Uk 14901 Website h55464 Unbranded Manufac Flu Vac v6

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Produced by Sanofi Pasteur MSD for educational purposes – all rights reserved UK14901 03/11
UK14664 12/10
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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 production
cycles per year for Northern and Southern hemispheres
 On time to meet vaccinating period prior to expected
circulation of influenza virus
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An introduction to the presentation. It is important to understand all steps

involved in the influenza vaccine manufacturing process to realise the
complexity and opportunities for delay.
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FEBRUARY – WHO
issues composition of
vaccine
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Seasonal variation causes flu strains to change every year leading to new
vaccines 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 change Sentinel Doctors
frequently due to genetic mutation (GPs throughout the UK)
 Thus, WHO co-ordinates an

international surveillance system National Influenza Centres
to monitor these viruses (135 centres in over 110 countries)
6 Collaborating Reference Centres for

Research against influenza
(Australia, China, Japan, United Kingdom,
and United States)
World Health Organisation

(WHO – Geneva)
Gerdil, Catherine. The annual production cycle for influenza vaccine. Vaccine 21. 2003; 1776-1779.
http://www.who.int/csr/disease/influenza/vaccinerecommendations/en/index.html
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The WHO coordinates a complete surveillance system to isolate and

identify influenza virus strains from different regions of the world. This
system allows for the detailed analysis of circulating influenza viruses
isolated from both humans and animals, especially birds and pigs, and is
able to detect newly-evolved antigenic variants of the influenza A and B
strains to which humans are likely to be susceptible.
The surveillance system in human populations begins with sentinel

physicians (GPs) carrying out nasopharyngeal swabs in patients showing
influenza-like symptoms. These samples are sent to the National
Influenza Centres (135 centres in 110 countries) for primary laboratory
analysis. When a new strain is detected, samples are sent to 6 WHO
Collaborating 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 WHO

Collaborating Centre investigators. The virus strains circulating in the
Northern Hemisphere are reviewed in February in order to determine
which variants are likely to be the cause of human disease the following
winter. The WHO experts decide which variants should be included in the
next season’s influenza vaccine anticipating an accurate cross match
between 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:
Influenza
Influenza type
type Laboratory
Laboratory first
first isolated
isolated Lab
Lab strain
strain number
number Year
Year identified
identified Sub-type
Sub-type
A/California/7/2009 (H1N1)
 Regulatory authorities must revalidate the manufacturing

process and evaluate immunogenicity and safety for
new strains
Gerdil, Catherine. The annual production cycle for influenza vaccine. Vaccine 21. 2003; 1776-1779.
CMO Letter The Influenza Immunisation Programme 2009/10. April 2009
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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 first
isolated, 3) strain number, 4) year of isolation, and 5) virus subtype.
A factor which contributes to the recommended composition of the vaccine
is 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 in
the upcoming year. They are grown from a clinical specimen in eggs or
unique pathogen-free chicken kidney cells.
Reference strains must be identified in time to allow for the production of
large amounts of virus to make the vaccine. Occasionally, a suitable new
reference vaccine virus cannot be identified in time for inclusion in the
upcoming year’s vaccine.
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http://www.who.int/csr/disease/influenza/vaccinerecommendations1/en/index.html accessed Nov 2010
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The Influenza A strain, particularly the H1N1 strain was fairly stable from
2000 - 2007 with very little drift. Consequently, annual flu vaccine
compositions were very similar and some protection was afforded from
previous flu seasons.
The H1N1/swine flu strain lead to the pandemic in 2009/10. This strain
has been the predominant circulating strain in consecutive seasons and so
is included in the seasonal influenza vaccine.
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FEBRUARY – WHO
vaccine
MARCH – Grow flu virus
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The first step in the manufacturing process is to cultivate the influenza

virus. 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 culture technique:
grow the virus
SEED
Obtain viral suspension

using surfactant & purify
100s million pathogen-free eggs,

certified by WHO, used every year1
PURIFICATION
1. http://www.cdc.gov/flu/about/qa/research.htm
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Vaccine specialist company Sanofi Pasteur alone uses 100s of millions of

eggs 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 live
virus is purified via filtration and centrifugation to produce a viral
concentrate. It takes at least six months to produce large quantities of
influenza virus for the vaccines.
The first major risk of delay occurs at this step due to the availability of
pathogen-free eggs. It is essential that the total number of pathogen-free
eggs needed is accurately estimated to minimise or eliminate any delay.
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FEBRUARY – WHO
vaccine
MAY – Formulate
vaccine
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The next stage in the manufacturing process is formulating the bulk

vaccine.
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1. Inactivation 2. Splitting of virion 3. Formulation
Viruses are inactivated Virion is disrupted and split
using formaldehyde up using surfactant
A/H1N1 A/H3N2
Three strains are B

mixed together Buffer solution
Bulk vaccine
formulated
1. http://www.cdc.gov/flu/about/qa/research.htm
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UK14664 12/10
The live virus is killed or inactivated using formaldehyde, the three vaccine
strains 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 the
laboratory. Manufacturers may begin to grow a strain and then discover
that it does not produce a high enough yield. Since all three strains are
mixed 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 one

of the virus strains which lead to most supplies of flu vaccine being
distributed either later than usual or, for some manufacturers, not at all.
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Split virion Sub unit Virosomal
Killed and split Killed, split and Killed and split
separated
Re-assembled
using phospholipids
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There are the 3 types of influenza vaccines in the UK.
1. Split virus vaccines consist of inactivated virus particles disrupted by

