uk 14901 website h55464 unbranded manufac flu vac v6

8/6/2019 Uk 14901 Website h55464 Unbranded Manufac Flu Vac v6

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UK14664 12/10UK14901 03/11Produced by Sanofi Pasteur MSD for educational purposes all rights reserved


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1. Complex Many steps involved

Internal and external quality control checks

2. Highly regulated

WHO

Regulatory authorities

Quality control agencies e.g. NIBSC

3. Seasonal variation Flu strains can change each year new vaccine each year

4. Delivery

Fixed deadlines for manufacturers, undertaking 2 productioncycles per year for Northern and Southern hemispheres

On time to meet vaccinating period prior to expectedcirculation of influenza virus

An introduction to the presentation. It is important to understand all stepsinvolved in the influenza vaccine manufacturing process to realise the

complexity and opportunities for delay.


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FEBRUARY WHO

issues composition ofvaccine

Seasonal variation causes flu strains to change every year leading to newvaccines being manufactured each year. In February, the WHO identifies

the strains which are to be included in the vaccine.


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Influenza viruses changefrequently due to genetic mutation

Thus, WHO co-ordinates aninternational surveillance systemto monitor these viruses

Gerdil, Catherine. The annual production cycle for influenza vac cine. Vaccine 21. 2003; 1776-1779.http://www.who.int/csr/disease/influenza/vaccinerecommendations/en/index.html

Sentinel Doctors(GPs throughout the UK)

National Influenza Centres(135 centres in over 110 countries)

World Health Organisation(WHO Geneva)

6 Collaborating Reference Centres forResearch against influenza

(Australia, China, Japan, United Kingdom,and United States)

The WHO coordinates a complete surveillance system to isolate andidentify influenza virus strains from different regions of the world. Thissystem allows for the detailed analysis of circulating influenza virusesisolated from both humans and animals, especially birds and pigs, and isable to detect newly-evolved antigenic variants of the influenza A and Bstrains to which humans are likely to be susceptible.

The surveillance system in human populations begins with sentinelphysicians (GPs) carrying out nasopharyngeal swabs in patients showinginfluenza-like symptoms. These samples are sent to the NationalInfluenza Centres (135 centres in 110 countries) for primary laboratoryanalysis. When a new strain is detected, samples are sent to 6 WHOCollaborating Centres (Australia, China, Japan, United Kingdom, and

United States) for further identification and detailed antigenic analysis.

Twice yearly, the surveillance data are carefully reviewed by WHOCollaborating Centre investigators. The virus strains circulating in theNorthern Hemisphere are reviewed in February in order to determinewhich variants are likely to be the cause of human disease the followingwinter. The WHO experts decide which variants should be included in thenext seasons influenza vaccine anticipating an accurate cross matchbetween vaccine composition and circulating strains.

(C Gerdil,Vaccine, 2003)

http://www.who.int/csr/disease/influenza/vaccinerecommendations/en/index.html


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WHO recommends 3 strains for every vaccine:2 subtypes of influenza A (H3N2 and H1N1) and 1 strain of influenza B

Naming the virus:

A/California/7/2009 (H1N1)

Gerdil, Catherine. The annual production cycle for influenza vaccine. Vaccine 21. 2003; 1776-1779.CMOLetter The Influenza Immunisation Programme 2009/10. April 2009

Influenza typeInfluenza type Laboratory first isolatedLaboratory first isolated Lab strain numberLab strain number Year identifiedYear identified Sub-typeSub-type

Regulatory authorities must revalidate the manufacturingprocess and evaluate immunogenicity and safety for

new strains

Each influenza vaccine consists of 3 strains: 2 subtypes of influenza A(H3N2 and H1N1) and influenza B. The nomenclature to describe the

type of influenza virus is 1) virus type, 2) geographic site where it was firstisolated, 3) strain number, 4) year of isolation, and 5) virus subtype.

A factor which contributes to the recommended composition of the vaccineis whether there is a valid reference strain available for the viruses

collected and analysed by the WHO Collaborating Centres.

A reference strain is one that can be used to make the vaccine.

These strains should offer protection against viruses likely to circulate inthe upcoming year. They are grown from a clinical specimen in eggs orunique pathogen-free chicken kidney cells.

Reference strains must be identified in time to allow for the production oflarge amounts of virus to make the vaccine. Occasionally, a suitable new

reference vaccine virus cannot be identified in time for inclusion in theupcoming years vaccine.


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http://www.who.int/csr/disease/influenza/vaccinerecommendations1/en/index.html accessed Nov 2010

The Influenza A strain, particularly the H1N1 strain was fairly stable from2000 - 2007 with very little drift. Consequently, annual flu vaccine

compositions were very similar and some protection was afforded fromprevious flu seasons.

The H1N1/swine flu strain lead to the pandemic in 2009/10. This strainhas been the predominant circulating strain in consecutive seasons and so

is included in the seasonal influenza vaccine.


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FEBRUARY WHO


MARCH Grow flu virus

The first step in the manufacturing process is to cultivate the influenzavirus. This requires cells for the virus to grow in and most types of flu

vaccines are prepared using the egg-based culture technique.


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Egg-based cul ture technique:

grow the virus

SEED

1. http://www.cdc.gov/flu/about/qa/research.htm

PURIFICATION

Obtain viral suspension

using surfactant & purify

100s million pathogen-free eggs,certified by WHO, used every year1

Vaccine specialist company Sanofi Pasteur alone uses 100s of millions ofeggs each year. These eggs must be certified as pathogen-free by the

WHO.(http://www.cdc.gov/flu/about/qa/research.htm)

After incubation, the virus is harvested to obtain the seed strain. This livevirus is purified via filtration and centrifugation to produce a viralconcentrate. It takes at least six months to produce large quantities ofinfluenza virus for the vaccines.

