| slide 1 of 63 april 2008 pharmaceutical development with focus on paediatric formulations who/fip...

| Slide 1 of 63 April 2008

Pharmaceutical Development with Focus on Paediatric formulations


WHO/FIP Training Workshop Hyatt Regency Hotel

Sahar Airport Road

Andheri East, Mumbai, India

28 April 2008 – 2 May 2008




Presented by: Dr A J van Zyl

Technical Officer

Head of Inspections

HSS/PSM/QSM

[email protected]


In this presentation… In this presentation… Prequalification Programme

Assessment of products and manufacturers– Standards

Information on generic ARVs , TB and Malaria products

Innovator and generic products

Agreement with USA FDA for exchange of information

Companies participating in WHO prequalification– Companies that succeed and fail

Capacity building

Incentives for manufacturers


Prequalification Programme: Priority Essential Medicines


Quality concerns - India 96 samples (chloroquine and antibacterials) collected in Nigeria

and Thailand - >36% failed pharmacopoeia standards (Shakoor O et al, 1997)

Rajasthan DCA - substandard medicines in 13% to 18% of samples (1996 and 2001) (Arlington, VA: Management Sciences for Health. 2003)

Delhi - 53 samples, 86% were substandard or counterfeit (Iyengar J. A, Asia

Times. 2002)

Maharashtra - 436 out of 1026 manufacturers reported non compliant with Schedule M and unwilling to upgrade (Deshmukh R. Mumbai Mirror 2005)

One out of four tablets sold in the market in UP reported as fake (Singh RK. Bitter pill: one out of four drugs in UP is fake. HT Nation. Mumbai. 2006)




Quality – China

Little information available in public domain

Fake artesunate:– 38% ('01); 53% ('03) - in Myanmar– 89% - Laos– Wellcome trust: 22 of 27 locations (in 15 - only fakes) (Lancaster IM 2006)

Strict control on compliance implemented and enforced– 07/07: "former head was executed for accepting bribes to approve untested

medicine"– Now "vowed to overhaul the agency, institute a recall system and strengthen

drug regulations" (Chicago Tribune, 11 July 2007)

– GMP again under revision




Also a problem in industrialized countries

1999 to 2000, Schering Plough USA had to recall about 59 million metered dose asthma inhalers

– 17 children died - no active ingredient

2003, TGA (Australia) recalled products of Pan Pharmaceuticals Ltd

– 219 products (local market) and 1650 for exports recalled and cancelled

2007, Roche recalled all batches of ARV Viracept – contamination with genotoxic substance

Death by GMP: MH Anisfeld. GMP Review. Vol 4 No 4 2006 Impact on the patient?




The prequalification program is an implemented action plan

for expanding access to medicines for patients with:

- HIV/AIDS

- Tuberculosis

- Malaria

-Ensures quality, efficacy and safety of medicines procured using international

funds (e.g. GFTAM)

Now also Reproductive Health Products and Avian Flu




Partners and role players include:

• UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank; Roll Back Malaria, Stop TB (Global Drug Facility), HIV/AIDS Department, UNITAID and the Gates Foundation

Role of WHO:

Managing and organizing the project on behalf of the United Nations.

• Provides technical and scientific support

• Ensures that international norms and standards are applied

• GMP, GCP, GLP, quality control

Assessors and Inspectors:

Mainly from National DRAs of ICH and associated countries, and PIC/S



In WHO - PQ team has its own Quality Assurance system:

Quality Assurance and Safety: Medicines (QSM)Organization chart, job descriptionsStandard Operating Procedures (SOPs)General Procedure for PrequalificationManuals and guidelinesNorms and standards (product dossiers,

manufacturers etc)



Program Manager

Head :Inspections

Head: Dossier assessments

LiaisonQuality Control

Technical Assistance

Inspector AssessorInspector Assessor

Admin Support


Expression of InterestProduct dossier

SMF

Additional data and information

Assessment

Steps in prequalification




SMF

Additional data and information Corrective actions

Assessment Inspections

APIs

FP

CRO



SMF

Compliance

Additional informationand data Corrective actions

Compliance

Assessment Inspections

Prequalification Monitoring



7th Invitationto manufacturers of antituberculosis medicines

to submit an Expression of Interest (EOI) for product evaluation to theWHO Prequalification Programme

June 2007: Interested manufacturers are encouraged to submit documentation for recommended dosage forms and strengths, as specified below, of medicinal products in the following categories.

