonated hen’s

eggs, test using chicken kidney cells, test for reticuloendotheliosis and chicken anemia virus have been performed

according to Ph.Eur. 2.6.24 test (see certificate CG/CG.DCQ.188.99 suite n°2 in Annex p. 278).


Merial Repeat-use


Only Leucosis virus test (sub-group J) in cells is not yet fully available and Merial commits itself to test, as soon

as the validation is finalized and before end 2007, the next working seed virus batch (to save exist ing master seed

virus stock).

RMS comment

The applicant has performed most of the work to comply to the new chapter 2.6.24. of the Ph. Eur. The RMS

considers acceptable the commitment to provide the missing data for the subgroup J of leucosis virus within the

year 2007, tak ing into account that the vaccines using the IB Master Seed (BIORAL H120 in particular) has been

used for years in the field with no suspicion of extraneous agent contamination and that the current ELISA used

for the leucosis virus testing should reveal the presence of a sub-group J virus (currently, the method is not fully

copliant only because the positivie control for subgroup J is not performed).

CMS comment


Conclusion

Solved.

Question 37 – 6th part (ES)



Controls:

H120 component – sterility testing. The applicant should be informed that a CMS (n°4) has the following

request: the applicant states that it complies with several Eur. Ph, but these pharmacopoeias are from 1970 to

1998; the test should comply with the current Eur.Ph.


In the part II, technique No.11 000 mentions in paragraph ‘6 history’ in a table, the reason to update technique: th is

is not implying that the technique is compliant with all these editions. The submitted technique was referring to Ph.

Eur 1998, 2.6.1. Technique is now in accordance with current Ph.Eur. test 2.6.1 (see technique 11 000, in Annex,

p. 319).

RMS comment

Satisfactory.

CMS comment

No further comment.

Conclusion

Solved.

Question 37 – 7th part (ES)



Controls:

H120 component - viral purity, request from CMS n°4: regarding the test for extraneous agents, the method

followed are from Ph Eur 1997.and Ph Eur 1989 The test should be performed according to the actual Ph Eur.

and results should be shown.


See beginning of answer to this question above. Merial commits itself to complete information before end 2007.

RMS comment

Satisfactory.

CMS comment


Merial Repeat-use


No further comment.

Conclusion

Solved.






WSVs are starting materials as other (even is more valuable) and are managed as any other starting materials as

soon specifications are met. WSVs are not unique and the production planning may require more than one WSV

batch to be use at a time. This is even truer when two sites are used to produce active ingredient. There is no

requirement to have the same WSV batch.

For the active ingredient batches already produced (reported in the dossier), WSV batches No. BI

H120/01/OEUF/L546/090797 was used in Lyon and Chignolo-Pô. It must be noted that this WSV may still be used

in Italy whereas a new one will be used in Lyon (end of current stock).

RMS comment

The RMS agrees with the applicant’s approach.

CMS Comment

None.

Conclusion

Solved.




The applicant should clarify the steps described in section 2.1.5.a.iv (vol. 4/12, p.125) : some

steps appears to be optional (clarification, addition of stabiliser; 0.45µm filtration; storage at –

40°C). Maximum duration of storage at +5°C and –40°C should be indicated and supported by

appropriate stability data. The consequences that this 2 different ways of storage would have on

the final product should be analysed.


For better understanding and as no steps are optional, the description should be read:

“The allantoic fluid is centrifuged and subsequently added with stabiliser 56 (one volume of stabiliser for one volume

of viral suspension).

“The mixture is clarified and treated by filtration 0,45µm.

“The suspension obtained constitutes the active ingredient (AI).

“The active ingredient is maintained at 5°C ± 3°C (less than two days) or stored frozen at a target temperature

lower than or equal to -40° C (maximum period of 21 months) until use in formulation.”

The IB active ingredient stability under frozen form was validated through repeated titrations over time (see table

below). Both old and current stabilisers were used.

Titers of IB AI after storage at –40°C in old (S26) and current (S56) stabilizers

S26 S56

Time 815 2H1205D04 2H1205E05 6H1205L36 6H1205N38 6H1205R40

0 7.9 7.93 8.3 7.97 / 7.81 7.64 / 7.98 7.58 / 7.78

3 - - - 7.67 7.56 -

6 7.9 7.51 7.78 7.74 7.64 -


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9 7.86 7.5 7.2 - 7.6 7.84

12 7.96 7.5 7.69 NT NT NT

15 7.69 7.6 7.8 NT NT NT

21 7.74 7.58 7.78 NT NT NT

These results demonstrate that the active ingredient is stable over 21 months and that both stabilisers have

equivalent properties.

This confirms the data obtained with the finished product. The 21-month storage period was already validated (see

report 04.0641.R in application dossier page 516, key data reported in the table below using the old stabilizer). As

the stabilizer S56 has the same properties the stability is the same. This was confirmed in recent study (including

the new data, see Annex JL/GeR/EBR.07.D198 p. 283):

Time (months) Titres (S26) Titres (S56)

0

8.5

8.1

8.3

8.7

8.5

8.6

6 Nt

8.3

8.6

8.8

9

8.4

8.4

8.4

8.5

8.4

8.4

12

8.3

8.1

8.4

8.8

8.6

-

15

8.2

8.3

8.4

8.6

8.8

8.4/8.7

Nt: not tested

-: non-validated session run

The impact on the viral titre due to storage condition is very limited. It must be underlined that at final testing level,

the titration will reflect the actual viral content of the ampoule. In any case should such a slight impact exists, this

will be detected by the titration at QC testing level, and the product will be released fully within its specification,

the impact of storage is not existing in such a case.

RMS comment

The production process is clarified. The stability data concerning the storage of the active ingredient at –40°C (1st

table) are satisfactory. The impact of the storage of the active ingredient at +5°C was already discussed in

question 33. The overall is satisfactory.

The other information concerning the new stability study (with stabilizer 56) is not assessed here, because not

related to the question (see question 48).

CMS Comment

None.

Conclusion

Solved.


Merial Repeat-use





It is indicated in section 2.1.5.a.iv that the stabiliser used is stabiliser 56 in Chignolo-Pô

Laboratories and stabiliser 26 in Lyon Laboratories. The applicant should justify this difference,

describe the differences between the 2 stabilisers and analyse the consequences for the

equivalence of the final products derives from the 2 different types of active ingredient. As a

consequence, the relevance of the batches of vaccines used to perform the analytical, safety and

efficacy studies has also to be analysed. In addition, it is a requirement of the TSE guidelines that

the lowest risk material should be used during production. Consequently the Applicant should use

the stabiliser with the lowest TSE risk .


As stated in answer to question 30 (and explained in answer to question 35c for the ND component), the change of

stabiliser (from 26 to 56) was indeed put into place to satisfy the TSE guidelines and Ph.Eur requirements. This

change replaces meat derivative by milk derivatives minimising therefore the BSE risk.

HatchPak range is a live vaccine range. The safety and efficacy being mainly linked with the content of live virus

(inoculated titers), the development study results are therefore fully relevant. It must be noted that in both case it is

protein hydrolysate (peptone from ‘meat and casein’ or ‘casein’ alone) and put in the exact same quantity (to

minimise differences) and will be processed after injection through the same metabolic pathway. The behaviour of

product produced with the new stabiliser has been demonstrated through comparative analysis (result described in

part II.A.3 development pharmaceutics). Quality (see table below) and stability (see answer above, Q35c) are

similar, demonstrating absence of impact.

Equivalence is demonstrated as both production sites, using different stabiliser at development time, obtained

product of similar quality (similar titres) and above minimum requirements (R≥6.5 log10 EID50/ml):

AI Batch Titre (LPA)

(S26)

Titre (Chignolo Pô)

(S56)

1 7.9 7.8

2 7.9 8.04

3 8.0 8.11

RMS comment

THE JUSTIFICATION FOR THE CHANGE OF STABILISER IS ACCEPTED BY THE RMS

(SEE QUESTION 30). Concerning the impact on the safety and efficacy of the vaccine, the arguments of the applicant are accepted by

the RMS (see also questions 50 & 73).

Concerning the data to support the equivalence of quality of the final product, the data provided are satisfactory.

Regarding the point of stability of the final product, please see the comments to questions 35 and 48.

CMS Comment

None.

Conclusion

Solved.



For the information of the applicant concerning the controls performed on the Master Seed Virus, to be taken

into consideration when providing further information on the extraneous agents testing:

Position of the RMS: If Mycoplasma testing was done on the Master Seed Virus by the culture method and

the epifluorescence test, it is not required to perform it again by both methods on the Work ing Seed Virus.

Ph. Eur. monograph 2.6.7. says “where the test for mycoplasmas is prescribed for […] a virus seed lot,

both […] methods are used” and the guidelines says “the Master Seed Virus shall pass the tests for

sterility and freedom from mycoplasma” without any indication concerning the Work ing Seed.



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As answered in question 37a, both culture method and epifluorescence tests for the MSV were carried out

satisfactorily. We agree on the assessment of the RMS and this question was forwarded to the Ph.Eur. (see

attached IFAH Europe’s letter in Annex p. 245) as European vaccine manufacturers share this understanding. Until

now, Ph.Eur. has not yet replied.

RMS comment

The RMS has no further comment, because the applicant’s approach is accepted (see question 35 10 th part).

CMS Comment

None.

Conclusion

Solved.

Question 38

Bovine albumin fraction V (vol. 4/12 p.148)

It is noted that the gamma-irradiation validation report provided is in support of 25kGy and not 35 kGy as indicated

in the RMS report, therefore clarification is required to confirm what level of irradiation is applied.


The validation report indeed deals with 25-kGy dose. In view of results and to ensure satisfactory effectiveness,

Merial decided at the time to increase the dose and implement a minimum of 35 kGy to all substances of animal

origin. This approach has been confirmed as today requirements for bovine serum is at least 30 kGy.

RMS comment

Satisfactory.

CMS Comment

None.

Conclusion

Solved.

Question 39




This question is going beyond current requirements that are designed for starting material (and not material to

produce another starting material: porcine enzyme is used for the preparation of casein hydrolysate).

Today, according to the current Ph.Eur. chapter 5.2.5:

“- The use of substances of animal origin as constituents of vaccines or diluents is not generally acceptable

except where such substances are sterilised by a suitable, validated method. Where the use of such substances

has been shown to be essential and sterilisation is not possible, the criteria described under Requirements apply.

- Substances of animal origin used during production are either subjected to a suitable, validated sterilisation or

inactivation procedure or the substance is tested for the absence of extraneous organisms in accordance with the

Requirements below”.


Merial Repeat-use


Merial is doing more than required as the final material (casein hydrolysate) is both tested and treated. The

country of origin is stated on documentation and is part of batch record but it is not part of specification as long as

the country of origin has a clean health status. For information, up to now the sources were Canada and USA.

RMS comment

The RMS can accept the applicant’s answer, tak ing in particular account of the controls for extraneous agents

performed on the material, the inactivation process, the species of origin of the material with regard to the target

species for the vaccine, and the route of administration. It is reminded that the chapter 5.2.5. Ph. Eur. is currently

under revision, in particular with regard to the description of the origin of the starting materials. However, the text

is not yet adopted and thus this request is not currently a requirement of the Ph. Eur.

Day 145 question

UK: The Applicant’s justifications are not acceptable. It is a requirement of Ph. Eur. monograph 0062 (Vaccines

for Veterinary Use) which states: “Ingredients that are derived from animals are specified as to the source species

and country of origin, and must comply with the criteria described in chapter 5.2.5.” Therefore, the Applicant

should provide information on the acceptable countries of origin for starting materials of animal origin as indicated

previously.


Question 40

Stabiliser 44 and stabiliser 26 are used in Lyon Laboratories.

The applicant should provide the information relevant to these stabilisers (composition, sterilisation

treatment, tests).

The applicant should also select one of the stabiliser for each active ingredient and justify this

selection, so that in the future, there is only one method of production whatever the site of production.

In addition, it is a requirement of the TSE guidelines that the lowest risk material should be used during

production. Consequently the Applicant should use the stabiliser with the lowest TSE risk.


As explained in answer to question 30, the choice was made and only one stabilizer is used (54 for ND and 56 for

IB) to use materials of the lowest TSE risk. To minimize impact, the same nature (peptone) in the exact same

quantity as in the previous stabilizers was used. This will be applied on both sites (one unique production method).

RMS comment

The RMS refers to question 30.

For the record, stabilisers 44 and 26 are no more used, because new stabilisers.54 and 56 are used to reduce the

TSE risk . Their composition was provided (question 30). Thus it is not requested anymore to detail the

sterilisation treatment and tests applying to these materials.

The question is solved.

CMS Comment

None.

Conclusion

Solved.


Buffered physiological saline pH 7.1: this physiological saline is sterilised by filtration and not by

autoclaving. It is an Ph.Eur. requirement that autoclaving should be used unless justified. There does not

appear to be a justification. An adequate justification should be provided or the saline should be sterilised

by autoclaving.


The buffered physiological saline pH 7.1 will be sterilised by autoclaving as required by Ph. Eur (5.1.1, current

edition).


Merial Repeat-use


RMS comment

Satisfactory.

Day 145 question

ES: A commitment of the applicant with a suitable timeframe should be provided.


Question 41

It is noted that the Certificates of Suitability R0-CEP-2000-166-Rev 03 and R0-CEP-2001-053-Rev 00 are not

current (should be R1-CEP-2000-166-Rev 00 and R1-CEP-2001-053-Rev 01). These should be supplied and an

updated format table and revised declaration provided.

The Applicant should clarify whether stabiliser has been used for storage of both master seed viruses and if so

whether any materials of ruminant origin have been used in the stabiliser. If appropriate a risk assessment and

certificates of suitability should be provided.


The updated certificate R1-CEP-2000-166-Rev 00 is attached in Annex p.292.

Concerning the other certificate, the supplier (Celiance, ex Serologicals proteins) had a certificate for each of the

bovine albumin products. A global application was made and accepted by EDQM under the number R1-CEP-2000-

195-Rev 00. The certificate R0-CEP-2001-053-Rev 0 is to be replaced by this new one identified as R1-CEP-2000-

195-Rev 00, enclosed in Annex p. 295. This change in reference of the certificate has no impact on the

specifications of the material supplied to MERIAL

The master for ND component was produced without any stabiliser. The risk assessment given in the application

dossier (part IIC3) is fully appropriate.

The master seed for IB component was produced with stabiliser S26 (i.e. containing meat and casein peptone of

bovine origin). Taking into the nature of the peptone (meat) and the date of use (the master seed was produced in

1975) being largely before the French BSE cases, the risk assessment given in the application dossier remains

fully appropriate.

The risk of transmitting is extremely minimized. HatchPak Avinew IB H120 fully complies with the requirements of

the “Note for Guidance on Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents via

Veterinary Medicinal Products” and the “Position Paper on the Assessment of the Risk of Transmission of Animal

Spongiform Encephalopathy Agents by Master Seed Materials Used in the Production of Veterinary Vaccines ”.

RMS comment

The certificates requested have been provided.

The 2nd part of the question is correctly answered.

CMS Comment

None.

Conclusion

Solved.



SOPs should be provided for sterilization and filling.


As required by the Ph Eur the sterilization is carried out using dry heat sterilization. Therefore the criteria for in-

process control are:

TEST NO.3 AND NO.3’ Technique: Monitoring of the sterilisation cycle.


Merial Repeat-use


Frequency: Control test carried out during sterilisation.

Function: To ensure the regularity of sterilisation and its compliance with the requirements of the current

European Pharmacopoeia edition.

Description: The sterilisation parameters (time and temperature) are continuously recorded.

Limits of acceptance: The evolution observed of the different parameters must comply with the requirements of

the current European Pharmacopoeia edition (i.e. equivalent at least 160°C during at least 2 hours). the Fh must

be greater than 30 minutes).

As described in part II.A.3, to guarantee that the volume of product to be frozen contains the required quant ities

of antigen, a volume of:

4.6 ml 0.05 ml is filled into each ampoule for the ND component with a minimum of 4.5 ml.

5.1 ml 0.05 ml is filled into each ampoule for the IB component with a minimum of 5.0 ml.

Those figures are considered as limits of acceptance. Therefore, knowing that weighing technique will not be

carried out, the in-process control test should read:

TEST NO.4 (ND COMPONENT) Technique: Checking the filled volume.

Frequency: Control test carried out every hour during the primary packaging operation.

Function: To ensure that the volume of filled product corresponds to the volume intended when adjusting the

filling machine.

Description: The volume is measured in a graduated container.

Limits of acceptance: The volume of product contained in the container must be greater or equal to 4.50 ml and

lower or equal to 4.70 ml per ampoule

TEST NO.4’(IB COMPONENT) Technique: Checking the filled volume.

Frequency: Control test carried out every hour during the primary packaging operation.

Function: To ensure that the volume of filled product corresponds to the volume intended when adjusting the

filling machine.

Description: The volume is measured in a graduated container or by weighing.

Limits of acceptance: The volume of product contained in the container must be greater or equal to 5.00 ml and

lower or equal to 5.20 ml per ampoule

RMS comment

Satisfactory.

CMS comment

No further comment.

Conclusion

Solved.

Question 42 – 2nd part (CZ – ES – DE)


clearly stated.




All these tests are routine in-process control tests performed at key steps of the production and detailed in the

corresponding parts of the analytical dossier.

Temperature (test No.2): these tests are carried out during the formulation of the ND vaccine (stages 1 and 2

detailed in Vol.4 p.21-23) and of the IB vaccine (stages 1' and 2' detailed in Vol.4 p.024). Temperature must be

included between +2°C and +8°C at all these stages.

Time (test No.1) is carried out during the formulation of the ND vaccine (stages 1, 2, 4 and 5 detailed in Vol.4

p.21-23) and of the IB vaccine (stages 1', 2' 4’ and 5' detailed in Vol.4 p.024). Time is recorded for all the above-


Merial Repeat-use


mentioned stages. A limit of acceptance is set for stages 1 and 1' in order to guarantee the homogeneity of the

blend and corresponds to at least 15 minutes. A limit of acceptance is set for stages 2 and 2’ (storage of the

bulk) and corresponds to at most 2 days. A limit of acceptance is set for stage 4 and 4' (after sealing of the

ampoules) and corresponds to at most 6 hours.

Freezing (Test No.6) and time (Tests 5 and 5'): as detailed in Part II.B (Vol.4 p.25), the product is frozen to finally

reach a temperature inferior to –120°C. The limit is therefore inferior to –120°C. This freezing must occur gradually;

time limits are therefore set at a minimum of 75 min and a maximum if 120 min.

Concerning EDQM templates, during joint sessions between OMCL and IFAH Europe representatives, common

final proposal templates were agreed upon. These templates will be implemented by April 1st, 2007. Merial has

decided to have all these protocols prepared by computerize system, and work is almost finished but not fully. At

the end of the current procedure, once final specifications will be defined and production ready for routine, batch

protocols will be compliant with these templates.

RMS comment

Satisfactory.

CMS comment


CZ: No further comment.

DE: The batch protocols need revision. They must be updated and completed according to the templates agreed

at the last Veterinary Pharmaceutical Committee meeting in March 2007 and published by EDQM (see:

www.edqm.eu). As Merial as a member of IFAH has already agreed to implement these templates for existing

products, it is not acceptable, that batch protocols of new products do not comply with the templates.

Day 145 question






Question 43

The Applicant appears to have provided test procedures that are relatively old (some last updated 1990) that refer

to previous versions of the Ph.Eur. and which relate to the procedures used for both seedlot testing and current

product testing. Whilst it is expected that test procedures used to test the seedlots are likely to be older the

Applicant should confirm whether these test procedures reflect the current test procedures used for in process and

finished product testing. Updated test procedures should be supplied. If no updates have taken place (in some

instances during the past 17 years) this should be justified.


The documentation included in the dossier accurately described what is implemented at manufacturing level. ND

and IB component are classical components, produced for years by Merial. The test methods applied since that

time did not require updates.

This explains as example the age of 18 years of technique No.000077 (Physico-chemical test, organoleptic

characteristics).

In some cases, such as technique No.000768 (test for extraneous agent in SPF chickens), the described method

refers to an old Ph Eur (in the present case Ph Eur 2nd ed) but is still matching what is effectively done at

laboratory level, and not inconsistent with new Ph Eur requirements. The non-updated of the reference

documentation is therefore not problematic.

When needed, updates are implemented and this is recorded in the history section in each technique at the end of

the text, with related dates.

RMS comment

Acceptable.

http://www.edqm.eu/

http://www.edqm.eu/


Merial Repeat-use


CMS Comment

None.

Conclusion

Solved.


Question 44 - a



manufacturing premises (Lyon and Chignolo-Pô) and demonstrate that the identification methods used are

able to discrimate between the vaccine strains and other IB and/or ND strains handled in the same premises.


As an introduction, it must be underlined that under GMP conditions, use of other antigens than those intended for

is not expected. Therefore having other strains in the vaccine should not happen.

Other strains handled in the manufacturing premises of HatchPak Avinew IB H120.

Manufacturing site Other IB strain than H120 Other ND strain than VG/GA

Lyon CR 88121 None

Chignolo Po H120 (Italian Master seed,

common origin)

La Sota

Hitchner B1

IB H120 strains (serotype Massachusetts) can easily be differenciated from CR88121, which is a different serotype

(also known in the literature as 793B or 4/91). The identity test performed on HatchPak IB H120 (technique

001925; one dose neutralised by a Mass antiserum) will allow differentiating from the CR88121 virus. As a matter

of fact the cross reaction between both serotypes is only 56% (log ratio) as mentioned in Le Gros FX, 1998. An

antiserum able to neutralise 1 dose of H120 strain (3.7 log 10) will only neutralise 2.1 log10 of IB strain CR88121.

During a specific assay, H120 and CR88121 were tested in parallel. Results (see table below) clearly

demonstrated that IB CR88121 cannot pass satisfactorily the release tests of HatchPak H120.

H120

(titer : 4.61 log10 EID50)

CR88121

(titer: 4.16 log10 EID50

Virus 4/4 4/4

Virus+Antiserum 0/4 4/4

Result of seroneutralisation of IB strain using the antiserum of

HatchPak identity technique (No.001925) – observed mortality in 4

inoculated eggs.

This neutralisation technique is obviously not able to differentiate the H120 strain derived from the Italian master

seed. Even if GMP conditions ensure absence of use of wrong antigen, the applicant commits to implement

specific management to re-enforce confidence. First, the identification system in place does not allow mixing

batch number (the active ingredient batch of HatchPak IB H120 will carry a ‘H’ letter to better differentiate batches).

Secondly, to avoid having two different batches of different H120 strains produced in the same period (risk of

mixing batch documentation) the applicant proposes not to start production of the IB H120 strain right after a

production using the other IB H120 strain, a different virus production will take place in the production area.

As described in the doc 00.0815.R the monoclonal antibody U11, allows differenciating the VG/GA strain from La

Sota and HB1 strains. This was also published independently (see answer below)).

RMS comment

The question is solved concerning the IB component in Lyon premises and ND component for both sites.

CMS Comment

None.


Merial Repeat-use


Conclusion

Solved.

Question 44 - b


CMS n°2 also considers that based on the immunofluorescence pictures provided in report 00.0815.R:

validation of identity test for Avinew Vaccine by IF (vol 5/12, p.450), a reliable identification of both the

Newcastle disease virus and the ND virus strain VG/GA is highly questionable. The use of the monoclonal

anti-VG/VA antibody U11 should be re-evaluated and properly justified by the company. Identification of the

virus should be done according to Ph Eur 0450.


The reported issue may be a problem linked to the quality of the reproduction (photocopy of the photographs).

They are however unequivocal:

The used monoclonal antibodies (U11) has been obtained from VLA-Weybridge (OIE reference laboratory for

Newcastle disease) and is described in Alexander et al., (1997), see Annex p. 298, table 1 code j).

In the report on p2/7 U11 gives a positive intracytoplasmic fluorescence with Avinew (photograph I) very distinct

from the background visible only with the La Sota strain (photograph II). In page 3/7 the same distinguishable non-

specific background is observed with the Hitchner B1 strain (photograph III). On the photograph IV the NDV group

specific used as a control is also giving as expected a very clear intra-cytoplasmic fluorescence in Avinew infected

cells. In page 4/7 and photographs V and VI, the same observation is obtained with La Sota and Hitchner B1

strains. In pages 5 and 6/7, photographs VII, VIII, and IX are repeating this observation (positive intra-cytoplasmic

fluorescence) with a polyclonal Newcastle reference anti-serum. The last photograph X is illustrating the negative

fluorescence obtained with a negative anti-serum on Avinew infected cells.

Monoclonal

antibody

VG/GA strain

Avinew 5AVW

5S81

La Sota strain

Sotasec 5STC

5F208

Hitchner B1 strain

Pestos 6PTS N110

U11 (type specific) + (photo I) - (photo II) - (photo III)

U85 (group specific + (photo IV) + (photo V) + (photo VI)

Positive serum

control + (photo VII) + (photo VIII) + (photo IX)

Negative serum

control - (photo X) - (not illustrated) - (not illustrated)

Such differentiation using U11 monoclonal antibodies has also been published by the VLA-Weybridge (OIE

reference laboratory for Newcastle disease, see publication above: Alexander et al, 1997): VG/GA Avinew strain is

belonging to the Group G (table 4, pattern 22), and HB1 La Sota strains to the group E, (page 11 and table 4 -

pattern 19/20).

Such use in the identity test is also recommended by the Ph Eur monograph 0450 (§3.1.2).

RMS comment

Concerning the literature cited, please refer to the copy of the article of Alexander et al, 1997, provided in the

answers of April 2007, vol.2/3, p.298.

The RMS is satisfied with the identification method used.

CMS Comment

None.

Conclusion

Solved.

Question 44 - c



Merial Repeat-use


CMS n°4 also requires a 2nd identification of the ND component: the applicant has performed the identification

of vaccine virus using monoclonal antibodies however the identification of the vaccine strain by the inhibition of

the agglutination assay should also be performed according to the Ph Eur monograph.


There is no major difficulty for the applicant to implement the haemagglutination inhibition (HI) test as mentioned in

Ph Eur 0450 §3.1.1. However this test will only bring the information that the strain is a Newcastle disease virus

and not specifically the Avinew (VG/GA) strain.

The use of the monoclonal antibody brings at once both information: Newcastle identity and Avinew identity, we

therefore think that adding the HI test is not useful. According to general notice of Ph.Eur.:

“The tests and assays described are the official methods upon which the standards of the Pharmacopoeia are

based. With the agreement of the competent authority, alternative methods of analysis may be used for control

purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance

with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or

dispute, the methods of analysis of the Pharmacopoeia are alone authoritative”

This informative test satisfactorily ensure result of HI test, the latter could be omitted.

This has been confirmed in a specific technique run. A monospecific ND antiserum (990705/060728) after dilution

by 0.56 log10 was able to stop haemagglutination provoked by the vaccinal virus (diluted 1.2 log10)

RMS comment

The RMS is satisfied with the identification method currently used and accepts the applicant’s justification.

CMS comment

No further comment.

Conclusion

Solved.


Question 45 (ES-


safety should be tested in chicks of the minimum recommended age of vaccination. Thus the applicant should use

for this test only day-old birds.

The Applicant should more closely define what are considered acceptable/unacceptable reactions in the batch

safety test. These criteria should be justified.

According to the Ph. Eur. monograph 62, in the case of a combined vaccine, birds of the safety test should receive

the combined product. As far as a batch protocol is provided for Hatchpak Avinew and another one for Hatchpak IB

H120, the RMS understands that the birds don’t receive the combined product. The applicant should confirm that

the safety test will be performed according to the Ph. Eur. monograph 62, that is by administration of both

components to the same birds.


The minimum recommended age of vaccination is now taken into account. A new technique was set up (see

technique No.200043, in Annex p. 319). Criteria have been defined taking into account the observation from safety

trials (part III); the respiratory signs were considered.

The safety test should now read:

Technique: No.2000043

Frequency: Control test carried out on a final lot of each batch.

Function: To evaluate the safety of the vaccine in SPF chicks.

Description: Complying with the current edition of Ph.Eur. monograph 0062.

Limits of acceptance: The animals do not display any symptom attributable to the vaccine. In particular during

clinical observation (without auscultation) no respiratory signs must be observed (dyspnea, coughing). Two non-

specific mortalities are tolerated.


Merial Repeat-use


HatchPak Avinew and HatchPak IB H120 batches were indeed tested separately as the quality of each individual

product in ampoule is satisfactorily demonstrated by all tests carried out for each product. The safety of the

association has been extensively demonstrated during safety development work (reported in Part III), there is thus

no reason that two batches of good quality (including safety) display a safety concern when administered together.

This way of testing is also linked to the production schedule (all batches are not available at the same t ime).

Nevertheless the applicant agrees to carry out the safety test of the batch after combination with a batch of the

other component.

RMS comment

As requested, the test is now conducted in day-old bird, to comply to the Ph. Eur. monograph 450. The limits of

acceptance set are acceptable, with regard to the safety profile of the vaccine described in part III of the dossier

(no severe respiratory signs – dyspnoea, polypnea – were observed after the administration of 10 doses in day-old

chicks).

The applicant is asked to performed the batch safety test on the combined product.

RMS question

The applicant is asked to performed the batch safety test on the combined product, and adapt the acceptance

limits if necessary. The applicant should note that the overdose study is awaited to set these acceptance limits

(see questions in part III).

CMS comment


Day 145 question

The applicant is asked to performed the batch safety test on the combined product, and adapt the acceptance

limits if necessary. The applicant should note that the overdose study is awaited to set these acceptance limits

(see questions in part III).

Solved.


Question 46 –1st part

Viral purity:


2.6.25. was published in 2005. The applicant should implement the new protocol of viral purity testing for avian

live viral vaccines prescribed by the Ph. Eur.; else, a detailed justification for this non compliance to the current

Ph. Eur. should be provided. Furthermore, for each possible extraneous agent, the applicant should

demonstrate that his testing methods are at least as sensitive as the test of the current Ph. Eur. and of an

appropriate specificity.


As already mentioned in answer to question 35a, all vaccine manufacturers in IFAH Europe were not in a situation

to readily implement the new tests. A period of at least two years was required. Merial underwent development

work and was also developing in parallel PCR test for specific viral purity.

The validation was heavy and results are almost fully available.

RMS comment

This explains the reason why the dossier was not compliant at the time of submission (summer 2006). See next

points for further analysis.

CMS comment

No further comment.

Conclusion

Solved.



Merial Repeat-use


Viral purity:


- For the ND component: The neutralising antiserum used for the purposes of identification and

neutralisation for extraneous agents had not been tested for antibodies to Haemorrhagic turkey

enteritis, PMV 1 and 4-9 (only 2 and 3 tested) nor Herpesvirus of turkeys. In addition an absence of

PMV 2 and 3 cannot be excluded because of a cross-reactivity of the anti-NDV (Paramyxovirus Type 1)

antiserum. The Applicant should justify the use of this serum and provide data to confirm the absence

of these potential extraneous agents.


The Haemorragic turkey enteritis virus does not multiply in chicken eggs used for production. As the absence of

Haemorragic turkey enteritis virus has been demonstrated in the MSV (only possible source of contamination). The

absence of antibody titration is therefore not critical.

The Newcastle disease virus is a Paramyxovirus Type 1, neutralising antiserum is necessarily positive.

The Ph Eur monograph 2.6.24§7 list the antibodies to be tested for neutralizing antisera, with the following

restriction: “Monospecific antisera for virus neutralisation can be assumed to be free of the antibodies against any

of these viruses if it can be shown that the immunising antigen could not have been contaminated with antigens

derived from that virus and if the virus is known not to infect the species of origin of the serum”

The anti serum is from chicken origin (SPF chickens) species on which only PMV1 and PMV2 are described.

Therefore PMV3-9 need not to be tested. Light cross reactivity between PMV2 and PMV1 may exist. Nevertheless

in the chicken test with no preliminary neutralization with antisera, no antibodies were found against both types

(PMV 2-3) confirming absence of such contaminants.

Herpesvirus of Turkeys and Marek’s virus share common antigens detectable by Agar Gel Precipitation test.

Therefore the satisfactory purity result of test focusing on MDV (test AGP in technique No.000708 enclosed in

Annex p. 319, see below proposal) also applied to Herpesvirus of turkeys.

RMS comment

Concerning the Haemorrhagic Turkey Enteritis virus, this virus is not known to multiply in hen eggs, which is the

support for the multiplication of the initial isolate and then the vaccine strain (see Diseases of Poultry, Ed. by

B.W. Calnek, p.625). The answer is satisfactory.

Concerning the different PMVs, the answer is satisfactory. The RMS also refers to Diseases of Poultry, Ed. by

B.W. Calnek, p.544 to support that chicken is not the host of PMV3-9.





Concerning the cross-reaction between PMV2-3 and PMV1, the answer is acceptable.

RMS question


Concerning the Herpesvirus of Turk ey, the applicant should provide the reference in literature supporting the




Day 145 question




Precipitation test. Therefore the satisfactory purity result of test focusing on MDV (Marek, tes t AGP) also applied


Question 46 - 3rd part

Viral purity:


Merial Repeat-use



- For the ND component: The extraneous agents test in eggs does not use the yolk sac route. The

Applicant should justify the omission of this route of inoculation and provide data to confirm how the

requirements of the Ph.Eur. have been fully met.


During validation work, it has been demonstrated that the ND strain cannot be satisfactorily neutralized to allow the

implementation of IV route. As a consequence and as recommended by Ph Eur 2.6.25 text in such a situation the

test method using chicks may be applied (see Ph.Eur. extract below).

2.6.25. Avian live virus vaccines: tests for extraneous agents in batches of finished product

General provisions

../..

f) Where specified in a monograph or otherwise justified, if neutralisation of the vaccine virus is required but difficult

to achieve, the in vitro tests described below are adapted, as required, to provide the necessary guarantees of

freedom from contamination with an extraneous agent. Alternatively, or in addition to in vitro tests conducted on

the batch, a test for extraneous agents may be conducted on chick sera obtained from testing the batch of

vaccine, as described under 6 Test for extraneous agents using chicks of chapter 2.6.24. Test for

extraneous agents in seed lots.../..

The current test using chicks is similar to the old version of Ph.Eur. requirements (test 2.6.6). Therefore, the

current description in the dossier No. 1036/EU-01, January 2006 is accurate and compliant with 2.6.25.