detergent or surfactant, which solubilises the viral membrane.
2. Subunit or surface antigen vaccines consist of purified
haemagglutinin and neuraminidase from which other viral components
have been removed. The internal subviral core is separated from
surface proteins on the basis of their differing sedimentation rates.
3. Virosomal vaccines are reformed from split viruses using
phospholipids (lecithin & cephalin) which spontaneously form
liposomes 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
Steps Quality Control
Raw materials Analyses
Microbial seeds Analyses
Cultures Analyses
Harvests Analyses
Purifications Analyses
Inactivations Analyses
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Biological products require rigorous quality assurance & quality control

checks. Quality control time takes up to 70% of the total production time
for flu vaccines. These checks are carried out both internally and
externally. Prior to the distribution of a batch of vaccine, the bulk and end
product are tested by an external agency who must give their approval for
its release.
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FEBRUARY – WHO
vaccine
MAY – Formulate
vaccine
JULY – Run clinical END OF MAY

trials and obtain licence – CMO Letter
Outlines strategy and implementation
of the upcoming vaccination campaign
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Upon announcement of the influenza vaccine strains, the Chief Medical

Officer (CMO) publishes a letter usually before the beginning of June
outlining the strategy and implementation of the upcoming vaccination
campaign.
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 Vaccine is tested in at least 100 individuals to ensure safety
and efficacy
 Licensing data is submitted to European Medicines Agency
(EMA)
 SPC becomes available once licensing is obtained
 Filling and production, including packaging and label

printing
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FEBRUARY – WHO
vaccine
AUGUST – Fill vaccine MAY – Formulate

and batch release vaccine

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Packing and filling of the influenza vaccines takes place through summer
months.
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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 must pass required agency test before being released for sale
Each batch is checked by the manufacturing site for packing accuracy
All necessary paperwork is checked
Batch is released
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The procedure for filling and packing batches of flu vaccines for release
for 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
vaccine
SEPTEMBER – Deliver MARCH – Grow flu virus


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Vaccines are delivered to GP surgeries from September, ready for the flu
clinics through the winter months.
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 Temperature-controlled nationwide
distribution from depots located around the
country
 Vaccines picked and packed in refrigerated
conditions
 Refrigerated vans maintain cold chain from
warehouse to customer’s fridge
 Nationwide deliveries planned and allocated
to vehicle routes
 Manufacturers distribute many millions

of doses each year
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Temperature readers are located on each batch of vaccines as well as

each truck. This ensures vaccines are maintained at the optimal
temperature during transport from the manufacturing site to the distribution
site.
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OCTOBER – JANUARY FEBRUARY – WHO
– Vaccinate issues composition of
vaccine


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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 all
those aged 6 months or over with chronic respiratory disease including
asthma, chronic heart disease, chronic renal disease, chronic liver
disease, immunosuppression and diabetes requiring insulin or oral
hypoglycaemic drugs.
(For more details, see Immunisation against infectious disease: The
Green 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
OCTOBER – JANUARY
– Vaccinate vaccine
RISK OF DELAY:
Egg supply
AUGUST
RISK OF– DELAYS:
Fill vaccine RISK
MAY OF DELAYS:
– Formulate
and batch
Testing
release Acceptable
vaccineyield
JULY – Run clinical END

END OF
OF MAY
MAY
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UK14664 12/10
If a delay occurs at any stage of the cycle, then all subsequent steps are
delayed. It essentially hinders the whole process.
The 3 stages which pose major risks of delay to flu vaccine supplies are
as follows:
•Growing the flu virus
•Formulating the vaccine
•Filling and releasing
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1

An introduction to the presentation. It is important to understand all steps

 Thus, WHO co-ordinates an

6 Collaborating Reference Centres for

World Health Organisation

The WHO coordinates a complete surveillance system to isolate and

The surveillance system in human populations begins with sentinel

Twice yearly, the surveillance data are carefully reviewed by WHO

 Regulatory authorities must revalidate the manufacturing

Each influenza vaccine consists of 3 strains: 2 subtypes of influenza A

MARCH – Grow flu virus

The first step in the manufacturing process is to cultivate the influenza

Obtain viral suspension

100s million pathogen-free eggs,

Vaccine specialist company Sanofi Pasteur alone uses 100s of millions of

MARCH – Grow flu virus

The next stage in the manufacturing process is formulating the bulk

Three strains are B

In the 2006 flu season, manufacturers encountered problems growing one

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

1. Split virus vaccines consist of inactivated virus particles disrupted by

Raw materials Analyses

Microbial seeds Analyses

Biological products require rigorous quality assurance & quality control

MARCH – Grow flu virus

JULY – Run clinical END OF MAY

Upon announcement of the influenza vaccine strains, the Chief Medical

 Filling and production, including packaging and label

MARCH – Grow flu virus

AUGUST – Fill vaccine MAY – Formulate

JULY – Run clinical END OF MAY

European and national testing agencies

Each batch is checked by the manufacturing site for packing accuracy

All necessary paperwork is checked

SEPTEMBER – Deliver MARCH – Grow flu virus

AUGUST – Fill vaccine MAY – Formulate

JULY – Run clinical END OF MAY

 Manufacturers distribute many millions

Temperature readers are located on each batch of vaccines as well as

SEPTEMBER – Deliver MARCH – Grow flu virus

AUGUST – Fill vaccine MAY – Formulate

JULY – Run clinical END OF MAY

Vaccination in the UK takes place from October through to January.

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

JULY – Run clinical END

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