Transcript WHO approaches in relation to guidance and strengthening

WHO Technical Specifications
and Pre-Qualification
UNICEF Vaccine Pre-Tender 2010-2012
Copenhagen Denmark 10 December 2008
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Carmen Rodriguez, Scientist WHO/IVB/QSS
10 December 2008
Outline of presentation
 Introduction
 UN tender specifications and WHO recommendations
 Changing landscape
 WHO approaches to address challenges
 Head-ups on Scientific Opinion and Expedited
Review Procedures
 Challenges faced with novel vaccines
 Main shortcomings and proposed solutions
 Last comments
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Purpose of WHO prequalification
 A service provided to UN purchasing agencies.
 Provide Independent opinion/ advice on the quality, safety
and efficacy of vaccines for purchase
 Ensure that candidate vaccines are suitable for the target
population and meet the needs of the programme
 Ensure continuing compliance with specifications and
established standards of quality
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Status of WHO prequalified vaccines
12
6
industrialized
country mfrs
developing
country mfrs
Brazil
Bulgaria

Belgium




Denmark
France

Cuba



Germany
The Netherlands
Hungary



India
Indonesia
Senegal

Italy





Japan
Rep. of Korea
USA
Switzerland
Sweden
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
21
manufacturers
82
pre-qualified
vaccines
used in 112
countries
53% total
population
Principles
GMP
Clinical data
Consistency
Consistencyofoffinal
final
product
productcharacteristics
characteristics
Meeting WHO requirements
and tender specs
Reliance on NRA
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Conditions for PQ evaluation
•
NRA of record fully functional
•
Vaccine is licensed by the responsible NRA (Scientific
opinion by EMEA accepted)
•
WHO guidelines/recommendations available
•
Listed in the vaccine priority list (low priority vaccines
may be postponed)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Conditions for prequalification
Ongoing oversight and commitments
by
the NRA Inspections at regular
Lot to lot release
Intervals.
Inform WHO of serious
GMP deviations
Post-marketing surveillance
for safety and efficacy
Inform WHO in case of reports
of serious AEFI
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Inform WHO in case of withdrawals
or recalls of lots and license
suspensions
Conditions for PQ evaluation
Commitments from the
manufacturer
Inform of WHO of problems
Report variations
to WHO
that may impact the quality,
safety, efficacy or timely supply
of product
Communicating
with WHO
Report serious
AEFI
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Provide regular updates
Of safety profile
Specific aspects considered
• General understanding of production process and quality control
methods
• Clinical data relevant for the target population in the
recommended schedules
• Production consistency at commercial scale (assessed by testing
of samples of final product)
• Compliance with GMP
• Compliance with WHO recommendations and UN tender
specifications including labels and inserts
• Programmatically suitable presentation
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Technical WHO recommendations
Good Manufacturing Practices
 Good Manufacturing Practices for Biological Products (WHO Technical Report
Series No. 822, 1992) and Guideline for National Authorities on Quality Assurance
for Biological Products (WHO Technical Report Series No. 822, 1992).
 Good Manufacturing Practices for pharmaceutical manufacturers (WHO Technical
Report Series No. 823, 1992).
 WHO Good Manufacturing Practices: Main principles for pharmaceutical products
(WHO Technical Report Series No. 908, 2003).
Regulation and licensing
 Regulation and licensing of biological products in countries with newly developing
Regulatory Authorities (WHO Technical Report Series No. 858, 1995)
 Guidelines for national authorities on quality assurance for biological products;
(WHO Technical Report Series No. No 822, 1992)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Technical WHO recommendations
 General Requirements for the Sterility of Biological Substances (WHO Technical
Report Series No. 530. 1973), Amendment 1995 (WHO Technical Report Series
No. 872, 1998)
 Requirements for the use of animal cells as in vitro substrates for the production
of biologicals (WHO Technical Report Series No. 878, 1998)
 Report of a WHO Consultation on Medicinal and other Products in relation to
Human and Animal Transmissible Spongiform Encephalopaties. WHO/BLG/97.2
 Recommendations on risk of transmitting animal spongiform encephalopathy
agents via medicinal products (WHO Technical Report Series No. 908, 2003)
 Guidelines on regulatory expectations related to the elimination, reduction or
replace of thiomersal in vaccines, (WHO Technical Report Series No. 926, 2004)
 Guidelines on stability evaluation of vaccines (WHO/BS/06.2049 2006)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Technical WHO recommendations
Clinical
 Guidelines on clinical evaluation of vaccines: regulatory expectations
(WHO Technical Report Series No. TRS 924, 2004)
Non clinical
 WHO guidelines on nonclinical evaluation of vaccines (WHO Technical Report
Series No. 927, 2005)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Technical WHO recommendations
 Revised requirements for dried BCG vaccine (revised 1985) (WHO Technical
Report Series No. 745, 1987), Amendment 1987 (WHO Technical Report Series
No. 771, 1988)
 Requirements for Diphtheria, Tetanus, Pertussis, and Combined vaccines
(Revised 1989) (WHO Technical Report Series No. 800, 1990) Amendment
2003 WHO Technical Report Series, No. 927, 2005)
 Recommendations for whole cell pertussis vaccine (WHO Technical Report
Series No. 941, 2007)
 Requirements for Haemophilus Type B conjugate vaccine (WHO Technical
Report Series No. 814, 1991). Revision, 1998 Recommendations (WHO
Technical Report Series No. 897, 2000).
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Technical WHO recommendations
 Revised requirements for Hepatitis B vaccine made by recombinant DNA
techniques (WHO Technical Report Series No. 786, 1989). Amendment (WHO
Technical Report Series No. 889, 1999)
 Biological products prepared by recombinant DNA technology (WHO Technical
Report Series No. 814, 1991)
 Revised requirements for Hepatitis B vaccine prepared from plasma. Revised
1987 (WHO Technical Report Series No. 771, 1988). Amendment (WHO
Technical Report Series No. 858, 1995)