In addition as already approved for some vaccines (especially Avinew [freeze-dried form] during the MRP) and as

the test in chicks will be kept due to technical difficulties in the in ovo test implementation, the applicant proposes

not to carry out tests except the test using chicks (see document JL/EBR.07.D181 in Annex p. 353) and the non

specific existing tests on kidney primary cells. Note that all purity tes t carried out up to now on Avinew (freeze-

dried form) are also valid for HatchPak AVINEW IB H120 as the active ingredient (possible source of

contamination) is strictly identical.

The final purity test will therefore be (see techniques in Annex p. 319):

Technique: No.13 001

Frequency: Control test carried out one final lot of each batch.

Function: To check the absence of contaminating viruses.

Description: Complying with the current Ph.Eur. edition “Test for extraneous viruses using cell cultures” using

kidney primary cells.

Limits of acceptance: No cytopathic effect nor haemadsorption must be observed.



Function: To check the absence of contaminating viruses in the vaccine.

Description: Complying with the current Ph.Eur. edition and Specific Requirements for Avian Vaccines

(III/3363/92).

Limits of acceptance: A minimum of 8 sera must be collected.




Description: Complying with the current Ph.Eur. edition.

Limits of acceptance: The seroconversion tests must not give evidence of any extraneous agent.




Description: Complying with the Specific Requirements for Avian Vaccines (III/3363/92).

Limits of acceptance: The seroconversion tests must not give evidence of any extraneous agent.

RMS comment

http://online6vm58.edqm.eu/NXT/gateway.dll?f=id$id=58-20624E.htm$t=document-frame.htm$3.0$p=


Merial Repeat-use


The RMS adds that the yolk sac route is now very sensitive, as indicated in Diseases of Poultry, ed. by Calnek,

p.548. Thus if the ND strain is not sufficiently neutralised, this route cannot be used for the testing of extraneous

agents of the ND component.

Concerning the overall extraneous agent testing of the ND component (Hatchpak Avinew):

Concerning the reduction of the number of tests to be conducted on the final product, the RMS refers to the

document provided in the answers of April 2007, vol.3/3, p.353. It summarises the arguments of the applicant and

agreements made during the Mutual Recognition Procedure for the extraneous agent testing of AVINEW (same

MSV as Hatchpak Avinew IB H120, same production method in eggs). There is no reason to come back on this

agreement and therefore, the RMS agrees with the applicant’s proposal. For the record, as for AVINEW, the tests

to be conducted on a representative number of batches of final product were done on 3 batches produced in

Chignolo-Po and 3 batches produced in Lyon (see initial dossier, vol.4/12, pp.202-203).

For the record: technique 13001 is the test in cell cultures, technique 768 is the test in SPF chicks, technique 708

& 1392 describe the serological tests performed after immunisation of SPF chicks (answer of April 2007, vol. 3/3,

pp.320-324)

CMS comment

No further comment.

Conclusion

Solved.


Viral purity:


- For ND and IB components: It is not clear from the information provided whether appropriate control

strains of mycoplasma as required by the Ph.Eur. were used during mycoplasma testing. Sufficient

information to enable confirmation that the requirements of the current Ph. Eur. have been met are

required.


Before using a medium in routine testing, the medium batch is ‘validated’ regarding its nutritive properties using the

appropriate micro-organisms:



- Mycoplasma orale

- Mycoplasma hyopneumoniaeMycoplasma gallisepticum;


As Merial is performing a high number of mycoplasma tests, a reduction in number of reference per session has

been implemented. During one test run, two references are used (including compulsorily one of the avian strains; M

synoviae and M gallisepticum alternatively). In addition, as the culture is maintained over 28 days, and as Merial is

carrying out at least one test per week, all the reference strains are in fact growing (at various culture time) on the

same media in the same QC laboratory.

This approach is fully acceptable as :

- nutritive properties of this medium batch is validated just after its production

- during all test runs two different references strains are used and confirmed the nutritive properties

- any difficulties in culturing the references should be known quickly either during the present test, or the

previous or the next one.

All information is therefore present to ensure Ph.Eur. compliance.

RMS comment

Acceptable.

CMS comment

No further comment.

Conclusion


Merial Repeat-use


Solved.

Question 46 – 5th part (PT)

Viral purity:


- For ND and IB components: Insufficient detail has been provided to confirm that the Ph.Eur.

requirements for testing in avian cell cultures have been met. It is also noted that the adsorption time

used is less than that recommended by the Ph.Eur. (20 minutes not 1 hour). In view of this the

Applicant should provide data to confirm how the requirements of the Ph.Eur. have been met.

The applicant should be informed that a CMS (n°3) requires the submission of the data of compliance with the

methods of section 2.6.25. of Ph. Eur:5 (availability of these data supposed to be in Dec 2006).


As mentioned above the development and validation work was performed. One of the conclusion was that the

neutralisation of the ND component is not possible (test in eggs, intra-vitelus route of injection) the applicant

therefore propose to keep only the test in chicks as currently described in the application dossier (see answer to

question 46b above).

Regarding the IB component, the general viral purity testing will be performed in embryonated hens’ eggs and in

chicken embryo fibroblast cells in compliance with the methods of section 2.6.25 of the Ph.Eur. after IB H120 virus

neutralization with the specific serum.

For the specific viral purity testing (EDS, MDV, TRTV and CAV), Merial has developed specific PCR techniques as

proposed by the section 2.6.25 of the Ph.Eur. instead of testing on cells in order to avoid the use of additional

number of chick embryos required by this testing on a routine basis.

The validation reports of the PCR techniques are enclosed in Annex (Documents 07.0007.R, p. 358; 07.0008.R, p.

377; 07.0009.R, p. 397, and 07.0010.R, p. 424). The obtained results show that the detection limit was at least

equivalent to the limit recommended in the section 2.6.25 of the Ph. Eur: detection of 10 CCID50 in 10 doses / 0.1

ml of tested product and in the PCR techniques at least 1 CCID50 in 1 dose / 0.1 ml of tested product is detected.

The specific testing through PCR techniques can thus be considered as compliant with the sec tion 2.6.25 of the

Ph.Eur.: “Other types of tests than those indicated may be used provided they are at least as sensitive as those

indicated and of appropriate specificity. Nucleic acid amplification techniques (2.6.21) give specific detection for

many agents and can be used after validation for sensitivity and specificity”.

The PCR techniques to be used on a routine basis are enclosed in Annex p. 319 (Techniques No.200025 (CAV),

No.200026 (EDS), No.200027 (MDV) and No.200028 (TRTV)) as well as the general testing techniques No.200012

and No.200011.

The viral purity test for HatchPak IB H120 should read:

Summary table of control tests and requirements applicable to HatchPak IB H120

II.E. Technique No. Limits of acceptance

6

Bacterial and fungal sterility 11 000 No growth

Mycoplasmic sterility 11 204 No growth

Viral purity

200012 Absence of embryo abnormalities or

death

200011 No cytopathic effect, no

haemadsorption, no haemagglutination

200026 Absence of egg drop syndrome virus

200027 Absence of Marek’s disease virus

200028 Absence of Turkey rhinotracheitis virus

200025 Absence of chicken anemia virus

VIRAL PURITY

Techniques: No.200012


Function: To check the absence of extraneous agents using eggs.


Merial Repeat-use


Description: Complying with the current Ph.Eur. edition “test for extraneous agents using embryonated hens’

eggs”.

limits of acceptance:: no test embryo shows macroscopic abnormalities or dies from causes attributable to the

vaccine and examination of the chorio-allantoic membranes and testing of the allantoic fluids show no evidence

of the presence of extraneous agents.



Function: To check the absence of extraneous agents avian primary cells.

Description: Complying with the current Ph.Eur. edition “test in chicken embryo fibroblast cells”.

limits of acceptance:: No cytopathic effect, no haemadsorption, no haemagglutination must be observed.



Function: To check the absence of egg drop syndrome virus.

Description: after extraction, purification of nucleic acids, and amplification with specific primers (EDSV), the

detection is performed by the mean of specific probe labelled with fluorophore at appropriate length wave.

limits of acceptance: No signal for the target virus (EDSV) must be detected with the vaccine under test.



Function: To check the absence of Marek’s disease virus.

Description: after extraction, purification of nucleic acids, and amplification with specific primers (MDV), the


limits of acceptance: No signal for the target virus (MDV) must be detected with the vaccine under test.



Function: To check the absence of Turkey rhinotracheitis virus.

Description: after extraction and purification of nucleic acids, cDNA is obtained using a reverse transcriptase.

After amplification with specific primers (TRTV), the detection is performed by the mean of specific probe

labelled with fluorophore at appropriate length wave.

limits of acceptance: No signal for the target virus (TRTV) must be detected with the vaccine under test.



Function: To check the absence of chicken anemia virus.

Description: after extraction, purification of nucleic acids, and amplification with specific primers (CAV), the


limits of acceptance: No signal for the target virus (CAV) must be detected with the vaccine under test.

RMS comment

Regarding the ND component, see previous point.

For the IB component, the applicant’s proposal is acceptable. For the record:

Technique 200012 is available in the answers of April 2007, vol. 3/3, p.338. The test for extraneous agents in

SPF hens’ eggs is compliant to the chapter 2.6.25.

Technique 200011 is available in the answers of April 2007, vol. 3/3, p.336. The test in chicken embryo

fibroblast cells is compliant to the chapter 2.6.25.

Technique 200026 (test for EDS virus by PCR) is available in the answers of April 2007, vol. 3/3, p.343.

Technique 200027 (test for MD virus by PCR) is available in the answers of April 2007, vol. 3/3, p.346.

Technique 200028 (test for TRT virus by PCR) is available in the answers of April 2007, vol. 3/3, p.349.

Technique 200025 (test for CA virus by PCR) is available in the answers of April 2007, vol. 3/3, p.340.

CMS comment


Conclusion

Solved.


Merial Repeat-use



Question 47

It is noted that there is a range in fill volume allowed during production. It is also noted that the presentations are

very high dose and therefore minor differences in filling volume will have greater implications for the number of

doses filled. In addition to this there is variability in the titration assay. The specification is reported as the quantity

of virus per dose, which is based on the nominal target number of doses. Because the presentation is wet frozen

there is no standardisation by way of reconstitution volume as would be the case with freeze-dried presentations.

The combination of these factors raises concerns relating to the consistency of product with respect to the final

numbers of doses contained within a vial of product. The Applicant should comment on this and provide data or a

justification to confirm how the consistency of the finished product is ensured.


In the part II.D (control tests during production, see answer to question 42a above) the volumes of filling were

stated as:

ND: between 4.5 and 4.7 ml

IB: between 5.0 and 5.2 ml

In term of injected quantity of virus (expressed in log10 EID50), if we consider the minimum content of the ampoule

as 9.5 (ND) or 7.7 (IB) log10 EID50 (minimum titre for a 10,000-dose presentation) the equivalent titres may be

calculated (see table below).

Volume/ampoule titre (ml) Titre/ampoule Difference

in log10

Target ND 4.6 8.83724217 9.5

Mini ND 4.5 8.83724217 9. 49045468 0.019

Maxi ND 4.7 8.83724217 9. 50934003

Target IB 5.1 6.99242982 7.7

Mini IB 5.0 6.99242982 7. 69139983 0.017

Maxi IB 5.2 6.99242982 7. 70843317

This change in volume is of non-significant impact on viral titre (less than 0.02 log10 EID50).

RMS comment

The initial concern is not really understood by the RMS. Indeed, the range for filling is approx. + 2% (0.1 ml/4.5

ml). Thus, the titre per dose may also vary of + 2%, which is not felt as a major issue. Furthermore, despite this is

a liquid vaccine, it is indeed reconstituted in water prior to nebulisation; thus, it is not different from the situation of

a lyophilisate.

In any case, the RMS doesn’t find any problem at this level.

CMS comment

No further comment.

Conclusion

Solved.



Question 48 – 1st part (ES – DE – CZ)

Hatchpak Avinew





Merial Repeat-use





CMSs n°6 & 8 remind that only stability data performed with batches, which contain the finally identified stabiliser

will be acceptable.


As stated in answer to questions 30 (and explained in answer to question 35c for the ND component), the change

of stabiliser (from 44 to 54) was put into place to satisfy the TSE guidelines and Ph.Eur. requirements. This

change replaces meat derivative by milk derivatives. In both case it is protein hydrolysate (peptone from ‘meat and

casein’ or ‘casein’ alone) and put in the exact same quantity (to minimise differences). The similarity of behaviour

of product produced with the new stabiliser has been demonstrated through comparative analysis (result described

in part II.A.3 development pharmaceutics and answer to question 30). This change was implemented to avoid

consequences and this has been confirmed with further titration time in stability study (see t able below including

new data demonstrating the good stability with loss of titre, see Annex p. 450)

Time

(months)

Titres

(S44)

Titres

(S54)

0

9.9

10.4

9.8

10.3

10.5

10.3

6 Nt

10.3/10.3

10.6/10.3

10.3/10.4

9

Nt

Nt

10.5

10.0

10.2

10.2

12

10.1

10.1

9.9

10.2

10.3

10.3

15

10.0

9.9

10.3

10.2

10.4

10.1

Nt: not tested.

As the results are close between both types of products with no loss over an already long period of storage (15

months in common), the whole storage period of 24 months is supported by data. HatchPak Avinew may be

granted a 24-month shelf life.

RMS comment

See next point.

Question 48 – 2nd part (ES – DE – CZ – UK)

Hatchpak IB H120








will be acceptable.


test.

A CMS (n°4) also requires to provide the safety data at the end of the shelf -life.


Merial Repeat-use



As stated in answer to questions 30 (and explained in answer to question 37c for the IB component), the change

of stabiliser (from 26 to 56) was put into place to satisfy the TSE guidelines and Ph.Eur. requirements. This

change replaces meat derivative by milk derivatives minimising. In both case it is protein hydrolysate (peptone from

‘meat and casein’ or ‘casein’ alone) and put in the exact same quantity (to minimise differences). The similarity of

behaviour of product produced with the new stabiliser has been demonstrated through comparative analysis (result

described in part II.A.3 development pharmaceutics and answer to question 30). This change was implemented to

avoid consequences and this has been confirmed with further titration time in stability study (see table below

including new data demonstrating the good stability with loss of titre, see Annex p. 450)

Additional data are available for 27-month storage period in stabilizer S26 (see Annex p. 450) confirming absence

of loss over time and validating a shelf life of 24 months also for this component.

Time

(months)

Titres (S26) Titres (S56)

0

8.5

8.1

8.3

8.7

8.5

8.6

6 Nt

8.3

8.6

8.8

9

8.4

8.4

8.4

8.5

8.4

8.4

12

8.3

8.1

8.4

8.8

8.6

-

15

8.2

8.3

8.4

8.6

8.8

8.4/8.7

Nt : not tested

The safety test was performed at the end of the study and was found satisfactory.

As the results are satisfactory and close between both types of products with no loss over an already long period

of storage (15 months in common), the whole storage period of 24 months is supported by data. HatchPak IB

H120 may be granted a 24-month shelf life.

RMS comment

The stability data are summarised:

Hatchpak Avinew


report 03.0549.R (initial dossier, vol. 5/12 p.485)


volume, titre; at release and after 27/28 months of storage, sterility and safety tests performed;



different from 0

the batches remains sterile (bacteria, fungi and mycoplasma) and safe until 27 months of storage


54 (answers of April 2007, vol.3/3, p.450)

The same protocol as described above is applies. The results are available for the first 15 months of storage:


the estimated slope of the linear model applied to assess the detitration over time is not

significantly different from 0

Hatchpak IB H120


report 04.0641.R (initial dossier, vol. 5/12 p.516 and answers of April 2007, vol.3/3, p.450)


Merial Repeat-use



volume, titre



different from 0


56 (answers of April 2007, vol.3/3, p.450)


the estimated slope of the linear model applied to assess the detitration over time is not

significantly different from 0

Hatchpak IB H120

The applicant should confirm the performance of the sterility and safety test after 27 months of storage (the

information is not clear from report provided in vol. 3/3, p.450).

Hatchpak Avinew and Hatchpak IB H120




question 35 – 7th part).

For the record, concerning the ND component, the slope for detitration is nearly significant (p=0.07), thus it further

supports the need of complete stability data.

RMS question

Hatchpak IB H120










CMS Comment


CZ: No further comment.

CMS question

ES: We support the RMS comments and the commitments should be provided with a justified timeframe.

UK: In the absence of completed stability data in support of 24 months shelf life for product formulated with new

stabiliser a shelf life of 12 months should be set.

Day 145 question

Hatchpak IB H120











Merial Repeat-use





Question 48 – 3rd part (ES – IE)

The applicant should clarify the stability data as 2 CMSs have observed discrepancies:

A CMS (n°4) requires the applicant to clarify the following inconsistency: “In pages 152 and 269 of the part II, the

vaccine titre is stated as 8.1-8-5 log10 EID50/ampoule. However, the titre of the ampoules supposes to be 3.7-4.7

log 10.”

CMS n°7 states:

- The average stability titration result for infectious titre for ND over three batches is ~10.1 log10 EID50/ampoule

(ref 03.0549.R, 5.2, table V) however the min and max titres for ND vaccine is 5.5 and 6.7 log10 EID50. Clarify

why a higher titre was used for stability purposes as compared to standard batches.

- The average titration result for stability studies for IB was ~ 8.4 log10 EID50/ampoule however the min and max

titres for IB are 3.7 and 4.7 log10 EID50. Clarify why a higher titre was acceptable for stability purpos es as

compared to standard batches.

CMS n°7 has the following requests:

- Study (ref 03.0549.R, 3.1.3) states animals used from 1-5 days of age however requirement states minimum age

chicks i.e. one day old. A justification is required.

- Two week old chicks were used during technique 000768. A justification is required.


The inconsistencies that have been observed are linked with an expression of virus content either per ampoule or

per dose. The table below gives the correspondence.

Titre (EID50)

per dose

Titre (EID50) per ampoule

(10 000

doses)

(15 000

doses)

Nd component

Minimum 5.5 9.5 9.7

Maximum 6.7 10.7 10.9

IB component

Minimum 3.7 7.7 7.9

Maximum 4.7 8.7 8.9

When doing all correspondences the data are all within the specifications.

The study method paragraph was referring to the technique No.18 100. The age was classically defined with this

range (1-5 days) and will be updated (see answer to question 45 and the newly proposed technique). In fact the

used chicken are usually 1-day old, the stated duration was more to cover exceptional delays (where hatching was

within the day before). The slight difference in time is not expected to have impact on the safety.

The serological evaluation for purity test was carried out according to Ph.Eur. (now test 2.6.4). This test requires a

2-week old chicken (this is not related to the minimum age of vaccination).

RMS comment

Satisfactory answers to these questions from ES and IE.

CMS comment



Conclusion

Solved.



Merial Repeat-use


Question 49

Hatchpak Avinew







The study related in part IIF item 2.2 HatchPak IB H120 has been completed with a similar test involving titrations

on HatchPak Avinew. This is reported in Annex p. 450. In this new data, HatchPak Avinew has been tested in

non-chlorinated tap water prior and after 2 hours of storage at room temperature. The loss in titer (0.15 log10

EID50) was within the expected variations for the titration technique No.15 001. No effective loss in titre was thus

observed after reconstitution in chlorine-free drinking water.

RMS comment

Acceptable answer.

CMS comment

No further comment.

Conclusion

Solved.

III. Safety

Question 50 – 1st part (DE)

The applicant should identify the stabilisers used in the vaccine batches/preparation which were used in the safety

tests.


All safety studies were performed with the ND strain produced with the 44 stabiliser and IB strain produced with

the 26 stabiliser. The modification of the stabilisers as described in the question 30 does not impact the clinical

results obtained. As explained in question 35 and 37, HatchPak range is a live vaccine range. The safety and

efficacy being mainly linked with the content of live virus (inoculated titers). The development study results are

therefore fully relevant. It must be noted that in both case it is protein hydrolysate (peptone from ‘meat and casein’

or ‘casein’ alone) and put in the exact same quantity (to minimise differences) and will be processed after injection

through the same metabolic pathway. The behaviour of product produced with the new stabiliser has been

demonstrated through comparative analysis (result described in part II.A.3 development pharmaceutics). Quality

(see questions 35 and 37) and stability (see questions 35 and 37) are similar demonstrating absence of impact (it

may be noted that this change was approved through recent mutual recognition procedure for Avinew, freeze-dried

product, No. FR/V/0123/001/II/03 ended on July 4th, 2006).

RMS comment

Taking into account the limited differences between the “old” and “new” stabilisers, and tak ing into account that

this is a live vaccine, it is agreed that the safety is mainly linked to the vaccine viruses (and not the stabiliser) and

the trials performed with vaccines containing the “old” stabiliser are thus relevant.

CMS comment

DE : no further comment.

Conclusion

Solved.


Merial Repeat-use


Question 50 – 2nd part (DE)





Although not really required by the Notice to Applicants, the summaries are additionally proposed by the applicant

for the convenience of the reader to better show the key elements of the dossier. We take the remark into account

for new dossier.

RMS comment

No further comment.

CMS comment


Conclusion

Solved.




Question 51





This was a mistake in the certificate of analysis (batch 3AWF7P15A), which was corrected in September 2005.

The corrected certificate is shown in report 03.0913.R or report 03.0916.R for example. A copy is enclosed for

convenience in the Annex p. 466.

RMS comment

Question solved. The RMS has checked that the certificate provided in annex p.466 corresponds to the batch

used in the trial (batch 3AWF7P15A).

CMS comment

No further comment.

Conclusion

Solved.




04.0571.R).


The controls did not receive spring water. Therefore, we are in a worst case scenario where vaccinated animals are

compared to controls without any other manipulation than usual care and that received no products that could

potentially interfere with their condition.


Merial Repeat-use


RMS comment

The answer is satisfactory.

CMS comment

No further comment.

Conclusion

Solved.






This was a mistake in the certificate of analysis (batch 3BIF7A01A), which was corrected in September 2005. The

corrected certificate is shown in report 03.0916.R. and enclosed in Annex p. 468.

RMS comment


used in the trial (batch 3BIF7A01A).

CMS comment

No further comment.

Conclusion

Solved.

Question 52 – 3rd part (ES)






Four birds in the group inoculated with an overdose of the vaccine showed diarrhoea on day 28. Three of these four

birds showed also lesions at necropsy. The applicant should comment on this, and justify why this is not

considered to be related with the vaccination since this symptom has been only observed in the vaccinated

animals and in none of the controls.(ES)


In this study, only one bird out of the 20 birds monitored for respiratory signs still showed signs on D14 that were

limited to very slight bronchial rales in both vaccinated groups (dose and overdose). In Study 04.0188.R, after the

administration of a dose of HatchPak Avinew IB H120 on D0 and D14, no more respiratory signs were recorded on

D21 in any of the 20 birds specifically monitored whereas 3 birds and 2 birds still showed respectively s light

bronchial rales and very slight bronchial rales on D14. Consequently, the probability that one bird inoculated with

one dose of HatchPak IB H120 on D0 still showed bronchial rales on D28 is very weak.

Therefore, even if the relationship between the inflammation of the trachea noted in one bird on D28 and the

inoculation of a dose of HatchPak IB H120 on D0 cannot be totally ruled out, it is very unlikely. Furthermore,

inflammation of the trachea had never been observed in any other bird included in the safety studies of HatchPak

Avinew IB H120 and necropsied for specific lesions of IB 21 or 28 days after vaccination ( i.e. around 200 birds).

This lesion can thus be regarded as incidental.

In addition, in the context of infectious bronchitis, diarrhoea is unexpected except if the virus infecting the birds is

known to be nephropathic. H120 strain has been widely used for many years as vaccine strain in several live

vaccines, in particular Bioral H120 for which cases of digestive disorders have never been reported. The


Merial Repeat-use


pharmacovigilance data for this product show that there was no declaration of adverse event for the period January

2001 to September 2006 while 2.5 billion of doses were sold in Europe. In addition, it has been demonstrated in

Study 04.0856.R that the administration of a high dose and an overdose of IB H120 vaccine strain had no adverse

effects on the kidneys as judged by macroscopic aspect and tissue histopathological examination. These results

thus confirmed that IB H120 strain was not nephropathic. Thus, diarrhoea cannot be considered as a specific

clinical sign in the context of a vaccination with HatchPak IB H120.

Therefore, it is very unlikely that diarrhoea signs (diarrhoeic droppings on the cloacal feathers and distended gut

sometimes with a watery content at necropsy) recorded on D28 in 4 birds out of the 30 birds inoculated with an

overdose of HatchPak IB H120 in Study 04.0581.R were directly due to the vaccination.

Besides, despite these symptoms, no significant differences were detected between the 2 groups on bodyweight

criterion neither at D7 nor at D28.

Therefore, the vaccination did not impact the general health of birds, as confirmed by the field trial performed on

large scale.

One hypothesis for these signs could be an expression of the sensitivity to the environmental conditions (such as

air flow) or to a not optimal food in the category of birds used. Indeed, such clinical signs were sometimes

observed in non inoculated control birds reared under similar experimental conditions (Study 04.1064.R). Moreover,

during the field safety trial where 22,032 conventional broilers were vaccinated with HatchPak Avinew IB H120 at

one day old, no diarrhoea signs were recorded confirming the safety of HatchPak IB H120 from the digestive

standpoint.

RMS comment

These explanations are acceptable.

CMS question

ES: no further question.

Conclusion

Solved.

Question 53

Report 05.0367.R.: safety of 1 dose in day-old conventional chicks:


04.0571.R).


The controls did not receive spring water. Therefore, we are in a worst case scenario where vaccinated animals are

compared to controls without any other manipulation than usual care and that received no products that could

potentially interfere with their condition.

RMS comment


CMS comment

No further comment.

Conclusion

Solved.


Question 54 (UK)

For the information of the applicant concerning this section:


Merial Repeat-use



Hatchpak Avinew IB H120 in birds with no maternally derived ant ibodies. Indeed, the safety of one dose in this


The RMS considers however, that the safety of the repeated administration of one dose was performed in SPF

birds (see section III.C.3.), providing relevant information to cover this section.

A CMS (n°1) notes that single dose safety for the product is addressed in the repeat dose study and considers

this acceptable providing the safety data is supplemented by data with administration of the vaccine by the

recommended route (spray) in an overdose safety test.


As underlined by the RMS, the safety of the repeated administration of one dose was performed in SPF birds (refer

to the study 04.0188.R), which demonstrates the safety of a common administration of a high dose of both

components. The results were also confirmed in the study 04.1064.R where the same amounts of combined

components were administered once to SPF chicks at day-old.

The oculonasal route of administration chosen is relevant because it reproduces the physical result of a coarse

spray application (which is not a respiratory route) while ensuring that the correct dose intended to be studied is

really administrated. From a safety point of view, it provides more assurance on the results observed.

Merial agrees that the safety of an overdose of the combined product may not have been adequately addressed

and commits itself to perform the study by the spray route and provide the results for D170 (15 th of June 2007).

RMS comment

The RMS welcomes the performance of an overdose dose study using the combined vaccine and the spray route

(normal route of vaccination not studied under laboratory conditions) but is however surprised that the procedure

was re-started prior the data are available for assessment.

Thus, the applicant should be informed that no definitive conclusion can be drawn until the results are available:

agreement on the delivery of a Marketing Authorisation and safety information to be reported in the SPC is

postponed until the trial is available.

RMS question

For the information of the applicant :

The performance of an overdose dose study using the combined vaccine and the spray route (normal route of

vaccination not studied under laboratory conditions) is welcome, but it is however surprising that the procedure




postponed until the new overdose trial is available.

CMS comment

No further comment.

Day 145 question










Question 55





Merial Repeat-use



This was a mistake in the certificate of analysis (batch 3AWF7P15A), which was corrected in September 2005.

The corrected certificate is shown in report 03.0913.R or report 03.0916.R for example and enclosed in Annex

p.466.

RMS comment


used in the trial (batch 3AWF7P15A).

CMS comment

No further comment.

Conclusion

Solved.




04.0571.R).


As explained in the questions 52a and 53, the controls did not receive spring water. Therefore, we are in a worst

case scenario where vaccinated animals are compared to controls without any other manipulation than usual care

and that received no products that could potentially interfere with their condition.

RMS comment


CMS comment

No further comment.

Conclusion

Solved.






Regarding the certificate, as mentioned in the answer of the question 52 b), there was a mistake in the certificate

of analysis (batch 3BIF7A01A), which was corrected in September 2005. The corrected certificate is shown in

report 03.0916.R and enclosed in Annex p.468.

RMS comment


used in the trial (batch 3BIF7A01A).

CMS comment

No further comment.

Conclusion

Solved.


Merial Repeat-use


Question 57

Conclusion (UK – ES)


Hatchpak Avinew IB H120. Indeed, the safety of an overdose is studied separately for each component. This is

not conform to the regulation (EC directive 2004/28). The applicant shall provide a trial demonstrating the safety of

an overdose of the vaccine (both component administered at the same time).

In addition, a CMS (n°1) considers that an overdose safety study by the spray route (nebulisation) of administration

is required before the product could be accepted.

In addition, CMS n°4 considers that for live vaccines, the overdose study is very important to assess the safety

profile of the product and therefore, the trial should be provided.


As explained in the Q54, Merial agrees that the safety of an overdose of the combined product may not have been

adequately addressed and commits itself to perform the study by the spray route and to provide the results for

mid-June 2007 (D170 of this procedure).

Regarding the route of inoculation, it is reminded that for a safety test, the oculonasal route of administration

chosen is very relevant because it reproduces the physical result of a coarse spray application (which is not a

respiratory route) while ensuring that the correct dose intended to be studied is really administrated. From a safety

point of view, it provides more assurance on the results observed.

RMS comment







The data are awaited to confirm the safety of the nebulisation route.

RMS question









CMS question

ES: Unacceptable response. We totally support the RMS comment and consider the need to receive the results of

the study before a conclusion can be drawn. The study should have been done before the procedure was started

and in any case before it was restarted.

Day 145 question


The performance of an overdose dose study using the spray route (normal route of vaccination not studied under

laboratory conditions) is welcome, but it is however surprising that the procedure was re-started prior the data are

available for assessment.







Merial Repeat-use


Question 58










recommended.


The impact on the growth was observed in none of the studies with IB H 120 used alone. Therefore, as suggested

in question 12, this could be due to the Newcastle strain.

A compilation of the results obtained further the monitoring of the weight following Newcastle vaccination has been

performed in the table here after:

Study

reference

Type of

chickens Number of injection

Observations regarding the

bodyweight

04.0571.R 40 SPF chickens 1 (simple dose and overdose) Significant group effect on D7 and

D21.

04.1064.R 30 SPF chickens 1 (high dose) with Vaxxitek

HVT+IBD

No significant group effect on D7.

Significant group effect on D28, only

detected in males.

04.0188.R 30 SPF chickens 2 (high dose) Significant group effect on D14 and

D28.

05.0367.R 40 broiler

chickens 1 (high dose)

No significant group effect on D6 and

D28.

03.0916.R 22 032 broiler

chickens 1 (commercial dose)

No difference as compared to the

control group vaccinated with

AVINEW and BIORAL H120.

This clearly shows that the effect on the weight concerns only SPF birds. Conventional birds, which will be the

ones vaccinated in the field are not impacted and this has been demonstrated on a large scale (22 032 birds).

Therefore, the growth retardation should not be mentioned on the SmPC.

Regarding the rales, in study 04.0188.R, only one bird out of the 20 birds vaccinated on D0 and D14 and followed

for specific respiratory signs still showed very slight bronchial rales on D19. At the two last examination dates

(D21 and D24), no more respiratory signs were recorded in any of the 20 birds monitored. Under the conditions of

the repeated administration of one dose of HatchPak Avinew IB H120 in SPF chickens, bronchial rales can be

recorded until D19, ie 5 days after the second administration.

However, under the recommended use of the vaccine, the safety of one dose in the target species, i.e. one-day-old

conventional chickens has been demonstrated in the report 05.0367.R on page 127 of the Part III of the dossier. In

this study, rales were observed only until 13 days, which has been reported in the initial proposed SmPC. In 2

other reports as reminded here.

Componen

t tested Trial

Titre per

dose Type and total

number of animals

included in the trial

Age of

animals

(vaccination)

Respiratory

observations H120

(log10 EID50)


Merial Repeat-use


IB 04.0581.R 4.7 95 SPF chickens Day-old

At most slight

bronchial rales from

D5 to D14.

Still very slight

bronchial rales in 1

bird out of 20 on

D14.

ND/IB 05.0367.R 4.7 85 conventional

chickens Day-old

From D3 to D13, at

most slight bronchial

rales.

Still very slight

bronchial rales in 1

bird out of 15 on

D13.

In this dossier, rales were observed only until 14 days, which has been reported in the initial proposed SmPC.

The Applicant would like to correct that during the field safety study (Report 03.0916.R), coughing was recorded up

to D26 and not up to D33. However, the applicant does not agree to use the results obtained during the field safety

study to document the SPC. Indeed, field trials are conducted for a confirmation under field conditions of safety

results obtained during experimental trials. These experimental trials are performed under well controlled

environmental conditions, in the most sensitive category of animals and in presence of a negative control; the

clinical results obtained are thus more relevant and accurate to document the SPC. On the contrary, in the field,

the environmental and sanitary conditions are not well controlled and much interference can occur. It is therefore

not relevant to attribute all the clinical signs observed during a field study to the vaccine tested. In addition, this

test was performed with the combined product HatchPak Avinew IB H120.

Therefore, the applicant proposes to keep the initial following proposal for the § 4.6. Adverses reactions (frequency

and seriousness) of the SmPC:

No general reactions or lesions were observed following the administration of one dose of vaccine except slight

and transient bronchial rales within the 2 weeks following vaccination.

The applicant takes note the SPC may need further modification depending on the results of the required overdose

study due to the lack of data with combined overdose study. It is underlined that for a safety test, the route used in

studies involving the two components independently is fully representative of the recommended route. As a matter

of fact the oculonasal route mimics the effect expected from a coarse spray application, while insuring a better

control of the actual dose delivered.

RMS comment

Regarding the growth retardation, the applicant’s answer is accepted (effect proven only in SPF birds, no effect in

conventional birds), based on the following analysis:

- Field trial 03.0916.R: no conclusion can be drawn on a potential detrimental effect of the ND component

on the growth, because the controls birds have received AVINEW and BIORAL H120 (the same vaccine

strains as in HATCHPAK AVINEW IB H120); thus it seems normal that there is no difference in growth

between birds vaccinated with HATCHPAK AVINEW IB H120 and birds vaccinated with AVINEW and

BIORAL H120

- Laboratory trial 05.0367.R: the birds which received HATCHPAK AVINEW IB H120 grew better than the

control birds, despite the improvement was not statistically significant.

