Vaccine security meeting - Overview of the who vaccine pre-qualification - O.Lapujade

WHO PREQUALIFICATION PROGRAMME
1
Assuring vaccine quality: Overview of Prequalification
Olivier Lapujade
Vaccines & Immunization Devices
Prequalification Unit
Regulation and Prequalification
Access to Medicines and Health Products
World Health Organization
Geneva, Switzerland
E-mails:
• lapujadeo@who.int
• vaccprequalification@who.int
Explore options to improve security of vaccine supply
against foot-and-mouth and other similar
transboundary diseases
Italy, Roma 22 Jan 2020

2
Outline
• Introduction/Background
• Overview on Prequalification process:
 Principles
 Pre-conditions for PQ evaluation
 Conditions for PQ
 Process
 Timelines
 PQ requirements
 Past/current challenges and solutions
 Role of the National Regulatory Authority (NRA)
 Monitoring/post PQ activities
 Why is Vaccines PQ important for user countries and its NRAs?
 PSPQ, VVM, CTC
• Public Health emergencies
• Vaccine supply chain

3
Strategic priorities
Secure the supply
base for priority
medicines
Facilitate access to
quality products for
developing
countries
Improve efficiency
of the
prequalification
procedure
Expand portfolio
according to needs
and options for
introduction

4
Access
Facilitate
access to
quality products
for developing
countries
Single standard of quality
(WHO recommended requirements)
Consolidated investigation, reporting and
communication in response to quality or
safety concerns
Implementation of an expedited/facilitated
registration procedure for prequalified
vaccines in receiving countries
Mechanisms to minimize wastage of
vaccines, facilitate outreach
(VVMs, MDVP, CTC)

5
“Access to Medicines and Health Products (MHP)” Division
Assistant Director General: Dr. Mariângela Batista Galvão Simão
Technologies Standards and Norms (TSN)
Regulatory Systems Strengthening (Team
has been splitted)
Prequalification Unit (PQT)
Safety and Vigilance (Team has been
splitted)
Regulation and Prequalification
Department (RPQ)
Health Products Policy and
Standards Department (HPS)
•Norms and standards for biological
products
•
•
•
•
5

6
RPQ’s main activities supporting best practices,
quality and access
Norms
Standards (moved
to HPS department)
Regulatory Sys
Strengthening
Prequalification
Safety &
Vigilance
Establish/maintain international standards
Promote unified standards, as well as a global
nomenclature
Strengthen NRAs for capacity building/efficiencies,
promote harmonization, reliance, best practices &
integrate framework for new products
Assure safe, effective & quality health products
for public health challenges
Respond to and minimizing health risks from
medical products by proactive, end-to-end,
actionable, smart safety surveillance
CrossCuttingChallenges
• AMR
• Benchmarking tools
• Data integrity
• Emergency
preparedness
• Environmental
issues
• Local production
• Non- communicable
diseases
• Paediatric
medicines
• Shortages
• Substandard &
Falsified
Prequalification is NOT stand alone activity.
Many other technical work areas support and link to prequalification (medicines, vaccines,
diagnostics and medical devices)

7
Structure of the Prequalification Unit
Prequalification
Unit Head
Vaccines & ID
Team
Medicines Team
In-vitro
Diagnostics Team
Vector Control
Products Team
Inspections
Unit Head’s office
Regulation and
Prequalification
Department (RPQ)
Technical
Assistance/Labs

8
Prequalification
Ensures the quality, efficacy and safety of medicines,
vaccines and immunization devices, in vitro diagnostics and
vector control products.
 Medicines:
• Prequalification programme for medicines (finished dosage forms)
• Prequalification of active pharmaceutical ingredients (APIs)
• Prequalification of quality control (QC) laboratories
• Expanding access to priority essential medicines: HIV/AIDS, tuberculosis,
Malaria, Reproductive Health and some other disease categories (e.g.NTD)
 Vaccines and immunization devices:
• Ensures that candidate vaccines are suitable for the target population
and meet the needs of the programme