The first major risk of delay occurs at this step due to the availability ofpathogen-free eggs. It is essential that the total number of pathogen-freeeggs needed is accurately estimated to minimise or eliminate any delay.


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MAY Formulatevaccine

The next stage in the manufacturing process is formulating the bulkvaccine.


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Buffer solution

Bulk vaccine

formulated

1. http://www.cdc.gov/flu/about/qa/research.htm

Viruses are inactivated

using formaldehyde

1. Inactivation 2. Splitting of virion 3. Formulation

A/H1N1 A/H3N2

BThree strains aremixed together

Virion is disrupted and split

up using surfactant

The live virus is killed or inactivated using formaldehyde, the three vaccinestrains mixed together and a buffer solution is added to make the bulk

vaccine.

This is the next major delay risk. Not all flu viruses grow easily in thelaboratory. Manufacturers may begin to grow a strain and then discoverthat it does not produce a high enough yield. Since all three strains aremixed in the final vaccine, the amount of flu vaccine that can be produced

is limited by the yield of the weakest flu strain.

In the 2006 flu season, manufacturers encountered problems growing oneof the virus strains which lead to most supplies of flu vaccine beingdistributed either later than usual or, for some manufacturers, not at all.


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Split virion

Killed and split

Virosomal

Killed and split

Re-assembledusing phospholipids

Sub unit

Killed, split andseparated

There are the 3 types of influenza vaccines in the UK.

1. Split virus vaccines consist of inactivated virus particles disrupted bydetergent or surfactant, which solubilises the viral membrane.

2. Subunit or surface antigen vaccines consist of purifiedhaemagglutinin and neuraminidase from which other viral componentshave been removed. The internal subviral core is separated fromsurface proteins on the basis of their differing sedimentation rates.

3. Virosomal vaccines are reformed from split viruses usingphospholipids (lecithin & cephalin) which spontaneously formliposomes with the antigens displayed on the surface.


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Each production step followed by internal Quality Control

If OK: release to next phase

If not OK: re-test

Raw materials

Microbial seeds

Cultures

Harvests

Purifications

Inactivations

Analyses

Analyses

Analyses

Analyses

Analyses

Analyses

Steps Quality Control

Biological products require rigorous quality assurance & quality controlchecks. Quality control time takes up to 70% of the total production time

for flu vaccines. These checks are carried out both internally andexternally. Prior to the distribution of a batch of vaccine, the bulk and endproduct are tested by an external agency who must give their approval forits release.


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FEBRUARY WHO


JULY Run clinicaltrials and obtain licence

END OF MAY CMO Letter

Outlines strategy and implementationof the upcoming vaccination campaign

Upon announcement of the influenza vaccine strains, the Chief MedicalOfficer (CMO) publishes a letter usually before the beginning of June

outlining the strategy and implementation of the upcoming vaccinationcampaign.


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Vaccine is tested in at least 100 individuals to ensure safetyand efficacy

Licensing data is submitted to European Medicines Agency(EMA)

SPC becomes available once licensing is obtained

Filling and production, including packaging and labelprinting


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FEBRUARY WHO


AUGUST Fill vaccineand batch release


Packing and filling of the influenza vaccines takes place through summermonths.


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Pre-filled syringes filled and packed in boxes(180,000-200,000 doses per batch)

European and national testing agencies

Each batch is checked by the manufacturing site for packing accuracy

Each batch must pass required agency test before being released for sale

All necessary paperwork is checked

Batch is released

The procedure for filling and packing batches of flu vaccines for releasefor use requires external and internal tests again. Another risk of delay

could arise if a batch fails testing and cannot be released.


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FEBRUARY WHO


SEPTEMBER Deliver


Vaccines are delivered to GP surgeries from September, ready for the fluclinics through the winter months.


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Temperature-controlled nationwidedistribution from depots located around thecountry

Vaccines picked and packed in refrigeratedconditions

Refrigerated vans maintain cold chain fromwarehouse to customers fridge

Nationwide deliveries planned and allocatedto vehicle routes

Manufacturers distribute many millionsManufacturers distribute many millions

of doses each yearof doses each year

Temperature readers are located on each batch of vaccines as well aseach truck. This ensures vaccines are maintained at the optimal

temperature during transport from the manufacturing site to the distributionsite.


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SEPTEMBER Deliver


FEBRUARY WHO


OCTOBER JANUARY Vaccinate

Vaccination in the UK takes place from October through to January.Influenza vaccines are recommended for patients over 65 years of age

and for other at risk groups. Other high-risk patient groups include allthose aged 6 months or over with chronic respiratory disease includingasthma, chronic heart disease, chronic renal disease, chronic liverdisease, immunosuppression and diabetes requiring insulin or oralhypoglycaemic drugs.

(For more details, seeImmunisation against infectious disease: TheGreen Book Chapter 19 Influenza -http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en

/documents/digitalasset/dh_123590.pdf)

The manufacturing process is a cyclical process which repeats each year.


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RISK OF DELAY:Egg supply

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RISK OF DELAYS:Acceptable yield

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RISK OF DELAYS:Testing


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SEPTEMBER Deliver


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OCTOBER JANUARY Vaccinate

If a delay occurs at any stage of the cycle, then all subsequent steps aredelayed. It essentially hinders the whole process.

The 3 stages which pose major risks of delay to flu vaccine supplies areas follows:

Growing the flu virus

Formulating the vaccine

Filling and releasing

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