However, It is also reminded that part of the safety information is not available (overdose study with the combined

vaccine) and therefore, safety information to be reported in the SPC is postponed until all the trials necessary to

assess the overall safety are available.

Regarding the bronchial rales, it is reminded that:

- no trial of a single dose of the combined vaccine is available for SPF chickens, thus leading to the

necessity to refer to other trials available (in particular repeated single dose of the comb ined vaccine –

report 04.0188.R)


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- no trial of an overdose of the combined vaccine is currently available, thus the overall safety profile cannot

be assessed

- no trial is available using the route of vaccination recommended (spray); the RMS has a concern regarding

the safety profile of the IB component when the spray vaccination is used – and thus potentially a deeper

penetration of the IB virus strain occur. The RMS doesn’t accept the statement that coarse spray

vaccination is equivalent to oculo-nasl route without any demonstration

- the RMS considers that the information to be put in the SPC shall reflect the observations made in both

the laboratory and the field trials (in particular, it is not acceptable to refer only to field data when it’s in

favour of the vaccine – i.e. for the effect on growth – and to refer only to laboratory trials when it’s again in

favour of the vaccine – i.e. for the bronchial rales).

The RMS is waiting for the overdose safety study conducted with the combined vaccine and using the s pray route

of vaccination to conclude on the warnings to be put in the SPC. However, the applicant should be aware that the

RMS considers its proposal for section 4.6 (Bronchial rales, not associated with respiratory distress or any general

sign, may be observed between 5 and 14 days after vaccination in up to 75% of the birds, attributable to the

Infectious Bronchitis vaccine strain) as more accurate and in line with current wording of SPC than the applicant’s

proposal.

CMS comments

No further comment. RMS position supported.

Day 145 question











The RMS is waiting for the overdose safety study conducted with the combined vaccine and using the spray route

of vaccination to conclude on the warnings to be put in the SPC. However, the applicant should be aware that

the RMS considers its proposal for section 4.6 (Bronchial rales, not associated with respiratory distress or any

general sign, may be observed between 5 and 14 days after vaccination in up to 75% of the birds, attributable

to the Infectious Bronchitis vaccine strain) as more accurate and in line with current wording of SPC than the

applicant’s proposal.


Question 59

Report 99.0339.R.: safety of AVINEW in pullets – monitoring of the onset of lay:



- the vaccine used is not the right one (monovalent ND lyophilised whereas Hatchpak Avinew IB H120 is

a bivalent frozen vaccine)





Once the frozen HatchPak Avinew is reconstituted for use in drinking water, it is strictly equivalent to the similarly

reconstituted Monovalent ND lyophilised vaccine used in this study. Indeed, the strain and formulation including

the stabiliser are the same in these 2 vaccines.

Vaccinating closer to the laying period (here 4 and 10 weeks of age) is a more severe condition from a safety point

of view on the laying criteria than the recommended schedule at one day old. In addition, the safety of


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administration at one day old has been demonstrated in other studies according to the Ph Eur 0450 (ND live

vaccines). It is underlined that the Ph Eur concerning safety does not make a specific case with the future layer

category opposite to the Ph Eur 0442 (IB live vaccines) where the scientific knowledge exist that early

administration of certain virulent strains may affect the genital tract (point successfully addres sed in the reports

04.0060.R and 97-43.) This is not the case for the live modified ND vaccines and thus the use of the vaccine at day

old doesn’t call for specific test in pullets. This test may however be needed for the later use of the vaccine strain

(4 weeks and later on) which explains the set up of the protocol 99.0339.R.

The safety of the simultaneous administration of a maximal dose of HatchPak Avinew and HatchPak IB H120 is

reported in 05.0367.R.

As soon as each of these strains was safe for pullets in the specific corresponding most sensitive test listed

above, there was no need to include in the trial 05.0367.R a specific criteria for pullets.

Concerning the growth observations in 99.0339.R, the primary objective of the trial was to study the layi ng

performance. The control group was thus set at the age of 19 weeks only, when the primary criteria for laying can

start to be observed. The growth was recorded in vaccinated groups as secondary criteria, for information only. Due

to the study schedule, it was not possible to obtain the growth curve of controls. So a reliable standard curve was

used, to assess the impact of the vaccination in the trial. As underlined in the trial, Merial was aware that the ISA

growth curve is a standard curve for Brown breed that cannot be considered as a strict reference for Leghorn

animals. In addition, the impact of the HatchPak vaccine on the growth is assessed in the other safety trials

designed to this objective.

From a scientific point of view, given that the vaccine used in the study is strictly equivalent after reconstitution to

HatchPak Avinew, and that the conditions of administration are even more severe regarding the safety for pullets,

the conclusions of this trial are therefore fully supportive of the HatchPak vaccine. The trial demonstrated that the

formulated strain is safe for the future layer birds and has no impact on the laying performance criteria.

RMS comment

The RMS agrees with the proposal of the applicant (see question 13) for the section 4.7. of t he SPC ("The vaccine

is only intended for use in newly hatched chicks and is not appropriate after the age of one day. The data available

on the properties of the strains are not indicative of a detrimental effect on the reproductive tract, in particular t he

IB strain is compliant to the specifications of the Ph.Eur. with regard to the safety for the reproductive tract."). The

RMS considers that the information provided is sufficient tak ing into account this warning.

CMS comment

No further comment.

Conclusion

Solved.

Question 60

Document 97-43: evaluation of the DOI of an hexavalent inactivated vaccine – CNEVA Ploufragan:


The report is of poor interest for the following reasons:





9. the birds were not the most susceptible ones: there were conventional breeders with antibodies to IB

and not SPF birds


particular, the harvest on the eggs was not conducted correctly (indeed it’s a trial to assess the

potency of the IBD component of an hexavalent inactivated vaccine)

In conclusion, the RMS doesn’t consider that this trial can support the safety for the reproductive performance

of the vaccine Hatchpak Avinew IBH120.


The target species of the HatchPak vaccine is the one day old chicken and not the pullets. This study was

presented only to provide data on the effect of this strain on the laying performance. It is a supportive study, the

regulatory study on this issue being the safety test on the reproductive tract according to Ph Eur 0442: 04.0060.R


Merial Repeat-use


Merial agreed that the study design was not written to assess the effect on lay but nevertheless, the data on the

lay are available and can be used to show that the lay performance is close to the usual expected one when using

this strain. The Bioral H120 vaccine contains the same strain and same stabiliser than the submitted HatchPak

vaccine; therefore after reconstitution in drinking water this product is identical to HatchPak IB H120. The use of

this vaccine is thus justified. The batch number is reported in page 5 of the report: batch 4BLP 3G 194 produced

on 24/10/1994. The titer used is close to the maximum titre for the IB strain of HatchPak Vaccine: 6.8log10

DIO50/fl so 3.8 log10 per dose.

In addition, Bioral H120 is used for years in future layer or future breeder pullets without any field adverse reactions

detected since.

So this study does not answer to a precise regulatory requirement but provide reassurance that the use of the

vaccine in one day old chickens does not wrongly impact their future potential use as layers.

RMS comment

No further comment. It is agreed that this trial is only supportive data.

CMS comment

No further comment.

Conclusion

Solved.

Question 61 (UK – ES – HU – DE)

Conclusion:

This vaccine is intended for use in newly hatched birds, thus this section is not mandatory. No further

information is required.


- the data provided are not sufficient to conclude that the use of Hatchpak Avinew IB H120 is safe in

pullets because no specific study was conducted with this vaccine (no data concerning simultaneous



- concerning the effect of the IB component on the reproductive tract, the trial of the Ph. Eur.

monograph 442 was performed by the applicant (see report 04.0060.R in section III.C.6.3 Reversion to

virulence) with satisfactory results




“The vaccine is not intended for use in breeders and layers. The data available on the properties of the strain

are not indicative of a detrimental effect on the reproductive tract, in particular the IB strain is compliant to the


CMS n°1 supports the RMS comments but does not support the RMS’s proposed SPC wording. The CMS n°1

considers that the vaccine should be contra-indicated in layers and breeders but that sufficient data to meet

requirements is provided on reproductive safety for use in any category of 1 day old chicks. If an additional

warning is required it must refer to the fact that no detrimental effect on the development of the reproductive

tract has been observed.

CMS n°4 position: The studies provided to demonstrate the innocuousness of the vaccine on reproductive

performance are not acceptable as the vaccine used, the posology, and the age of the animals are not the ones

of this applicantion. More studies should be provided, or the vaccine should be contraindicated not only during

pregnancy and reproduction period, but also in animals intended for breeding.

CMS n°5 position: No data are available to support the use of the Hatchpak Avinew IB H120 vaccine in breeders

and layers, so the vaccine should not be used in these categories of chickens. SPC should be changed

accordingly.

CMS n°6 position: Doc. 04.0856.R and 0.4.0006.R and Doc. 97-54

These trials are only performed with the IB-component. The laboratory trials are performed with MSV+1, the

field trial with Bioral H 120. No trials are available with the combined vaccine Hatchpak Avinew IB H 120. These

trials can only be considered, when supporting data from a field trial with Hatchpak Avinew IB H 120 performed

in layers will be provided.


Merial Repeat-use



Given the answers provided in the two last questions and the argument raised by the RMS, Merial agrees with the

RMS proposal as the intended category of birds is only the one day old chicken. However these birds can be

future layers and breeders so the proposed wording should be “the vaccine is only intended for use in newly

hatched chicks and is not appropriate after the age of one day” rather than. “The vaccine is not intended for use in

breeders and layers”

Regarding the CMS n°1, n°4 and n°5 comments, it must be underlined that these vaccine strains are widely used

for many years in reproductive animals, through either Avinew or Bioral H120 vaccines, manufactured by Merial,

that have both a layer and breeder indication. Therefore, even in the case of a mistake where HatchPak would be

accidentally used in these categories of animals, there are sufficient safety data to ensure that no serious adverse

reactions would be observed.

Regarding the comment of the CMS n° 6: The trial 04.0856.R intended to provide data on the safety of the vaccine

for the kidneys. As required by the Monograph 0442 of the European Pharmacopoeia, it was performed using " a

vaccine virus at the least attenuated passage level that will be present between the master seed lot and a batch of

the vaccine"

The trial 04.0006.R is not presented in the dossier. It is likely that the number of the report is 04.0060.R. This trial

intended to provide data on the safety of the vaccine for the reproductive tract. As required by the Monograph 0442

of the European Pharmacopoeia, it was performed using "a vaccine virus at the least attenuated passage level that

will be present between the master seed lot and a batch of the vaccine"

Therefore, Merial fully complies with the European Pharmacopoeia requirements and the data are valuable to

support the vaccine.

In the trial 97-54, the vaccines used contained the same strain of Infectious Bronchitis than the one used in

HatchPak Avinew IBH120 and the same stabiliser than the one used for the clinical trials. Therefore, the data used

are relevant to provide data on the effect of this strain on the laying performance. As said above in question 59 and

60, the target species is the one day old chicken and not the pullets. So this trial is presented to provide additional

assurance of the safety of the strain on the layer pullets. The safety has been demonstrated in the target category

and the Infectious Bronchitis strain complies with the reproductive requirements of the European Pharmacopoeia.

To conclude, the applicant accepts the following wording for the section 4.7 of the SmPC:

“The vaccine is only intended for use in newly hatched chicks and is not appropriate after the age of one day. The


particular the IB strain is compliant to the specifications of the Ph.Eur. with regard to the safety for the reproductive

tract.”

RMS comment

The RMS agrees with the proposal of the applicant for the section 4.7. of the SPC (see question 13). The RMS

considers that the information provided is sufficient tak ing into account this warning.

CMS comment



Conclusion

Solved.




Question 62

Document ND-06-88: contact passage of TNDV EP5 virus:


vol.7/12 p.24 (see tables below). The applicant is asked to solve them.


Merial Repeat-use




1-day-old contact 0/5 1/5 1/5 3/5




1-day-old contact 0/5 1/5 1/5 2/5



The summary provided in the dossier is wrong and should be read as follows:


1-day-old contact 0/5 1/5 1/5 2 3/5

2-week-old contact 0/5 1 4/5 1 5/5 3/5

Merial apologizes for the inconvenient.

RMS comment

This was a question to clarify the data of the dossier (see 1st step assessment report, p.44). However, in any case,

the strain spreads from vaccinated to contact birds, and therefore, the clarification given by the applicant doesn’t

modify this conclusion. The point is solved.

CMS comment

No further comment.

Conclusion

Solved.



Question 63 (ES)

For IB component, it is well known that the virus can be disseminated to the bird cloaca (Cavanagh.D. severe

acute respiratory syndrome vaccine development: experiences of vaccination against avian infectious brobchitis

coronavirus. Avian pathol. 2003. Dec: 32(6): 567-82). The applicant should justify why the virus isolation on faeces

were not performed.


Infectious Bronchitis viruses (IBV) cause an acute, highly contagious viral respiratory disease in chickens

characterised by tracheal rales, coughing and sneezing. In the article cited, Cavanagh mentioned that it causes

deciliation of the ciliated epithelia of the nose and trachea. Therefore, in accordance with the Ph Eur monograph

0442 that specifies safety test for the trachea (and kidney), or suggest in vivo passage from tracheal extract for the

reversion to virulence test, the study 04.0022.R dealing with the dissemination in the vaccinate animal has focused

on the most relevant site from a clinical point of view: the trachea.

As mentioned in the question, the excretion by faeces is well known but the proposed reference also underlined

that the presence of the virus in bird cloaca is not usually accompanied of clinical effects. In addition, the cloaca is

not the only organ where the virus disseminates as it reaches many parts of the alimentary tract together with

kidneys and oviduct. Again, this dissemination has no clinical impact on the animal.

Therefore, we agree on the fact that the strain can be spread both by respiratory and fecal routes but the excretion

of the virus through the respiratory tract is an essential parameter to be followed within the frame of the evaluation

of the dissemination of the strain in the vaccinated animal. On the contrary, the isolation on faeces would not have


Merial Repeat-use


brought relevant information, other than to confirm what was already known. The absence of these data has no

impact on the safety profile of the product.

RMS comment

As far as both the CMS and the applicant agree that the IB vaccine strain disseminate to the bird cloaca, this

point is considered as solved. In any case, this information does not modify the safety profile of the vaccine.

CMS comment


Conclusion

Solved.



Question 64

Document 05.0061.R: ND strain VG/GA reversion to virulence study by 5 successive passages:

The applicant should provide further information concerning the clinical follow-up of the birds (duration and

frequency of observation, parameters recorded…).


The clinical follow-up was done during the daily care, therefore once a day at least or once more if any

manipulation was scheduled.

In the course of such observations routinely carried out, the observers pay specific attention to the general

conditions of the birds (including picking problems, respiratory signs, apathy, nervous disorders, and digestive

troubles). As mentioned in the report, these observations were daily recorded. The clinical observations recorded

during the study were mentioned in the report (paragraph 5.1) and are detailed in Table below.

As mentioned in the report and reported in Table below, there were no specific clinical sign and no death during all

the study, some birds from each group being kept until 13 to 21 days under daily observation (euthanasia of the

remaining birds at least 13 days after the group setting up).

Table I: Recording of the clinical observations during study 05.0061.P (report 05.0061.R)

Dates

(days of the trial) Observations

Contact

between

groups

D0 to D3 No sign observed in groups G1 and G2 (all birds are in good condition).

D4 No sign observed in G1 and G2. Euthanasia for organ sampling (trachea and

intestine) of 3 birds from G1 (Nos. 473, 475, and 481).

Contact

G1 with G2

(D3 to D7)

D5

Some birds of groups G2 and G1 are dirty (faeces stuck on the feathers),

probably due to the dirty paper covering the isolation unit floor during the

contact between G1 and G2. This dirty paper is eliminated. No other sign is

observed.

D6

One bird in G2 (No. 483) has its right leg injured and shows difficulties to

move. Four birds from G2 with faeces stuck on the anal feathers.

No other sign is observed in groups G1 and G2.

Euthanasia for organ sampling of 3 birds from G1 (Nos. 471, 477, 478).

Replacement of a clean paper covering the isolation unit floor.

D7

One bird from G1 with a small size (No. 472).

Three birds from G2 (Nos. 483, 485 and 487) euthanasied for organ sampling.

No other sign is observed in G1, G2 and G3 birds


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Dates

(days of the trial) Observations

Contact

between

groups

D8 Euthanasia of 3 birds from G2 (Nos. 490, 491 and 484) for organs sampling.

No sign is observed in G1, G2 or G3 birds.

Contact

G2 with G3

(D7 to D14)

D9 to D10 No sign observed in G1, G2 or G3 birds.

D11 No sign observed in G1, G2 or G3 birds.

Euthanasia of 3 birds from G3 for organ sampling (Nos. 495, 502, 505)

D12 No sign observed (groups G1, G2 and G3)

D13 No sign observed (groups G1, G2 and G3)

Euthanasia of 3 birds from G3 for organ sampling (Nos. 496, 498, 501)

D14 to D17 No sign observed in groups G1, G2, G3 and G4.

Contact

G3 with G4

(D14 to D21)

D18 No sign observed in groups G1, G2, G3 and G4.

Euthanasia for organ sampling of 3 birds from G4 (Nos. 507, 510, 511)

D19 No sign observed in groups G1, G2, G3 and G4.

D20 Euthanasia of 3 birds from G4 for organ sampling (Nos. 508, 513, 514).

No sign observed in groups G1, G2, G3 and G4.

D21 No sign observed in groups G1, G2, G3, G4 and G5.

Euthanasia of the remaining birds in G1, G2 and G3 (6 birds in each group).

D21 to D24 No sign observed in groups G4 and G5.

Contact

G4 with G5

(D21 to D28)

D25 No sign observed in groups G4 and G5. Euthanasia of 6 birds from G5 for

organ sampling (Nos. 519, 527, 528, 529, 537 and 541)

D26 No sign observed in groups G4 and G5.

D27 No sign observed in groups G4 and G5. Euthanasia for organ sampling of 12

birds from G5 (Nos. 522 to 525, 532 to 536, 539, 540 and 542)

D28 No sign observed in groups G4 and G5.

Euthanasia of the 6 remaining birds in group G4.

D29 to D33 No sign observed in group G5.

D34 Euthanasia of the 6 remaining birds in group G5.

RMS comment

The information requested is provided and doesn’t modify the original assessment with regard to the follow-up of

the clinical signs.

CMS comment

No further comment.

Conclusion

Solved.

Question 65


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The applicant should provide the clinical follow-up for 21 days of birds inoculated with the highest passaged strain

(test 2.4.4.C), as required by the Ph. Eur. monograph 450.


The two tests performed on the in vivo passaged strain (Intra Cerebral Pathogenicity Index, genetic sequence at

the cleavage site of F protein) are a very precise pathogenic marker, which brings much more information than the

safety test 2.4.3. As a matter of fact the only observation performed in 2.4.3 is relative to general clinical signs.

Given that,

the original strain is a naturally apathogenic strain and not an attenuated strain, thus the possibility of

reversion to virulence by passage is very theoretical,

the original strain is not eliciting a respiratory reaction, such absence impedes that this can be enhanced by

passage,

the Intra-Cerebral Pathogenicity Index of the passaged strain was not modified after passage, during a 10 day

observation period,

No mutation occurred on the passaged strain at the cleavage site F1-F2, thus not introducing any virulence

factor,

It was very unlikely that the test 2.4.3 would reveal anything abnormal. This test was thus not performed in the idea

not to use animals without a clear justification for ethical reasons.

Additionally, the deletion of this test was proposed in 1999 by the French Authorities when commenting the draft

Monograph, as shown in the document "Vaccin vivant de la Pseudopeste aviaire (maladie de Newcastle):

Observations des autorités françaises" (literally: Newcastle Disease vaccine (live): Observation of French

Authorities). On page 4, it was mentioned to "suppress this test which does not bring additional information"

enclosed in Annex p. 470 (Sentence written as: Supprimer ce test qui n'apporte pas d'informations

supplémentaires)

This position was supported, during the recent revision of the Ph Eur monograph 0450 and more generally on live

avian vaccines in 2002 by IFAH who questioned the interest of this test, as shown on page 2 of the document

"FEDESA Comments on revised drafts for the revision of Ph.Eur. monographs on Live Virus Vaccines For Poultry"

enclosed in Annex p. 478:

"Regarding the number of comparative tests to be performed: … In all monographs the section on the increas e in

virulence test requires that the unpassaged and the maximally passaged vaccine virus are compared in all the

other safety tests. In our view this is an ‘overk ill’ of tests and, hence, of test animals. In order to reduce the use of

experimental animals, we propose to restrict the testing of the unpassaged and the passaged vaccine virus to one

safety test. This should be the safety test likely to be most sensitive to pick up changes in the safety

characteristics of the vaccine virus.

In particular, we propose to select the following tests for safety comparison of passaged and unpassaged vaccine

virus in the increase in virulence test: …

… Newcastle disease: - 2.4.1 (intracerebral pathogenicity index)"

At that time, the applicant understood that sequence and ICPI would replace it in the final monograph

Merial considers therefore that the studies performed were sufficient and that the compliance with the Ph.Eur.

monograph 450 is achieved.

RMS comment

Regarding the comments made by the French Authorities to the Ph. Eur., it is reminded that there were done 8

years ago, and that the position of the French Authorities is not necessarily in total accordance with the ANMV

(Agency for registration of veterinary immunological products).

However, tak ing into account that the vaccine strain VG/GA is well-known (having been used for years in the

vaccine AVINEW), the RMS accepts the applicant’s answer.

CMS comment

No further comment.

Conclusion

Solved.


Merial Repeat-use



Question 66

Report 04.0060.R.: safety for the genital tract after vaccination with the vaccine strain and passaged strain






The raw data collected were all reported on Annex 4 (Clinical Follow-up) and Annex 5 (Bodyweights, weights and

examination of the oviduct on D70) of the report 04.0060.R.

These data were reviewed by the quality assurance, as described on page 4 of the document which ensures that

all the observations made are reported. Even if available (in French), it seems to the applicant there is no additional

value to provide the raw data.

For clarification, the incidents recorded in the group vaccinated with the vaccine strain (G1, n=110 birds) are

recalled hereafter:

- Between D7 and D18: 4 deaths without clinical signs or specific lesions at necropsy.

- Between D8 and D30:

5 birds in poor general condition (weakness) among which 1 bird died.

4 birds in poor general condition (weakness) and showing diarrhoea among which 1 was

euthanased for ethical reason.

Globally, 6 birds died among the 110 vaccinated birds (5.5%), whereas 1 bird died among the 30 controls (3.3%).

The rate of death is therefore similar.

Moreover, no significant differences were detected between the 3 groups on bodyweight criterion at D70 which

confirmed that the vaccination had no impact on the general health condition of the birds. The field trial performed

on large scale also confirmed that the safety of the vaccine was satis factory.

The incidents observed in Study 04.0060.R can be explained by slightly different environmental conditions. As

described in the paragraph 2 of the Report “Study dates and locations”, groups were housed separately in different

rooms and even separate buildings.

The safety of the strain is on another hand confirmed in various studies using overdose or repeated doses. This

confirms that the condition observed in some birds of the G1 group was not related to the vaccination.

RMS comment

Concerning the number of birds per group, the RMS makes the following clarification :

Group G1 unpassaged strain G2 6th passaged strain G3 controls

Number of birds included in the trial 110 107 30

Number of deaths between day 0 and day 42 6 (5.5%) 0 1 (3.3%)

Number of males euthanised on day 42 49 56 15

Remaining females for the study 55 51 14

In the summary of the report provided by the RMS, only the remaining females (of interest for the purpose of the

trial) were indicated. However, the death of birds in the firs t weeks of the study concern all the birds included on

day 0 (including males) and therefore, the percentage of death is indeed not very different between group 1

(vaccinates) and group 3 (controls).

Therefore, the initial concern is solved .

CMS comment

No further comment.

Conclusion

Solved.



Merial Repeat-use




The applicant states that 4.9 log10 pfu/dose is closed to the maximum titre of 1 dose of VAXXITEK HVT+IBD,

which should be confirmed by the applicant by providing the highest release dose for VAXXITEK HVT+IBD.


The applicant confirms that the highest release dose of VAXXITEK HVT+IBD is 5.0 log10 PFU (Plaque Forming

Units).

RMS comment

This answer is satisfactory, because the batch of VAXXITEK used for the assessment of the safety of the

interaction is closed to the maximum titre.

CMS comment

No further comment.

Conclusion

Solved.








In the trial 04.1064.R, transient diarrhoea signs were observed in the vaccinated group (9 out of the 30 vaccinates,

distributed between D5 and D23) but also in the control group: 2 among the 30 unvaccinated birds showed

diarrhoea signs on D5. Therefore, as mentioned in the report, both groups were impacted.

As explained in question 52c, one hypothesis for these diarrhoea signs could be an expression of the sensitivity to

the environmental conditions (such as a too high air flow in the isolator) or to a non optimal food in the category of

birds used as suggested by the occurrence of the same clinical signs in some unvaccinated control birds. This

hypothesis tends to be confirmed by the results obtained in another laboratory trial involving the concomitant

administration of Vaxxitek HVT + IBD (04.1011.R) presented in part IV of the dossier. Signs of diarrhoea were

observed in one dead control bird whereas no diarrhoea signs were recorded in the vaccinated group.

In study 04.1064.R, despite these diarrhoea signs observed, the results obtained for all the parameters monitored

were similar or even better in the group vaccinated with HatchPak Avinew IB H120 and Vaxxitek than those

obtained in birds that received only HatchPak Avinew IB H120 or HatchPak IB H120:

- respiratory signs noted after vaccination were similar to those observed following the use of HatchPak IB

H120 (04.0581.R) and corresponded to common adverse effect associated to the use of IB live vaccine,

- bodyweight monitoring (7 and 28 days after vaccination) showed no statistical difference between the

vaccinated group and the non-inoculated controls except for males on D28, which correspond to better

results than those obtained after the administration of HatchPak Avinew IB H120 (04.0188.R).

Therefore, results of study 04.1064.R are confirmed and demonstrate the safety of the simultaneous administration

of HatchPak Avinew IB H120 and Vaxxitek HVT+IBD.

RMS comment

The RMS accepts that no major adverse effect is detected after the administration of HATCHPAK AVINEW IB

H120 and VAXXITEK HVT+IBD at the age of 1 day. The growth retardation detected in the males is in the opinion

of the RMS attributable to the ND component (already shown to induce growth retardation in SPF animals under

laboratory conditions).


Merial Repeat-use


As indicated in the initial report, the safety of the administration of HATCHPAK AVINEW IB H120 and VAXXITEK

HVT+IBD at the age of 1 day is considered as established, now that the point on diarrhoea is solved.

These comments concerning HATCHPAK AVINEW IB H120 also apply for HATCHPAK IB H120.

CMS comment

No further comment.

Conclusion

Solved.


Question 68 – 1st part (including ES)

Report 03.0916.R.: field safety of HATCHPAK AVINEW IB H120, compared to AVINEW and BIORAL

H120:

There was no statistical analysis of the results; the applicant should discuss why it was not planed in the

protocol and provide a statistical analysis supporting the equivalence of both groups.


Field trials regarding general condition and production parameters in avian production are exposed to the influence

of numerous zootechnical factors that may differ within the crops and that are not related to the treatment under

study (local temperatures in the house, local ventilation, accuracy of food and water supply, exposure to wind, sun

or humidity etc...). As a matter of fact, field trials have to take place in usual farming facilities, where groups are

located in different buildings even though on the same site. The vaccine used which are spread by contact, as well

with the usual equipment available; do not allow the allocation of groups within the same building according to

hazard experimental plan to avoid zootechnical bias. Therefore these trials are only a confirmation under field

conditions of experimental trials studying the safety features of the vaccine with more accuracy through statistical

comparisons with negative controls.

Because it is assumed in these field trials that statistical differences not related to the treatm ent may be

evidenced between groups, the protocol of such trials generally plans only a description and a discussion of these

observations. This was the case here.

However, the applicant conducted the following statistical analysis taking into account the questions raised after

the evaluation of the dossier: it compares the bodyweight data and results of the monitoring of clinical signs

(coughing and individual examinations) between birds vaccinated with HatchPak Avinew IB H120 and birds

vaccinated with Avinew and Bioral H120

Global examination of clinical signs (coughing)

To assess the possible statistical difference between birds vaccinated with HatchPak Avinew IB H120 (group P1)

and birds vaccinated with Avinew and Bioral H120 (group P2) on “cough” criterion, the number of birds

coughing/coughs heard during a 3-minute period was compared between both groups by a two-sided Fisher’s

exact test as follows:

- on D12, where the difference between both groups was higher and in favour of AVINEW+BIORAL H120

vaccination;

- on the whole period of monitoring (D5 to D33).

The total number of birds considered in both groups was the initial number of birds settled in each building, i.e.

22,032. The significant threshold was set at 5%.

The results of both comparisons are given in Table I.

Table I: Study 03.0916.R. Statistical comparison of group P1 (vaccinated with HatchPak Avinew IB

H120) and group P2 (vaccinated with Avinew and Bioral H120) on “cough” criterion.

Date or period Group P1 Group P2

p value of the

Fisher’s exact test

Number of birds

coughing or

coughs heard

D12 15 (0.07%) 10 (0.05%) 0.42


Merial Repeat-use


during a 3-minute

period (%)

N = 22,032 / group D5-D33 44 (0.20%) 42 (0.19%) 0.91

two-sided Fisher’s exact test.

p ≥ 0.05: the null hypothesis is accepted

The statistical analysis of the results of global examination of respiratory signs (coughing) confirmed there was no

significant difference between birds vaccinated with HatchPak Avinew IB H120 and birds vaccinated with Avinew

and Bioral H120.

Individual examination of clinical signs (nasal discharge, lacrimation, respiratory signs)

For both groups, at all the examination sessions, at most one sign was observed in the affected birds and the

maximal score was at most 1 whatever the sign considered. Taking this into account, the number of birds showing

one of the monitored clinical signs was compared between both groups by a two-sided Fisher’s exact test, on

each day of observation (D5 to D33). The significant threshold was set at 5%.

The results of each comparison are given in Table II.

Table II: Study 03.0916.R. Statistical comparison of group P1 (vaccinated with HatchPak Avinew IB

H120) and group P2 (vaccinated with Avinew and Bioral H120) on “individual clinical signs” criterion.

Date or period Group P1 Group P2

p value of the

Fisher’s exact test

Number of birds

showing one of the

monitored clinical

signs (%)

N = 50 / group

D5 1 (2%) 2 (4%) 1

D7 5 (10%) 2 (4%) 0.44

D9 6 (12%) 6 (12%) 1

D12 7 (14%) 11 (22%) 0.44

D14 9 (18%) 10 (20%) 1

D16 10 (20%) 3 (6%) 0.07

D20 0 (0%) 1 (2%) 1

D23 2 (4%) 2 (4%) 1

D26 0 (0%) 0 (0%) -

D28 0 (0%) 0 (0%) -

D30 1 (2%) 0 (0%) 1

D33 2 (4%) 1 (2%) 1

two-sided Fisher’s exact test.

p ≥ 0.05: the null hypothesis is accepted

The statistical analysis of the results of individual examinations of clinical signs confirmed there was no significant

difference between birds vaccinated with HatchPak Avinew IB H120 and birds vaccinated with Avinew and Bioral

H120 at any of the examination date.

Bodyweight

The mean individual bodyweight data recorded in birds vaccinated with HatchPak Avinew IB H120 (group P1) were

statistically compared with those obtained in birds vaccinated with Avinew and Bioral H120 (group P2). To this aim,

the growth curves were compared through pairwise comparisons of regression lines (Y=a+bX, with Y for the mean

individual bodyweight and X for the age). This comparison allowed to assess if there was a significant difference

between both slopes (b) and both intercepts (a) of the 2 lines compared. The p-values given by a Fisher’s exact

test for the comparison of these two parameters are given in Table III. The significant threshold was set at 5%. The

growth curves obtained for groups P1 and P2 are shown in Figure 1. Mean bodyweights of P1 and P2 birds and

lines fitted to these values using linear regression are shown in Figure 2.


Merial Repeat-use


0

250

500

750

1000

1250

1500

1750

2000

2250

2500

1 6 11 16 21 26 31 36 41 46 51 56 61

Age (in days)

Mean b

odyw

eig

ht

(g)

Group P1 - M713(ND) + M713(IB) at one day old

Group P2 - AVINEW + BIORAL H120 at one day old

Figure 1: Study 03.0916.R. Growth curves of groups P1 and P2.

At D49 and D58, the weighings were performed at slaughter house whereas all the other weighings were carried

out during the rearing phase.

Group

P1P2

Plot of Fitted Model

0 10 20 30 40 50 60

Age in days

0

400

800

1200

1600

2000

2400

Mean b

odyw

eig

ht

in g

Figure 2: Study 03.0916.R – Mean bodyweights of P1 and P2 birds between 1 and 58 days of age and

lines fitted to these values using linear regression.

Table III: Study 03.0916.R. Statistical comparison of mean individual bodyweight data obtained in birds

vaccinated with HatchPak Avinew IB H120 (group P1) and birds vaccinated with Avinew and Bioral H120

(group P2) by comparison of regression lines.

Intercept Slope

Estimate standard error

Group P1 -232.49 74.67 41.70 2.30

Group P2 -240.77 69.61 42.08 2.00

Comparison of regression lines

Group P1 vs. Group P2 p=0.94 p=0.90


Merial Repeat-use


Fisher F-test

p ≥ 0.05: the null hypothesis is

accepted

The statistical analysis of bodyweight data confirmed there was no significant difference between birds vaccinated

with HatchPak Avinew IB H120 and birds vaccinated with Avinew and Bioral H120.

RMS comment

The statistical analysis of the data confirm the initial assessment that no safety concern is identified from field

use, in this single trial involving a control group receiving the same vaccine strains as HATCHPAK AVINEW IB

H120.

CMS comment


Conclusion

Solved.


Report 03.0916.R.: field safety of HATCHPAK AVINEW IB H120, compared to AVINEW and BIORAL

H120:




HATCHPAK

AVINEW

9.87 LOG10 EID50/ampoule 15,000 5.7 LOG10 EID50



BIORAL H120 - 5,000 4.1 LOG10 EID50





If the vaccine had been compared to a commercial available concurrent product, the titer would even not have been

known.

In this case, the batch of AVINEW vaccine tested was not “chosen” but received at random among available

commercial batches before the beginning of the field trials (this batch was also used for ND booster in this field

trial). This batch showed a titre representative of those found in routine production and used in the field.