9
Prequalification
WHO uses the same scientific principles to assess the
products safety, quality and efficacy/performance as well-
resourced national regulators:
• Scientific assessment of documentary evidence for
quality, safety and efficacy
• Assessment of suitability for use of the vaccine in the
intended settings
• Site inspections for GMP, GLP and GCP
• Control of variations to products and their
manufacturing processes
• Post-approval monitoring of quality and safety

10
Extensive multilayer collaboration:
working with regulators … for regulators
• Not duplicating work done by stringent regulatory authorities
– SRA approval of new and generic products – abridged procedure
– US FDA tentative approvals – based on confidentiality agreement
including in the PQ products list
– European Medicines Agency (EMA) – Art 58 … and beyond
– Collaboration with EDQM, in particular in the area of APIs
(confidentiality agreements with US FDA, EDQM, EMA …)
• Active participation and involvement of
– Regulatory authority experts from well resourced and less resourced
settings WORKING TOGETHER for common goal

11
 A service provided to UN purchasing agencies.
 Provides independent opinion/advice on the quality,
safety and efficacy of vaccines for purchase
 Ensures that candidate vaccines are suitable for the
target population and meet the needs of the programme
 Ensures continuing compliance with specifications
and established standards of quality
Purpose of WHO Vaccines PQ Programme (1)
11
PQ is not a regulatory body

12
12
Purpose of WHO Vaccines PQ Programme (2)
• PQ of Vaccines
• started 1987, originally request by UNICEF and PAHO to evaluate quality,
safety and efficacy of vaccines in the context of national immunization
programmes,
• 148 vaccines prequalified to-date (238 presentations)
• Facilitates registration in developing countries
• Countries can rely on PQ assessment, inspection, lot
testing, etc.
• PQ can also rely on other assessments

13
Principles
Consistency of final
product characteristics
Clinical data
GMP
Reliance on NRA
Meeting WHO requirements
and tender specifications

14
 Reliance on the NRA of the exporting country
• NRA evaluated by WHO NRA Global Benchmarking Tool
• NRA’s status needs to be sustained over time
• Continued regulatory oversight by NRA is required as well as communication with WHO about
potential problems with the vaccine
• Agreements are established with the NRAs for information exchange when a vaccine is about to
be prequalified
• Streamlined or abridged procedure also possible
 Vaccine is licensed/registered by the responsible NRA (e.g. Scientific
opinion by EMA is accepted)
 Follow WHO guidelines/recommendations approved by the ECBS*
(published in the WHO Technical Report Series (TRS))
 Listed in the PQ vaccine priority list
* Expert Committee on Biological Standardization
14
Pre-conditions for PQ evaluation for
Vaccines

15
WHO concept of Vaccine Regulation
Before 2015
National Regulatory System: Governance + 6 regulatory functions
1. Marketing Authorization (MA) and Licensing Activities
2. Post-marketing activities including surveillance of Adverse Events
Following Immunization (AEFI)
3. NRA Lot Release
4. Laboratory access
5. Regulatory Inspections
6. Authorization/Approval of Clinical Trials

16
Required functions according to vaccine
source
Vaccine
Source
MAA &
licensing
PMS Lot
release
Lab
access
Regulatory
Inspections
Authorization &
monitoring CT
UN agency
supply
Direct
purchase
Producing
country
RegulatorySystem
Exporting country NRA+ WHO-PQ
Exporting Country
NRA
AllcountrieswhereCTsareperformed

17
17
WHO recommended regulatory functions for Medicines
and Vaccines based on product lifecycle
Since 2015
PRE MARKETING
Pre-clinical Clinical
Production
& Quality
Control
Marketing
and sales
Post-
Marketing
Non Common
Regulatory
Functions (vaccine)
Common
Regulatory Functions for:
medicines & vaccines
(2015)
Next steps: Medical
devices, Blood & (2017)
POST MARKETING
PRODUCT
LIFECYLCE
National Regulatory System (RS)
Regulatory Inspection (RI)
Laboratory access and Testing (LA)
Clinical Trial’s Oversight (CT)
Vigilance (PV)
Licensing premises (LI)
Registration & marketing
authorization (MA)
Market surveillance and
Control (MS)
NRA Lot release (LR)