1. Single ingredient first-line antituberculosis medicines- Ethambutol, tablet 400 mg- Isoniazid, tablet 300 mg- Pyrazinamide, tablet 400 mg- Rifampicin, capsule 150 mg; 300 mg-Streptomycin, powder for injection 1g (vial)

2. Fixed dose combination products of first-line antituberculosis medicines- Isoniazid + Rifampicin, tablet 75 mg + 150 mg; tablet 150 mg + 150 mg- Ethambutol + Isoniazid, tablet 400 mg + 150 mg- Ethambutol + Isoniazid + Rifampicin, tablet 275 mg + 75 mg + 150 mg- Ethambutol +Isoniazid +Pyrazinamide +Rifampicin tablet 275mg +75mg +400 mg +150mg


7th Invitationto manufacturers of antituberculosis medicines

to submit an Expression of Interest (EOI) for product evaluation to theWHO Prequalification Programme

3. Single ingredient second-line antituberculosis medicines- Amikacin, 250 mg/ml (vial 2 ml, 4 ml); powder for injection 1g (vial)- Capreomycin, powder for injection 1g (vial)- Cycloserine, capsule 250 mg- Ethionamide, coated tablet 125 mg; 250 mg- Kanamycin, powder for injection 1g (vial)- Levofloxacin, tablet 250 mg- Moxifloxacin, tablet 400 mg- Ofloxacin, tablet 200 mg; 400 mg- Prothionamide, coated tablet 250 mg- P-aminosalicylic acid, granules 4g- P-aminosalicylic sodium, granules 100 g

4. Scored solid dosage formulations for children, preferably dispersible- Ethambutol, tablet 100 mg- Isoniazid, tablet 50 mg; 100 mg- Isoniazid + Rifampicin, tablet 60 mg + 60 mg; tablet 30 mg + 60 mg- Isoniazid + Pyrazinamide + Rifampicin, tablet 30 mg + 150 mg + 60 mg- Pyrazinamide, tablet 150 mg


In this presentation… In this presentation… Prequalification program






Capacity building



www.who.int/prequalwww.who.int/prequal


Innovator product: Abbreviated procedure

• Approved by stringent authorities like EMEA and US FDA

• Trust scientific expertise of well-established DRAs

Submit:

• Assessment report from Drug Regulatory Authority (DRA),

• WHO Certificate of Pharmaceutical Product (CPP),

• Batch certificate

• Update on changes

Assessment procedure- Product dossiersAssessment procedure- Product dossiers


Generic Product

Generic product: 1. To contain the same active ingredients as the innovator drug2. To be identical in strength, dosage form, and route of administration3. To have the same indications for use 4. To meet the same batch requirements for identity, strength, purity and quality5. To be manufactured under the same strict standards of GMP required for innovator products.6. To be bio-equivalent

Prequalification requirements for generics– Fully in line with major regulatory agencies– See also FDA requirements for generic drugs (www.fda.gov/cder/ogd)

What if not generics– Full data to prove safety (including preclinical toxicology) and efficacy has to be presented

Not all non-innovator products in prequalification pipeline can be defined as generics– no innovator may be available



Multisource (generic) products Submit: Full dossier with all the data and information requested (quality; safety

and efficacy)

• Quality: (Information on)

• Starting materials (API, exipients)

• Finished product

• Specifications, stability data, formulation, pharmaceutical development, (QBD), manufacturing method, packaging, labelling etc

• Efficacy and safety:

• Bio-equivalence study / clinical study report (WHO and ICH)

• Commercial sample• Requested, but not always analysed before prequalification.