Its high titre is a feature of this freeze-dried vaccine and is explained by a known higher loss of titre during storage

as compared to the frozen vaccine HatchPak Avinew. A significant overage has thus to be implemented on Avinew

to insure its efficacy all along the 16 months shelf life. Incidentally, on that criterion the frozen vaccine HatchPak

Avinew will allow the delivery of less variable titers according to the duration of storage, which is an improvement

from a quality and safety point of view.

In addition, the batch of AVINEW was used in beginning of year 2004 (vaccinations on 26 February 2004: D1) while

it was produced by the end of 2002. As a matter of fact the regulatory stability study of Avinew has evidenced a

loss of 0.8 log10 EID50 over 19 months, mainly observed during the first 6 months of storage.

The titre of this batch was thus smaller than indicated on the certificate (titration performed just after producti on in

November 2002).

To conclude, it cannot be considered that there is a bias in this study.

RMS comment

The answer is satisfactory. The RMS consider that both vaccinated groups were exposed to similar amounts of

vaccine virus, thus there is no bias associated to the dose received.

CMS comment


Merial Repeat-use


No further comment.

Conclusion

Solved.



The applicant is informed that this report may only support field safety of the monovalent vaccine HATCHPAK IB

H120, as far as the birds didn’t receive either AVINEW or HATCHPAK AVINEW.


The field safety of HatchPak Avinew IB H120 at the age of one day, is supported by the trial 03.0916.R. We agree

that the document 97-54 is given as additional supportive information for HatchPak IB H120 only.

RMS comment

No further comment.

CMS comment

No further comment.

Conclusion

Solved.






As mentioned in amendment No.2 dated 17august 1998, the comparison with reference breeds data is difficult

since the flocks monitored in studies reported in document 97-54 included different commercial breeds of layers or

broiler breeder.

Moreover the difficulty was also to obtain contemporary data of the studies (dated years 1994 to 1996)

However, to provide comparison, data from different strains are given hereafter. These strains taken for references

are as follows:

- for broiler breeders: strain Cobb500 (technical data dated 1987 and 2006) and strain ISA vedette 15

(technical data dated 1981).

- for egg-table layers: strains ISA Brown and ISA White (technical data dated 2006), ISA BabcockB300

(dated 1988).

Laying curves are drawn hereafter.


Merial Repeat-use


Laying curves for egg-table layers

0

10

20

30

40

50

60

70

80

90

100

18 23 28 33 38 43 48 53 58 63 68 73 78

Age( weeks)

Eg

g p

rod

uc

tio

n (

%)

ref. Babcock B300 (1988)

ref. ISA brown (2006)

Ref. ISA White (2006)

Layers tested- report 97-54

Laying curve for broiler breeders

0

10

20

30

40

50

60

70

80

90

100

20 25 30 35 40 45 50 55 60 65

Age (weeks)

Eg

g p

rod

uc

tio

n (

%)

ref. Cobb500 breeders (1987)

ref. ISA Vedette 15 (1981)

ref. Cobb500 breeders (2006)

Broiler breeders- Report 97-54

Mortality observed during the laying period:


Merial Repeat-use


Mortality during the laying period in broiler breeder flocks

0

10

20

30

40

50

24 28 32 36 40 44 48 52 56 60 64 68

Age (weeks)

Cu

mu

lati

ve m

ort

ali

ty (

%) ref. Cobb500 breeders (1987)

according to curve

ref. ISA Vedette 15 (1981)

Broiler breeders- Report 97-54

Mortality during the laying period in egg-table layer hens

0

10

20

30

40

50

18 22 26 30 34 38 42 46 50 54 58 62 66 70

Age (weeks)

Cu

mu

lati

ve

mo

rta

lity

(%

)

ref. ISA Babcock B300 (1988)

ref. ISA brown (2006)

Ref. ISA White (2006)

Layers tested- report 97-54

For both criteria (egg production and mortality) the results obtained in studies reported in document 97-54 are in

line with those mentioned for standard reference. The results obtained in broiler breeders were slightly better than

references (good egg–production and lower mortality) contrary to the results obtained in egg-table layers (lower

egg-production and higher mortality than references). However, in this second case, the reference technical data

are not taken at the same time (2006 vs. 1994/96). These performances might have been improved between these

two dates (as observed for laying curves of Cobb 500 breeders (2006 vs 1987).

The data used for the figures are shown in the document referenced CPh/GeR/EBR.07.D190 and provided in Annex

p. 496.

RMS comment

The answer is satisfactory. This report is of a limited interest for the bivalent vaccine HATCHPAK AVINEW IB

H120 but acceptable to support the field safety of the monovalent vaccine HATCHPAK IB H120, as far as the

birds were vaccinated with BIORAL H120 (see further explanation in the initial assessment report).

CMS comment


Merial Repeat-use


No further comment.

Conclusion

Solved.



Coughing was observed till day 33. The applicant should comment on this in the context of the safety warnings,

(see comment under repeat dose safety).


No coughing were reported in the report 97-54. There may be confusion with report of safety field trial 03.0916.R.

RMS comment

Indeed, this question raised by a CMS applies probably to report 03.0916.R. The applicant has not answered. The

RMS can indicate that in report 03.0916.R, coughing was not reported at the examinations performed 28, 30 and

33 days after vaccination; last record of coughing was on day 26 (see initial dossier, vol9/12, pp.683, 697 and

698).

CMS comment

No further comment.

Conclusion

Solved.



Divergent opinion:

A CMS (n°1) considers the request for laying curves is not relevant as safety of the IB component for the

development of the reproductive tract has been demonstrated and the vaccine will be contraindicated for use in

breeders and layers.


The target species of HatchPak Avinew IBH120 is the one day old chicken. The relevant field safety is supported

by the trial 03.0916.R.

However these birds can be future layers and breeders. That is the reason why the document 97-54 was provided,

as additional supportive information for HatchPak IB H120. The laying curves can be considered as relevant criteria

in the field of the impact of the IB component for the development of the reproductive tract.

The demonstration of safety of the IB component regarding the reproductive tract has been successfully

demonstrated, in accordance with the Monograph 0442 of the European Pharmacopoeia, in the study 04.0060.R

As detailed in the answer to the question 61 and given that the intended category of birds is the one day old

chicken, the following mention in the paragraph 4.7 is proposed:

“4.7 Use during pregnancy, lactation or lay

“The vaccine is only intended for use in newly hatched chicks and is not appropriate after the age of one day. The


particular the IB strain is compliant to the specifications of the Ph.Eur. with regard to the safety for the reproductive

tract.”

RMS comment

The RMS agrees with the applicant’s proposal (see also question 61).

CMS comment

No further comment.

Conclusion


Merial Repeat-use


Solved.

Question 70 (DE)

No field trial with Hatchpak Avinew IB H 120 performed in layers is provided. The lack of these date should be

justified.


Given that the vaccine is intended for one day old chickens only, there are no reasons to perform a field trial in

layers. These field trials should be performed with the vaccines proposed to be used as booster at a later age. As

a matter of fact, one day old layers are not a different category of birds than one day old broilers.

In addition, as underlined in the questions 59, 60 and 61, data on the safety on the reproductive performance have

been provided and are not indicative of a detrimental effect on the reproductive tract.

RMS comment

Acceptable (see also RMS comments to question 61).

CMS comment

No further comment.

Conclusion

Solved.

III.E. ECOTOXICITY

Question 71 (DE)









The presentation intended for HatchPak are 10,000 or 15, 000 doses. Therefore, it is very unlikely that the vaccine

will be used in backyard. In addition, the vaccine is intended for one day old chicken. At that age, birds are always

kept closed for good husbandry reasons: the environment temperature around the young chicks must be close to

32°C for the first 10 days of life to avoid early mortality, decreasing progressively afterwards. Even in “free range

conditions”, the birds are kept in closed conditions for about 4 to 5 weeks for these physiological reasons.

Moreover, both strains are used for years in the field through others vaccines, including in open conditions and no

safety issues regarding the spread to other species has been yet identified.

For instance, Merial has forwarded in March 2007 an internal report to the EFSA (European Food Safety Agency)

following a questionnaire on the routine application of Newcastle vaccination in wild species in Europe (answers

came mainly from French breeders). A summary of the available data is proposed in the following table:

Table: Use of the vaccines in field

Species vaccinated

(other birds) Number of doses Outcome

Guinea-fowl

(Numida meleagris)

Avinew (VG/GA)

100,000s doses yearly Positive: large scale use

Pheasant

(Phasianus cholchicus)

Avinew (VG/GA)

Imopest (Ulster 2C)

100,000s doses yearly for both vaccines

Positive: large scale use

Red partridge

(Alectoris rufa)

Avinew (VG/GA)

Killed combo with ND (Ulster 2C)

100,000s doses yearly for both vaccines

Positive: large scale use

Muscovy duck Killed combo with ND (Ulster 2C) Positive: large scale use


Merial Repeat-use


(Cairina moschata)

Pekin duck

(Anas platyrhynchos)

100,000s doses yearly

Given the already existing wide use in exotic species, the risk of exposure of the other species and the wide

knowledge and use of these strains, the Applicant considers that the proposed restriction to close stable would

not be relevant.

RMS comment

The RMS agrees with the applicant’s answer.

CMS comment

DE: question not solved

CMS question

DE doesn’t consider that the initial question is solved.

Day 145 question



Question 72 (UK- ES - HU)



nebulisation route because the conventional birds are not the most sensitive bi rds and this field trial compared

2 groups both vaccinated by nebulisation. It is agreed that using the oculo-nasal route is appropriate to control

as much as possible the dose received by each bird. However, by nebulisation, the vaccine may penetrate

more deeply in the respiratory tract and may cause a different safety profile. The applicant should thus justify

why the safety of the nebulisation was not confirmed in laboratory trials.


route:

- The CMS n°1 requests that an overdose safety study using the spray (nebulisation) route is provided

with bivalent product to meet Ph.Eur. requirements and to support the other safety data provided where

vaccination was not carried out by the recommended route.

- The CMS n°1 considers that if the overdose safety study by the spray (nebulisation) route, as required

for the Hatchpak Avinew IB H120 is carried out, it will be sufficient to support this requirement for

Hatchpak IB H120.



acceptable the ocular and nasal route to assure the amount of vaccine virus given to each animal,

taken into consideration that nebulization allows the virus to get to the animal by more routes and

deeper, it would be advisable to perform at least one laboratory safety study using the nebulization

route.


laboratory trials.


Regarding the RMS and CMS n° 4 comments, it is not exact to say that the nebulisation would allow the product

to penetrate the vaccine may penetrate more deeply in the respiratory tract and may cause a different safety

profile. A coarse spray is to be used and not a fine one.

It is generally recognized that the size of the micro-droplets that could reach the trachea should be inferior to 10

µm and to obtain a deep pulmonary deposition of the product, the size should be inferior to 5 µm (although in one

day old birds, mouth breathing allows a higher but still limited proportion of 10-20µm particles to reach air sacs as

mentioned in Corbanie et al. Avian path, 35(6), 475-485, Fig7, enclosed in Annex p. 504).

As the device recommended for the administration of the vaccine is a coarse spray, (please, refer to the question

78 b), there is no chance that the product penetrates deeply in the lungs.


Merial Repeat-use


However, as explained in the questions 54 and 57, Merial agrees that the safety of an overdose of the combined

product may not have been adequately addressed and commits itself to perform the study by the spray route as

required and to provide the results for D170 (15th of June 2007).

RMS comment







RMS question






SPC is postponed until the new overdose trial is available.

CMS question

ES : Unacceptable response. We totally support the RMS comment and consider the need to receive the results

of the study before a conclusion can be drawn. The study should have been done before the procedure was

started and in any case before it was restarted.

DE: It is strange that the RMS has accepted the restart of the procedure before all data could be provided. This is

not acceptable. No decision on the safety of the product will be possible before these data are available.

Day 145 question


FR: The performance of an overdose dose study using the spray route (normal route of vaccination not studied

under laboratory conditions) is welcome, but it is however surprising that the procedure was re-started prior the

data are available for assessment.








IV. Efficacy

Question 73 – 1st part (DE)

The applicant should identify the stabilisers used in the vaccine batches/preparation which were used in the

efficacy tests.


All efficacy studies were performed with the ND strain produced with the 44 stabiliser and IB strain produced with

the 26 stabiliser. The modification of the stabilisers as described in the question 30 does not impact the clinical

results obtained. As explained in question 35 and 37, HatchPak range is a live vaccine range. The safety and

efficacy being mainly linked with the content of live virus (inoculated titers). The development study results are

therefore fully relevant. It must be noted that in both case it is protein hydrolysate (peptone from ‘meat and casein’


Merial Repeat-use


or ‘casein’ alone) and put in the exact same quantity (to minimise differences) and will be processed after injection

through the same metabolic pathway. The behaviour of product produced with the new stabiliser has been

demonstrated through comparative analysis (result described in part II.A.3 development pharmaceut ics). Quality

(see questions 35 and 37) and stability (see questions 35 and 37) are similar demonstrating absence of impact (it

may be noted that this change was approved through recent mutual recognition procedure for Avinew, freeze-dried

product, No. FR/V/0123/001/II/03 ended on July 4th, 2006).

RMS comment

Taking into account the limited differences between the “old” and “new” stabilisers, and tak ing into account that

this is a live vaccine, it is agreed that the safety is mainly linked to the vaccine viruses (and not the stabiliser) and

the trials performed with vaccines containing the “old” stabiliser are thus relevant.

CMS comment


Conclusion

Solved.

Question 73 – 2nd part (DE)





Although not really required by the Notice to Applicants, the summaries are additionally proposed by the applicant

for the convenience of the reader to better show the key elements of the dossier. We take the remark into account

for newt dossier.

RMS comment

No further comment.

CMS comment


Conclusion

Solved.




For the record:

Report 04.1011.R only documents the serological response after vaccination of conventional broilers with

maternally derived antibodies for the duration of rearing of broiler chickens. It’s however difficult to conclude, that

there is no incompatibility between VAXXITEK and HATCHPAK AVINEW IB H120, as far as there were no groups

of birds receiving only 1 of the 2 vaccines, in order to compare the serological response of birds receiving the 2

vaccines with birds receiving only 1 of them. Also, it’s not possible to conclude from this trial on the duration of

immunity as far as no protective serological titre is defined.


The study 04.1011.R was mainly conducted for vaccinating, rearing of the birds and serology monitoring.

Regarding the ND and IB strains, the duration of immunity and compatibility between the vaccines were therefore

more particularly studied through the different ND and IB challenge tests carried out on birds, reared in this

previous experimental part related in the report 04.1011.R, as shown in the following table:


Merial Repeat-use


Study reference Objective Challenge Results of challenge

04.0509.R* Impact of concomitant

administration of

Vaxxitek HVT + IBD on

HatchPak Avinew

IBH120 efficacy

IB at 22 days 90% in vaccinated birds

04.0512.R IB at 42 days 95% in vaccinated birds

04.1012.R ND at 21 days 90% in vaccinated birds

04.0508.R* ND at 42 days 100% in vaccinated birds

All challenges provided satisfactory results, thus confirming the absence of impact of a concomittent

administration of Vaxxitek HVT+IBD with both components of HatchPak Avinew IB H120.

Regarding the IBD component, the serology monitoring in the study 04.1011.R allows to confirm the condition of

the study (vaccine take or not) but is also indicative of the duration of immunity. A direct correlation between the

anti-IBDV antibody level (seroneutralising antibodies) and protection against IBDV challenge is known from the

literature (refer to the article of PD Lukert and YM Saif, enclosed in Annex p.518.)

In the study 04.1011.R, there is a clear seroconversion between the vaccinated and control birds regarding IBD

strain, as shown in the following table:

D0 D21 D28 D35 D42 D56

G0 (controls at D0) 4.2 - - - - -

G1 (vaccinated) - 1.9 1.70 1.70 2.1 2.2

G2 (Controls) - 2.3 1.70 < 1.2 0.8 <0.7 Titre expressed in log10

To complete this picture, a further study referenced 06.0349.R monitoring the compatibility between HatchPak

Avinew IBH120 and Vaxxitek HVT+IBD, (enclosed in Annex p. 522) has been performed since and included an IBD

challenge at day 14. It confirmed the lack of impact of the concomitant vaccination of Vaxxitek and HatchPak

Avinew IB H120.

The summary of this study is proposed below:

This study aimed at studying the compatibility of the concomitant administrations of vaccines M713(ND),

M713(IB) and RMB 533 in one day-old SPF chickens, particularly regarding the protection provided by vaccine

RMB 533 against a Gumboro disease (IBD) challenge.

M713(ND) is a frozen live vaccine against Newcastle disease (ND), containing the strain VG/GA.

M713(IB) is a frozen live vaccine against avian Infectious Bronchitis (IB), containing the strain H120.

RMB 533 is a frozen live recombinant vaccine against Infectious Bursal Disease (IBD or Gumboro disease) and

Marek’s Disease, containing a HVT vector expressing the VP2 gene of IBD virus. This vaccine is also called

“Vaxxitek HVT+ IBD”.

The vaccines were administered according to one of the recommended route for each of these products:

M713(ND) and M713(IB) were administered simultaneously using a nebuliser, at one commercial dose of each

vaccine per bird. RMB 533 was administered subcutaneously in the thigh of each bird at low dose (3.0 log10 PFU)

per bird.

On Day 0 of the study (D0), 85 one day-old SPF chicks were split into four groups (G0, G1, G2 and G3) as

defined in the following Table:

Group Number of birds

at setting-up (D0) Treatment

G0 5 Serological controls, bled and euthanased on D0

G1 30 Vaccination w ith RMB 533 on D0

G2 20 Simultaneous administration of vaccines M713(ND) and M713(IB) by spray on D0

G3 30 Concomitant vaccination w ith RMB 533 and w ith vaccines M713(ND) and M713(IB) on D0


Merial Repeat-use


On D14, 20 birds in each group G1 and G3 (vaccinated with RMB 533) and 10 birds in G2 were randomly chosen

and were challenged with virulent IBDV strain Faragher. These birds formed the sub-groups E (G1E, G2E and

G3E). The remaining birds in each group were kept as unchallenged controls and formed the subgroups T (G1T,

G2T and G3T) from this date (D14).

Challenged birds were observed during 10 days after challenge (i.e. until D24). Any sick and/or dead birds were

noted. Any dead bird was necropsied to look for IBD lesions (haemorrhages on breast and leg muscles and

macroscopic appearance of the bursa of Fabricius (BF)).

At the end of the post-challenge observation period (D24), all the surviving challenged birds (subgroups E) and 3

chickens from each subgroup T were euthanased and necropsied.

Particular attention was paid to IBD gross lesions. The birds from subgroups T (unchallenged birds) served as

controls for normal size and appearance of the bursa of Fabricius.

During this final necropsy, the bursa of each euthanased bird was sampled for histology.

Blood samplings were carried out on D0 on G0 chicks and on D28 on all remaining birds in subgroups T, to look

for the antibodies against IB, ND and IBD in individual sera.

The serology data validated the conditions of the study: absence of maternally -derived antibodies on D0 and

serological conversions in G1, G2, and G3 birds coherent with vaccine treatment of each group.

All the birds of G2E (not vaccinated with RMB 533) were affected, which validated the challenge performed and

indicated that it was highly severe.

There was 100% protection (no morbidity or mortality) after challenge in the groups vaccinated with RMB 533 (G1

and G3), this level exceeding the 90% protection threshold required by the Ph.Eur. Monograph.

In the conditions of the study, a low dose of RMB 533 gave very good and similar protection against a challenge

with vvIBDV, when it was administered alone or when it was administered concomitantly with M713(IB) and

M713(ND) vaccines. These results showed the compatibility of these 3 vaccines regarding the efficacy of

RMB 533 vaccine against Gumboro disease (IBD).

The lack of impact of the concomitant administration of HatchPak Avinew IBH120 with Vaxxitek HVT+IBD

regarding the Gumboro strain is therefore fully demonstrated.

Finally, the efficacy of VAXXITEK HVT IBD against IBD can be considered as a good indicator of its efficacy

against Marek’s disease. As a matter of fact, there is only one component in this vaccine which is an HVT virus

expressing an IBD antigen. The protection elicited by the correct expression of this IBD antigen is thus a

demonstration of the expected development of the HVT virus, which also bears the efficacy against MD.

Moreover, the potency test against Marek’s disease (MD) includes 30 control birds challenged and kept for a long

period (70 days) suffering the disease as the clinical expression is slow and lengthy (and early euthanasia would

compromise the test conclusion). Adding this test was considered un-ethical as strong indications were already

present that there no interference is expected.

Therefore, the compatibility of both vaccines regarding all the strains involved in these vaccines can be considered

as demonstrated.

RMS comment

With regard to the duration of immunity

The demonstration of the duration of immunity was performed by challenges against ND and IB 6 weeks after

vaccination. Currently the claim for the duration of immunity after a single administration is 6 weeks. Therefore,

the claim is demonstrated and the question for the duration of immunity is solved.

With regard to the interaction of VAXXITEK HVT+IBD with HATCHPAK AVINEW IB H120:

The new study (06.0349.R) modifies the initial position with regard to the efficacy of the association of HATCHPAK

AVINEW IB H120 with VAXXITEK HVT+IBD.

The RMS has studied the report 06.0349.R and has no correction to add to the summary provided above by the

applicant (in particular, the RMS confirms that a low dose of VAXXITEK HVT+IBD was used). The RMS agrees

with the applicant that if the efficacy of the IBD component (IBD antigen expressed by an HVT virus) is

demonstrated, there is no reason that the efficacy of the vector virus (HVT component) is impaired.

The report 06.0349.R thus demonstrates that HATCHPAK AVINEW IB H120 has no detrimental effect on the

efficacy of VAXXITEK HVT+IBD.


Merial Repeat-use


The reports 04.0508.R and 04.0512.R provided in the initial dossier have already demonstrated that VAX XITEK

HVT+IBD has no detrimental effect on the efficacy to a respectively a ND and an IB challenge when birds are

vaccinated with VAXXITEK HVT+IBD and HATCHPAK AVINEW IB H120 at the age of one day.

The report 04.1064.R provided in the initial dossier has established the safety of the association.

Therefore, the RMS is now ready to accept the compatibility statement in section 4.8. of the SPC (see question

14):

“No information is available on the safety and the efficacy from the concurrent use of this vaccine with any other

except with MERIAL recombinant HVT expressing the protective antigen of the Infectious Bursal disease virus. It is

therefore recommended that no other vaccines than this should be administered within 14 days before or after

vaccination with the product.”

CMS comment

No further comment.

Conclusion

Solved.


For the record:



vaccines.


The report 04.0508.R only demonstrated that there are no impacts on the efficacy of the HatchPak vaccine

regarding the Newcastle strain, as shown in the table of the question 74a.

As explained below, two other studies have monitored the impact of HatchPak Avinew IB H120 on Vaxxitek

HVT+IBD, as reported in the following table:

Study reference Objective: Challenge strains

04.1011.R Impact of HatchPak Avinew

IBH120 on Vaxxitek HVT + IBD

efficacy

Serological follow-up only

06.0349.R IBD at 14 days

Both studies provide clear indications (seroconversion and 100% of resistance to the challenge among the

vaccinated) that the concomitant administration of both vaccines does not have a detrimental effect on the IBD and

thus HVT component of the Vaxxitek HVT+IDB vaccine.

RMS comment

Agreed (see comment under question 74 –1st part).

CMS comment

No further comment.

Conclusion

Solved.


For the record:



vaccines.



Merial Repeat-use


The report 04.0512.R demonstrated that the concomitant administration of Vaxxitek HVT+IBD and HatchPak

Avinew IB H120 have no impacts on the efficacy of the HatchPak vaccine regarding the Infectious Bronchitis strain

as shown in the table of the question 74a.

As reported in the previous questions, the absence of effect regarding the Vaxxitek HVT+IBD strains when

administered simultaneously with HatchPak Avinew IB H120 is demonstrated in the study referenced 04.1011.R

provided on page 112 of the part IV and further in a more recent study 06.0349.R enclosed in Annex p. 522.

RMS comment

Agreed (see comment under question 74 –1st part).

CMS comment

No further comment.

Conclusion

Solved.


Question 75

The applicant should confirm that the levels of MDA observed in the trial birds is reflective of the range observed in

the field.


As explained in the previous question 74, the studies 04.1012.R, 04.0508.R, 04.0509.R and 04.0512.R, provided in

the dossier under the part "Influence of the maternal Derived Antibodies", are the continuation of the initial study

04.1011.R (Duration of immunity in conventional broilers) enclosed in Part IV page 112.

The level of the maternally derived antibody observed in this study 04.1011.R was as follows:

- ND HI titres on D0: mean HI titre = 6.3 log2 (with standard deviation = 1.06)

- IB SN titres on D0: mean SN titre= 2.1 log 10 (with standard deviation = 0.32)

These values were compared to all the antibodies titres measured at D0 in day old chicks during the development

of HatchPak ND and HatchPak IB vaccines from 2004 to 2005. In addition, new analyses were conducted in sera

collected recently in 2007 in day old broilers from 3 different hatcheries (named A, B and C hereafter). All these

results have been analysed and are reflected in the graphs below, for which a legend table is provided. The new

data from 2007 are quoted as field sera (n° serie 9, 10 and 11) in the table.

Ref. final report Farm/building No.serie

03.0913.R Farm 1/P1 1

03.0913.R Farm 1/P2 2

03.0913.R Farm 2/P1 3

03.0913.R Farm 2/P2 4

03.0916.R Farm 1/1 5

04.0939.R Farm 1/P3 6

04.0939.R Farm 2/P1 7

04.1011.R Merial CRSV/204 8

Field sera Hatchery A 9

Field sera Hatchery B 10

Field sera Hatchery C 11


Merial Repeat-use


TABLE OF THE CORRESPONDENCE BETWEEN SERIES SHOWN IN THE GRAPHS

AND ORIGIN OF THE SERA CONCERNED.

Box-and-Whisker Plot

HIT

ND

(lo

g 2

)

Serie

1 2 3 4 5 6 7 8 9 10 11

4

5

6

7

8

9

8

Graph 1: Comparison of the MDA level between the field data and the HatchPak 04.1011.R for ND strain

Box-and-Whisker Plot

SN

BI

(log10)

Serie

1 2 3 4 5 6 7 8 9 10 11

1

1.4

1.8

2.2

2.6

3

8

Graph 2: Comparison of the MDA level between the field data and the HatchPak 04.1011.R for IB strain

These results show:

The antibody titre observed in study 04.1011.R (serie n°8) are completely representative of the levels of

maternal antibodies that may be observed in day old broilers for the 2 concerned disease (Newcastle disease

and Infectious Bronchitis), both in term of mean value or scattering.

In particular these levels of maternal antibodies are in the range of those observed in field trials:

- range for ND HI titres on D1: mean HI titre = 5.33 log2 (03.0913.R - farm2) to 6.7 log2 (04.0939.R – farm2)

- range for IB SN titres on D1: mean SN titre = 1.6 log10 (03.0913.R – farm1) to 2.2 log10 (03.0916.R*)

(* field safety trial for which a control of the serological level of MDA has been performed)

RMS comment

Satisfactory.


Merial Repeat-use


CMS comment

No further comment.

Conclusion

Solved.

OVERALL CONCLUSION ON THE LABORATORY TRIALS



The applicant should justify why the compliance of the combined vaccine HATCHPAK AVINEW IB H120 to the

Potency test of the Ph. Eur. monographs 442 and 450 was not demonstrated; currently, this is established only for

the monovalent vaccines HATCHPAK AVINEW and HATCHPAK IB H120. CMS n°6 states that this Potency test

is necessary.


The potency tests according to Ph.Eur. requirements were established for each monovalent vaccines HatchPak

AVINEW (monograph 442) and HatchPak IB H120 (monograph 450) in the studies 03.0641.R and 04.0989.R as

each of these vaccines, once registered, are intended to be used either alone or in association.

The efficacy of the association of both vaccines (as HatchPak AVINEW IB H120) was studied in conventional

broilers and conditions of challenge tests reported in documents 04.1012.R (ND challenge 21 days after

vaccination) and 04.0509.R (IB challenge 22 days after vaccination) were very close to the requirements of Ph.Eur.

monographs (see comparison in document CPh/GeR/EBR.07.D184 enclosed in Annex p. 558).

Indeed there were very few differences with Ph.Eur. Requirements for potency test and these differences are quite

negligible:

- Origin / Status of the birds: Conventional instead of SPF. The efficacy tests in conventional broilers should

be more severe than potency in SPF birds' conditions taking into account interference of maternal

antibodies. It is underlined that unvaccinated SPF controls were however available, demonstrating the

sufficient severity of the various challenges.

- Delay and route of challenge for IB challenge (see 04.0509.R): the challenge was performed at 22 days

instead of 21 days after vaccination and the virulent IB strain was inoculated by intratracheal route instead

of eye-drop. The deviation regarding the date of challenge (1 day later) is negligible. For the route of

inoculation of the challenge strain, the tracheal route may be more severe than ocular route as the virus is

directly inoculated at the site of the infection and, whenever it is not the required route, the challenge was

anyway validated as regard to the re-isolation rate in unvaccinated controls. The intratracheal route of

challenge was also recommended in previous versions of the Ph Eur 442 (1990)

- Rate of affected birds in unvaccinated controls after ND challenge (04.1012.R): there were only 60 % of

affected birds in unvaccinated conventional controls. However the challenge induced 100% of mortality

within 3 days after challenge in the unvaccinated SPF controls, which indicates the severity of the

challenge and is in compliance with the requirement of Ph.Eur. Moreover the protection obtained in the

vaccinates was in compliance with the minimum threshold required in the Ph.Eur. monograph (90%) and

was statistically significant as compared to the unvaccinated conventional controls (Chi-square test on

number of protected/ affected birds in G1 and G2, p-value = 0.01 with Yates’correction).

Consequently, European Pharmacopoeia criteria were followed for both strains when associated, as well as for

monovalent vaccines. When some slight deviations are observed, they lead to more severe conditions than

required. According to the position paper on Compliance with veterinary vaccine monographs of the European

Pharmacopoeia (EMEA/CVMP/140/97-FINAL, page 3, enclosed in Annex p. 563), there is therefore no need to

perform again the potency test on the combined vaccine.

RMS comment

Taking into account the different laboratory and field trials available, the RMS shares the applicant’s conclusion

that there is no need to perform a new Potency test according to the Ph. Eur. for the combined vaccine.

The data available from reports 04.1012.R and 04.0509.R give the insurance of the efficacy of the combined

vaccine to an IB and a ND challenge. These studies were performed in conventional birds instead of SPC ones,

which in the opinion of the RMS induce 2 bias:


Merial Repeat-use


- 1 bias in favour of the vaccine: indeed, the conventional birds have remaining maternally derived

antibodies which reduces their susceptibility to a challenge. However, the severity of the challenge is

confirmed by the morbidity in SPF controls and the difference of protection between conventional

vaccinated and conventional unvaccinated birds, which is high and significant for both components

- 1 bias in disfavour of the vaccine: in conventional birds, the maternally derived antibodies present at

vaccination may reduce the efficacy of the protection induced by the vaccine when compared to the

protection afforded to SPF birds, and therefore reduce the ability to reach the high level of protection set

in Ph. Eur. monographs for SPF birds

The RMS doesn’t consider that the very small difference in delay between vaccination and challenge (only for the

IB challenge), and the route of challenge are susceptible to impair the relevance of these trials.

CMS comment


DE: No further comment

Conclusion

Solved.

Question 77
















Comment as to whether it is considered that the recombinant vaccine VAXXITEK HVT+IBD caused an increase in

efficacy for Hatchpak Avinew IB H120.


As explained in questions 74, the applicant considers that based on the studies provided and the knowledge of the

products, sufficient data are provided to demonstrate the compatibility of HatchPak Avinew IB H120 with Vaxxitek

HVT+IDB.

Regarding the CMS n°1 comment, this compatibility is reciprocal for both products as the data listed in the

following table demonstrated that the protection is ensured for both vaccines, whatever the disease:

Study reference Objective Challenge Results

04.0509.R Impact of concomitant

administration of Vaxxitek

HVT + IBD on HatchPak

Avinew IBH120 efficacy

IB at 22 days 90% in vaccinated birds

04.0512.R IB at 42 days 95% in vaccinated birds




Merial Repeat-use


04.1011.R Impact of concomitant

administration of HatchPak

Avinew IBH120 on

Vaxxitek HVT + IBD

efficacy

Serological follow-up

only Seroconversion obtained

06.0349.R IBD at 14 days 100% in vaccinated birds

As explained in the question 74, the efficacy of RMB 533 (Vaxxitek HVT+IDB) against IBD is fully representative of

its efficacy against Marek’s disease, given that there is only one component in this vaccine which is an HVT virus

expressing an IBD antigen. The protection elicited by the correct expression of this IB D antigen is thus a

demonstration of the expected development of the HVT virus, which also bears the efficacy against MD.

Therefore, the reciprocal compatibility of Vaxxitek HVT + IDB and HatchPak Avinew IB H120 is demonstrated for

all strains of both vaccines.

Regarding the CMS n°6, several studies with the HatchPak Avinew IB H120 alone used as intended are provided in

the efficacy part of the dossier. The references of these studies are recalled in the table hereafter:

Trial reference Number of animals involved Type of trial

03.0775.R 118 SPF chickens Laboratory – IB challenge on D28

03.0913.R 85,680 conventional chickens Field trial – Serological follow-up

04.0939.R 44,164 conventional chickens Field trial – Serological follow-up

03.0914.R 100 conventional chickens - 20 SPF

chickens

Field trial – Challenge against ND 3 or 4

weeks further vaccination


chickens

Field trial – Challenge against ND 3 or 4

weeks further vaccination


chickens

Field trial – Challenge against IB 4 weeks

further vaccination

Table 1: Reference of the clinical studies performed with HatchPak Avinew IB H120 used

alone These studies performed with the product alone and involving more than 130 000 animals are completed by those

concerning HatchPak Avinew or HatchPak IBH120 used alone and by those concerning the product used with

other vaccines. Therefore, the applicant considers that a sufficient amount of data is provided to assess the

efficacy of the vaccine.

Regarding the comment of the CMS n°7, there are no indications that the recombinant vaccine Vaxxitek HVT+IBD

could cause an increase in efficacy for any of the components present in HatchPak Avinew IB H120. As a matter

of fact, routes of administration are different (injection vs coarse spray), all components are distinct (HVT +

Infectious Bursal Disease insert vs Newcastle and Infectious Bronchitis vaccinal strains), target cells for vaccine

growth as well (Peripheral blood lymphocytes vs epithelial cells of respiratory or digestive tract). Moreover, the rate

of protection required for ND and IB strains alone being respectively 90 % and 80% at least in SPF birds, it is not

very easy to detect whether the Vaxxitek HVT+IBD vaccination could enhance these already high results. In

addition, it is known, as underlined in question 83 p.92; that antibodies titres do not correlate with the protection

level against ND and IB. Therefore, the use of serological results is not relevant to answer this point.