18
18
WHO GBT Performance Maturity Levels
No formal
approach
Reactive approach Stable formal
system approach
Continual
improvement
emphasized
1 2 3 4
ISO9004
Regulatory system
operating at advanced
level of performance
and continuous
improvement
Evolving national
regulatory system
that partially
performs essential
regulatory functions
Stable, well-
functioning and
integrated regulatory
system
Some elements of
regulatory system
exist
Can be consider as functional if rely on
other regulators for some specific
functions
Target of WHA
Resolution 67.20
Advanced/reference
Regulatory Authorities
WHOGBT

19
Conditions for prequalification
Ongoing oversight and commitments by the
NRA
Lot to lot release
• Inspections at regular
intervals.
• Inform WHO of serious
GMP deviations
• Post-marketing surveillance
for safety and efficacy
• Inform WHO in case of
reports of serious AEFI
• Inform WHO in case of
withdrawals or recalls of lots and
license suspensions

20
Communicating
with WHO
Conditions for PQ evaluation
Commitments from the manufacturer
Report
variations to
WHO
Report serious
AEFI
Provide regular updates
of safety profile
Inform of WHO of problems
that may impact the quality,
safety, efficacy or timely supply
of product

21
Prequalification process
• Scientific review of quality
dossier
• Scientific review of clinical data
• Testing of samples
• Consultation with responsible
NRA
• Site audit to manufacturing
facilities

22
Dossier Submission
(PSF* or CTD** format)
Screening
Dossier
evaluation
Inspection
1) CAPA
2) FU Inspection (if
needed)
Answers
Prequalification decision
NRA
Functional/Maturity level 3
PSPQ (Programmatic Suitability of Vaccine
Candidates for WHO Prequalification)
Testing
270days
Testing Inspection
Expeditedprocedure Prequalification process
* Product Summary File
** Common Technical Dossier

23
Prequalification process: timelines
(excluding applicant response times)
Submission of
variation
Screening
90 days internal
time
Submission of
application for PQ
Screening (30
days + 90 days if
there is critical
PSPQ non
compliance)
270 days internal
time
Streamlined based
on SRA approval
and sharing of NRA
reports
90 days internal
time

24
Prequalification requirements

25
Past and current challenges
Quality Clinical Programmatic GMP
• Incomplete dossier
• Lack of data at
commercial scale
• No history of
characterization
Master and
Working cell banks
• Inappropriate
devices: nasal
administration
• Lack of clinical
consistency data,
unclear ethical
oversight
• Clinical trial
comparator
product not
acceptable
• Lack of access to
data and/or old
data not meeting
current GCP
• Lack of registration
of CTs
• Deviation
Programmatic
suitability criteria
(PSPQ):
• eg, non
autodisable
prefilled syringes,
stability profile and
VVM (Vaccine Vial
Monitor)
• Quality systems
• Manufacturing
process
Regulatory • National Vs WHO requirements:
• Test methodologies and GMP
• Schedules and target population
• Monodose Vs multidose presentation (preferred)

26
Past/current Challenges and solutions
• Post-PQ
monitoring
• Regulatory
• Quality, safety
and efficacy
• Programmatic
suitability
criteria
Publication of
PSPQ criteria
and
establishment
of Standing
committee on
PSPQ
Briefing on PQ
expectations
(workshops and
webinar)
Guidance
documents
Pre-submission
meetings
Consolidated
investigation,
reporting and
communication
in response to
quality or safety
concerns
Collaboration
agreements
with National
Regulatory
Authority of
record for PQ

27
• Meetings with manufacturers at early stages of vaccine
development. Advice on product characteristics and
clinical development.
• PQ briefing workshops
• Support to IFPMA and DCVMN
• Support to regulatory networks: DCVRN, AVAREF
Technical assistance and capacity building

