Guidelines

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Target Product Profile and technical
requirements
Pre-tender Meeting
Pneumococcal Vaccines under the AMC
Unicef Supply Division, Copenhagen
26 August 2009
Dr. Nora Dellepiane, Scientist Quality Safety and Standards
Department of Immunization, Vaccines and Biologicals
The thirteen attributes for AMC eligibility
A. Vaccine serotypes
H. Product presentation
B. Immunogenicity
I. Product formulation
C. Target population/ target age groups
J. Storage and cold chain requirements
D. Safety, reactogenicity and contraindications
K. Packaging and labelling
E. Vaccine dosage schedules
L. Product registration and prequalification
F. Interference and co-administration
M. Post Marketing Surveillance
G. Route of administration
2
PRODUCT CHARACTERISTICS
Attribute
Minimally Acceptable Profile
A. Vaccine serotypes
The serotypes in the vaccine formulation must cover at least
60% of the invasive disease isolates in the target region, and
must include serotypes 1, 5 and 14 which are the most
frequent isolates in GAVI eligible countries.
Serotypes 1 and 5: most common and epidemic-prone types in regions relevant to GAVI
particularly Asia and Africa
Serotype 14: most common serotype in children under 5 in all regions
60% coverage: balance between public health benefit and likelihood of success in
developing pneumococcal vaccines for the GAVI market.
A formulation covering 60% of invasive disease possible with only 6 serotypes. Less
number of serotypes less complexity of the vaccine.
3
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
B. Immunogenicity
Immunogenicity should be demonstrated in accordance with WHO
criteria, which are based on non-inferiority to a licensed
pneumococcal vaccine as outlined in WHO Recommendations for the
production and control of pneumococcal conjugate vaccines. (WHO
Technical Report Series, No 927, 2005 and any subsequent
published guidance).
The threshold antibody concentration for invasive disease is 0.35mg/ml (ELISA).
Antibody titres of 0.20– 0.35mg/ml correlate well with opsonophagocytic antibody
titre of 1:8, which correlates well with protective efficacy.
4
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
C. Target population/ The vaccine must be designed to prevent disease among children <5
target age groups
years of age and in particularly be effective in those < 2 years of age.
Pneumococcal disease rates are highest in children <5 years of age and in the elderly and
in developing countries. (US 96/100,000 children <5 years before vaccine introduction vs
estimated incidence in Kenya of 597/100,000 children <5 years of age per year).
Pneumococcal conj vaccines maximal public health impact for disease prevention in
children <5 years of age particularly in those < 2 years of age.
5
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
D. Safety,
reactogenicity and
contraindications
The safety and reactogenicity profile should be comparable to, or
better than that of the currently licensed pneumococcal conjugate
vaccine. Contra-indications should be restricted to known
hypersensitivity to any of the vaccine components.
The WHO Global Advisory Committee on Vaccine Safety (GACVS) recently reviewed the
current evidence on the safety of PCV7 and other pneumococcal conjugate vaccines and
found it reassuring. Monitoring of unexpected effects after introduction in the target
population remains critical. Since developing countries have a high prevalence of
malnutrition and LBW infants, studies in those populations are important.
6
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
E. Vaccine dosage
schedules
Vaccine scheduling must be compatible with national infant
immunization programmes and consist of not more than 3 doses in
the first year of life. The first dose must be shown to be administrable
at 6 weeks of life or earlier.
The possibility of alternative schedules (e.g. two or less infant doses and a later dose at 912 months) should also be explored.
Information on the need for booster doses may be desirable in the future to answer
questions on herd immunity effects and persistence of protection.
Data on immunogenicity of a single dose in older children is worth seeking.
7
PRODUCT CHARACTERISTICS
8
Attribute
Minimally acceptable profile
F. Interference and
co-administration
with other vaccines
There should be no clinically significant interaction or
interference in relation to safety and immunogenicity with
concurrently administered vaccines.
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
G. Route of
administration
Intramuscular or subcutaneous.
Vaccine developers are encouraged to explore other routes of administration (intra/trans
dermal, intranasal, aerosol, etc .
9
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
H. Product
presentation
The vaccine must be available in mono-dose or low multi-dose
presentations. Mono-doses must be either in single dose vial or in autodisable compact pre-filled device. Low multi-dose presentations must
be formulated and labelled in compliance with WHO policy or
guidance.
The preferred presentation for WHO is a monodose in vial or prefilled autodisable syringe
or low multidose vial with preservative. If a low multi-dose vaccine contains no
preservative, it needs to be discarded at the end of the immunization session, and at latest
6 hours after the vial has been opened. To distinguish such products from those
containing preservative, specific labeling of the vial and training at field level will be
required. WHO is currently revising its policy on the use of opened multi-dose vials (The
use of opened multi-dose vials of vaccine in subsequent immunization sessions,
WHO/V&B/00.09). A final position on acceptability of such presentations will be available
shortly.
10
PRODUCT CHARACTERISTICS
11
Attribute
Minimally acceptable profile
I. Product
formulation
Liquid formulation with a standard volume of 0.5 ml/dose
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
J. Storage and
cold chain
requirements
The product must be stable at 2-8°C with a shelf-life of at
least 24 months and a vaccine vial monitor should be
attached as outlined in Making use of vaccine vial monitors.
Flexible vaccine management for polio (WHO/V&B/00.14).
Vaccines with increased shelf life and thermostability are desirable because they permit
more flexible use of the vaccine and ideally, new vaccines would not need a cold chain.
12
PRODUCT CHARACTERISTICS
13
Attribute
Minimally acceptable profile
K. Packaging
and labelling
Name and labelling must be in accordance with WHO
Recommendations for the production and control of
pneumococcal conjugate vaccines. (WHO Technical Report
Series, No 927, 2005). Packaging must ensure minimal storage
space requirements as set out in Guidelines on the international
packaging and shipping of vaccines (WHO/IVB/05.23).
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
L. Product
registration and
prequalification
The product must be WHO pre-qualified in accordance with
Procedures for assessing the acceptability, in principle, of
vaccines for purchase by United Nations agencies
(WHO/IVB/05.19).
A pre-requisite to prequalification is the licensure or Marketing Authorization by the
responsible NRA or NRA of record, usually that of country of origin. For registration for
the vaccine in user countries, WHO has developed guidelines on how to expedite
registration of a pre-qualified vaccine (see Procedure for expedited review of imported
prequalified vaccines for use in national immunization programmes (WHO/IVB/07.08)).
14
PRODUCT CHARACTERISTICS
Attribute
Minimally acceptable profile
M. Post
Marketing
Surveillance
Post-marketing surveillance should be conducted in accordance with
national regulatory authorities and WHO prequalification requirements
as set out in Guideline for preparation of the product summary file for
vaccine prequalification (WHO/IVB/06.16) , Guidelines on clinical
evaluation of vaccines: regulatory expectations (WHO Technical
Report Series, No 924, 2004) and any relevant published guidance.
Monitoring through PMS for safety, effectiveness in target population, herd immunity and potential
serotype replacement following widespread use of the vaccine is critical. WHO has established a
Post-Marketing Surveillance Network of 10 countries worldwide to monitor the safety of newly
introduced vaccines.
Individual countries need to continue efforts to strengthen their systems. For countries wishing to
introduce low multidose vaccines without preservative the ability to detect AEFI should be extremely
high because of the risks related with product contamination. Further strengthening of monitoring
systems will require support from manufacturers, WHO and other partners
15
WHO PQ and AMC requirements
Attribute
WHO prequal
Meet
Meet
TPP compliance
Not meet
Meet
C. Target population/ target
age groups
Meet
Meet
D. Safety, reactogenicity and
contraindications
Meet
Meet
E. Vaccine dosage schedules
Meet
Meet
Meet
Meet
A. Vaccine serotypes
B. Immunogenicity
F. Interference and coadministration with other
vaccines
17
WHO PQ and AMC requirements
Attribute
WHO prequal
Meet
TPP compliance
Not Meet
H. Product
presentation
Meet
Meet
I. Formulation
Meet
Meet
Not Meet
Meet
K. Packaging and
labelling
Meet
Meet
L. Product
registration and
prequalification
Meet
Meet
M. Post Marketing
Surveillance
Meet
Meet
G. Route of
administration
J. Storage and cold
chain requirements
18
Conditions for prequalification