Nevertheless, the following table provides comparison of the challenge results obtained after HatchPak Avinew IB

H120 vaccination, administrated with or without Vaxxitek HVT+IBD

Study

reference

Type of

chickens

Vaccination

titre

Challenge

dose per

bird

Date of

challenge /

vaccination

% of protection

ND (log10 EID50) (log10 LD50)

03.0641.R SPF 5.5 5.3 3 weeks 100

04.0508.R* Conventional 5.5 5.0 6 weeks 100

04.1012.R* Conventional 5.5 5 3 weeks 90

03.0914.R Conventional Commercial

dose 5 3 to 4 weeks

65 & 85 % for field reared

chickens, 100% for Merial reared


Merial Repeat-use


chickens


dose 5

3 weeks 83 % for field reared chickens, 80%

for Merial reared chickens

4 weeks

43 % for field reared chickens

without ND booster, 90 % for field

reared chickens with ND booster &

80% for Merial reared chickens

IB (log10 EID50) (log10 EID50)

03.0775.R SPF G1: 3.7

G2: 4.1 3 4 weeks

G1: 83..3

G2: 100

04.0989.R SPF 3.7 3.3 3 weeks 90




dose 3.3 4 weeks

85 % for field reared chickens in

Farm 1 (non validated challenge),

90 % for field reared chickens in

Farm 2 and 90% for Merial reared

chickens

* in this study, simultaneous administration of Vaxxitek HVT+IDB

In all studies, the challenges were validated except one in the 03.0915.R because of a passage of wild infectious

bronchitis in the field. The conditions of the challenge were equivalent in all studies: same severity (similar dose of

challenge strain inoculated), similar titre of vaccination. The results are coherent and satisfactory between all

studies.

Therefore, the applicant considers that the compatibility with Vaxxitek HVT+IDB has been fully demonstrated and

this mention could be kept in the SmPC.

RMS comment

The RMS is now ready to accept the compatibility statement claimed in the SPC (see question 74 – 1st part).

CMS comment

IE (n°7): The applicant’s response is acceptable.

DE (n°6): Based on the currently provided data, the concurrent use of Vaxxitek HVT+IBD is not acceptable. No

data on the efficacy against Marek infections is presented. The conclusion that protection against IBD

automatically assures protection against MD is not acceptable.

Moreover, no controlled trials with Hatchpak Avinew IB H 120 and Hatchpak IB H 120 alone are provided.

Therefore the assessment of the efficacy of Hatchpak Avinew IB H 120 and Hatchpak IB H 120 themselves is not

possible.

Day 145 question

DE: Based on the currently provided data, the concurrent use of Vaxxitek HVT+IBD is not acceptable. No data on

the efficacy against Marek infections is presented. The conclusion that protection against IBD automatically

assures protection against MD is not acceptable.

Moreover, no controlled trials with Hatchpak Avinew IB H 120 and Hatchpak IB H 120 alone are provided. Therefore

the assessment of the efficacy of Hatchpak Avinew IB H 120 and Hatchpak IB H 120 themselves is not possible.


METHOD OF VACCINATION All efficacy trials with spray vaccination were done with spring water diluted vaccine, and in the SPC for







Merial Repeat-use



In order to cover the field situation and be consistent with the wording used in the Summary of Product

Characteristics of Avinew freeze-dried vaccine, Merial proposes to use the wording "non-chlorinated drink ing

water".

RMS comment

Acceptable. See also question 15 (SPC).

CMS comment

No further comment.

Conclusion

Solved.

Question 78 –2nd part

METHOD OF VACCINATION It should be clarified what particular size can be used in the coarse spray. SPC should be changed accordingly.


The size of the coarse spray is variable, depending on the device used. The technical documentation of the devices

is not always precise enough to be able to give a valuable range of the droplets sizes. As mentioned in the

Corbanie publication (see question 72), coarse spray have by definition size of droplets that does not allows to

reach the deep airways, whereas inhalable aerosol target them. Therefore, the wording of coarse spray is

considered to be precise enough.

Merial proposes to keep the following sentences for the § 4.9.3 Method of administration

- "The vaccine is intended for mass vaccination of chicks in the hatchery, the vaccine solution should be

applied as a coarse spray whilst the chicks are in their chick boxes.

- For effective vaccine distribution, make sure that birds are closely confined together during spraying."

RMS comment

The RMS accepts the argument of the applicant.

CMS comment

No further comment.

Conclusion

Solved.

Question 79

ONSET OF IMMUNITY Request from CMS n°1:

The CMS considers that onset of immunity has not been established for the ND component of the vaccine when

administered as per the vaccination schedule. Study 04.1012.R using conventional birds provides some additional

information but the difference in the level of protection between vaccinates and un-vaccinated birds means it is not

sufficient to support a claim for an onset of immunity of 3 week for the ND component. The applicant should

address this lack of onset data for the ND component.


The proposed onset of immunity for the ND component is based on the results of the different studies that have

been performed during the development of the vaccines.

The list of these studies is provided in the following table, with the results of the challenge:

Trial

reference Vaccine used Challenge condition Results

03.0641.R HatchPak Avinew 23 SPF birds challenged at 21 100% of protection in


Merial Repeat-use


days vaccinated birds

04.1012.R

Vaxxitek HVT + IBD

& HatchPak Avinew

IBH120

20 conventional birds challenged

at 21 days

90% of protection in vaccinated

birds

04.0508.R

Vaxxitek HVT + IBD

& HatchPak Avinew

IBH120

40 conventional birds challenged

at 42 days

100% of protection in

vaccinated birds

03.0914.R HatchPak Avinew IB H120

100 conventional chickens & 20

SPF chickens(controls)

challenged at 21 or 28 days

Merial reared field birds: 100%

Field reared birds: from 65 to

85% (significant difference with

unvaccinated animals)

04.0940.R HatchPak Avinew IB H120

240 conventional chickens &

40 SPF chickens (controls)

challenged at 21 or 28 days

Merial reared field birds: 80%

Field reared birds: from 43 to

83% (significant difference with

unvaccinated animals)

This table shows that at D21, a significant protection has been observed for the ND component, either used alone

with HatchPak Avinew, or mixed with HatchPak IB H120 and even with the concomitant administration of Vaxxitek

HVT+IBD, and this in the laboratories trials as well as in the field.

To focus on the results of the report 04.1012.R that is questioned, 90 % of protection was obtained (18 protected

birds out of 20 challenged) in vaccinates and only 40% (4 protected birds out of 10 challenged) in unvaccinated

conventional control birds. The SPF birds all died within 6 days following the challenge, as required by the

Monograph 0450 of the Eur. Pharmacopoeia.

The protection obtained in the vaccinated was in compliance with the threshold required by the Ph.Eur. (at least

90% protection in vaccinates).

Moreover, statistical Chi-square test showed that there was a statistically significant difference between the

number of protected birds in each group (p-value = 0.013 with Yates’correction).

The vaccine HatchPak Avinew IB H120 induced a satisfactory and statistically significant protection against a

Newcastle disease challenge 21 days after vaccination of one day-old conventional broiler chickens, even when

administered with another vaccine (here Vaxxitek HVT+IDB). As demonstrated in the question 77, there is no

impact of this concomitant administration of both vaccines and in particular, no increase of the efficacy of

HatchPak Avinew IB H120 vaccine. Therefore, this report can be used to validate the onset of immunity requested.

The onset of immunity is thus confirmed at 21 days after vaccination for the ND component.

RMS comment

Satisfactory.

CMS comment

No further comment.

Conclusion

Solved.

IV.D. FIELD TRIALS




The applicant should confirm that the vaccinates received a dose of vaccine close to the minimum titre claimed,

with regard to the ND component.


According to the table below, the birds received 5.6 or 5.7 log10 EID50 of vaccine HatchPak AVINEW on D0.

These doses are very close to the minimum titre claimed (5.5 log10EID50/dose). However, it should be noted that

according to the recommendations of EMEA (ref. EMEA/CVMP/852/99 –paragraph 4.1), there is no obligation to

test the vaccine with the minimum titre in efficacy field trials, provided the efficacy has been demonstrated in the

laboratories studies at the minimum dose.


Merial Repeat-use


Calculation of the dose of HatchPak Avinew vaccine administered in study reported in 03.0914.R

Ref. Batch Titre of the container Nb doses/container Titre/dose

Farm 1 3AWF7P15A 9.87 LOG10 EID50/ampoule 15,000 5.7 LOG10 EID50

Farm 2 3AWF7S17A 9.81 LOG10 EID50/ampoule 15,000 5.6 LOG10 EID50

RMS comment

Satisfactory.

CMS comment

No further comment.

Conclusion

Solved.




In study ref 03.0914.R ND challenge was given at 23 and 28 days; of the birds reared in the field only 65%

conferred protection at 23 days challenge and 85% at 28 days. This would not be supportive of 21 days onset of

immunity in the field, based on this study the onset of immunity should be 28 days in the field. The applicant is

asked to provide a comment.


All the results of ND challenge in conventional broiler chickens after vaccination with HatchPak AVINEW and

HatchPak IB H120 are detailed in document Protection percentage against Newcastle Disease challenge after

vaccination with M713 (ND) and M713 (IB) in one-day old conventional broilers referenced CPh/GeR/EBR.07.D189

in Annex p.567.

The report 03.0914.R showed there was only 65% conferred protection against ND challenge at 23 days in birds

vaccinated and reared in the farm 1, but there were 85% conferred protection against ND challenge at 28 days in

vaccinates reared in farm 2 and 100% protection in birds from the same origins (farms 1 and 2) and ages (23 and

28 days respectively) reared in Merial facilities. As mentioned in the report, this lesser protection observed in birds

reared in the field are a consequence of stress or concurrent infections with immunosuppressive agents of the

birds reared in field conditions, impairing the optimal expression of the potential of the vaccine in these birds as

evidenced by the full protection obtained when the birds were reared in Merial facilities. With this point of view, the

conditions in farm 2 seemed to be safer than those in farm 1 at the time of this study. The difference in protection

(65% vs. 85%) observed is related to these conditions and not an onset of immunity that would be longer than 21

days post vaccination.

In addition, this has been confirmed in further field studies such as the report 04.0940.R carried out in birds from

same origin (same hatchery and farms) but around 9 months to 1 year after than study 09.0913.R, the protection

observed after the ND challenge performed three weeks after HatchPak vaccination, in the vaccinates either reared

in Merial facilities (80%) or in field (83%) was similar and statistically significantly higher as compared to the

unvaccinated controls (40%). These results confirmed the good protection conferred three weeks after

administration of the HatchPak at the hatchery and are thus consistent with an onset of immunity at 21 days after

vaccination (as justified for question Q79), even in field conditions.

On an other hand, according to report 04.0940.R the protection against ND challenge dropped to 40-45% at four

weeks after vaccination in birds reared in the field in the conditions of this trial , whereas the vaccinated birds from

same origin but reared in a protected and well-controlled facility (Merial) showed 80 % protection. This difference

showed again the significant effect of the concurrent infection with immunosuppressive agents or stress of the

birds reared in certain field conditions.

In that context, it was shown that the ND booster vaccination of the birds at 21 days of age in the field improved

significantly the protection against the ND challenge at 4 weeks (85-95% conferred protection).


Merial Repeat-use


These data confirmed the results of the in house trial 04.1012.R where 90% protection was demonstrated 21 days

after vaccination of conventional broilers, when unvaccinated controls displayed only 40% resistance to challenge

(due to passive immunity).

The Applicant therefore maintains that a 21 days onset of immunity is supported in the field by the global analysis

of the different trials available.

RMS comment

The applicant’s explanation is shared by the RMS. The onset of immunity for the ND component should be kept at

21 days after vaccination. (initial question from IE).

CMS comment


Conclusion

Solved.

Question 81


established by a controlled ND challenge:








The batch of AVINEW vaccine tested was not “chosen” but received at random among available commercial

batches before the beginning of the field trials. This batch showed a titre representative of those found in routine

production and used in the field.

As explained in the question 68b, its high titre is a feature of this freeze-dried vaccine and is explained by a known

higher loss of titre during storage as compared to the frozen vaccine M713(ND). A significant overage has thus to

be implemented on Avinew to insure its efficacy all along the 16 months shelf life. Incidentally, on that criterion the

frozen vaccine HatchPak Avinew will allow the delivery of less variable titers according to the duration of storage,

which is an improvement from a quality and safety point of view.

In addition, the batch of AVINEW was used by in January 2005 (vaccinations on D21) while it was produced on the

05th August 2004. As a matter of fact the regulatory stability study of Avinew has evidenced a loss of 0.8 log10

EID50 over 19 months, mainly observed during the first 6 months of storage.

The titre of this batch was thus smaller than indicated on the certificate (titration performed just after production by

the end of August 2004).

According to the recommendations of EMEA in the Note for Guidance on Field Trials with Veterinary Vaccines

(EMEA/CVMP/852/99 – paragraph 4.1), there is no obligation to test the vaccine with the minimum titre in efficacy

field trials, provided the efficacy has been demonstrated in the laboratories studies at the minimum dose. This is

the case for Avinew vaccine. The data collected here remain fully reliable; they are simply representative of a field

situation.

RMS comment

Taking into account the explanation concerning the stability of AVINEW, it is considered that the dose received

was not the maximum titre.

It is not considered relevant here to make reference to the Note for Guidance on Field Trials with Veterinary

Vaccines, because this is not a field trial for confirmation of a laboratory result, as far as the efficacy of AVINEW

used as a booster at the age of 3 weeks was not studied under laboratory conditions.

However, the product under registration is HATCHPAK AVINEW IB H120 and it is not the purpose here to validate

the efficacy of AVINEW, which is a vaccine already assessed and registered.

Therefore, the RMS considers that the data available are acceptable to validate the recommendation of a boos ter

vaccination with AVINEW at the age of 3 weeks.


Merial Repeat-use


CMS comment

No further comment.

Conclusion

Solved.


Question 82 (DE

Efficacy trials on conventional chickens were performed on broiler chickens. No efficacy trial was done on

conventional layer type chicken. As the level of maternally derived antibodies decrease slower in the layer than the

broiler type chickens this may cause a delay in the onset of immunity.

Efficacy of the vaccine is not proved in layer type conventional chickens.

Use should be retricted to broiler chickens, unless additional trials in layers is provided.


The efficacy in presence of maternal antibodies has been demonstrated at the age of one day. At that age the level

of passive immunity is driven by the antibody levels in the female breeders transferred to the yolk -sac in the eggs,

and is comparable between broiler and layer type chickens, as it is along the first week of life. Indeed, during the

vitellus resorption (and when the growth speed remains comparable between these two types of birds, the

concentration of maternal antibodies in the body fluids remains comparable. Afterwards it is well known as

mentioned that the fast growing chickens (broiler types) due to their higher increase in body mass, displays a

faster decrease in their passive antibody levels than slow growing chickens (layer types) through a mechanical

dilution event. However this is unlikely to have any effect on the vaccine-take as the viral multiplication takes place

in the very first days after vaccination when maternal antibodies are at their maximal and comparable levels.

As a matter of fact the freeze dried vaccines identical to HatchPak Avinew IB H120 (Avinew and Bioral H120) are

already used in one day old layer type chickens in Europe and abroad, without observations of decreased efficacy.

There are thus no reasons to perform efficacy trials in layers.

Therefore, the proposal of the Applicant is to limit the use of the vaccine to chickens at age of one day, without

distinction of the production type.

RMS comment

This is an acceptable argumentation and proposal.

CMS comment


Conclusion

Solved.

Question 83 (DE) The various trials are difficult to compare. Concerning the serological results for both antigens, there is a significant

decline in titres from potency tests to laboratory tests to field trials. As antibody titres do not correlate directly with

the protection level against ND and IB the assessment of the overall protection is not easy. Nevertheless, the

applicant should explain the possible reasons for this decline.


All serology results are compiled in the following documents:

IB serology in conventional birds, referenced CPh/GeR/EBR.07.D192 enclosed in Annex p. 570

IB serology in SPF birds, referenced CPh/GeR/EBR.07.D193 enclosed in Annex p. 574

ND serology in conventional birds, referenced CPh/GeR/EBR.07.D194 enclosed in Annex p. 576

ND serology in SPF birds, referenced CPh/GeR/EBR.07.D195 enclosed in Annex p. 581

Decline in titres from potency tests to laboratory tests


Merial Repeat-use


The results of the following studies are compared:

Reference of the trials Title

04.1011.R Duration of immunity in conventional broilers

03.0914.R, 03.0915.R and 04.0940.R Efficacy by challenge in broilers from field trials

03.0641.R Potency test in SPF chickens regarding ND

03.00775.R and 04.0989.R Potency test in SPF chickens regarding IB

In SPF chickens the serological conversion against Newcastle was very clear and high 21 days after the

vaccination with HatchPak Avinew (03.0641.R – mean HIT titre = 6.2 log2 on D21 in vaccinates) whereas the SPF

chickens vaccinated with HatchPak IB H120 as expected did not demonstrate yet a complete serological

conversion at 21 or 28 days after the vaccination (mean SN titre <0.88 log10 on D28 in report 03.0075.R and mean

SN titre < 0.75 on D21 in 04.0989.R).

In conventional broilers vaccinated with HatchPak vaccines and reared in Merial facilities, the serological

conversion is difficult to be clearly assessed 3 to 4 weeks after vaccination taking into account the subsiding

maternally derived antibodies. The range of HI titres against Newcastle disease were 2.90 log2 (group G1 on

D21 and D28 - 04.1011.R) to 3.70 log2 (group G1/farm 2, on D19 - 04.0940.R). The range of SN titres against IB

were 0.9 log10 (group G1, on D21 - 04.1011.R) to 1.50 log10 (group G1E, on D29 – 03.0915.R).

According to these results, the serological conversion seems to be equivalent in SPF birds for IB serology. better

in SPF birds than in conventional broilers reared in laboratory conditions regarding Newcastle disease. However

the same trend is not observed for IB serology. The lower ND antibody titres observed in conventional broiler than

SPF chickens are probably due to interference of maternally antibodies. This was already mentioned in the expert

report on efficacy (conclusion on duration of immunity p7/15)

“The presence of maternally derived antibodies at the moment of vaccination, likely hampered the development of

HI antibodies, as titres obtained at 28 days post vaccination did not exceed 3.0 against ≥6.0 in the potency test.

They did not affect the development of protection against challenge infection.”

Decline in titres from efficacy test in broilers reared in laboratory conditions to field trials.

The results of the following studies are compared:

Reference of the trials Title

04.1011.R Duration of immunity in conventional broilers

03.0914.R, 03.0915.R and 04.0940.R Efficacy by challenge in broilers from field trials

03.0913..R, 03.0916.R and 04.0939.R Field trials in broiler chickens

In conventional broilers vaccinated with HatchPak vaccines and reared in the field, the range of antibody titres

observed 3 to 4 weeks after vaccination are as follows:

- Mean ND HI titres: 1.90 log2 (Farm1, on D20 – 04.0939.R) to 4.00 log2 (Farm2, on D19 – 04.0939.R)

- Mean IB SN titres: 0.43 log10 ((Farm1, on D20 – 04.0939.R) to 1.0 log10 (Farm1, on D22 – 03.0913.R).

These titres seemed to be lower but close to those observed in broilers reared in laboratory conditions, depending

of the titres in maternally derived antibodies at day-old and of the decline of this immunity.

The comparison is easier in birds from same origin and reared in the two conditions in parallel (cf. efficacy by

challenge in broiler from field trials - reports 03.0914.R, 03.0915.R and 04.0940.R):

Analysis for the ND component

Regarding antibodies against ND, results showed in reports 03.0914.R and 04.0940.R for serology at 3 or 4 weeks

after vaccination (D19/20/23 or D26/28/29) were not always in favour of vaccinates reared in Merial facilities.

For example, in the case of farm 2 of the report 03.0914.R, the ND antibody titres seemed to be slightly higher on

D28 in birds reared in the field (G2 - mean ND titre ≤ 3.20 log2 ) than in birds reared in Merial (G1 - mean ND titre ≤

2.70 log2), as underlined in the following table:

Study 03.0914.P

(Efficacy against ND

challenge in broilers

from the field efficacy

trial 03.0913.P)

Group treatment Farm 1 (D23) Farm 2 (D28)

G0

conventional

unvaccinated birds

reared in Merial

Mean titre (in log2) ≤ 2.80 ≤ 2.20

Standard deviation 0.42 0.42

G1 Mean titre (in log2) ≤ 3.00 ≤ 2.70


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conventional

HatchPak vaccinated

birds reared in Merial


G2

conventional

HatchPak vaccinated

birds reared in field



G3

SPF unvaccinated

control birds



However, the statistical analyses on the serology titres showed there was no statistically significant difference

between the results in the 2 groups (p[Kruskall –Wallis-test]= 0.26).

In the second example (report 04.0940.R), the difference between the serology levels against ND in the two groups

G1 (birds reared in Merial) and G2 (birds reared in the field) were not significant (p[Kruskall –Wallis-test] >0.05) on

D19/20 or D26/28/29 as well. Mean antibody titres are underlined in the following table:

Study 04.0940.P/report

04.0940.R (Efficacy

against ND challenge

in broilers from the

field efficacy trial

04.0939.P)

For serology on D0 see

04.0939.R

NT: Not tested

Farm

1

Group treatment D19/D20 D26/D28 D49

G0

Unvaccinated birds

reared in Merial

Mean titre (in

log2) ≤ 2.60 ≤ 2.10 ≤ 1.00

Sd 0.97 0.74 0.00

G1

HatchPak vaccinated

birds

reared in Merial

Mean titre (in

log2) 2.90 2.80 2.40

Sd 0.88 1.14 0.97

G2

HatchPak vaccinated

birds

reared in field

Mean titre (in

log2) ≤ 2.40 ≤ 2.40 NT

Sd 0.84 1.51 NT

G3

HatchPak + ND booster

vaccinated birds

reared in field

Mean titre (in

log2) NT ≤ 3.10 NT

Sd NT 1.20 NT

Farm

2

Group

treatment D19 D29 D57

G0

Unvaccinated birds

reared in Merial

Mean titre (in

log2) 2.70 ≤ 1.90 ≤ 1.00

Sd 0.48 0.57 0.00

G1

HatchPak vaccinated

birds

reared in Merial

Mean titre (in

log2) 3.70 3.60 ≤ 3.0

Sd 1.77 1.43 1.76

G2

HatchPak vaccinated

birds

reared in field

Mean titre (in

log2) 3.80 ≤ 4.10 NT

Sd 1.69 3.00 NT

G3

HatchPak + ND booster

vaccinated birds

reared in field

Mean titre (in

log2) NT ≤ 3.60 NT

Sd NT 1.76 NT

Analysis for the IB component


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Regarding antibodies against IB, results showed in report 03.0915.R revealed a statically significant difference

between birds reared in the field (G2) compared to birds reared in Merial (G1) for Farm 1 (p[Kruskall –Wallis-test]

=0.03) but not for birds in Farm 2 (p[Kruskall –Wallis-test]= 0.34)

Study 03.0915.P/report

03.0915.R (Efficacy

against IB challenge in

broilers from the field

efficacy trial 03.0913.P)

Farm 1 (D31) Farm 2 (D29)

Group G0E

conventional

unvaccinated birds

reared in Merial

Mean titre (in

log10) ≤0.50 ≤0.20


G1E

conventional HatchPak

vaccinated birds reared

in Merial

Mean titre (in

log10) 1.60 ≤1.50


G2E

conventional HatchPak

vaccinated birds reared

in field

Mean titre (in

log10) 1.15 ≤ 1.30


G3E

SPF unvaccinated

control birds

Mean titre (in

log10) < 0.50 < 0.50


Thus globally, it was not possible to detect a frank trend of decrease of the serological answer among the trials

during the development of the vaccine. In addition, the comparison of such results is particularly difficult as the

birds reared in the field might have been contaminated by wild viruses and other agents which could interfere on

the serological conversion. Moreover, as underlined in the question, the serological level of antibodies is not

correlated to the protection.

To conclude, except the difference observed between SPF and conventional birds regarding ND antibodies, easily

explained by an interference with maternally derived antibodies, no conclusion regarding a decline of the antibodies

level can be raised from the analysis of the serological answers in the various trials, whatever the component.

RMS comment

The RMS doesn’t consider that serology provides relevant information with regard to the efficacy of the vaccine.

The analysis requested by a CMS is provided by the applicant but is of poor interest from the RMS point of view.

CMS comment


Conclusion

Solved.

Question 84 (DE – BE)


into account:





Position of CMS n°9: Duration of immunity stated in the SPC is 6 weeks (for both Newcastle Disease Virus and

Infectious Bronchitis virus). Although this duration of immunity (rather duration of protection) has been

demonstrated by challenge in laboratory conditions following the administration of a single dose in day-old

chickens, it is well known, and again demonstrated in the Applicant’s field study , that a single vaccination may

not be sufficient in some cases (as described for Group G2.2. in report 04.0490.R). The Applicant righ tly

recommends a second vaccination using Avinew. However, we are of the opinion that the SPC text is quite

misleading. We propose the following modifications in the SPC (section 4.2.):


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Onset of protection: 21 days after the first administration.

Duration of protection:

-IBV: 6 weeks after a single dose

-Newcastle Disease Virus: a duration of immunity of 6 weeks has been demonstrated after a single dose in

laboratory conditions. However, to maintain an adequate level of immunity in field conditions, a 2nd vaccination

using Avinew is recommended.


Merial did not validate the vaccination schedule that includes an IB booster. The objective of development was to

demonstrate either in laboratory or in field conditions protection of the chickens vaccinated at day old in the

hatcheries against IB Mass infection, with an economical life long duration of immunity (up to 6 weeks of age), as

widely prescripted in the EU. A booster can indeed be performed in the field, likely with a heterologous vaccine

strain, but given that no data was provided by the applicant, it cannot be included into the SmPC.

Regarding the position of the CMS n° 9, Merial agrees with the proposed sentence, which has been included in the

SmPC (refer to question 8).

RMS comment

Acceptable (see question 8) and 16.

CMS question

DE: The PEI supports the opinion of the RMS that a booster vaccination with Avinew is necessary to obtain a

satisfactory level of protection under condition. For common vaccination schedules a booster against IB is

normally performed at the 3rd or 4th week of live. This should be discussed and probably mentioned in the SPC.

Day 145 question





Merial Repeat-use







2ND STEP – DAY 150 CLOQ

FR/V/0171/001/DC

PRODUCT DETAILS








69007 LYON

France

Phone number (33) 472 72 39 72

Fax number (33) 472 72 33 68





MOLINA)

[email protected]



Day 150 : 26/05/2007

Day 198 : 13/07/2007

Day 210 : 25/07/2007


NL, PL, PT, SK, UK

RMS DETAILS


assessment report

France




12418


state

Not applicable




Phone number (33) 299 94 78 82



Merial Repeat-use


Fax number (33) 299 94 78 88


POSITION OF THE MS AT DAY 145

AT


BE (N°9)


CZ (N°8)

The Czech National Agency agrees with the overall conclusion of the RMS and is prepared to grant a marketing

authorisation for the above DC product.

DE (N°6)

The Paul-Ehrlich-Institut is of the opinion that there are potentially serious animal health concerns related to the

use of this product and is, at present, not prepared to grant a marketing authorisation for Hatchpak Avinew IB

H120.

The PEI fully supports the questions posed by the RMS and expects that these question will be part of the

consolidated LOQs. The questions mentioned below are additive to the RMS’s questions.

EL


ES (N°4)

The AEMPS agrees with most of the points/questions addressed by the RMS but considers the following

outstanding points should be additionally addressed (see questions in the report below).

FI (N°2)


FR

The "ANMV" (French National Agency for Veterinary Medicinal Product) is of the opinion that there are potentially

serious public health concerns related to the use of this product (see below) and is, at present, not prepared to

grant a marketing authorisation.

HU (N°5)

The Directorate of Veterinary Medicinal Products (DVMP) agrees with the comments and conclusions of the RMS

in the D120 Assessment Report and has given acceptance to the applicant ’s responses to Hungarian questions

raised at Day 100.

IE (N°7)

The Irish Medicines Board (IMB) agrees with the comments and conclusions of the RMS in the D120 Assessment

Report and has given acceptance to the applicant’s responses to IE questions raised at Day 100 (see below).

The IMB notes the applicant’s commitment to address all national Product Labelling and package leaflet issues on

completion of the decentralised procedure.

The IMB would like to remind the applicant that in Ireland, the Product Literature must comply with the requirements

of Directive 2001/82/EC as amended by Directive 2004/28/EC using the same template outlined by the EMEA and

the Quality Review of Documents group and tak ing into account national labelling requirements as outlined in Notice

to Applicants: Volume 6A - Chapter 7: General Information.

Please note that, should the application be successful, full colour mock -ups of the Product Literature will be

required before the licence can be issued. Mock -ups are to be supplied within 30 days after day 210 (90) of the

procedure. Please indicate prior to Day 210 (90) if joint packaging with the UK is to be implemented.

IT



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LT


LU


LV

State Agency of Medicines agrees with the overall conclusion of the RMS and is prepared to grant a marketing

authorisation for the above mentioned veterinary medicinal product.

NL


PL


PT (N°3)

Although the Direcção Geral de Veterinária agrees with the overall conclusions of the RMS and a satisfactory

response to the questions raised by the RMS is required, is also of the opinion that the hereafter comments have

to be addressed (see below in the report).

SK

Institute for State Control of Veterinary Biologicals and Medicaments agrees with the overall conclusion of the

RMS and is prepared to grant a marketing authorisation for the above DC product.

UK (N°1)

The Veterinary Medicines Directorate agrees with the comments and conclusions of the RMS in the D120

Assessment Report but considers that the following outstanding points should also be addressed (see below in

the report).


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The initial questions are listed, with the indication whether they are solved or whether questions remain.

Question 1 (FI)





CMS position




Question 2 (ES)

Solved.

I.A.2 Source

Question 3 (UK)

Solved

I.B.1 SPC

Question 4


outstanding points.

Day 145 question

For the record:

In the light of the outstanding points raised by the RMS, there may be changes required in light of the responses

received.







Day 145 question




titre.



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Question 6 (ES)




Day 145 question




4.1. Target species

Question 7

Solved




ES


Day 145 question




Question 9 (ES)

Solved.




section to:





considered as safe.




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Day 145 question





Question 11 (ES – PT)

Solved.


Question 12


to:






- the results of the new overdose dose study requested by the spray route of administration (see questions i n




Day 145 question





Question 13 (ES-UK)

Solved.


Question 14

Solved.


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Solved.

4.9.2 Posology

Question 16

Solved.


Question 17 (DE)

The spray application should be described in more detail especially with regard to the characteri stics of the


Day 145 question

DE:



Example











tract.








No question 18


Question 19

Solved.


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mentioned.

Day 145 question






Question 21

Solved

6.3. Shelf-life

Question 22



Day 145 question






Question 23

Solved


Question 24 (ES)


Day 145 question





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6.6. Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the

use of such products, if appropriate

Question 25 (ES)

Solved


Question 26











Solved







Day 145 question





proposal:



information.








Day 145 question

ES:


Merial Repeat-use


Labelling:





package leaflet.



Package leaflet









here.



















PT

As there won’t be a label on the outer package, a comb ined label-package leaflet, with all the information




FR






Merial Repeat-use


II. Analytical part




perform the assessment of the dossier. One of them (DE) informs the applicant that in fut ure, dossiers in this


Day 145 question










Day 145 question




Question 30 (ES-DE)









Day 145 question














accordingly.


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Question 31

Solved.

Question 32






Day 145 question





Question 33

Solved.




Solved.


SPF eggs: the Applicant should confirm that 100% of SPF birds are initially tested (by b oth suppliers) in











Day 145 question








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No question 35

No question 36




Controls:









Day 145 question



Question 37 – parts 2 to 11

Solved.

Question 38

Solved.

Question 39



Day 145 question





previously.



Solved.


Buffered physiological saline pH 7.1: this physiological saline is sterilised by filtration and not by

autoclaving. It is an Ph.Eur. requirement that autoclaving should be used unless justified. There does not

appear to be a justification. An adequate justification should be provided or the saline should be sterilised


Merial Repeat-use


by autoclaving.

Day 145 question



Question 41

Solved.



Solved.



clearly stated.



Day 145 question






Question 43

Solved.


Question 44

Solved.


Question 45

Solved.


Question 46

Solved.


http://www.edqm.eu/


Merial Repeat-use


Question 47

Solved.



Question 48

Hatchpak IB H120








will be acceptable.


test.

A CMS (n°4) also requires to provide the safety data at the end of the shelf-life.

Day 145 question

Hatchpak IB H120












Solved.


No question 49

III. Safety

Question 50


Merial Repeat-use


Solved.




No question 51

Question 52

Solved.

Question 53

Solved.


No question 54



No question 55

Question 56

Solved.

Question 57

Conclusion



Day 145 question











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Question 58


The signs observed (bronchial rales) after administration of one dose should be reported in the SPC.





recommended.

Day 145 question


















No question 59

Question 60

Solved.

Question 61

Solved.




No question 62



Question 63


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Solved.



No question 64

No question 65


Question 66

Solved.


Question 67

Solved.


Question 68

Solved.

Question 69

Solved.

Question 70

Solved.

III.E. ECOTOXICITY

Question 71 (DE)








Day 145 question



Question 72 (UK- ES - HU)



nebulisation route because the conventional birds are not the most sensitive birds and this field trial compared


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why the safety of the nebulisation was not confirmed in laboratory trials .


route:



Hatchpak IB H120.






route.


laboratory trials.

Day 145 question












IV. Efficacy

Question 73

Solved.



Question 74

Solved.


Question 75

Solved.


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No question 76

Question 77


















Day 145 question






Question 78

Solved.

No question 79

IV.D. FIELD TRIALS

No question 80

No question 81


Question 82

Solved.


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Question 83

Solved.

Question 84


into account:





Day 145 question





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2ND STEP – DAY 190 RMS assessment report

FR/V/0171/001/DC

PRODUCT DETAILS








69007 LYON

France

Phone number (33) 472 72 39 72

Fax number (33) 472 72 33 68





MOLINA)

[email protected]



Day 150 : 26/05/2007

Day 198 : 13/07/2007

Day 210 : 25/07/2007


NL, PL, PT, SK, UK

RMS DETAILS


assessment report

France




12418


state

Not applicable




Phone number (33) 299 94 78 82

Fax number (33) 299 94 78 88



Merial Repeat-use




The initial questions are listed with their initial number (except those solved).

