WHO Prequalification of Medicines
General overview and update
Dr Milan Smid
WHO Prequalification of Medicines Programme
Amman, June 2013
UN Prequalification Programme
for Priority Essential Medicines
Action plan of UN from 2001 for expanding
access to selected priority medicines
• To ensure quality, efficacy and safety of medicines procured using
international funds (e.g. GFTAM, UNITAID) to serve patients in
developing countries
• Evaluation of Quality, Safety and Efficacy of prioritised Essential medicines
(FPPs and APIs), inspections of manufacturers and monitoring of the
products after their prequalification.
• Prequalification of quality control laboratories.
• Building capacity of regulators, manufacturers and quality control
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Categories of medicines invited
• Primary categories of medicines:
– Malaria
– Tuberculosis
• Later added:
Reproductive health
Acute diarrhoea
Neglected tropical diseases
• Potentially other categories of products, if there is the need
• Prequalification also applicable for APIs!
• Published in invitations for Expression of Interest
(EOI) on Prequalification website
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Example - invited SL TB medicines
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Two prequalification routes
Invitation for
expression of Interest
Medicine not
assessed by SRA
Medicine assessed
by SRA
Dossier and SMF
submitted for assessment
and accepted
Valid for innovators and generics
WHO assessment
and inspections
SRA registration
(assessment and
compliance check)
Simplified review
Post-PQ maintenance
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Essential steps of PQ evaluation
• Need is specified and agreed by WHO treatment programmes
• Invitation for Expression of Interest (EOI) is published
• Interested parties submit dossiers
• Dossiers receive initial screening
• Full dossiers are assessed
• Inspections are conducted at manufacturing sites and at CROs
• Samples are tested, if needed
• If outcome is positive, pharmaceutical product is listed on the
website, including product information (SPC, PIL),
assessment report (WHOPAR) and inspection report
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Essential steps of monitoring of PQ
• Variations to the dossier of prequalified product
• Sampling and Testing
• Re-inspections
• Requalification
• Management of complaints
• De-listing or suspension (if and when appropriate)
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• WHO standards as defined in WHO guidelines and
International Pharmacopoeia are applied in
prequalification process
• If these not exist, ICH guidelines are applied
• In case of need, guidelines of stringent regulatory
authorities, which are involved in ICH process
• Pharmacopoeias (Ph.Int., USP, BP, Ph.Eur., JP) as
minimum standard
• Depending on product, assessors may ask for additional tests or tightening limits
• Same principles applied in prequalification as valid for
national regulatory approvals by stringent authorities
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WHO guidelines and monographs
Medicines related guidelines:
New or revised:
Many opened for comments!
Guidelines relevant for WHO prequalification:
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Evaluation procedure
 Assessment of product dossiers
(Quality specifications, pharmaceutical development, production,
control, stability, bioequivalence etc.).
 Teams of professionals from national Drug Regulatory
Authorities (DRA): Including Brazil, China, Canada, Denmark, Estonia,
Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain,
South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe ...
Copenhagen assessment week
8 to 20 assessors together during one week at least every two
months at UNICEF in Denmark
Every dossier is assessed by at least four assessors.
An assessment report is issued - signed by assessors
Letter summarizing the findings and asking for clarification and
additional data if necessary is sent first by e-mail to the applicant
followed by surface mail
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• Team of inspectors for each inspection
• WHO PQ inspector plus PIC/S member country plus local
country inspector (observer)
• Some cases – capacity building (recipient country)
• Inspections are product oriented
• APIs and Bioequivalence studies inspected based on risk
• Public inspection report is posted on PQP website
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Outcomes of PQ procedure
Information in public domain:
Lists of PQ medicinal products
WHOPAR (SPC, PIL, labelling)
WHOPIR (both FPP and API)
Notices of Concern and Suspensions
Information on progress of assessment procedure and
• Supportive documents: WHO guidelines, description of
PQ procedure, training materials
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Prequalified 425 medicines (March 2013)
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Prequalified 425 medicines (March 2013)
99 medicines listed based on the
- approval and/or tentative approval by US FDA (95)
- approval within Canada's Access to Medicines Regime
- approval by EMA according to Article 58 (3)
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Prequalified medicines according to
countries of manufacture (December 2012)
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Producers of WHO prequalified FPPs
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Capacity building - objectives
• Good quality submissions for PQ supported by
compliance with "good practices"
– Platform for improvement of drug development, manufacturing,
documentation and quality control
• Fast regulatory approvals of PQ medicines in recipient
– Technical education of regulators as a platform for strengthening
expertise, regulatory efficiency and networking
• Reliable quality monitoring
– Technical education of staff of QCLs to strengthen expertise,
effectiveness of quality monitoring and networking
PQP standards and PQP example support strengthening
of regulatory systems and capacity of manufacturers in
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Technical Assistance
• Provision of expert consultants to
– Manufacturers, Quality control laboratories, Regulators
• Assistance focuses on
– GMP, GCP or GLP compliance
– Dossier development
• Assistance is separated from the assessment /
inspections and may be followed by specific trainings
• Collaboration with partners, who organize free of charge
assistances with the objective to accelerate submissions
of good quality application and GMP compliance
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Countries assisted by PQP
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API Prequalification
Intended for: UN agencies, National medicine authorities, FPP
manufacturers, public
• API Prequalification is a programme run by the WHO to
assess the Quality of listed APIs (HIV/AIDS, TB, malaria,
RH) and GMP status of API manufacturers.