28
Role of NRA during PQ process
As part of the evaluation procedure, consultation with
NRA
• To discuss regulatory status of the concerned vaccine/s
• Clinical performance in country of manufacture if used
• Quality evaluation, outcome of recent GMP inspections
• Compliance with specifications (trends from lot release data)
• Regulatory actions
• Informal agreement for information sharing with WHO
recorded in Consultation report

29
• Variations
• Annual Report evaluation
• Reassessment (frequency defined on risk analysis basis)
• Targeted testing program with contracted laboratory: once a year
testing of samples of lots shipped to countries to ensure continuing compliance with
specifications
• Monitoring/Investigation of vaccine quality and cold chain
complaints
• Monitoring/investigation of Adverse Events following
immunization (AEFI) (with collaboration of the responsible
NRA)
• Collaborative National Registration
• Technical Review of tenders for UNICEF
Monitoring performance of PQd vaccines -
Post Prequalification activities

30
Why is Vaccines PQ important for user countries
and its NRAs?
• It represents a source of vaccines of "assured quality"
• In addition the evaluation is focused on programmatic needs
• WHO follows up on complaints and reports of AEFIs and
publishes the outcome of investigations
• WHO monitors the quality of prequalified vaccines on a
continuing basis, through testing of samples, reassessment
of the products, targeted audits, and delists vaccines if they
do not meet the established specifications and/or standard
• Opportunity for NRAs in user countries to save resources to
focus on other priorities, since registration can be granted
through a facilitated and shortened procedure

31
Ensure that vaccines used in low and middle income countries
can be used safely and effectively, given the constraints and
conditions of their immunization systems
Nicaragua, rotavirus delivery, Photo: Gates Foundation Mali, polio campaign, Photos: WHO/Olivier Ronveaux
Programmatic Suitability for PQ (PSPQ)
31

32
Programmatic Suitability for PQ
Objectives :
 Judge the programmatic suitability against defined mandatory,
critical and preferred characteristics
Benefits :
 Give clear directions to vaccine manufacturers before PQ
submission
 Reduce decision making time
32

33
Mandatory
• Compliance is compulsory
• Failure to meet this characteristic will prevent the vaccine to be further considered for
pre-qualification
Critical
• Compliance is also compulsory
• However, deviations in vaccine characteristics will be reviewed by the Programmatic
Suitability for WHO Prequalification (PSPQ) Standing Committee
• Under special circumstances exceptions can be granted to vaccines that deviate from
the critical characteristics.
• Decision can only be taken by the PQ Secretariat and will include consideration of
recommendations from the PSPQ Standing Committee and consideration of topics
such as public health need and access to vaccines.
Unique or innovative characteristic
• the product will be referred to the PSPQ Standing Committee for independent review
of the characteristic.
PSPQ criteria

34
Programmatic suitability
Vaccines produced in developed countries may not have
taken into account programmatic challenges in developing
countries.
Examples:
• Non auto-disable prefilled syringe presentations
• Stability of components in the event of cold chain breakdown
WHO PQT has always considered programmatic suitability
but it was in 2012 that a written guidance (PSPQ) was
developed and put in place

35
Vaccine vial monitor
Programmatic
Challenges:
VVM category
similar type of
vaccine
Stability data
matching VVM
category
Custom
made
VVM

36
Mali, polio
campaign,
Photos: WHO/Olivier
Ronveaux
Nationalcoldroomduringthecampaign
Contribution development
of Controlled Temperature Chain
Project Optimize: PATH/WHO
Transport to health centre
Nicaragua, rotavirus delivery, Photo: Gates Foundation
36|

37
Allow specific vaccines to be kept and administered at
ambient temperatures, up to 40oC
For one, limited period of time immediately preceding administration
For vaccines meeting a number of stability conditions
Current focus: vaccines administered during campaigns and special strategies:
eg Meningo conjugate A, Yellow Fever, Pneumo, Hepatitis B, Rota, Cholera
Manufacturers
Studies to enable on
label use of vaccines
under CTC and
regulatory
submissions
Regulators
•Regulatory
pathways
•Review data for
licensing under
CTC
WHO
CTC Guidelines(Norms)
Work w/regulators to define
Regulatory Pathways and
prequalification (vPQ)
Field studies to show
programmatic challenges ,
opportunities and impact of
CTC (EPI-IVB)
37 |