Question 1 (FI)





CMS position



Given that the leaflet CMDv template proposes a specific wording for this kind of situation, Merial propose to add it

in the section 10 of the SmPC as well as in the Section 12 (Special warnings) of the leaflet:

The import, sale, supply and/or use of HatchPak Avinew IB H120 is or may be prohibited in certain Member States

on the whole or part of their territory pursuant to national animal health policy. Any person intending to import,

sell, supply and/or use HatchPak Avinew IB H120 must consult the relevant Member State’s competent authority

on the current vaccination policies prior to the import, sale, supply and/or use of the product.

RMS comment

Satisfactory.

I.B.1 SPC

Question 4


outstanding points.

Day 145 question

For the record:

In the light of the outstanding points raised by the RMS, there may be changes required in light of the responses

received.


For readability improvement, Merial proposes in Annex a Product Information document including an updated

SmPC compiling all the proposals detailed hereafter. This document has been updated from the one provided in

the dossier. It is proposed in two versions: track mode (p.048) compared to the dossier and final proposal (p.066).

RMS comment

No further comment.



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Day 145 question




titre.



Agreed, the composition will therefore be stated as follows:


Active substance:

Live Infectious Bronchitis virus, H120 strain ................................................................... 3.7 to 4.7 log10 EID50*

Adjuvant(s):

Not applicable

Excipient(s):



RMS comment

Satisfactory. The RMS has checked that the SPC was updated accordingly.


Question 6 (ES)




Day 145 question




The visual appearance of the product (yellow color) will be added.

RMS comment

Satisfactory. The RMS has checked that the SPC was updated accordingly.


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ES


Day 145 question




Agreed, the wording "Duration of Immunity" will be used.

In addition, as proposed in the question 84, the following sentence for the IB booster will be added:

"-IBV: 6 weeks after a single dose. Depending on the field epidemiological situation, a booster with a relevant IB

strain can be performed at the appropriate timing evaluated by the veterinarian."

RMS comment

Solved concerning the duration of immunity.

The RMS doesn’t support the addition with regard to booster with IB vaccines (see question 84 for detailed

explanation).




section to:





considered as safe.








Day 145 question




Regarding the change of "birds" to "chickens", Merial agreed and the Product Information has been amended

accordingly.

However, for the spread to other avian species, as detailed in question 71, there are no doubts regarding the safety

of the vaccines and the use of the vaccine should not be restricted to close areas.

Therefore, the final wording is:


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Vaccine viruses can spread to unvaccinated birds. Infection of unvaccinated chickens with t he vaccine virus from

vaccinated chickens does not cause any signs of disease. Reversion to virulence trials carried out in the laboratory


chickens.

RMS comment

“Vaccine viruses” to be replaced by “vaccine virus”, leading to:


vaccinated chickens does not cause any signs of disease. Reversion to virulence trials carried out in the


passages in chickens.


Question 12 (ES – UK)


to:

“Reduced weight gain attributable to the Newcastle Disease vaccine strain may be observed after vaccination.










Day 145 question




However, this proposal may be revised depending on the results obtained in the awaited overdose study.

ES: awaiting on-going overdose study.


According to the answer of the question 58, the applicant proposes the following wording:


days after vaccination in less than 15% of the birds."

RMS comment

THE FOLLOWING IS ACCEPTABLE (SEE QUESTION 57 FOR DETAILED

JUSTIFICATION OF THE RMS POSITION) : "Bronchial rales, not associated with respiratory distress or any general sign, may be observed between 5 and 14

days after vaccination in up to 15% of the birds."


Question 17 (DE)



Day 145 question

DE:


Merial Repeat-use




Example









For revaccinations in older birds an improved immunity is achieved by application of the vacc ine as a fine spray or


tract.








As explained in the question 57, the results of the overdose trial are similar to what was expected. Thus, there are

no impacts on further safety recommendations.

The applicant still considers that given the satisfactory safety results and the large variability of the devices, too

many details would be useless. However, in order to provide detailed criteria to perform a correct application,

Merial proposes the following wording for the § 4.9.3 Method of administration:



- Spray the vaccine solution above the birds using a sprayer that enables production of drops of 100 µm or more




RMS comment

Acceptable proposal.





mentioned.

Day 145 question






Merial strongly disagrees with the full disclosure of all the excipients in a public document such as the Summary

Product of Characteristics for the reasons provided in the Memorandum on the Compatibility with EC Law of the

Request for a "Full" List of Excipients with their "Full" Names as provided in the Guideline on the Summary of the


Merial Repeat-use


Product Characteristics for Veterinary Medicinal Products Pharmaceuticals and Immunologicals, enclosed in

Annex p.173.

This legal analysis has been forwarded to the European Commission who has been requested to provide an official

position regarding the disclosure of excipients in the SPC.

While waiting for it and taken into account the recent obligations put on applicants during various procedures,

MERIAL reluctantly accepts to update the SPC and for the Newcastle part, the proposal is based on what has

been approved for Avinew.

Therefore, as explained in the question 29, the proposed list of excipient would be as follows:

Protein hydrolysate

Mannitol

RMS comment

This is an acceptable proposal.

6.3. Shelf-life

Question 22



Day 145 question






As detailed in the question 48, we confirm that the shelf-life claimed is 24 months; the SmPC has been updated

accordingly.

The D106 SmPC was amended as requested regarding the sentence "Use immediately after opening the vials and

administer within 2 hours after preparation of the vaccine for use”.

RMS comment

Satisfactory (please see also the answer to question 48).


Question 24


Day 145 question





Regarding the code color, it concerns the cane that carries ampoules. The canes carrying the HatchPak IB H120

ampoules will be yellow. Vials themselves remain transparent.

Thus, the following wording for the SmPC is proposed:

"Type I glass ampoule, 4- yellow ampoules canes.


- 10,000 doses: 10,000-dose ND ampoule + 10,000-dose IB ampoule

- 15,000 doses: 15,000-dose ND ampoule + 15,000-dose IB ampoule


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Not all pack sizes may be marketed."

RMS comment

Satisfactory.


Question 26











The applicant confirms that it will do its best to take into account the IE national labelling requirements during the

national phase of the procedure, as far as they are compatible with the very specific packaging constraints. The

addition of the marketing number in the leaflet has been proposed in the answer to the question 27. The supply

conditions are also written in the section 15 of the leaflet: "Veterinary medicinal product subject to prescription".

No issue should therefore occur.

RMS comment

No further comment : national issues.







Day 145 question




There is sufficient place on the bottle to write the route of administration: "spray". Therefore, the product

information has been updated accordingly.

RMS comment

Acceptable.



proposal:



information.


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Day 145 question

ES:

Labelling:





package leaflet.



Package leaflet









here.


Please, reword the sentences: “Use immediately after opening. Use within 2 hours af ter reconstitution.” to



The phrase “Don not mix with any other medicinal product” should be reworded to include the information stated in


disease containing Merial VG/GA strain”.












PT




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FR






Concerning the possibility to have all information of the outer package put into the leaflet or a combined label -

leaflet, the applicant prefer to add the missing information of the outer package on the leaflet.

Consequently, the leaflet will also carry out the following information of the outer package which are not mentioned

in the classical leaflet template:

Section 13 of the outer package: "For animal treatment only" reported in section 15 of the leaflet.

Section 16 of the outer package: Marketing authorisation number reported in section 15 of the leaflet.

However, there are no technically possibility to print on line the batch number and the expiry date on the leafle t.

But it must be noted that both batch number and expiry date are written on the ampoules only for Vaxxitek

HVT+IBD, another frozen vaccine registered centrally by Merial. Thus, if this situation is acceptable for Vaxxitek

HVT+IBD without endangering public or animal health, then it should be acceptable for HatchPak Avinew IB H120,

which has exactly the same features regarding the packaging constraints and supplying conditions.

Regarding the item 3 of the package leaflet, the composition will include the maximum titre and a description of

the visual appearance of the pharmaceutical form will be added.

Regarding the section 6. Adverse reactions: Merial agrees to add “If you notice any serious effects or other effects

not mentioned in this leaflet, please inform your veterinary surgeon", as requested in the CMD(v) Annotated QRD

Template.

Regarding the code color, it concerns the cane that carries ampoules. The applicant proposes to add the sentence

in the item 3 of the section 8 (Reconstitution of the vaccine), as follows:


vaccination session. The ND ampoules are carried by a green cane whereas the IB ampoules are carried by a

yellow cane.





The sentence on the reconstitution have been accorded to the ones used in the SmPC

Finally, the route of administration will be mentioned on the ampoules as requested by the RMS.

RMS comment

Acceptable.

II. Analytical part




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Day 145 question





Merial takes note of the remark and will follow as previously explained the format of the new annex I of Directive

2001/82/EU.

RMS comment

No further comment.







Day 145 question





To avoid discussion on excipient definition, Merial agrees to list the stabilizer components in the list of excipients

(see answer to question 20 concerning SPC paragraph 6.1).

Protein hydrolysate

Mannitol

RMS comment

THIS IS IN LINE WITH THE AGREEMENT MADE FOR AVINEW AND PROPOSAL FOR

HATCHPAK AVINEW IB H120. ACCEPTABLE.

Question 30 – 2nd part (ES – DE)




The final composition of antibiotics and stabilizer should be clearly stated. (ES)

Day 145 question









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UK: The UK does not accept the Applicants argument that s tabiliser is not an excipient. The stabiliser forms a




accordingly.


See answer to question 29.

The table of Qualitative and quantitative Particulars are updated accordingly below.

HATCHPAK IB H120

Names of ingredients Quantity per dose Function References

Active ingredient Live infectious bronchitis virus

(H120) component

3.7 R 4.7 log10

EID50

Supply of antigen MERIAL

Constituents of the

adjuvant

NA NA NA NA

Constituents of the

excipient

Stabilizer qs 1 dose Stabilizer MERIAL

containing: Per 1 ml:

Casein hydrolysate 80 mg

Mannitol 80 mg

Constituents of the

diluent

NA NA NA NA

Constituents of the

pharmaceutical form

NA NA NA NA

NA: Not Applicable

RMS comment

The proposal is acceptable with the following amendment: inclusion of the water quantity of water for injection.

Day 190 Question

The applicant is asked to indicate the water in the table of ingredients (proposal underlined):

HATCHPAK IB H120

Names of ingredients Quantity per dose Function References

Active ingredient Live infectious bronchitis virus

(H120) component

3.7 R 4.7 log10

EID50

Supply of antigen MERIAL

Constituents of the

adjuvant

NA NA NA NA

Constituents of the

excipient

Stabilizer qs 1 dose Stabilizer MERIAL

containing: Per 1 ml:

Casein hydrolysate 80 mg

Mannitol 80 mg

Water Qs 1 ml

Constituents of the

diluent

NA NA NA NA

Constituents of the

pharmaceutical form

NA NA NA NA

NA: Not Applicable


Question 32



Merial Repeat-use


The validation was performed for the Mass 41 strain whereas the vaccine contains the H120 strain. The appli cant




Day 145 question





Raw data for both viruses (H120 virus and Mass 41 virus) are presented in document CCh/JL/EBR.07.D374,

attached annex p.084).

RMS comment

Satisfactory.















Day 145 question







It is noted that VN titers were always greater but the observed difference between ELISA and VN tests was at

most one dilution (as stated in the report). The small difference could be accepted as within Ph Eur requirements

those two methods are also given as equivalent.

Indeed in the Ph.Eur., the detection of avian leucosis antibodies is mentioned at two levels:

Ph Eur 5.2.2 (SPF flocks testings):

- detection of antibodies against leucosis viruses: the reference technique is VN test

Ph Eur 2.6.24 (extraneous agents in seeds):

- detection of antibodies against leucosis viruses, the reference techniques are SN (VN) test or EIA (ELISA)

As a matter of fact this last text was revised more recently than the monograph 5.2.2 and the equivalence of these

techniques was accepted by EDQM, in particular VN and EIA regarding antibody detec tion. There is no scientific

reason this should not apply as well to the control of SPF flocks.

Couvoir de Cerveloup is the suppliers of SPF eggs to Merial. Indeed, the routine serological testings are delegated

to LBAA. The latter is managing satisfactory performance of all tests with approved laboratory (therefore sub-


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delegates those tests). The laboratory actually performing the tests are clearly stated on the LBAA certificate

(page 217 of the LOQI answer document, and re-enclosed in annex p.086 for convenience). LTZ (‘Lohamnn

Tierzucht) is stated in the column ‘LABORATORY’. All those relations are described in written documents and no

change may be applied without prior agreement.

RMS comment

Acceptable answer.






Controls:









Day 145 question




The results will be forwarded as soon as available.

RMS comment

Satisfactory.

Question 39



Day 145 question





previously.


It must be underlined that enzyme is not the ingredient that are used in the manufacture of the vaccine (it is used

to produce an ingredient).

Exact origin will be part of the batch documentation. If a list is to be drawn up, the following countries will be

regarded as possible origin:

USA, Canada, Australia, New Zealand, EFTA countries (i.e. European Union and Norway, Iceland, Switzerland,

Liechtenstein).

RMS comment

Satisfactory.


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Buffered physiological saline pH 7.1: this physiological saline is sterilised by filtration and not by autoclaving. It

is an Ph.Eur. requirement that autoclaving should be used unless justified. There does not appear to be a

justification. An adequate justification should be provided or the saline should be sterilised by autoclaving.

Day 145 question



This autoclaving treatment will be implemented for active ingredient production from next run.

RMS comment

Satisfactory.




clearly stated.



Day 145 question






Batch protocols have been aligned with EDQM templates. Please find in annex p.099 and p.110 an example of

these templates.

RMS comment

Satisfactory.



Question 48 (ES – DE – CZ - UK)

Hatchpak IB H120








will be acceptable.


test.

A CMS (n°4) also requires to provide the safety data at the end of the shelf -life.

http://www.edqm.eu/


Merial Repeat-use


Day 145 question

Hatchpak IB H120












We confirm that sterility and safety tests will be performed at 27 months of storage. Results will be part of the final

report to be submitted during first quarter 2008 after QA processing.

We agree with RMS proposals to set the stability for both products at 24 months. Indeed the new stabilizer do not

differ form the previous one as explained in our answer to LOQI, and Merial paid great attention to keep differences

at the minimum level (same quantity is used). Should an impact exists this should exist from the beginning. In

addition it should be noted that in condition of storage more stringent for the product (freeze dried nature and

storage between +3°C - +8°C), use of new starting material in substrate had no impact on the product. The

equivalence in behaviour is also observed with another virus (VG/GA strain) (see table below).

Time

(in month)

H120 freeze-dried presentation (Infectious titer : log10 EID50/dose)

Old stabiliser (S26) New stabiliser (S56)

2BPLP7731 2BLP7881 3BLP7891 6BLP4301 6BLP4321 6BLP4331

0 4.17 4.41 4.27 4.13 4.24 4.0

3 4.44

6 4.17 4.35 3.99 4.06

9 4.36 4.19 3.94 3.95 3.9

15 3.78 4.40 4.31

21 4.49 4.11

Time

(in month)

VG/GA freeze-dried presentation (Infectious titer : log10 EID50/dose)

Old stabiliser

(S44)

New stabiliser (S54)

2AVW3671 2AVW3681 2Avw3761 5AVW3161 5AVW3181 5AVW3281

0 6.5 6.8 6.7 6.4 6.6 6.6

3 6.4 6.5 6.0 5.8

5 6.4 5.5

6 6.2 6.0 6.1

9 6.4 6.0 6.2

10 6.5 6.1

15 6.0 6.3 6.0 5.6 5.6 5.7

Moreover, new data for the Hatchpak AVINEW IB H120 products are now available (see figure below and data in

annex p.121 and p.123) confirming the good stability of the product.

The last stability time point confirmed the previous data demonstrative of the absence of loss during storage.


Merial Repeat-use


stab Hatchpak IB H120

3,7

3,9

4,1

4,3

4,5

4,7

4,9

5,1

0 5 10 15 20 25

time (month)

titr

e/d

ose (

log

10 D

IO50)

Therefore as:

- the change in nature is equivalent for both products (meat and casein peptone replaced by casein

hydrolysate)

- the quantity in old and new stabilizers was kept identical and no other changes took place,

- the available data show no impact on stability-in a worst situation (freeze-dried, cold temperature), no

impact was seen as well

- recent data confirm absence of impact and good stability

- deep-frozen storage is very effective fort stability purposes,

A shelf life of 24 months can be granted and will be later confirmed within the stability final reports.

RMS comment

Acceptable. To refer to the UK position, stability data are now available for 21 months with no indication of

detitration. Tak ing into account these results and the very limited difference between the old and the new

stabilizers (batches produced with these stabilizers were demonstrated as stable for 27 months), it is reasonable

to accept a duration of stability of 24 months with the commitment to provide the complete results within 9

months.

III. Safety






Question 57

Conclusion



Day 145 question


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Merial takes into account the fact that the procedure will not be finalised without the requested safety data.

However, these data are now available (see further in the answer) and the rational for not having performed the test

before the application is provided below:

Given that:

- Both strains can be considered as well established use in Europe (IB strain was registered for the first

time in Europe in 1971 through BIORAL H120 vaccine and ND strain in AVINEW in 1995). The IB strain is

in addition widely used worldwide, in vaccines manufactured in the USA without any safety issue

detected.

- Several safety studies with the combined product HatchPak Avinew IB H120 were performed (with one

dose or repeated doses) with satisfactory results and no detection of any increase of safety issues

induced by the mixing of strains.

- Overdose safety studies were performed on both monovalent products with again satisfactory results.

- Safety studies were performed with an occulo-nasal administration which is more severe than the

recommended spray

- There is a need to reduce the animal testing as required by the European Convention for the

Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes,

it was considered that performing an overdose trial with the combined product would not bring significant

information, and therefore, the applicant decided not to perform this test.

However, given the number of reactions in the list of questions received during the first phase of the Decentralised

Procedure, questions that raised not only the overdose aspect but also the spray administration, the applicant

finally decided to perform this study to secure the outcome of the procedure.

Therefore, please find enclosed in Annex p.125 the report regarding this overdose study by spray, the summary of

which is reminded there:

07.0150.R - M713 – Newcastle Disease and Infectious Bronchitis frozen vaccines - Safety of the

simultaneous administration of a high dose and of an overdose of M713(ND) and M713(IB) vaccines

administered by spray in SPF chickens. 2007, Merial.

This study was performed to assess the safety of the administration of high doses and overdoses of M713(ND) and

M713(IB) vaccines when administered simultaneously by spray in SPF one-day-old chickens.

M713(ND) and M713(IB) are frozen live vaccines against Newcastle disease (ND) and avian Infectious Bronchitis (IB)

respectively.

The safety of these administrations was assessed through a clinical monitoring (respiratory signs were particularly

looked for), a body weight monitoring and a final post-mortem examination.

On Day 0 of the trial (D0), seventy-five one-day-old SPF chicks were individually identified, weighed then allocated to

3 groups of 25 birds using randomisation according to the body weight.

The 3 treatment groups are defined in the following table.

Table I. Definition of the groups.

Group N Treatment


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G1 25 Unvaccinated controls

G2 25 Vaccinated with a high dose of each vaccine M713(ND) and M713(IB) on D0

[6.7 log10 EID50 of M713(ND) and 4.7 log10 EID50 of M713(IB)]

G3 25 Vaccinated with an overdose of each vaccine M713(ND) and M713(IB) on D0

[7.7 log10 EID50 of M713(ND) and 5.7 log10 EID50 of M713(IB)]

The birds of groups G2 and G3 were vaccinated using Spravac apparatus on D0. All the birds were then observed during 21 days (from D0 to D21) with daily global clinical monitoring, individual

examination of the respiratory signs on a regular basis between D4 and D14, individual weighing on D6 and D21 and

full necropsy on D21.

No specific gross lesions were recorded at necropsy in any of the treatment groups.

No abnormal general clinical signs related to the vaccination were observed throughout the study except for wet

faecal droppings in few vaccinates (2 birds in G2 and 4 birds in G3).

The respiratory signs observed in vaccinated groups were limited to at most slight bronchial rales and were transient

since they resumed within 12 days after the administration of the vaccines. These signs were also observed in only 2

to 3 birds out the 15 birds monitored in each group.

In addition, no effect of the simultaneous administration of the vaccines was evidenced as the respiratory signs

observed were similar to those recorded following the administration of the vaccine M713(IB) alone (no respiratory

signs had been observed following the administration of the M713(ND) vaccine).

The bodyweights of the vaccinates (G1 and G2) were more heterogeneous on D21 but not statistically significantly

different as compared to the control birds (G1) on D6 and D21.

In conclusion, the simultaneous administration of high doses or overdoses of vaccines M713(ND) and M713(IB)

vaccine by nebulisation in SPF chicks was well tolerated regarding respiratory signs and growth criteria. Some

digestive disorder (wet faecal droppings) were transiently observed in few birds around 2 weeks after the

administration for at most 4 days, probably due to high doses of IBV H120 strain. The safety results obtained were

consistent with those observed following administration of high doses of each vaccine separately.

As expected, respiratory signs were slighter than in the occulo-nasal administration of the product, the later being a

more severe route of administration than the spray.

The bodyweight of vaccinated birds was not significantly impacted compared to the controls

As already mentioned in some previous studies, slight digestive disorders have been observed in less than 1 0% of

the vaccinates (considering birds vaccinated with the high doses), without any impact on the general conditions of

the birds. The symptoms observed in the study 07.0150.R may be due to IB H120. Indeed, where diarrheas were

observed in previous studies, it concerned HatchPak IB H120 vaccine and never HatchPak Newcastle.

However, this observation does not exactly match the one reported in the literature who mentions that only

nephropathic strain are likely to induce diarrheas (see in particular page 515 of the reference Cavanagh & Naqi.,

"Disease of Poultry in Annex p.156). Nevertheless, this incidence is very low and the reproducibility is inconsistent

in the trials.

In particular, no wet (faecal) droppings were observed in the following groups of birds:

- vaccinated with a high doses: study 04.0581.R (30 SPF chickens) and study 02.0674.R (25 SPF vaccinated

chickens)

- vaccinated with an overdose dose: study 04.0856.R / 04.0474.R (20 SPF chickens)

And it must be underlined that in several studies (04.1064.R, 05.0367.R), control birds were also concerned.

In addition, no wet (faecal) droppings were observed in the field trial with more than 22 032 birds vaccinated at

commercial dose.

Finally, the Pharmacovigilance data had never reported any diarrheas for the Bioral H120 vaccine from January

2001 to September 2006 while 2.5 billion of doses were sold in Europe (as noted in the previous set of answer).

It seems that this problem could be a multifactor one and environmental conditions (such as air flow) or a non

optimal food used in this sensitive category of SPF birds may increase the expression of this symptom.

Therefore, given, that this observation is limited to SPF chickens (a more sensitive category) and not conventional,

the inconstant reproducibility, the absence of field observation since 1971, the probability of interference with

environmental factors, this symptom should be considered as remaining incidental.

In conclusion, as foreseen, this overdose study administered by spray performed confirm ed the previous results

and conclusions on the safety profile of the HatchPak Avinew IB H120 vaccine remain valid.

RMS comment


Merial Repeat-use


The RMS provides the summary of the new study.

Report 07.0150.R.: safety of 1 dose and of an overdose in day-old SPF chicks, by nebulisation

Answer of June 2007 - Vol. 1/1 – p.125

Animals 75 1-day-old SPF chickens randomised in 3 groups of 25 birds

Vaccine Hatchpak Avinew IB H120 (M713 ND - batch 83825 & M713 IB batch 83828)



Vaccine scheme Group 1: unvaccinated controls

Group 2: 1 dose of 4.7 log10 DIO50/bird (IB) and 6.7 log10 DIO50/bird (ND) at the age of

1 day

Group 3: 1 overdose of 5.7 log10 DIO50/bird (IB) and 7.7 log10 DIO50/bird (ND) at the

age of 1 day


Individual examination of respiratory reaction on 15 birds/group: on day 4, 6, 8, 10,

12 & 14; scoring of the signs


On day 21, sex determination, euthanasia and post-mortem examination


On respiratory score

Results Non specific mortality: 1 bird in each vaccinated group (day 3 and 4); 2 control

birds euthanasied for poor condition on day 4; no lesions at necropsy

Transient wet faecal droppings in 8% of the birds vaccinated with a single dose

and 17% of those vaccinated with an overdose


in up to 13 % of the vaccinates, score of 1 or 2, no birds showing a score of 3

in the overdose group, the rales appeared on day 6 and had disappeared by

day 10 after vaccination

in the single dose group, the rales appeared on day 4 and had disappeared by

day 12 after vaccination


no statistically significant difference of score between the 3 groups


With regard to the impact of the vaccination on growth, the RMS fears that the number of b irds per group is too

reduced to detect a statistically significant effect, due to a probably limited power of the test. However, the effect

on growth was previously discussed (see the RMS assessment report of Day 150) and it was agreed that the

negative impact on growth was only observed only in SPF birds and therefore, no warning was included in the

SPC.

With regard to the bronchial rales associated to the IB component, it appears that the vaccination by spray (as

claimed by the applicant) induces a reduced incidence of bronchial rales than after a vaccination by eye-drop (data

of the initial dossier). The severity of the signs is not modified (bronchial rales with no respiratory distress).

Therefore, the RMS agrees with the proposal of the applicant, slightly modified (underlined):


days after vaccination in less than up to 15% of the birds, attributable to the Infectious Bronchitis vaccine strain."

With regard to the wet faecal droppings, the RMS accepts the applicant’s explanation and doesn’t require any

specific warning in the SPC.

Question

With regard to the bronchial rales associated to the IB component, the RMS agrees with the proposal of the

applicant, slightly modified (underlined):


days after vaccination in less than up to 15% of the birds, attributable to the Infectious Bronchitis vaccine strain."



Merial Repeat-use


Question 58











recommended.

Day 145 question


















The results of the safety of the simultaneous administration of a high dose and of an overdose of both ND and IB

components in SPF chickens by spray is now available (see report 07.0150.R appended and summary given in

Q57). This study showed that:

- Respiratory signs observed in both vaccinated groups (high doses and overdoses) were reduced to slight

bronchial rales from D6 to D8 (for high doses) and from D4 to D10 (for overdoses) and were observed in

very few birds (up to 13.3 % of the vaccinated birds with high doses and up to 20 % for vaccinated with

overdoses).

- Regarding the growth, there was no statistically significant difference in the bodyweight between

vaccinates and controls until 21 days after vaccination.

By comparison with other safety studies involving high doses of IB component, the respiratory signs obtained after

administration by spray (study 07.0150.R) were lower than in studies involving administration by oculo-nasal route

as demonstrated by the following table:

Study Route of

administration Duration

Bronchial rales observation

High dose Overdose

04.0581.R

Occulo-nasal

D5-D14 Up to 75% Up to 70%

04.0188.R D5-D19 65% -

04.1064.R D5-D14 55% -

05.0367.R D3-D13 40% -

07.0150.R Spray D6-D8 13.3% 20%


Merial Repeat-use


Indeed, the administration by oculo-nasal route represents more severe conditions than the spray,

In addition, the results of field safety trial (03.0916.R) showed that up to 6.7 % of the birds examined after

vaccination by spray showed respiratory signs.

The SmPC adverses reactions section should be based on the results of safety studies conducted with the

combined vaccine, using the recommended route of vaccination (spray), which will be the conditions met in the

field i.e the 07.0150.R and the field trial. Therefore, the applicant proposes the following warning in the section 4.6:


days after vaccination in less than 15% of the birds, attributable to the Infectious Bronchitis vaccine strain”.

RMS comment

See question 57 for RMS comments and question.

III.E. ECOTOXICITY

Question 71 (DE)








Day 145 question



The IB strain is well-known for many years now and the use can be considered as well-established and safe.

Indeed, it is registered for more than 36 years for the IB H120 strain via BIORAL H120 vaccine (registered in 49

countries worldwide, among which 10 European countries). BIORAL H120 is intended for active immunisation of

chickens against avian infectious bronchitis from one day of age or more. At the time of the first registration (in

France), stables may not have been as closed as they can be today and the product may have been widely used

in open air holdings and backyard holding. Thus, it is very likely that wild species have been in contact with this

strain. No safety issues have ever been detected since.

Therefore, given the well established use of both strains and the total absence of field concerns for wild and exotic

species for many years, there are absolutely no sound grounds to restrict the use of the vaccine in closed stables

only.

RMS comment

Taking into account the use of the IB H120 strain in the field for years without any notified problem, the RMS

agrees with the applicant’s approach.


Question 72 (UK- ES – HU)


administration; however, this field trial is not sufficient to confirm the safety of the vaccine adminis tered by the

nebulisation route because the conventional birds are not the most sensitive birds and this field trial compared




why the safety of the nebulisation was not confirmed in laboratory trials.


Merial Repeat-use



route:



Hatchpak IB H120.






route.


laboratory trials.

Day 145 question













Please, refer to the answer 57 where all details on the rational for this lack of safety data are provided (mainly a

well established use in Europe since 1971 for IBV H120 strain and 1995 for Newcastle VG/GA strain and previous

satisfactory safety data) as well as results of the requested safety study.

RMS comment

See question 57 for RMS comments and question.

IV. Efficacy



Question 77









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Day 145 question







Regarding the absence of a group vaccinated with HatchPak vaccines only in compatibility trials regarding efficacy

against Newcastle disease or Infectious Bronchitis (04.1012.R, 04.0508.R, 04.0509.R and 04.0512.R), there were

following justifications:

- vaccines against Marek’s disease or Gumboro disease were never described as enhancer of immunity

against Newcastle disease or Infectious Bronchitis.

- the studies were linked to protocol for rearing and serological monitoring (cf. 04.1011.R) of the birds and

any supplementary groups of vaccinated controls would have involved more birds for few relevant

information.

Moreover, these efficacy tests against Newcastle Disease and Infectious bronchitis gave very satisfactory

protection level (90 to 100 % protection), which was above the Eur. Ph. thresholds (90% protection against ND

challenge and 80 % for IB challenge) and the challenge was validated by the presence of non vaccinated birds.

Results were similar to those observed on other studies using HatchPak vaccine alone and non vaccinated

controls and provided in the efficacy dossier.

Therefore, the absence of controls vaccinated with HatchPak vaccine alone has no impact on the conclusion

raised.

Regarding the compatibility with Vaxxitek regarding Marek’s disease, the applicant still considers that sufficient

elements are provided in the efficacy dossier to support the compatibility with the vaccine Vaxxitek HVT+IBD. As

said in the previous set of answers, the efficacy of VAXXITEK HVT IBD against IBD can be considered as a good

indicator of its efficacy against Marek’s disease. As a matter of fact, there is only one component in this vaccine

which is an HVT virus expressing an IBD antigen. The protection elicited by the correct expression of this IBD

antigen is thus a demonstration of the expected development of the HVT virus, which also bears the efficacy

against MD.

However, despite the ethical concern of the Marek challenge, Merial could confirm it in a study using similar

design as the efficacy test against Infectious Bursal disease (see 06.0349.R):

GROUPS/ Birds: around 110 one day-old SPF chicks on D0 splitted into 3 groups:

- Vaccinated with Vaxxitek alone ; N = around 36 on D0

- Vaccinated with Hatchpak Avinew IB H120; N = around 36 on D0.

- Vaccinated with Vaxxitek and Hatchpak Avinew IB H120; N= 36 on D0

SCHEDULE:

- D0: vaccination of the chicks with Vaxxitek (low dose, SQ route) and Hatchpak Avinew IB H120

(commercial dose, spray).


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- D9: Marek’s disease challenge (all the birds)

- D79: Euthanasia and final necropsy

D0 to D79: clinical monitoring on a daily basis; any sick or dead bird is noted. Any dead bird is necropsied.

The applicant wishes a confirmation that the CMS requires this study. If so, it commits itself to perform it by mid of

the 2008 year.

The compatibility should nevertheless remains on the SmPC, as there are strong indications of the efficacy of both

vaccines when used simultaneously.

RMS comment

The RMS has no objection to the applicant’s proposal.


Question 84


into account:





Day 145 question



normally performed at the 3rd or 4th week of live. This should be discussed and probably ment ioned in the SPC.


As previously said in the answers referenced CPh/JL/GeR/EBR.07.D41, Merial did not validate the vaccination

schedule that includes an IB booster. The objective of development was to demonstrate either in laboratory or in

field conditions protection of the chickens vaccinated at day old in the hatcheries against IB Mass infection, with

an economical life long duration of immunity (up to 6 weeks of age), as widely prescript in the EU.

It is acknowledge that a booster can indeed be performed in the field, likely with a heterologous vaccine strain, but

given that no data was provided by the applicant, Merial believes that this cannot be included into the SmPC.

However, should the Members States still willing to add an advice on an IB booster, the applicant proposes the

following sentence:

Duration of immunity:

…/…

-IBV: 6 weeks after a single dose. Depending on the field epidemiological situation, a booster with a relevant IB

strain can be performed at the appropriate timing evaluated by the veterinarian.

RMS comment

The RMS supports neither the proposal of the applicant, nor the request of the CMS to mention a recommended

booster.

Indeed, concerning Hatchpak Avinew IB H120, the indication with regard to the booster wi th Avinew is supported

by safety and efficacy of the proposed vaccination schedule, whereas no data is available for the IB component.

Therefore, the RMS doesn’t consider appropriate to give any advice in the SPC which is not supported by data in

the dossier.

For the record, the RMS doesn’t consider mandatory for the applicant to propose a complete vaccination schedule

for the protection against IB, tak ing into account that it will depend on the epidemiological situation (including

pressure of infection and strains present in the field) and the duration of breeding of the birds. This is going

beyond the requirements for the granting of a Marketing Authorisation.


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Variations reports

VARIATION FR/V/0171/001/II/001


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MUTUAL RECOGNITION PROCEDURE

Type II variation

D60 ASSESSMENT REPORT

FR/V/0171/001/II/001

PRODUCT DETAILS Name of product HATCHPAK IB H120




Type of application Type II variation



69007 LYON

France

Phone number 33 4 72 72 39 76

Reference number of application FR/V/0171/II/001

VARIATION DETAILS :

Present product particular Proposed change

Current SPC

4.8 Interaction with other medicinal products

and other forms of interaction

No information is available on the safety and efficacy

from the concurrent use of this vaccine with any other

except with a frozen live vaccine against Newcastle

disease containing VG/GA strain and with a

recombinant HVT vaccine expressing the protective

antigen of the Infectious Bursal disease virus. It is

therefore recommended that no other vaccines than

these should be administered within 14 days before or

after vaccination with the product.