 Requirements for Measles, mumps and rubella vaccines and combined
vaccines, freeze dried (Live) (WHO Technical Report Series No. 840, 1994)
(WHO Technical Report Series No. 848, 1994)
 Requirements for Yellow Fever vaccine (WHO Technical Report Series No. 872,
1998)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Technical WHO recommendations
 Requirements for Meningococcal Polysaccharide vaccine (WHO Technical
Report Series No. 594, 1975) Amendment (WHO Technical Report Series No.
658, 1980), Amendment (WHO Technical Report Series No. 904, 2002)
 Recommendations for the production and control of Meningococcal group C
conjugate vaccines, (WHO Technical Report Series No. 924, 2004) Amendment
(WHO Technical Report Series No. 926, 2004)
 Recommendations to assure the quality, safety and efficacy of Group A
Meningococcal Conjugate vaccines WHO/BS/06.2041-2006)
 Recommendations for the production and control of pneumococcal conjugate
vaccines WHO Technical Report Series, No. 927, 2005)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Technical WHO recommendations
 Guidelines to assure the Quality, safety and efficacy of recombinant Human
Papillomavirus virus-like particle vaccines, WHO/BS/06.2050, 2006
 Guidelines to assure the quality, safety and efficacy of live attenuated rotavirus
vaccines (oral) (WHO Technical Report Series No. 941, 2007)
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Shipping Guidelines
 Guidelines on the international packaging and shipping of vaccines
WHO/IVB/05.23
 International shipping guidelines to be revised in 2009 with a target to
publish the revised version in Q3.
 WHO-UNICEF policy statement on the use of vaccine vial monitors in
immunization services
 VVM PQS performance specification WHO/PQS/E06/IN05.1
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Model inserts
 Traditional vaccines:
No changes foreseen
 Novel vaccines:
Model inserts under preparation
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
PREQUALIFICATION STEPS
 Scientific review of quality dossier
 Testing of samples
 Consultation with responsible NRA
 Site visit to manufacturing facilities
 Scientific review of clinical data
http://www.who.int/immunization_standards/vaccine_quality/pq_suppliers/en/index.html
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Changing landscape
(Partners perspective)
GAVI- expanding vaccine
portfolio (support for 7 new
vaccines)
Efforts made to accelerate
introduction of underutilized
vaccines
Efforts made to increase
coverage to achieve measles
elimination/control goal
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Increased demand for concerned
vaccines
Expectations of expanding PQ
portfolio and of accelerating (fast
tracking) prequalification
procedure
Changing landscape
(Manufactures & respective NRAs perspective)
Challenge for producers to ensure
New partnerships
to produce
adequate/std
processes
and procedures
combination
across
sites and novel vaccines
(multiple sites)
Challenging
Regulatory Pathways
Demonstration/assessment
Sophisticated technologies,
of quality, safety and efficacy
is challenging,
issues
in addition
with consistency,
assessment of
programmaticpresentation,
suitability is stability,
a challenge
other?
No "One size fits all" possible
PMS monitoring
Since they for
aresafety
novel,and efficacy is
an issue
no performance experience
May
Some
notnovel
be licensed
vaccines
in country of origin
or
not
licensed
required
forinexport
country
purposes
of originonly
NRA in country of origin may not have
Additional
expertise
and human
resources
required
expertise,
enough
resources
required for
their methods
regulation
challenging
testing
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Changing landscape
(User countries perspective)
Direct
New partnerships
procuring countries
to produce
purchasing
such
combination
vaccinesand
may
novel
find vaccines
their regulation
quite
(multiple
challenging
sites)
Product
Sophisticated
profile may
technologies,
not be fully
suitable
issuesto
with
theconsistency,
conditions of the
country
presentation,
and represent
stability,
a challenge
other?
for introduction
PMS monitoring
Since they
forare
safety
novel,
and efficacy is
an issueno performance experience
If not licensed in country of origin
Some novel vaccines
or licensed only for export, importing
not required in country of origin
country may not be able to license
Licensing novel vaccines may be
Additional expertise and resources
challenging, lack of expertise and the
required for their regulation
required resources
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
WHO approach: regulatory oversight
PMS
MAA
Licensure
For
export
Manufacturer
Art. 58
Lot release certificate
MAA thru WHO
Expedited
procedure
Documentation
samples
Receiving country
WHO Sentinel Network
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
PMS
Lot release certificate
Country of origin
NRA
Regulatory
inspections
What is the CHMP Scientific Opinion
procedure (Art. 58)
 It is an opinion issued by the CHMP, the
scientific committee of the EMEA, in
collaboration with the WHO. This opinion is
based on the evaluation of an application
containing data on the quality, safety and
efficacy of the product, and concludes on the
benefit-risk of the product
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
What is the CHMP Scientific Opinion
procedure (Art. 58)
 It is a procedure applicable exclusively to products
(vaccines and other medicines) designated as "eligible"
by WHO
 WHO "eligibility" for vaccine products applies to vaccines
to be used in the Expanded Programme on Immunization
for protection against a WHO public health priority
disease
 Applicants or their contact points must be established in
the EEA (Member State of the EU , Norway, Iceland or
Liechtenstein)
 Procedure mimics the EMEA centralized procedure for MA
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Two important features
 WHO observers and representatives from NRAs from
target countries take part in the procedure
 The assessment of clinical data takes into consideration
the target population and the epidemiology in target
countries
Concluding remarks: CHMP has established a procedure
that is of the same standard as the centralized procedure
for registration of medicines in Europe, which has the
additional benefit of taking into consideration suitability
of data for target population
Prequalification process can be streamlined
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Procedure for expedited review of PQd vaccines
SCOPE AND CONDITIONS