38
Public Health emergencies
PHEIC*
Ebola
smallpox
zika
Pandemic
flu
* Public Health Emergency
of International Concern

39
Vaccines for emergency (PQ and non PQ
activities)
• Yellow Fever, cholera and meningococcal vaccines:
 Fractional dose (YFV)
 Alternative suppliers
• Pandemic influenza preparedness
• Vaccines Emergency use and assessment process
listing EUAL
• Other vaccines such as smallpox (stockpile)

40
ENSURING THE VACCINE SUPPLY CHAIN
The role of Immunization Devices in ensuring the safe
transport, storage, distribution and administration
of vaccines

41
COLD CHAIN CHALLENGES
INCREASE IN VACCINE VOLUME
• Increased number of vaccines
• Extension of immunization targets
• Increased supplementary immunization activities (SIAs)
• Growth of single dose presentations
• Integration of vaccine with device
• Incorporation of the diluent
 THIS CAN BE OFFSET IN FUTURE BY
• Controlled Temperature Chain (CTC)
• Intradermal administration (requires less dose for same immune
response)

42
International Shipments of Vaccines –
Guidance 1
• The ‘Guidelines for International Shipment of Vaccines’
published in 2005 is the main guidance document for
packaging and shipment of vaccines
• Currently under revision with publication of the revised
version (planned for March 2020)
• Purpose of the revision is to incorporate changes in
technology and policies over the last 10 years since the
first version was published

43
Guidance 2
• Guidelines contain a section on insulated packaging
standards for OPV, Freeze dried vaccines (BCG, Measles,
MR, MMR, Meningococcal A&C, yellow fever) and freeze
sensitive vaccines (DTP, DTP Hep-B, IPV, TT, etc…)
• Also contains sections on temperature monitoring devices,
storage volume standards, labelling and packaging and
shipping arrival procedures

44
Monitoring Devices
• Electronic shipping indicators
 Single use pre-programmed electronic time-temperature loggers
which accompany vaccines from the manufacturers warehouse
to the receiving country’s primary store.
 They display the shipment’s time-temperature exposure without
the need for download onto a PC
• Cold Chain Monitors (CCMs)
 Provide a warning when excessive heat exposure occurs during
transport.
 They are used primarily to monitor the international shipment of
freeze-dried vaccine consignments where dry ice is used as the
cooling medium.

Reference documents
Vaccine PQ website: https://www.who.int/immunization_standards/vaccine_quality/vq_index/en/
PQT/VXA procedure [TRS 978, Annex 6 (2013]
http://www.who.int/entity/immunization_standards/vaccine_quality/TRS_978_61st_report_Annex_6_
PQ_vaccine_procedure.pdf
PQ vaccines: Priority setting and Review
http://www.who.int/immunization_standards/vaccine_quality/pq_priorities/en/
Programmatic Suitability for Prequalification
https://www.who.int/immunization_standards/vaccine_quality/ps_pq/en/
Clinical
http://who.int/entity/biologicals/vaccines/clinical_evaluation/en/index.htm (especially TRS1004)
http://who.int/biologicals/vaccines/nonclinial_evaluation_of_vaccines/en/
http://www.who.int/immunization_standards/vaccine_quality/pq_vaccine_evaluation/en/
Variations to prequalified vaccines
http://who.int/immunization_standards/vaccine_quality/variations_pq_vaccine/en/
WHO contracted testing laboratories
http://www.who.int/immunization_standards/vaccine_quality/contracted_labs_vaccines/en/

Good Manufacturing Practice
WHO GMP for biological products, Annex 2, WHO TRS 999, 2016,
http://who.int/biologicals/areas/vaccines/Annex_2_WHO_Good_manufacturi
ng_practices_for_biological_products.pdf
WHO GMP for pharmaceutical products: main principles, Annex 2, WHO
TRS 986, 2014
WHO GMP for sterile pharmaceutical products, Annex 6, WHO TRS 961,
2011
Reference documents

47
Thank you

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