Concerning the association with the recombinant HVT

vaccine expressing the protective antigen of the

Infectious Bursal disease virus, the safety has been

established and the efficacy has been demonstrated

by challenge for the Infectious Bronchitis and Gumboro

New SPC

4.8 Interaction with other medicinal products

and other forms of interaction

No information is available on the safety and efficacy

from the concurrent use of this vaccine with any other

except with a frozen live vaccine against Newcastle

disease containing VG/GA strain and with a

recombinant HVT vaccine expressing the protective

antigen of the Infectious Bursal disease virus. It is

therefore recommended that no other vaccines than

these should be administered within 14 days before or

after vaccination with the product.


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strains.

INTRODUCTION

HatchPak Avinew is a live frozen vaccine against Newcastle disease (ND), VG/GA strain. It is also named M713

(ND), as it was its internal reference during development.

HatchPak IB H120 is a live frozen vaccine against Infectious Bronchitis (IB) containing the H120 st rain. HatchPak

IB H120 is also named M713 (IB), as it was its internal reference during development.

HatchPak Avinew IB H 120 is a live frozen vaccine against Newcastle disease (ND), VG/GA strain and live

Infectious Bronchitis virus, H120 strain. It is made up of two ampoules: one containing the ND component -also

named M713(ND) - and one containing the IB component - also named M713(IB).

As committed during the HatchPak procedures, Merial has performed a compatibility study with Vaxxitek

HVT+IBD vaccine. The recombinant HVT vaccine, also named RMB 533 vaccine or Vaxxitek HVT+IBD vaccine, is

a live vaccine based on the use of a recombinant turkey Herpesvirus (HVT) expressing the viral protein 2 (VP2)

gene of the Infectious Bursal Disease Virus (IBDV). This inserted gene, related with immunogenicity, allows

claiming for this vaccine a dual protection against Gumboro disease and Marek's disease.

In order to complete the efficacy data of the HatchPak range vaccines as regard the association with the

recombinant HVT vaccine, the applicant submits to the Authorities a study (Document 07.0326.8. RMB 533

vaccine - Compatibility with vaccines M713 (ND) and M713 (IB)).

Preliminary assessment report

Report 07.0326.R: RMB533 vaccine- Compatibility with vaccines M713 (ND) and M713 (IB) – Efficacy

against a Marek’s disease challenge in SPF chickens after concomitant administration of the 3 vaccines

at one day old.

Animals 108 day-old SPF chickens allocated to 3 groups and vaccinated at D0:

G1 : 36 animals with RMB 533 (VAXXITEK HVT+IBD)

G2: 36 animals with M713 (ND) and M713 (IB) (HATCHPAK AVINEW IB H120) =

control group

G3: 36 animals with RMB 533, M713 (ND - HATCHPAK AVINEW) and M713 (IB -

HATCHPAK IB H120)

Vaccine HATCHPAK AVINEW IB H120, batches 73B025 & 83825 – 4.56 log10 EID50 of

H120/bird and 6.14 log10 EID50 of VG/GA/bird - Diluent: spring water

VAXXITEK HVT+IBD – commercial batch – 1 dose of 0.2 ml titrating 3.7

log10PFU/bird


Challenge Challenge of the 3 groups 9 days after vaccination, with MDV strain GA22 by IP route

(3.3 log10 PFU/bird)

Follow-up Daily observation for 70 days after challenge. Post-mortem examination to check MD

lesions.

Serology on D79 in ten birds of each group: ND antibodies (HIT), IB (SN) and IBD (SN)

Statistical analysis Number of protected and affected birds in each group compared by Chi-square’s test or

Fischer’s exact test


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Results Before the challenge (D5-D7), 3 birds from group 1 were found sick or dead. It was

considered as an early non-specific mortality.

Clinical results:

Group Dead with

lesions/total dead

Birds with

lesions/surviving

Total affected/total

challenged

G1 0/3 1/30 3% (1/33)

G2 control 3/3 23/33 26/36 (72.2%)

G3 0/1 1/35 2.8% (1/35)

Statistical significant difference between G1 and G2, G3 and G2 and not between G1

and G3.

Relative protection score (RPS): group G1: 95.4%, G2: 0%, G3: 96%

Serology results:

Group IBD IB ND

G1 > 4.40 0 < 1.0

G2 0 1.75 2.60

G3 > 4.30 2 < 2.90

RMS comments

This study is compliant with the immunogenicity test of the Ph. Eur. monograph of live Marek vaccine (2008/589).

The results indicate that the vaccine VAXXITEK HVT+IBD administered at the minimum dose induces a

satisfactory protection when administered alone (RPS of 95.4%) or the same day as HATCHPAK AVINEW IB

H120 (RPS of 96%). According to the study results, a high percentage of birds (72.2 %) of the birds not vaccinated

with VAXXITEK HVT+IBD showed lesions specific of Marek's disease, thus validating the challenge performed

aecording to the European Pharmacopoeia requirements.

Therefore, the absence of interaction after the use of the three vaccines is considered demonstrated.

Conclusions The RMS considers that the compatibility of the 3 HatchPak vaccines regarding the efficacy of VAXXITEK

HVT+IBD vaccine against Marek's disease (MD) was demonstrated.

The RMS is therefore ready to accept the variation.

At day 55, DE, IE, IT and CZ have indicated that they are ready to accept the variation. No comments were

received from the other countries. Therefore, the procedure is considered accepted.


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Type II variation


FR/V/0171/001/II/002

PRODUCT DETAILS Name of product HATCPAK IB H120

Active ingredient(s) Live Infections Bronchitis virus, H120 strain


One day old



Name and address of applicant MERIAL SAS


69007 LYON

Phone number (33) 04.72.72.39.76

Fax number (33) 04.72.72.34.30

Reference number of application FR/V/0170/001/II/002

VARIATION DETAILS :

Subject: Addition of LPA site as alternative site for the production of the Live Infections Bronchitis virus, H120

strain


Manufacturing site


254, rue Marcel Mérieux

69007 LYON

FRANCE

MERIAL ITALIA SPA

Manufacturing site



69007 LYON

France

MERIAL ITALIA SPA


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ITALY



ITALY

MERIAL Laboratoire Porte des Alpes

Rue de l’Aviation

69800 SAINT PRIEST

FRANCE

Introduction

In order to increase its product management efficacy, to optimise human resources, technical and financial

means, MERIAL continues to develop its manufacturing strategy based on the principle of dedication of one site to

specific productions, ensuring focussed continuous investments that guarantee a high level of quality of its

vaccines in accordance with the state of the art.

The implementation of this strategy has lead to the creation and further development of the site Lyon Porte des

Alpes (LPA) with the objective that it becomes eventually the site of excellence for Merial's biological products

manufacturing in Europe.

The strategy implementation is still ongoing and recently some additional investments were confirmed for the LPA

site. The final picture for production is eventually:

- To finalise the relocation to LPA of manufacture of vaccines

- To relocate progressively the manufacture of all remaining viral active ingredients to LPA in three steps, due to

sortie constraints (workload associated with all validation data generation):

o Step 1: active ingredients produced by roller bottles technology

o Step 2: live active ingredients produced in eggs

o Step 3: active ingredients produced in bioreactors

- Finally, to close definitely the production plant of Lyon Gerland (LLG).

Initially, step 1 and step 2 were planned to be managed simultaneously as a global validation plan based on the

"family approach", however due to timing and manufacturing constraints, Merial decided to split this global

validation in 2 steps.

Currently, Merial is in the process of relocating progressively the production of its live viral active ingredients

produced in eggs from the historic site of Lyon Gerland (LLG) to the new site Lyon Porte des Alpes (LPA). This

step correspond to the step 2 defined above.

As this change will be a progressive relocation with a transitional period of time during which the productions could

be conducted on both sites, the relocation is managed as an addition of alternative manufacturing site. The

implementation of this addition of LPA site impacting 5 active ingredients is only the continuation of the step 1

regarding the relocation for active ingredient produced by roller bottle technology and is managed with the same

strategy. Strategy already validated by authorities and successfully implemented for 33 ac tives ingredients.

Documentation submitted

The Marketing Authorisation Holder submitted the following documentation:

Administrative data

Expert Report

The validation documentation including experimental data

The manufacturing authorisation for LPA site


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1. EGGS TECHNOLOGY VALIDATION FOLLOWING OF THE "FAMILY APPROACH"

1.1. The LPA site

The LPA site is regularly inspected by French inspection services and is appropriately authorised and GMP

compliant to manufacture biological products.

Manufacturing activities are already routinely performed in LPA site: formulation, freeze-drying and filling

operations. Some of these activities are also performed in LLG, thus, all the managers are already dealing with

both LLG and LPA laboratories: The quality management is headed by the same people who implement the same

policies and systems in both sites. The personnel of LPA have the same training as personnel of LLG. And due to

the fact that the 2 sites are closed together some people who are producing now in LLG will produce at the new

site and inversely people who work at LPA could work at LLG.

Merial is already used to qualify different buildings of the same site in LLG for active ingredient productions:

qualification of premises and equipments is an already mastered activity within Merial. Thus, LPA site addition is

similar to this activity. The premises and equipments in LPA will not be product -dedicated and will be used for

several active ingredient productions. Thus, if these premises are validated with some representative active

ingredients (see paragraph "representative active ingredients") they will be suitable/validated for all other active

ingredients.

Implementation of the same quality policies means that documentation, procedures, specifications and

instructions are similar in both LLG and LPA.

Additionally, technical devices and starting materials used are identical, emphasising the equivalence of the

laboratories.

All concerned active ingredients are already controlled in LPA site (approved for both QC activities and release

activities). Thus, no change in the control techniques and control laboratories will be associated to the productions

relocation: the data obtained for batches produced at LPA is directly compared to data obtained for batches

obtained at LLG without inter-laboratory variability as in some site transfers.

Thus, this site addition within MERIAL is a very specific case due to the above-mentioned particularities.

1.2. The "family grouping": definition

As already implemented for active ingredients produced in roller bottle technology (i.e. step 1), some data

generated from one active ingredient may be applicable to others if some big features are kept. This lead Merial to

define a manageable but valuable strategy allowing a reduction of the amount of data to be generated without

decreasing quality of information required for validation.

Merial continues to work with the so-called "family approach" based on a reasoned choice of 3 main criteria

families that define each of the relocated components:

- The nature of the micro-organisms: distinguished per antigenic families (based on viral/bacterial taxonomia)

- The nature and type of tells on which the micro-organisms are cultured: distinguished by multiplication support

families (knowing that the multiplication support concerned by the present step 2 is only SPF hen eggs)

- The nature of the production technology performed on the harvested culture: distinguished by process families

(frozen, mechanical homogenization, ...)

In fact, each active ingredient is defined by 3 different families: antigenic family, multiplication support family and

process family. The validation plan consists in using at least once, any representative of the defined families to

validate the relocation of the concerned active ingredients. With that "family approach", if representative active


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ingredients and formulated vaccines are righteously chosen, validation work with some active ingredients and few

vaccines validate the quality of all active ingredients in all vaccines.

It is important to remind that this step 2, as already said, is only the continuation of the global validation strategy

beginning with the transfer of active ingredient produced by roller bottle technology (step 1) and, for this reason,

some data of the step 1 validation will be used in the validation of this step 2 (in such case, cross -references are

indicated).

To place the step 2 in the context of the global strategy in order to understand accurately what remains to do, 2

global recapitulative tables are presented in the variation document (p. 6-7):

- the first one taking into account the antigenic family and multiplication support family

- the second one taking into account the antigenic family and process family

As it can be concluded from these tables, only the picornaviridae family remains to be validated and only the

multiplication support corresponding to SPF chicken hen eggs remains to be validated, although it was chosen to

generate additional data from the paramyxoviridae family (Newcastle disease virus).

1.2.1. Antigenic families of active ingredients impacted

The repartition per antigen families of active ingredients is displayed below (representative active ingredients are in

bold):

Antigenic Family Active ingredients already validated by

the step 1

Active ingredients impacted by the

step 2

Coronaviridae

Inactivated Bovine Coronavirus Attenuated Infectious Bronchitis virus,

strain CR88 121

Live strain Infections Bronchitis virus, Hl

20

Paramyxoviridae

Canine Attenuated Para-influenza type

2

component

Inactivated Canine Para-influenza type 2

component

Attenuated Distemper virus

Live SHSV component (VC03 strain)

Live SHSV (PL-21 strain°

Live Newcastle disease virus,

VG/GA

strain

Picornaviridae

None Modified duckling hepatitis virus

(E52

strain)

Attenuated infections encephalomyelitis

virus, Calnek 1143 strain

In the global validation plan including step 1 (Active ingredients produced by roller bottle technology) and step 2

(Active ingredients produced by eggs technology) Merial proposed to include at least one virus per antigenic family

to carry out the validation plan (representative of this family or this support). Then, if the manufacture of the

representative virus(es) was satisfactory (production of two batches of each one), it could be concluded that

normally, for any virus of the family, a successful production will be obtained.

As observed in the table above, each antigen family is represented, at least, once in both steps and only

Picornaviridae family remains to be validated in this step 2.

1.2.2. Multiplication support families

In the step 2, the multiplication support to validate is only SPF hen eggs.


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Then, if the manufacture of the representative production support was satisfactory (in this case, production of two

batches of active ingredients in eggs), it could be concluded that the personnel is qualified to produce active

ingredients in eggs in a given environment and that normally, a successful production will be obtained for any virus

growing on this multiplication support in similar environment.

1.2.3. Process families

All process families were already validated during the step 1 of the relocation with the conclusion that the

premises, equipments and personnel are qualified to perform those families of process. So, all process families

concerned by the step 2 of the validation are validated see the recapitulative table on p.9.

As shown in this table, it was decided that most of process families will be val idated at least one more time in this

step 2 of the validation for the following active ingredients: live Newcastle disease virus, strain VG/GA and modified

duckling hepatitis virus, strain E52.

1.3. The representative active ingredients

The representative active ingredients are those for which direct validation was performed in order to validate the

transfer of all the active ingredients impacted by the site addition. They were chosen in a combined way to be in

accordance with the following rules:

- All antigenic families are involved at least once

- All the multiplication supports are involved at least once

- All the process families are involved at least once.

The simple application of these rules allows to conclude that one active ingredient from the picornaviridae family

can be defined as representative of the only antigenic family and multiplication support (i.e. SPF hen eggs)

remaining to validate. The modified duckling hepatitis virus (E52 strain) included in the vaccine HEPATOVAX was

chosen.

Moreover, MERIAL decided to add 1 representative active ingredient multiplied by eggs technology to this

validation step 1, the live Newcastle disease virus, VG/GA strain, which is the more frequently Newcastle disease

strain produced at MERIAL.

For these 2 representative active ingredients, the validation plan (thus generated data) includes:

- the production of 2 batches and quality of these production runs is assessed through the obtained batch-to-batch

consistency data (key process parameters such as time of culture, treatment parameters...) and control results

(bacterial and fungal sterility, infective titre...). They are compared to data obtained from 2 batches produced in the

currently approved LLG site.

- the formulation of one vaccine using these representative active ingredients to confirm their antigenic quality

through the control test results of the finished products.

2. VALIDATION DOCUMENTATION

For each active ingredient (AI) impacted by the site addition, the data are presented in 1 or 2 pages as per the

sequence listed in the table below:

Active ingredient Validation (Direct

or indirect)

page

Live Infections Bronchitis virus, H120 strain Indirect p.0014

Live Newcastle disease virus, VG/GA strain Direct p.0017

In this report, only data related to the vaccines Hatchpak Avinew IB H120, Hatchpak IB H120 and Avinew are

presented.


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2.1 AI: Live infections bronchitis virus, H120 strain

For the Al: Live infections bronchitis virus, H120 strain, cross-validation data were obtained from the representative

active ingredients (2x3 batches) and vaccines (3 batches formulated) as detailed in the Table below:

AI: IB H120 component

Antigenic family Multiplication

support

Process family Supporting

documentation

Key features of

the AI

Frozen + Used

extemporaneously

+ Clarification

filtration

Cross validated

by:

Representative AI:

Inactivated Bovine

Coronavirus

Vaccine:

Coriniffa RC

Coronaviridae NA

Step 1

(data in annex

p.0055)

Representative AI:

Live Newcastle

disease

VG/GA strain

Vaccine:

AVINEW

NA SPF hen eggs Frozen + Used

extemporaneously +

Clarification by

filtration

AI: P.0017

Vaccine: p.0034

Representative AI:

Modified Duckling

hepatitis virus (E-

52 strain)

Vaccine:

HEPATOVAX

NA SPF hen eggs Used

extemporaneously

AI: p.0019

Vaccine: p.0044

NA: Not Applicable

Even with no specific data related to Al: Live infections bronchitis virus, H120 strain, scientific information

confirmed by satisfactory cross-validation data based on the results obtained from 2 successive production

batches of the representative active ingredients and from the vaccines formulated allow to validate the addition of

LPA.

In conclusion, the relocation to LPA of the production of AI: Live infections bronchitis virus, H120 strain

is validated for:

- HATCHPAK IB H120 vaccine (see updated list of site in annex p.0079)

- HATCHPAK AVINEW IB H120 vaccine (see updated list of site in annex p.0082).

2.2 AI: Live Newcastle disease, VG/GA strain

For the AI: Live Newcastle disease, VG/GA strain, as representative ac tive ingredient, direct validation data were

obtained on the following virus family, multiplication support, and process family (see Table below):

AI: Live Newcastle disease VG/GA strain

Cross validation by: Antigenic family Multiplication

support

Process family Supporting

documentation


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Representative AI: Frozen + AI: p.0017

Live Newcastle disease Used VG/GA strain Paramyxoviridae SPF hen eggs extemporaneously

+

Vaccine: Clarification by

AVINEW filtration Vaccine: p.0034

NA: Not Applicable

Representative AI: the results obtained from 2 successive production batches of active ingredient carried out at

LPA were satisfactory, in particular titres, and in accordance with the approved specifications thus confirming the

absence of impact on the quality of the active ingredient.

Vaccine (1 batch): all the control results were satisfactory, in particular the infective titre results were within the

required norms. Therefore, the manufacture and control tests of the vaccine formulated with active ingredients

produced at LPA and the specifications have not been modified by the addition of the new AI manufacturing site,

and comply with the registration file (sec certificate of analysis in annex p.0034 + certificate of analysis of vaccine

with active ingredient produced at LLG in annex p.0039 for comparison)

In conclusion, the addition of LPA for the production strain is validated for:

- AVINEW vaccine (see updated list of site in annex p.0088)

- HATCHPAK AVINEW vaccine (see updated list of site in annex p.0090)

- HATCHPAK AVINEW IB H120 vaccine (see updated list of site in annex p.0082)

ACTIVE INGREDIENT: LIVE NEWCASTLE DISEASE, VG/GA STRAIN

Summary of the characteristics of the 2 batches of Live Newcastle disease, VG/GA strain, AI produced at LLG

and 2 batches produced at LPA

Characteristics AI Batch No.

7VG5Y22 7VG5A24 7VGLPA01 7VGLPA02

Date of manufacture 01/06/2007 08/06/2007 11/10/2007 18/10/2007

Manufacturing site LLG LLG LPA LPA

Summary of the production parameters of the 2 batches of Live Newcastle disease, VG/GA strain, AI produced at

LLG and 2 batches produced at LPA

Parameters AI Batch No.

7VG5Y22 7VGSA24 7VGLPA01 7VGLPA02

Culture

Number of eggs used 10906 11644 1379 1311

Volume of inoculum 0,2 0,18 0,2 0,21

Date of viral inoculation 29/05/2007 05/06/2007 08/10/2007 15/10/2007

Harvest

Date of harvest 01/06/2007 08/06/2007 11/10/2007 18/10/2007

Volume of allantoïc fluid 96 litres 109,5 litres 7,3 litres 6,7 litres

Volume of antibiotics (1%

gentamicin and 3% polymyxin)

1595 ml 1818 ml 121 ml 111,2 ml

Treatments

Date of clarification

Volume of stabiliser

01/06/2007

97,5 litres

08/06/2007

111,3 litres

11/10/2007

7,2 litres

18/10/2007

6,5 litres

Active ingredient

Volume of active ingredient 181,5 litres 212 litres 10,35 litres 9 litres


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Date of storage

Storage temperature

01/06/2007

+5 & -40°C

08/06/2007

+5 & -40°C

11/10/2007

+5°C

18/10/2007

+5°C

Summary of the control test results obtained with the 2 batches of Live Newcastle disease, VG/GA

strain AI produced at LLG and 2 batches produced at LPA

Technique

(No.)

Limit of

acceptante

A

I

B

a

t

c

h

N

o

.

AI Batch No.

7VG5Y22 7VG5A24 7VGLPA01 7VGLPA02

Infective titre

(15 001)

R 8.0

Log10EID50/ml

9 6

EID50/ml

9,6 EID50/ml 9,5 EID50/ml 9,6 EID50/ml

Bacterial and

fungal

sterility

(11 000)

No growth No growth No growth No growth No growth

RMS Conclusions

The proposed variation is adequately justified. The provided data show that the production parameters and results

of quality control tests were all found satisfactory, demonstrating the equivalence of vaccine quality whatever the

manufacturing site, i.e. LLG and LPA.

No stability data were provided in the documentation. This is justified by the particularities of the LPA site (same

QA, QC and Production Management, identical policies, staff has the same training and is interchangeable,

identical starting material, similar equipment, same production process making that the transfer is like an internal

relocation).

LIST OF QUESTIONS

Before D55

The Paul-Ehrlich-Institut is prepared to accept the above mentioned variation provided the following commitments

are accepted by the applicant:

-to notify when the LLG site will be closed for the production of active ingredient ND strain VG/GA.

-to mention the production site of active ingredients in every batch protocol complying with the EDQM until the

closure of the LLG site has occurred.

-to provide the batch protocols of the three first antigen batches of IBV strain H120 manufactured at the LPA site,

as no direct validation has been performed with this antigen.

RMS comments

The CMS has accepted the variation after the MAH has provided a letter of commitments.

At D59

1. It is noted that the applicant has presented final batch results for only one batch of the vaccine produced in

eggs. The applicant should present the results of another batch for satisfactory comparison.

2. It is noted that no direct validation data is presented for the component. We would suggest that the

applicant commits to providing the batch test results for the first two batches produced at the LPA site

prior to the marketing of the product in the EU.


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3. The applicant should explain how Coronaviridae is represented in both steps 1 and 2 as stated in the last

paragraph of section 2.2.1, page 8.

RMS comments

The MAH has given the commitment to provide the batch protocol of one batch of vaccine using the active

ingredient produced in eggs at the LPA site.

The results of two batches of active ingredient produced at the LPA site are provided.

The MAH confirms that the production of a representative member (IB H 120 strain) of the Coronavirus family at the

LPA site is satisfactory.

Final Conclusion:

At D55, CZ, DE, IT, HU, SK and IE supported the conclusion of the RMS and were prepared to accept the variation

request. No comments were received from other CMS except UK that agreed with the overall conclusion but had

questions.

The UK comments were taken into account by the applicant. The applicant provided adequate answers to the UK

questions on 2/12/2008..

The RMS concluded that the requested variation on HATCHPAK AVINEW IB H120 is acceptable and can be

approved.

The manufacturing agreed sites are :

Name and address -

batch release

Merial

Rue de l’aviation

69800 Saint-Priest

France

Name and address -


product

Merial

Rue de l’aviation

69800 Saint-Priest

France



Allée des cypress

01150 Lagnieu

France




Merial


69007 Lyon

France

Merial

Rue de l’aviation

69800 Saint-Priest

France

MERIAL ITALIA SPA



Italy




(2 sites)

Merial


69007 Lyon

France

MERIAL ITALIA SPA



Italy


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Type II variation


FR/V/0170/001/II/003

PRODUCT DETAILS Name of product HATCHPAK AVINEW IB H120

Active ingredient(s) Live Newcastle disease virus, VG/GA strain

Live Infectious Bronchititis virus, H120 strain Target species Chickens one day old





69007 LYON- France

Phone number (33) 04 72 72 39 76

Fax number (33) 04 72 72 34 30

Reference number of application FR/V/0170/001/II/003

VARIATION DETAILS : Subject: Addition of LPA site as alternative manufacturing site for the finished product (formulation, filling and

deep-freezing).


Formulation and primary packaging sites of Hatchpak

Avinew IB H120 vaccine:



69007 LYON

France

MERIAL Italia SPA


27013 CHIGNOLO PO (Pavia)

Italie

Formulation and primary packaging sites of

Hatchpak Avinew IB H120 vaccine:



69007 LYON

France

MERIAL Italia SPA


27013 CHIGNOLO PO (Pavia)

Italie

MERIAL Laboratoire Porte des Alpes

Rue de l’Aviation


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69800 SAINT PRIEST

France


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Introduction

In order to increase its product management efficacy, to optimise human resources, technical and financial

means, MERIAL continues to develop its manufacturing strategy based on the principle of dedication of one site to

specific productions, ensuring focussed continuous investments that guarantee the high level of quality of its

vaccines in accordance with the state of the art.

The implementation of this strategy has lead to the creation and further development of the site Lyon Porte des

Alpes (LPA) with the objective that it becomes eventually the site of excellence for Merial's Biological products

manufacturing in Europe.

In this way, vaccines manufactured in Laboratory Lyon Gerland (LLG) are transferred progressively to LPA.

Both Manufacturing sites are MERIAL sites. Biological Manufacturing and Quality Operations (QA and QC) of each

site are respectively part of the Biological Manufacturing department managed by the same head i.e. currently Dr

Michel Dauvergne for Production and Dr Pierre-Jean Consalvi for Quality Operations.

The addition of LPA site for the production of active ingredients of HATCHPAK vaccines (Infectious B ronchitis virus

strain H120 component and Newcastle disease virus, VG/GA strain, component) was accepted recently.

The applicant requests now the addition of the new manufacturing site, LPA, for the manufacturing process of

HATCHPAK vaccines finished product (formulation, filling and deep-freezing) without any other change.

Documentation submitted

The Marketing Authorisation Holder submitted the following documentation:

Administrative data

Expert Report

The validation documentation including experimental data

The manufacturing authorisation for LPA site (manufacturing authorization of LPA site and its GMP

certificate in Annex p.008 and p.015)


1. Description

Vaccines concerned are the following:

HATCHPACK AVINEW

HATCHPACK AVINEW IB H120

HATCHPACK IB H120

Hatchpak vaccines consists of frozen live suspensions of the VG/GA strain of Newcastle disease virus (Hatchpak

Avinew) or a frozen live suspension of the H120 strain of Infectious bronchitis virus (Hatchpak IB H120) or both

(Hatchpak Avinew IB H120).

LPA site is a pharmaceutical establishment, EU GMP compliant (please find enclosed the manufacturing

authorization of LPA site and its GMP certificate in Annex p.008 and p.015)

The site addition is internal to MERIAL (no third external party), close and transparent collaboration between LLG

and LPA sites is fully ensured.

All working documents describing the formulation, filling and freezing of each vaccine concerned are shared

between both sites. The technicians of both sites are part from the same team and they are susceptible to work on

both sites.


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Moreover, equipments used for the formulation and the primary packaging (filling and deep-freezing) are similar

equipments in both sites and LPA site is already qualified to run out the operations of blending and filling for more

that 5 years.

Finally, HATCHPAK vaccines are already controlled in LPA site (approved for both QC and release activities).

Thus, no change in the control techniques and control laboratories is associated to this production relocation:

obtained data are directly compared to current data without inter-laboratory variability as in some site transfers.

Also, no change in the specifications of the vaccine is associated to this relocation.

All those elements justify that a very limited impact is expected on the quality of the vaccines.

2. Validation Data

The production and the control data of 3 batches manufactured in LLG site are compared with 2 batches

manufactured in LPA site for each vaccine HATCHPAK AVINEW and HATCHPAK IB H120.

2.1 Production parameters

Table 1: Summary of production parameters of the 3 batches of HATCHPAK AVINEW vaccine produced at LLG

and 2 batches produced at LPA

Characteristics

Batch No.

LLG (7LPA01) LPA (7LPA02)

3AWF7Pl5A* 3AWF7R16A* 3AWF7S17A* 7AWFLPA01

(7LPA01)

7AWFLPA02

(7LPA02)

Active ingredient

No.

3VG5P41 3VG5R43 3VG5D54 7VGLPA01 7VGLPA02

Volume of Active

ingredient (ml)

4000 (1) 4000 (2) 4000 (3) 10350 9000

Total volume of

bulk prepared

(ml)

4000 (1) 4000 (2) 4000 (3) 10350 9000

Date of blending 11/03/2003 13/03/2003 02/07/2003 11/10/2007 18/10/2007

Date of filling 11/03/2003 13/03/2003 02/07/2003 11/10/2007 18/10/2007

Date of deep-

freezing

11/03/2003 13/03/2003 02/07/2003 11/10/2007 18/10/2007

Number of filled

ampoules

392 360 360 1944 1476

Packaging 5-ml type I glass 5-ml type I glass 5-ml type I glass 5-ml type I glass 5-ml type I glass

LLG: Lyon Gerland Laboratory

LPA: Lyon Portes des Alpes Laboratory

* 2 final lots were prepared from each bulk

(1) Volume for bulk 3AWF7P15 ; (2) Volume for bulk 3AWF7R1; (3) Volume for bulk 3AWF7S17

Table II: Summary of production parameters of the 3 batches of HATCHPAK IB H120 vaccine produced at LLG and

2 batches produced at LPA

Characteristics

Batch No.

LLG LPA

3BIF7A0IA* 3BIF7B02A* 33BIF7C0A* 7IBFLPA01

(7LPA01)

7IBFLPA02

(7LPA02)

Active ingredient

No.

3VG5P41 3VG5R43 3VG5D54 7H120LPA01 7H120LPA02

Volume of Active

ingredient (ml)

4000 (1) 4000 (2) 4000 (3) 14000 13200


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Total volume of

bulk prepared

(ml)

4000 (1) 4000 (2) 4000 (3) 14000 13200

Date of blending 03/11/2003 03/11/2003 04/11/2003 27/09/2007 04/10/2007

Date of filling 03/11/2003 03/11/2003 05/11/2003 27/09/2007 04/10/2007

Date of deep-

freezing

03/11/2003 03/11/2003 05/11/2003 27/09/2007 04/10/2007

Number of filled

ampoules

356 352 343 1944 1944

Packaging 5-ml type I glass 5-ml type I glass 5-ml type I glass 5-ml type I glass 5-ml type I glass

LLG: Lyon Gerland Laboratory

LPA: Lyon Portes des Alpes Laboratory

* 2 final lots were prepared from each bulk

(1) Volume for bulk 3AWF7P15 ; (2) Volume for bulk 3AWF7R16; (3) Volume for bulk 3AWF7S17

2.2 Control results comparisons

A comparison of control tes t results of 3 batches of HATCHPAK AVINEW vacc ine produced at

LLG and 2 batches produced a t LPA are presented in Table III, and 3 batches of HATCHPAK IB

H120 vacc ine produced at LLG and 2 batches produced at LPA are presented in Table IV.

The complete cert i ficates of analys is corresponding to the 5 HATCHPAK AVINEW batches are

at tached in Annex p.025 and the 5 HATCHPAK IB H120 batches are at tached in Annex p.046.

Table III: Summary of the control test results obtained with the 3 batches of HATCHPAK AVINEW vaccine

produced at LLG and 3 batches produced at LPA

Technique (No.)

Requirements

Batch No.


3AWF7P15A* 3AWF7R16A* 3AWF7Sl7A* 7AWFLPA01

(7LPA01)

7AWFLPA02

(7LPA02)

Appearance (10

001)

Yellow suspension Yellow

suspension

Yellow

suspension

Yellow

suspension

Yellow

suspension

Yellow

suspension

pH (10010) 6.8 R 7.8 7.2 7.2 7.3 6,8 6,8

Volume (10011) R 4.5ml 4.6 4.6 4.64 5.1** 5.1 **

Identif ication of the

active

ingredient(002302)

Assay of the

active ingredient

(15001)

Specif ic

f luorescence

5,5 R 6.7 log10

EID50 per dose

Specif ic

f luorescence

5.69 log10 EID50

per dose

Specif ic

f luorescence

6.13 log10 EID50

per dose

Specif ic

f luorescence

5.63 log10

EID50 per dose

Specif ic

f luorescence

5,8 log10

EID50 per dose

Specif ic

f luorescence

5,8 log10

EID50 per dose

Bacterial and

fungal sterility

(11000)

Mycoplasmic

sterility (11204)

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

* Pilot registration batches

** the volume w as set erroneously at 5.1 ml/ampoule instead of 4.6 ml/ampoule as declared in the dossier

The manufacture and control tes ts obtained from 2 success ive product ion batches of HATCHPAK

AVINEW vacc ine carried out at LPA were sat is fac tory , and in accordance with the approved

spec ificat ions.

Table IV: Summary of the control test results obtained with the 3 batches of HATCHPAK IB H120 vaccine

produced at LLG and 3 batches produced at LPA


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Technique (No.)

Requirements

Batch No.


3BIF7A01A* 3BIF7B02A* 3BIF7C03A* 7IBFLPA01

(7LPA01)

7IBFLPA02

(7LPA02)

Appearance (10

001)

Yellow suspension Yellow

suspension

Yellow

suspension

Yellow

suspension

Yellow

suspension

Yellow

suspension

pH (10010) 7.0 R 8.0 7.3 7.3 7.3 7,1 7,1

Volume (10011) R 5.0 ml 4.79** 4.71** 4.84** 5.1 ml 5.1 ml

Identif ication of the

active

ingredient(001925)

Assay of the

active ingredient

(15003)

One dose

neutralised

3.7 R 4.7 log10

EID50 per dose

One dose

neutralised

4.27 log10

EID50 per dose

One dose

neutralised

3.96 log10 EID50

per dose

One dose

neutralised

4.15 log10

EID50 per dose

One dose

neutralised

4 log10

EID50 per dose

One dose

neutralised

4,4 log10

EID50 per dose

Bacterial and

fungal sterility

(11000)

Mycoplasmic

sterility (11204)

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

No grow th

* Pilot registration batches

** the volume w as set at 4.7 ml/ampoule for pilot registration batches.

As observed, the manufacture and control tests obtained from 2 successive production batches of HATCHPAK IB

H120 vaccine carried out at LPA were satisfactory, and in accordance with the approved specifications.

All those results confirm the absence of impact of the production site on formulation, filling and deep-freezing, and

demonstrate that HATCHPAK vaccines production is equivalent in both sites.