During the PQ evaluation, WHO will review all quality, safety and efficacy related data
including the 13 attributes required by the AMC

WHO will also review compliance with the UNICEF tender specifications

When the process is completed, WHO will provide outcome of evaluation to GAVI in a
report on the basis of each of the 13 attributes and any other relevant reasons (New
procedure)

WHO will provide a letter to UN indicating whether the vaccine is acceptable, in principle,
for purchase by UN agencies or not as per normal practice

The IAC will independently review the following attributes:
– Vaccine serotypes
– Target population/Target age groups
– Product formulation
– Dosage Schedule
– Route of Administration

On the basis of the WHO report plus their own assessment of the attributes above, the
IAC will determine whether the product meets or not the TPP
19
Conditions for prequalification
Tender specifications
 Compliance with
– Good Manufacturing Practices TRS, 822, 823, 902 (Annexes 5 and 6),
908 (Annex 4) and 929 (Annexes 2 and 3)
– General Requirements for Sterility of Biological Substances TRS 530
AND 872
– Recommendations on risk of TSE. TRS 908
– Regulatory expectations related to E/R/R of thiomersal in vaccines TRS
924
– Guidelines on stability evaluation of vaccines WHO/BS/06.2049
– Guidelines on clinical evaluation of vaccines TRS 924
– Guidelines on non-clinical evaluation of vaccines TRS 927
– Recommendations for production and control of pneumococcal
conjugate vaccines TRS 927
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Conditions for prequalification
Tender specifications
 Changes in production method, formulation, equipment, facilities, etc,
requiring approval from NRA should be communicated to WHO within one
month of approval. If change does not require approval, WHO should be
consulted in timely manner before changes are introduced.
 Primary container labels and diluent containers should be the same as
agreed by WHO during the PQ process or as revised and approved by
WHO. Affixed with water resistant adhesive. Adsorbed vaccines shall have
the warning "DO NOT FREEZE"
 Package insert as approved by WHO during PQ process or as revised and
approved printed in English, French, Portuguese and Russian.
 Closures should conform ISO standards 8362-2 to 7
 Vaccine lots shall be subject to release by the NRA of record. 50 samples
per lot to be retained for testing purposes
21
Conditions for prequalification
Tender specifications
 Problems in production, control or release must be communicated to
UNICEF and WHO/QSS in timely manner
 Supplier shall inform UNICEF and WHO/QSS of any serious issues
regarding vaccine safety and provide information sufficient to consider
such issues. UNICEF and WHO will rapidly notify the supplier in case of
serious adverse events
 Supplier shall promptly notify WHO/QSS and UNICEF in case of recall or
withdrawal of vaccine or any field alert regarding the vaccine
 Supplier shall permit access to UNICEF and WHO or its representatives to
the manufacturing facilities to assess/reassess the vaccines
 Supplier shall comply with VVM labelling and WHO prequalified data
loggers included in shipments.
 Remaining shelf life for pneumo vaccine should not be less than 20 months
22 at time of shipment.
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