• Prequalified APIs are publicly identified on the WHO
website as suppliers of quality API.
• There is no FPP involvement in this process.
• Project has multiple benefits for manufacturers of FPPs
and APIs and regulators.
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Producers of WHO prequalified APIs
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Expert review panel (ERP) process for
risk categorization of medicines to assure
quality for procurement needs
• Eligibility:
a. FPP manufacturing site is GMP compliant as
certified by WHO PQP, SRA or PIC/S
b. In case of medicines invited for WHO-PQP, a
product dossier has been accepted for
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Expert review panel (ERP) process
- risk categorization serving procurement
• The following major product attributes are used
as the basis for risk categorization (assuming
the eligibility criteria are met):
a. FPP manufacturing process and FPP
b. Stability data
c. Evidence of therapeutic equivalence
d. API source and API quality
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ERP - possible outcomes of review
• Risk category 1: "No objection" against
• Risk category 2: "No objection" against
procurement, but there are certain observations
• Risk category 3: "Objection" against
procurement, but still acceptable in case of
extreme need
• Risk category 4: "Objection" against
procurement, not recommendable at all
• Request for additional data
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ERP - possible outcomes of review
• Recommendations are provided within 6-8
weeks and are time limited:
• validity maximum 12 months.
• can be extended only under certain
• ERP status does not replace WHO PQ or
SRA approval but should be seen as a
step towards WHO PQ/SRA approval
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WHO Collaborative Procedure to accelerate
registration of prequalified medicines
Procedure drafted in wide consultation, approved by WHO
advisory expert committee. Approved by WHO Executive
Board in May 2013.
Pilot testing ongoing with 11 interested countries:
• Botswana
• Nigeria
• Ethiopia
• Tanzania (incl. Zanzibar)
• Ghana
• Uganda
• Kenya
• Zambia
• Kyrgyzstan
• Zimbabwe
• Namibia
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Principles of proposed process
1. Procedure voluntary for manufacturers and NMRAs
and providing benefits to both parties.
2. Being asked by PQP holder (manufacturer), PQP
shares full PQP assessment and inspection
outcomes with interested NMRAs and provides
advice to facilitate national regulatory decisions
(registrations, variations, withdrawals). Applicable
only for medicines assessed by PQP.
3. No interference with national legislation, decision
making process and regulatory fees – availability of
PQP expertise.
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Principles of proposed process
4. Co-operation among PQP holder (manufacturer),
NMRA in interested country and PQP necessary to
overcome confidentiality issues, assure information
flow and product identity. Registration dossier in
countries in principle the same as approved by
5. Each participating authority commits to adopt
registration decision within 90 days from having
available full PQP assessment and inspection
outcomes and has the right to
decline to adopt procedure for individual medicines
decide differently from PQP, but keep PQP informed and
clarify the reasons for deviation.
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Steps of the procedure: agreement
Interested NMRAs agree
to participate in the procedure
and designate focal persons
PQP lists committed NMRAs
on its website and gives to focal
persons access to
restricted-access website
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Steps of the procedure: registration
PQ product is submitted for national registration
to NMRA participating in the procedure
NMRA is informed about the interest to follow PQP
Manufacturer informs PQP about national submission
gives consent with information sharing
Participating NMRA confirms its interest to
participate in procedure for specific product
PQP shares with participating NMRA
outcomes of assessment and inspections
Participating NMRA reviews WHO PQP outcomes,
decides within 90 days decides upon the national
registration and informs PQP about its decision
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Steps of the procedure: post-registration
PQP informs NMRAs
about important variations
NMRAs inform PQP about
variations and decisions leading to
inconsistency with PQP conditions
De-registrations and de-listings
WHO PQP informs NMRA about
withdrawals, suspensions or de-listings
of prequalified medicinal products
NMRAs inform PQP about
national de-registration
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Major and other new developments
• Pre-inspection GMP assessments with public
outcome - if compliance confirmed
• New guidelines proposed e.g. in GMP area,
quality data requirements for prequalification,
post-prequalification variations
• New monographs in International
• Prequalification fees considered for the future
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Frequent misunderstandings
• Manufacturers/manufacturing sites are prequalified
• PQP issues WHO GMP certificates
• PQP provides direct financial support
• Prequalification gives right to succeed in tenders
• PQ substitutes national authorization (registration) in
recipient countries
• All medicines used in treatment of HIV/AIDS and
tropical diseases are invited for PQ
• Prequalified medicines may bear WHO logo
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Potential benefits from participation in
WHO-PQP for manufacturers
• Participation in tender procedures organized by
international procurers and financial profit
• Recognition as being WHO listed company
• Facilitated registration in some recipient countries
• Reduction of inspections from recipient countries
• Possibility to be assisted by expert consultants (GMP,
• Learning process improving company's chance to
succeed with submissions to SRAs
• Recognition of prequalified APIs
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For some applicants WHO
prequalification is difficult. Why?
Wrong paradigm of generic product development
Compliance with good manufacturing practice
Reliable source of good quality raw materials
Inappropriate process and product control
Lack of comparability with reference product
Difficulty to assure complementary functions
relevant for development and production of
generics (bioequivalence, comparator,
standards, …)
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Introduction to WHO Prequalification of Medicines Programme