RMS comments

For Hatchpak Avinew, due to an error the two batches produced at the LPA site had a higher volume than the

volume specification (5.1 ml instead of 4.5 ml). For Hatchpak IB H120, as the three batches produced at the LLG

site were pilot batches, they had a lower filling volume than the volume specification (4.7-4.8 ml instead of 5.0 ml).

At the end of the development, the filling volume was finally set to 5.0 ml. Despite these differences of filling

volume, there is no impact on viral titre and on the compliance with the specifications of the finished product.

No stability data were provided in the documentation. This is justified by the particularities of the LP A site (same

QA, QC and Production Management, identical policies, staff has the same training and is interchangeable,

identical starting material, similar equipment, same production process making that the transfer is like an internal

relocation).

The applicant has provided the results for two batches produced at LPA site and the results of a third batch is

requested.

Nevertheless, it is considered that the provided data show that the production parameters and results of quality

control tests are satisfactory, demonstrating the equivalence of vaccine quality whatever the manufacturing site,

i.e. LLG and LPA.

RMS Overall Conclusion: The RMS is of the opinion that the requested variation on HATCHPAK AVINEW IB H120 is acceptable if the

applicant takes the commitment to provide the results for a third batch of vaccine produced at the LPA site.

At day 55, the Irish and the German authorities have indicated that they are ready to accept the variation. UK had

a question on the GMP certificate of the LPA site. The applicant has confirmed that a GMP inspection was

performed in 2008 and he will provide the corresponding certificate as soon as available. The UK authorities have

confirmed that it is acceptable.

No comments were received from the other countries. Therefore, the procedure is considered accepted.


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The manufacturing agreed sites are :

Name and address -

batch release

Merial

Rue de l’aviation

69800 Saint-Priest

France

Name and address -


product

Merial

Rue de l’aviation

69800 Saint-Priest

France



Allée des cypress

01150 Lagnieu

France




Merial


69007 Lyon

France

Merial

Rue de l’aviation

69800 Saint-Priest

France

MERIAL ITALIA SPA



Italy




(3 sites)

Merial


69007 Lyon

France

Merial

Rue de l’aviation

69800 Saint-Priest

France

MERIAL ITALIA SPA



Italy


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VARIATION FR/V/0171/001/IA/005/G

Change in the name of a manufacturing site resulting in the following agreed sites

Name and address -

batch release

Merial

Rue de l’aviation

69800 Saint-Priest

France

Name and address -


product

Merial

Rue de l’aviation

69800 Saint-Priest

France



Allée des cypress

01150 Lagnieu

France




Merial


69007 Lyon

France

Merial

Rue de l’aviation

69800 Saint-Priest

France

IZO



Italy




(3 sites)

Merial


69007 Lyon

France

Merial

Rue de l’aviation

69800 Saint-Priest

France

IZO



Italy

VARIATION FR/V/0171/001/IA/006/G

Deletion of a manufacturing site resulting in the following agreed sites

Name and address -

batch release

Merial

Rue de l’aviation

69800 Saint-Priest

France

Name and address -


product

Merial

Rue de l’aviation

69800 Saint-Priest

France



Allée des cypress

01150 Lagnieu

France




Merial

Rue de l’aviation

69800 Saint-Priest

France

IZO



Italy




(3 sites)

Merial


69007 Lyon

France

Merial

Rue de l’aviation

69800 Saint-Priest

France

IZO



Italy


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VARIATION FR/V/0171/001/IB/007

COMMENTS FROM THE SPANISH MEDICINE AGENCY (AEMPS)

Overall conclusion:

The AEMPS agrees with the overall conclusion of the RMS and is therefore prepared to grant a marketing

authorisation for the product provided that the remaining points raised are addressed satisfactory.

PART II ANALYTICAL DOCUMENTATION

II.G. Stability

The marketing authorisation holder might clarify a question related with the batch safety test. A summary table of

this study has been provided on the 5.2.3 Safety point at the final report and question about those results has

arisen. It has been assumed, regarding the monograph 5.2.9. Evaluation of safety of each batch of veterinary

vaccines and immunosera that the animal number considered for this test was 10, as thus has been shown on the

table.

The deaths occurred have been classified simply as “non-specific” by the applicant. The CMS requests further

details on these mortalities to ensure they can be classified as “non-specific”.

ANSWER OF THE APPLICANT

Routinely the release safety test approved and applied on HATCHPAK IB H120 vaccine batches corresponds to

technique No.200043.

This test was applied during the stability study of HATCHPAK IB H120 at the release step, at 27 m onths

(supporting the current shelf life) and at 39 months (to support the proposed shelf life).

This test is carried out on SPF chicks aged of at most 2 days old, administered by ocular route with 10 doses of

vaccine under a volume of 0.05 ml and observed daily for 21 days.

The vaccine complies with the test if none of the chicks shows any serious respiratory or nervous signs.

If, during the period of observation, more than 2 chicks die accidentally, the test should be repeated.

During the stability study, some non-specific mortalities were observed.

The conclusion of the non-specificity was based on the daily observation of the animals and on the necropsy of the

dead animals.

The results of the postmortem examinations are presented in the table below :

The mortality observed is early, during the first half (<10 days) of the 21 days observation.

The mortalities are also observed at each time of the study (T0, T27, T39) , so independent of the aging of the

product .

The mortalities in this study were either a congenital problem as a vitellus not resorbed and/or individual weakness

as a small size.

Otherwise no animal display any clinical signs as nervous or respiratory signs (dyspnea, coughing) during clinical

observation, neither lesion during necropsy attributable to the Infectious Bronchitis disease.

The mortalities are much more linked to the fragility of the animal used since they are vaccinated at day -old which

explained why the limit of acceptance of the test tolerates two non-specific mortalities.

In conclusion, the applicant confirms that the deaths observed (4 out 60 animals vaccinated) are non–specific

mortalities and, are not the consequence of HATCHPAK IBH120 vaccination.

POSITION OF THE RMS

A single question was received from ES, and solved by day 30 of the procedure.

The variation is therefore accepted, with the following conclusion: shelf life of the vaccine extended to 36 months.

Therefore, section 6.3. Shelf life of the SPC is changed to:


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Shelf life of the medicinal product as package for sale: 3 years 2 years


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RENEWAL

AGENCE NATIONALE DU

MEDICAMENT VETERINAIRE

HATCHPAK IB H120

Company: MERIAL


FINAL ASSESSMENT REPORT FOR RENEWAL

FR/V/0171/001/R/001


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PRODUCT DETAILS Name of product HATCHPAK IB H120

Active ingredients Live infectious Bronchititis virus, H120

strain


Indications In one day-old chickens: active

immunisation against Infectious Bronchitis

in order to reduce infection

with Massuchusetts serotype of Infectious

Bronchitis virus.

APPLICATION DETAILS Type of application Renewal



69007 LYON- France

Phone number (33) 04 72 72 39 76

Fax number (33) 04 72 72 34 30

Date of receipt for assessment

report

11/01/2012

Person for communication on

behalf of the applicant during the

procedure

Isabelle PERRET

[email protected]

+ 33 (0) 472724492

Reference number of application FR/V/0171/001/R/001

Timetable Clock start: 30/01/2012

Day 40: 10/03/2012

Day 55: 30/03/2012

Day 60: 13/04/2012

Day 80: 3/05/2012

Day 90: 13/05/2012

Concerned Member States CZ, DE, EL, ES, HU, IT, LT, LV, PL, SK

REFERENCE MEMBER STATE DETAILS Assessment report prepared by France


Reference number of application in

the Reference Member State

Dossier N° 12418

Date of the first marketing

authorisation in the RMS

14/09/2007

Contact Name Céline LORTEAU-SOURGEN- Caroline

Guittré

Address ANSES-ANMV

BP 90203 - 35302 Fougères CEDEX, FR

Phone number 33 2 99 94 78 82

Fax number 33 2 99 94 78 88

E-mail for Applicants

E-mail for CMSs [email protected]




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[email protected]



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Introduction

HATCHPAK IB H120 was approved in France and in CMS on 25/07/2007 via decentralised procedure

FR/V0171/001/DC.

For the current decentralised renewal procedure, the Data Lock Point is 31/10/2011.

In support of the application for renewal, the following documentation has been submitted:

European renewal application form

Currently-approved SPC, in English, with relevant national translations

Periodic Safety Update Report: covering 01/08/2011 to 30/10/2011 and summary bridging report from May

2007 to October 2011.

Clinical expert statement, concluding that there is no need to update the SPC and to carry out additional

studies

Labels (for national approval only)

Package leaflet/insert (for national approval only)

Statement of GMP compliance (from competent authority) for the different manufacturing sites:

Ministerio Della Salute, Italy, dated 18/10/2010 (Izo, Chignolo Po, Italy)

Anses-ANMV France, dated 06/04/2011 (for Merial, Lyon, France), 26/08/2010 (for Merial, Saint-Vulbas,

France) and 28/01/2011 (for Merial, Saint-Priest, France).

List of variations of any type approved since the grant of the marketing authorization

Variation FR/V/0171/001/II/001: Compatibility of Hatchpak with Vaxxitek HVT+IBD (Marek strain), submitted on June

2008 and approved on 06/10/2008

Variation FR/V/0171/001/II/002 : Transfer of active ingredient production produced in eggs from LLG (Merial,

Lyon, France) to LPA (Merial, Saint-Priest, France), submitted on August 2008 and approved on 11/01/2009

Variation FR/V/0171/001/II/003 : Addition of LPA site (Merial, Saint-Priest, France) for formulation and primary

packaging, submitted on January 2009 and approved on 31/03/2009

Variation FR/V/0171/001/IA/004: Refined acceptance criteria for sterility test, submitted on July 2011 and approved on

17/08/2011

Variation FR/V/0171/001/IA/005/G: Change in name of manufacturer for Chignolo Po site in Italy, submitted on January

2012 (in process).

RMS COMMENT

Variation FR/V/0171/001/IA/005/G: this variation is submitted (proposed timetable: day 0 on 15/02/2012, day 30 on

16/03/2012); however, in the application form, the new name (IZO) of the site of manufacture in Chignolo Po, Italia is alread y

indicated. Please find in page 26 (translation in page 28) the approval of IZO by the Italian competent Authorities

New information obtained since the delivery of the MA

Following variation FR/V/0171/001/II/002, the following commitment was made and not yet resolved :

- To notify when LLG site will be closed for production of IBV strain H120 active ingredient.

- To provide the batch protocols for the first three batches of IBV strain H120 active ingredient

produced at LPA site.”

This applicant states that this commitment will be answered in Q1 2012.

Qualitative and quantitative particulars of the constituents

Name of ingredients Quantity per dose Function

Live infectious Bronchititis virus, H120 strain 3.7 to 4.7 log10 EID50 Active ingredient

Protein hydrolysate q.s 1 dose stabilizer

Mannitol q.s 1 dose stabilizer


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The applicant states that the quality of the product, in respect of the methods of preparation and control, has been

regularly updated by variation procedure to take account of technical and scientific progress in accordance with

Article (27)1 of Directive 2001/82/EC as amended by Directive 2004/28/EC. The product conforms with current

CPMP/CVMP quality guidelines where relevant. He confirms that no changes have been made to the product

particulars other than those approved by the Competent Authority.

RMS COMMENT

Satisfactory.

Periodic safety update report (PSUR)

Product name HATCHPAK IB H120

ANMV file code 12418

Period covered by the PSUR 01/05/2007 – 31/10/2011

Date PSUR received 09/02/2012 – PSUR provided for renewal

Procedure and Procedure Number Decentralized procedure – FR/V/0171/001/DC

Product type / Active Substance Immunological - Infectious Bronchitis vaccine

Marketing Authorisation Holder Merial

Concerned Member States

Czech Republic, Germany, Greece, Hungary, Ireland

(until 11/2011), Italy, Latvia, Lithuania, Poland, Slovakia,

Spain (11 CMSs)

Author of the assessment Cédric COLMAR ([email protected])

NO SUSPECTED ADVERSE EVENTS RECORDED

Sales vo lum es During the period, 500,025,000 doses of vaccine were sold in the EU/EEA

(502,785,000 worldwide).

Estim ation of the

num b er of an im als

treated

As recommended in Volume 9B, the number of doses sold is considered equal

to the number of animals vaccinated. Therefore, 500,025,000 animals were

vaccinated in the EU/EEA (502,785,000 worldwide).

Conclusion/

Recommendation

As no adverse events were reported so far, there are no changes to the

evaluation of benefits and the risks afforded by the product. On the basis of the

above findings, continued use of this product as described in the current SPC

can be recommended.

No changes to the product literature or other regulatory actions are necessary.

Status of the assessment Final

Date of submission of next

PSUR

The next PSUR will be the 1st 1-year PSUR, covering the period from

01/08/2011 to 31/07/2012, and is expected on the latest by 29/09/2012.

Summary of product characteristics (SPC)

The updates agreed during the procedure are introduced:

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

HATCHPAK IB H120, frozen suspension for nebuliser suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION


Active substances:



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Live Infectious Bronchitis virus, H120 strain .......................................................... 3.7 to 4.7 log10 EID50*

Adjuvant(s):

Not applicable

Excipient(s):



3. PHARMACEUTICAL FORM

Frozen suspension for nebuliser suspension. Yellow.

4. CLINICAL PARTICULARS

4.1 Target species


4.2 Indications for use, specifying the target species

In one day-old chickens: active immunisation against Infectious Bronchitis in order to reduce infection with

Massuchusetts serotype of Infectious Bronchitis virus.


Duration of immunity: 6 weeks after a single administration.

4.3 Contraindications

None

4.4 Special warnings for target species




chickens.

4.5 Special precautions for use

Special precautions for use in animals


Special precautions to be taken by the person administering the veterinary medicinal product to

animals


manipulation should take place only in well ventilated place to prevent fatal suffocation .




break.



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4.6 Adverse reactions (frequency and seriousness)


days after vaccination in up to 15% of the birds.

4.7 Use during pregnancy, lactation or lay

The vaccine is only intended for use in newly hatched chicks and is not appropriate after the age of one day. The


particular the strain is compliant to the specifications of the Ph. Eur. with regard to the safety for the reproductive

tract.

4.8 Interaction with other medicinal products and other forms of interaction

No information is available on the safety and efficacy from the concurrent use of this vaccine with any other except

with a frozen live vaccine against Newcastle disease containing VG/GA strain and with a recombinant HVT vaccine

expressing the protective antigen of the Infectious Bursal disease virus. It is therefore recommended that no other

vaccines than these should be administered within 14 days before or after vaccination with the product.

4.9 Amounts to be administered and administration route


1. Prepare a container filled with the appropriate quantity of clean non-chlorinated drinking water (7 to 30 ml

per box of 100 chicks according to the type of sprayer used in the hatchery).


when handling liquid nitrogen should be taken. Refer to the section 4.5. Special precautions for use.

3. Remove from the liquid nitrogen container only those ampoules carried by a yellow cane which are to be

used during the vaccination session.


step.















13. Discard any ampoules that have been accidentally thawed. Do not re-freeze under any circumstances.

4.9.2 Posology

One administration from day-old, via the respiratory route (spray application).





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4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary



4.11 Withdrawal period(s)

Zero days.

5. IMMUNOLOGICAL PROPERTIES


The vaccine contains live infectious Bronchitis virus, H120 strain (Massachusetts serotype). The vaccine

stimulates active immunity against Infectious Bronchitis.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Protein hydrolysate

Mannitol

6.2 Incompatibilities

The presence of disinfectant and/or antiseptic in water and material used for the preparation of the vaccine

solution is not compatible with effective vaccination.

Do not mix with any other medicinal product, except a live frozen vaccine against Newcastle disease containing

VG/GA strain.

6.3 Shelf life

Shelf life of the medicinal product as package for sale: 2 years 24 months.

Use immediately after opening the vials and administer within 2 hours after preparation of the vaccine for use.


Store and transport the vaccine in liquid nitrogen (-196°C) and regularly check the level of liquid nitrogen.


6.5 Nature and composition of immediate packaging

Type I glass ampoule, 4- yellow ampoules cane.


- 10,000 doses IB ampoule

- 15,000 doses IB ampoule

Not all pack sizes may be marketed.

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste

materials derived from the use of such products


Merial Repeat-use


Dispose of waste material and any unused veterinary medicinal product by boiling, incineration or immersion in

an appropriate disinfectant in accordance with national requirements.

7. MARKETING AUTHORISATION HOLDER

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

RMS COMMENT

Considering the date of approval of the MA via DC (25/07/2007), the following is proposed

Date of renewal: 25/07/2012

10 DATE OF REVISION OF THE TEXT

RMS COMMENT

Proposal 25/07/2012

PROHIBITION OF SALE, SUPPLY AND/OR USE

The import, sale, supply and/or use of HatchPak IB H120 is or may be prohibited in certain Member States on

the whole or part of their territory pursuant to national animal health policy. Any person intending to import,

sell, supply and/or use HatchPak IB H120 must consult the relevant Member State’s competent authority on

the current vaccination policies prior to the import, sale, supply and/or use of the product.

Overall Conclusion

PL and IT were prepared to grant the renewal but had comments, essentially on the SPC and product literature. No

comments have been received from the other CMS: CZ, DE, EL, ES, HU, LT, LV, SK. The comments were taken

into account by the applicant and the SPC has been amended (SPC, product literature and answers provided on

12/04/12 and detailed below).

The RMS considers that the answers, the SPC and the product literature which are provided are acceptable.

The ANMV-ANSES is of the opinion that there are no serious public health concerns (human or animal) related to

the use of the product HATCHPAK IB H120. There are no objective reasons not to renew the marketing

authorisation.

The marketing authorisation for HATCHPAK IB H120 will be unlimited.


Merial Repeat-use


ANSWERS TO THE CLOQ – RMS COMMENTS

1. Periodic Safety Update Report

Total sales volume provided in the Summary Bridging Report is 502 785 000 doses.

According to PSURs total sales volume are (between 01.05.2007 and 31.01.2009 the product was not sold):

01.02.09-31.07.09: 16 830 000

01.08.09-31.01.10: 27 510 000

01.02.10-31.07.10: 57 795 000

01.08.10-31.01.11: 131 370 000

01.02.11-31.07.11: 145 560 000

01.08.11-31.10.11: 128 730 000

TOTAL: 507 795 000 doses not 502 785 000.

The applicant should explain this difference.

Applicant’s Response:

The Applicant would like to stress that the data basis from which the sales are extracted is on

perpetual move. Indeed, the sales indicated in each PSUR are the sales known and effective at the

moment of the extraction of this information.

There is a difference of the sales between the whole 6-month PSURs and the summary bridging

report because the sales extraction done again in 2011 for the summary bridging report reflects the

more recent real sales registered by MERIAL. This more recent extraction takes into account the

possible return of products in MERIAL (following cancel of orders, unsold...).

So, the sales mentioned in the summary bridging report are the last updated number of doses sold

by MERIAL including eventual sales return done that could not be planned in the 6-month PSURs.

RMS comment

Satisfactory.

2. SPC, labelling, package leaflet 2.1. SPC

2.1.1 Name of the Veterinary Medicinal Product

The full name of the veterinary medicinal product should be: “HatchPak IB H120, frozen

suspension for nebuliser suspension”.

Poland

Applicant’s answer:

The Applicant agrees with this proposal. Please find enclosed in Annex 1 the modified SPC in track-

mode.

RMS comment

Satisfactory.

2.1.2 Section 2: the sentence “Adjuvant(s): Not applicable” should be deleted

Italy



mode.

2.1.3 Section 6.3: This section should be changed as follows: Shelf life of the medicinal

product as package for sale: 2 years

Italy



mode.

RMS comment


Merial Repeat-use


Satisfactory.

2.1.4 Shelf life: Shelf life of the veterinary medicinal product as packaged for sale should be 2

years, not 24 months.

Poland


Same question than above : the Applicant agrees with this proposal. Please find enclosed in Annex 1

the modified SPC in track-mode.

RMS comment

Satisfactory.

2.1.5 Section 6.5 : The structure of the package should be clarified (e.g. carton box

containing 1 ampoule of 10000/15000 doses or carton box containing 4-yellow ampoules

cane of 10000/15000)

Italy


The Applicant would like to remind that there is no outer packaging for this product, as it is a product

stored in liquid nitrogen (see explanation in question 2.2.1.)

Thus, there is no need to add anything on this section of the SPC.

RMS comment

Satisfactory.

2.1.6 The Applicant is also required to clarify what does “IB” mean in the following

“10000/15000 doses IB ampoule”

Italy


IB mention was indicated to clarify the component Infectious Bronchitis, useful for the bivalent

Hatchpak Avinew+IB H120 vaccine.

As this vaccine has been withdrawn in all countries, the Applicant proposed to delete the IB mention.

RMS comment

Satisfactory.

2.2. Labelling 2.2.1 Add : Live Infection Bronchitis virus

Italy


The Applicant would like to remind that due to the particularities of the vaccine (frozen suspension in

5-ml ampoule stored in liquid nitrogen), the content of the label was already discussed and approved

during the registration of this product.

Please find below the information given in the registration dossier and also the corresponding

discussion provided in the answer document referenced CPh/JL/GeR/EBR.07.D40 dated April 2007,

for your convenience:

RMS comment

Satisfactory.


Merial Repeat-use


“ Regarding the limitations of the labelling on the primary packaging, the justification is discussed in

the Part IB of the dossier, and some important parts are recalled hereafter for your convenience:

... Ampoules are clipped on metallic carriers (4 ampoules per carrier). Carriers are stored and sold in

liquid nitrogen containers (-196°C). This system is already implemented in the field with other

marketed frozen vaccines of MERIAL Marek ’s range (e.g. VAXXITEK HVT+IBD, CRYOMAREX

HVT, CRYOMAREX RISPENS or CRYOMA REX RISPENS+HVT).

The conditions of production have direct consequences on labels, since the primary packaging of

the vaccine suspension is very small (5 ml-ampoule), and there is no possibility to perform any

labelling operation after freezing (product is very sensitive to thawing).

In addition, the conditions of supply have direct consequences on packaging elements for the

following reasons:

- there is no possibility to have an outer package for this k ind of frozen product. The vaccine

suspension is stored directly in the liquid nitrogen container,

- depending on the order from a given hatchery, the same liquid nitrogen container may include

several frozen vaccines (with different strains).

Therefore, the following solutions are proposed:

- due to the size of the ampoule, only crucial information should be included in the labels, the

section of the template: "Minimum particulars to appear on small immediate packaging units" was

therefore used. In addition, the ampoule labelling must be performed before filling, sealing and

freezing, since these operations are carried out consecutively in closed circuit. Moreover, the final

geographical destination of the product in the European market is unknown at production stage.

In order to be able to supply “big” and “small” markets altogether, this implies that only a unique

“harmonised” label is stuck on ampoules with the same information provided throughout Europe. ...

We are confident that the amount of information is sufficient for a safe use of the product. Indeed the

product is used in very specialized area (hatcheries) where:

- the choice of the vaccine is determined before its use (not at the time of vaccination, using supplied

leaflet),

- the vaccine is administered by a professional that underwent special training before acting.

as no package leaflet nor secondary packaging can be immersed in the liquid nitrogen, we propose, in the

same way as what has already been in place for the other marketed frozen vaccines of MERIAL, to have a

package leaflet slipped within a plastic transparent wallet which is stuck on the container. The wallet

stuck on the container contains as many relevant package leaflets as vaccine types present in the

container,

- in order to easily distinguish the different vaccines stored in the container, MERIAL has implemented a

system of tabs stuck on the top of the carriers. The tab has its own colour coding depending on the nature

of the vaccine strain. ...

So the information on the direct packaging will be stickered or engraved on each ampoule before freezing.

Regarding the two first mentioned positions of the CMS, as explained above, the space does not allow

adding the withdrawal period. [...].”

Thus, there is no possibility to add the requested information in the labelling.

2.2.2 Add: zero days

Italy


Please see the answer to the above questions No. 2.2.1.

RMS comment

Satisfactory. 2.2.3 National issue: The manufacturer for batch release should be indicated in this label

Italy


For the same reasons explained above, there is no possibility to add this information on the label.

RMS comment


Merial Repeat-use


Satisfactory.

2.2.4 No label for outer box was attached. Why?

Italy


As already explained above, there is no possibility to have an outer package for this kind of frozen

product. The vaccine suspension is stored directly in the liquid nitrogen container. Please see the

answer to the question No. 2.2.1.

RMS comment

Satisfactory.

2.3. Package leaflet

2.3.1 Statement of the active substance(s) and other ingredient(s).

This section should contain visual description of the pharmaceutical form:

“Yellow suspension”.

Poland


The color indication is already mentioned in the leaflet in section 2 : “Frozen suspension for

nebuliser suspension. Yellow” . Therefore, there is no need to add it also in section 3.

RMS comment

Satisfactory.

2.3.2 General note

The labelling and package leaflet should be prepared in line with any changes made

to the SPC.

Poland


As already explained, there is no possibility to change the labeling text.

RMS comment

Satisfactory.


Merial Repeat-use


REPEAT USE


Merial Repeat-use


HATCHPAK IB H120

Company: Merial


Repeat use

LOQ, ANSWERS and MS OPINION

Date: 12/04/2013

FR/V/0171/001/E/001

PRODUCT DETAILS




APPLICATION DETAILS

Type of application Mutual recognition Procedure – repeat use

Name of applicant Merial


Person for communication on behalf of the

applicant during the procedure

Nathalie BOURGUIGNON-GELE

[email protected]

33 4 72 72 31 11


Day 54 : 19/03/2013

Day 78 : 12/04/2013

Day 90 : 24/04/2013

New concerned Member States AT*, BE*, BG, CY, IE*, NL*, RO, SI, UK*


First round, where MA still valid

CZ, DE, EL, ES, HU, IT, LT, LV, PL, SK


First round, where MA withdrawn

AT*, BE*, FI, IE*, LU, NL*, UK*

* these countries have registered the vaccine in 2007, but MA was withdrawn thereafter; they are

now involved in the repeat-use

REFERENCE MEMBER STATE DETAILS

Assessment report prepared by France


Date of the first marketing authorisation in the RMS 14/09/2007

Contact Name Dr Céline Lorteau

Address ANSES - ANMV

8 rue Claude Bourgelat - Parc d'activités de la

Grande Marche - Javené - BP 90203



Merial Repeat-use


35302 Fougères Cedex - FRANCE

Phone 33 2 99 94 78 60 (or 33 2 99 94 78 82)

E-mail [email protected]

D54 CONCLUSION ON THE MEDICINAL PRODUCT

AT, BG, CY, CZ, DE, EL, ES, FI, HU, IE, IT, LT, LU, LV, NL, PL, RO, SK, SL No comments received by day 54. BELGIUM The Belgian Federal Agency for Medicines and Health Products support RMS assessment and is prepared to grant a marketing authorization. No additional comments. IRELAND The Irish Medicines Board agrees with the overall conclusion of the RMS and is therefore prepared to grant a marketing authorisation for HATCHPAK IB H120, providing the final SPC and label/package leaflet is acceptable. The SPC and labelling as submitted in the repeat use application is considered acceptable, and no changes are requested. UNITED KINGDOM The Veterinary Medicines Directorate agrees with the overall conclusion of the RMS and is therefore prepared to grant a marketing authorisation for HatchPak IB H120 providing the final SPC and label/package leaflet are acceptable.

POTENTIALLY SERIOUS HUMAN OR ANIMAL

HEALTH OR ENVIRONMENTAL CONCERNS THAT

COLD LEAD TO ARBRITATIONS

None.

SPC-POINTS FOR CONSIDERATIONS

UK



Merial Repeat-use


A number of proposed changes to the SPC, packaging leaflet and labelling are included for consideration.

4.9.2 Posology

One administration from one day-old of age, via the respiratory route (spray application).


The standard term for this hen category used on the field by avian professional is “day old” as used by DEFRA

department guidelines for the poultry supply. The applicant would like to keep the standard terms used on the field

by the poultry industry.

In addition, if the SPC is updated in this way during this procedure, a variation would be necessary to update the

SPC of the countries of the first DCP round for administrative reason only. This is not foreseen in the

classification guideline. Time and effort would be disproportionally high in front of the administrative workload

consequences for such editorial change.

The Applicant proposes to keep the text as it is.

RMS COMMENT

See comment under 4.10.


- The vaccine is intended for mass vaccination of chicks one day old chickens in the hatchery, the vaccine solution

should be applied as a coarse spray whilst the chicks are in their chick boxes.







The word “chicks” used in this text is a general term and the sentence in which it is used intents to explain the

way to prepare and administer the vaccine. In any case, there is no doubt about the category of chickens used

since the age of vaccination is clearly mentioned in the previous section 4.9.2 Posology.

In addition, as mentioned above, if the SPC is updated in this way during this procedure, a variation would be

necessary to update the SPC of the countries of the first DCP round for administrative reason only. This is not

foreseen in the classification guideline. Time and effort would be disproportionally high in front of the administrative

workload consequences for such editorial change.


RMS COMMENT

See comment under 4.10.


Data on the safety of a dose higher than 5.7 log10 EID50 could not be located. The reference to ‘more than’ 10

times should therefore be deleted as follows:




The wording of §4.10 is the one proposed and approved during the first registration procedure of HATCHPAK IB

H120 based on the Safety part of registration dossier provided, referenced No.1033/EU-01 dated January 2006.

From the first registration step, the Safety situation of the vaccine remains unchanged.


Merial Repeat-use


This proposal was not questioned during the procedure because it was based on Part III of the registration dossier

of HATCHPAK IB H120 in which the safety of the strain was demonstrated using samples titrating 8.3 log10 EID50

/ml in the reversion to virulence trials.

Samples coming from the 5th passage of the reversion to virulence study 02.0673.R (Part III, vol 8/10, page 336)

were used to inoculate a 6th passage group of birds, study 04.0022.R (Part III, vol 8/10, page 354).

The titre observed for the 5th passage samples was 8.3 log10 EID50/ml.

A volume of 0.1 ml of 5th passage sample was inoculated to each of the 10 chickens used for the 6th passage

group, i.e. a virus titre of 7.3 log10 EID50 per animal.

Since no clinical signs were observed during the study, which is an indication of the safety of the strain, the

Applicant considers that the mention “more than 10 times” in §4.10 of the SPC remains applicable.

In addition, if the SPC is updated in this way during this procedure, a variation would be necessary to update the

SPC of the countries of the first DCP round for another reason than having identified a potential serious

risk(s) for human or animal health or for the environment.

This is not foreseen in the classification guideline. Time and effort would be disproportionally high in front of the

administrative workload consequences compared to the added value of the information requested.


RMS COMMENT

The RMS accepts the argument of the applicant and proposes to follow the best practice guide which states that

minor editorial changes should not be implemented during the Repeat Use but will be incorporated at the renewal

or next variation.

As there are no request for changes to the SPC based on potential serious risk for human or animal health or the

environment, the RMS proposes to keep the SPC as it stands.

Please note also that the wording as it stands was agreed by all the CMSs (including the CMS raising the

questions) during the initial MR.

OTHERS OBJECTIONS

IE - National labelling issues:

The VPA number is 10857/075/001

The abbreviation POM must be included on all packaging components. On the package leaflet it

must be followed by the explanatory text ‘Prescription Only Medicine’. Please note that, should the application be successful, full colour mock-ups will be required before

the authorisation can be issued. If these are not supplied within 30 days after day 90, the authorisation may be issued in the absence of mock-ups, at the discretion of the Irish Medicines Board. In this case mock-ups must be submitted for approval, with appropriate fee, prior to marketing of the product.


Please refer to the RMS e-mail dated 22 March 2013 and the answer document referenced NBo/LCM.13.D0227

dated March 2013 sent to Irish Authorities.

RMS COMMENT

National labeling issues not discussed by the RMS.

UK


Merial Repeat-use


The applicant is reminded that satisfactory colour mock-ups or artwork of these items will be required before final issue of the Marketing Authorisation in the UK. The applicant should note that if a Marketing Authorisation is issued in the UK the number will be 01387/2012.


The UK requests will be managed locally during the national phase of the procedure.

RMS COMMENT

National labeling issues not discussed by the RMS.

UK

A further stability study on two batches of Hatchpak IB H120 07.0457.R indicate a shelf-life of 36 months for this product. However, the last time point at 39 months shows that batch 71BFLPA02 had a Log10 EID50/dose of 4.9 which is above and outside the limits of acceptance. The applicant should comment on this discrepancy.


Given that the vaccine is stored in liquid nitrogen at a temperature inferior or equal to -196°C, there is no doubt about its stability. The infectious titres observed at the last time point T39 months of both batches followed in the stability study 07.0457.R are higher than the other infectious titres observed during the stability study. This titration session can be considered as optimistic. Moreover, the safety test carried out in parallel at T39 months, testing 10 doses of each batch does not shown any safety problems. The infectious titration was not repeated particularly for batch No.7IBFLPA02, the stability profile of the vaccine in liquid nitrogen was confirmed until 39 months.

RMS COMMENT

Acceptable answer.

UK

Clarification should be provided whether the commitment to test a batch of WSV for avian leucosis subgroup J has been fulfilled.


As provided by the RMS e-mail dated 22 March 2013, the commitment to test a batch of WSV for avian leucosis

subgroup J has been fulfilled to all CMS the 7th of June 2010 by the RMS.

The documentation was sent by the Applicant the 31st of May 2010 and corresponds to e-mail referenced

RMM/LCM.10.E491.

It was also part of the compiled documentation sent for the Repeat-Use procedure (Registration part, electronic

document : “26_RMM-LCM-10-E491.pdf”).

RMS COMMENT

Satisfactory.


Merial Repeat-use


D78 CONCLUSION ON THE MEDICINAL PRODUCT

AT, BG, CY, CZ, DE, EL, ES, FI, HU, IE, IT, LT, LU, LV, NL, PL, RO, SK, SL No comments received by day 75. BELGIUM The Belgian Federal Agency for Medicines and Health Products support RMS assessment on the

answers of the applicant to the CLOQ and is prepared to grant a marketing authorization.

IRELAND The Irish Medicines Board agrees with the overall conclusion of the RMS and is therefore prepared to grant a marketing authorisation for HATCHPAK IB H120, providing the final SPC and label/package leaflet is acceptable. UNITED KINGDOM The Veterinary Medicines Directorate agrees with the overall conclusion of the RMS and is therefore

prepared to grant a marketing authorisation for HatchPak IB H120 providing the final SPC and

label/package leaflet are acceptable.

The Veterinary Medicines Directorate also agrees to the RMS proposals to address other specific

changes during the next renewal or next variation.

RMS

The repeat-use is therefore concluded by an approval of all the CMSs and no modification of the SPC (provided

page 7 of this report).