uk 14901 website h55464 unbranded manufac flu vac v6
TRANSCRIPT
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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
issues composition ofvaccine
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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FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
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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MARCH Grow flu virus
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
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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MARCH Grow flu virus
MAY Formulatevaccine
JULY Run clinicaltrials and obtain licence
FEBRUARY WHO
issues composition ofvaccine
AUGUST Fill vaccineand batch release
END OF MAY CMO Letter
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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MARCH Grow flu virus
MAY Formulatevaccine
JULY Run clinicaltrials and obtain licence
AUGUST Fill vaccineand batch release
FEBRUARY WHO
issues composition ofvaccine
SEPTEMBER Deliver
END OF MAY CMO Letter
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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MARCH Grow flu virus
END OF MAY CMO Letter
JULY Run clinicaltrials and obtain licence
AUGUST Fill vaccineand batch release
SEPTEMBER Deliver
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
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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FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
FEBRUARY WHO
issues composition ofvaccine
RISK OF DELAY:Egg supply
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
RISK OF DELAYS:Acceptable yield
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
END OF MAY CMO Letter
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
END OF MAY CMO Letter
JULY Run clinicaltrials and obtain licence
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
END OF MAY CMO Letter
JULY Run clinicaltrials and obtain licence
AUGUST Fill vaccineand batch release
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
END OF MAY CMO Letter
JULY Run clinicaltrials and obtain licence
RISK OF DELAYS:Testing
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
END OF MAY CMO Letter
JULY Run clinicaltrials and obtain licence
AUGUST Fill vaccineand batch release
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
END OF MAY CMO Letter
JULY Run clinicaltrials and obtain licence
AUGUST Fill vaccineand batch release
SEPTEMBER Deliver
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
MARCH Grow flu virus
END OF MAY CMO Letter
JULY Run clinicaltrials and obtain licence
AUGUST Fill vaccineand batch release
SEPTEMBER Deliver
MAY Formulatevaccine
FEBRUARY WHO
issues composition ofvaccine
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