Guidance for applicantsGuidance for applicants


Assessment of product dossiers

Ongoing and

Copenhagen assessment week: Teams of professionals from national Drug Regulatory Authorities (DRA): Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe

• 8 to 20 assessors - at least every two months at UNICEF in Denmark• Every dossier is assessed by at least four assessors. • An assessment report is issued - signed by assessors• Letter summarizing the findings and asking for clarification and additional data if

necessary



Team of inspectors for each inspection– WHO PQ inspector plus PIC/S member country plus local

country inspector (observer)– Some cases – capacity building (recipient country)

APIs, Finished products, BE studies– GMP, GCP, GLP, GSP, GDP. . .

Preparation:– SMF– Product information– Inspection reports, complaints etc

Assessment procedure - inspectionsAssessment procedure - inspections


Assessment procedureProduct dossiers received

Assessment procedureProduct dossiers received

0

10

20

30

40

50

60

70

HIV/AIDS

2005 2006

2007

0

2

4

6

8

10

12

14

16

18

Tuberculosis

2005 2006

2007

0

1

2

3

4

5

6

Malaria

2005 2006

2007



0

10

20

30

40

50

60

70

80

90

Total number of dossiers

2005 2006

2007

0

10

20

30

40

50

60

70

80

90

100

Dossiers evaluated 2007

HIV

TB

Malaria

ReproductiveH


Manufacturers: Normally over 3 days

Covers all aspects of GMP– Quality management, Quality

assurance, Premises, Equipment, Documentation, Validation, Materials, Personnel, Utilities (e.g. HVAC, water) . . .

Also data verification (dossier) including stability data, validation (process), development batches and bio batches

Quality control laboratory – specifications, reference standards, methods of analysis, validation and qualification

Clinical sites: Normally over 2 days

Covers all aspects of GCP and GLP– Ethical considerations, Protocol,

Volunteers etc

Data verification

Clinical part– Clinic, Pharmacy and related areas,

data verification

Bio-analytical part– Laboratory and data verification

Statistical analysis

Assessment procedure - inspectionsAssessment procedure - inspections


Inspections 2006Inspections 2006

0

5

10

15

20

25

Inspection sites

India

China

Belgium

France

Switzerland

Canada

Malaysia

Kenia,Cameroon

USA

South Africa


2.2.2 Parma. developmentTB 4FDC tablets

2.2.2 Parma. developmentTB 4FDC tablets

FPPs (packed products)

Unpacked tablets (control)

After 5 days at 40°C/75% RH

After 5 days at 40°C/75% RH + Light

S. Singh, Int. J. Tuberc. Lung. Dis., 7, 298 (2003)

ProductsB A

Quality of the products not known

“bleeding”


Standards International consultation

process

The WHO Expert Committee – review and adopts

Executive Board

World Health Assembly

Printed in respective TRS and WHO web site


min0 1 2 3 4 5 6

Norm.

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50

100

150

200

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28 -

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New York Times 2007




HIV/AIDS products

Started 2001 – largest pool of generic antiretroviral dossiers

Initially, many problems including:

Manufacturers lacked knowledge and experience in international standards

Only 2 monographs in pharmacopoeia and official reference standards

Often no specifications, no bioequivalence studies, no stability data, no data on API manufacturing and profile

Fixed Dose Combinations (FDCs)


Anti-tuberculosis products

Relatively "older" products

Low profit margins

Mainly manufactured in developing countries

Mainly purchased by governments

Limited number of API and FP manufacturers

– first and second line products

Lack in stability data (e.g. Schedule M)

FDCs

Lack of bioequivalence studies

No clear comparator product or product no longer the same

Incompatibilities

. . .






Anti-malaria products Recommended treatment – artemesinin combinations

– resistant malaria

Mainly products (single component) from Asia (China)

Lack of specifications– initially no pharmacopoeia monographs (excluding CP) - now Ph. Int.