Intended for countries that source their vaccines through UN
agencies, or that use the WHO prequalification as a basis for
selection of vaccines for purchase

Guidance on how NRAs of such countries can expedite the
regulatory review for such products.

Applies to vaccines used in National Immunization Programmes

Not intended to affect post-approval activities in these countries

For adoption, national regulations must contain provisions to allow
to shorten the normal regulatory approval process.
Details of the "Procedure for expedited review of imported
prequalified vaccines for use in national immunization programmes.
WHO/IVB/07.08 at
http://www.who.int/immunization_standards/vaccine_quality/pq_su
ppliers/en/index.html
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Novel vaccines- Challenges for
evaluation by WHO (1)
 Need to ensure that adequate regulatory pathway is in
place, that product is licensed or licensable, continuous
regulatory oversight in place
 Need to ensure supply through existence of long term
agreement
 Need to assess quality
Adequacy of production process
Adequacy of quality control methods and specifications
Stability data
Transferability of testing methods to NCL and independent
labs
– Consistency of production
– GMP compliance, adequate Quality Management System in
place
–
–
–
–
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Novel vaccines- Challenges for
evaluation by WHO (2)
 Need to assess suitability of clinical data
– Adequacy of available clinical trial protocols and data
– Relevance of existing data for target population and
immunization schedules
– Co-administration with other EPI vaccines or other
interventions
– Immunization schedules, route of administration, etc
– Inter-changeability with other brands of same vaccine
– Safety profile. Phase IV studies may be required,
strong pharmaco-vigilance system in place crucial.
– Indications, labelling and inserts
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Novel vaccines- Challenges for
evaluation by WHO (3)
 Need to assess programmatic suitability
–
–
–
–
Tender specifications met
Adequacy of presentation
Cold chain requirements, stability profile
Temperature indicators: VVMs, data loggers for
shipment, etc
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Main shortcomings and solutions
Testing methodologies
not always available in
independent labs
Need to start transfer of
methods at the beginning
of evaluation or before this
is started
Meetings with
manufacturers ahead of
submission and during
evaluation highly
recommended
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Main shortcomings and solutions
Available clinical
information not always
sufficient/adequate
For combination vaccines
all existing clinical info for
the same antigens in
different products taken as
supportive evidence, this
is not applicable to novel
products
Meetings with
manufacturers highly
recommended
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Main shortcomings and solutions
Some novel products do
not fully meet the
programmatic needs but
are still considered useful
for countries in absence of
the ideal alternative
Increased demand for evaluation
Acceleration of introduction
Some products are not "mature"
at time of submission. Submission
In parallel with licensure has not
been successful
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Recommended for use
rather than prequalified
Target timelines for evaluation
established
Need for clinical protocols/data
at time of submission
Last comments
Need to revise multidose
vial policy.
Need for solution for small
multidose vials without
preservative
Addressing information issue
Web list
Advocacy with partners, NGOs
and receiving countries NRAs
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Ongoing, will take time
Interim solution,
a) Add thiomersal
b) Addition of text on labels,
boxes and inserts (not
encouraged) + training +
VVM on cap + colour?
New webpage under
development
Thanks to all manufacturers
for information provided
Publication of basis for
PQ (WHO PARs) under
consideration
 Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
[email protected]
 Ms Carmen Rodriguez, Scientist WHO/IVB/QSS
[email protected]
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008
Dr. Nora Dellepiane, Scientist WHO/IVB/QSS
Ms Carmen Rodriguez Hernandez, Scientist WHO/IVB/QSS
10 December 2008