Lack of safety and efficacy data

Innovator products? Generics – few in ICH countries

Limited regulatory experience in ICH region

FDCs and bi-layer tablets




First inspections - Number of non-compliances in each area

0

100

200

300

400

500

600

700

800

Area of manufacturing

Nu

mb

er

of

ob

serv

atio

ns

All Major

All 687 282 238 207 164 156 108 104 97 62 48 36 22 14

Major 301 107 79 95 59 77 54 26 50 29 27 10 12 3

Prod QC Rec Smp Doc Wgh Val PackPack Mat

Micro

HVAC

H2OCl val

Fin gds




Clinical Sites

Volunteer selection and participation

Ethics committee operations

Clinic and bio-analytical laboratory

Archives

Pharmacy

CRFs

Source data– including chromatograms, ECGs


Generally, in all three groups:

In addition to non compliance with standards (e.g. GCP, GMP), also:

Products not controlled (appropriately registered) in countries of manufacture

Products produced only for export purposes

• Most manufacturers can overcome these problems if motivated.

However, it may take a lot of time . . .






Not only "bad news" …


Publications 2005/2006Publications 2005/2006

Updated prequalification web site launched in November 2006: http://who.int/prequal/

Articles:

– 1. Prequalification of medicines. WHO Drug Information, 2005, 19:1.

– 2. WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2.

– 3. Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalifi cation Programme. Journal of Generic Medicines, 2006, 3(2):96–105.


Transparency: WHO Public Reports (WHOPIRs and WHOPARs)

Transparency: WHO Public Reports (WHOPIRs and WHOPARs)

Name of manufacturerAurobindo Pharma Limited, Unit - VIII

AddressSurvey N° 13Gaddapotharam (Village), IDA- Kazipally, Jinnaram (Mandal),Medak District, Andhra Pradesh- 502319India

Postal addressSame as above

Telephone number+91 8458 277115

Fax number+91 8458 277114

Summary of activities of manufacturer (e.g. manufacturing, packing) .

Indicate dosage forms and type of products (e.g. tablets; cephalosporin containing products)

Manufacturing and control of anti-retroviral active ingredients, including but not restricted to the manufacturing process of Zidovudine and Efavirenz..

Date of inspection:14 & 15 March 2006

Project:Prequalification Programme

Part 2: Summary and conclusion of the inspection.Summary:


Increased transparency about the "pipeline"


Recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO Prequalification)

Same approach will soon apply for EU Art58 and Canadian JCPA procedure




In this presentation… In this presentation… Prequalification program






Capacity building





Companies participating in prequalification

ICH region Other regions GlaxoSmithKline

Abbott

Roche

Bristol Myers Squibb

Merck Sharp & Dohm

Boehringer Ingelheim

Gilead . . .

Cipla Ltd

Ranbaxy Ltd

Aurobindo

Aspen Pharmaceuticals

Strides Ltd

Hetero Drugs Ltd . . .


Companies that succeed and fail

Compliance with standards

Exposed to international environment

Local requirements similar or the same as international or stringent national requirements

Willing or motivated to comply even if local requirements are less stringent

Business incentive – share of the market





Capacity buildingAssessors - Copenhagen

Assessors – rotational post

Inspectors – local DRA

Indirect – local manufacturer

and CROInspectors – recipient country



Capacity buildingAssessors - Copenhagen

Assessors – rotational post

Inspectors – local DRA

Indirect – local manufacturer

and CROInspectors – recipient country

Technical Assistance -Independent-




- Acceptance

- Facilitate

registration

- GFTAM

- UnitAID

- GDF




€

£

¥

$


Since 2005 annual reports; 2006 annual report on the web


Thank youThank you

| slide 1 of 63 april 2008 pharmaceutical development with focus on paediatric formulations who/fip...

Documents

revision slide

avian flu slide

prequalification companies

safety of medicines

generic products agreement

malaria products innovator

reproductive health

products local market