WHO Prequalification – Medicines

assessment quality aspects

Andrew Chemwolo, Technical Officer

Prequalification Team – Medicines Assessment

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 Prequalification of Medicines
 Started in March 2001 as a Pilot Project: Focus on HIV/AIDS

 Partners included WHO, UNICEF, UNFPA, UNAIDS and

supported by World Bank

 Quickly expanded to include Tuberculosis, Malaria,

Reproductive Health, Influenza and others

 Funded by donors – mainly UNITAID and Bill & Melinda

Gates Foundation

 Fees introduced on 1 Sept 2013 (for new dossiers, major

variations)
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 Therapeutic areas

 Therapeutic areas invited are:

HIV/AIDS
Malaria
Tuberculosis
Reproductive Health (RH)
Influenza
Acute diarrhoea in children (zinc)
Neglected Tropical Diseases (NTDs)
 EOIs containing list of invited products is published on PQP web site

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 Invitation for Expression of Interest (EOI)

 A list of medicines invited for prequalification

 Priority public health medicines
 Only product dossiers for medicines included in this list are invited
for prequalification.

 List prepared by WHO clinical experts/departments (HIV, TB,

Malaria, RH, Influenza, Diarrhoea (Zinc), NTD)
 Based on inclusion in WHO treatment guidelines and/or WHO model
list of essential medicines

 List revised as needed to capture new developments

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 Current Expressions of Interest

Currently 8 EOIs are published:

 HIV/AIDS – 11th
 Influenza – 2nd
 Malaria – 10th
 Neglected Tropical Diseases (NTD) – 3rd
 Reproductive Health – 5th
 Tuberculosis – 12th
 Diarrhoea (Zinc) – 1st
 Active Pharmaceutical Ingredients – 6th

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 The PQ Process Flow

It is simple, straight-forward and designed for

complete product review

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 Prequalification process
Expression
of Interest

Product dossier
+ Site Master File
Assessment Inspections
Additional information Corrective
and data actions
Acceptable Compliance

Prequalification
Maintenance and monitoring

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 Prequalification of FPPs
 Common PQ process for all therapeutic areas.
 Stages:
 Receipt of application
 Screening and acceptance for assessment
 Assessment of Quality and Efficacy/Safety data
 Inspection of manufacturing sites (FPP, API) and CROs
 Prequalification/listing
 Maintenance/Monitoring of the products after prequalification
• variations, requalification, inspections, random QC sampling,
investigation of complaints

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 Screening
 Confirmation of eligibility (listed on the EOI)

 Review of data in the Application Forms and Dossiers

 Mainly a qualitative check to confirm presence of data
 Some selected quantitative checks also done e.g. duration of stability
studies, number of batches used etc.

 Ensure administrative and technical completeness

 A screening checklist is used

 Letter of acceptance for assessment issued to the applicant and a

WHO reference number allocated

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 Dossier assessments
 Quality and Efficacy/Safety parts of dossier assessed in parallel

 Several rounds of communication with applicants

 API section of dossier can be supported by prequalified API, CEP,

APIMF or full API data.

 QA step at the end of the assessment process

 Close coordination with inspectors

 Product listed (prequalified) once all requirements are met and

letter of prequalification issued to applicant.

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 Dossier assessments
 WHO, ICH and specific PQP guidelines and the International
Pharmacopoeia/recognized pharmacopoeias are applied:
 Guideline on Preparation of product dossiers (PDs) in Common
Technical Document (CTD) Format
 Guideline on submission of documentation for a multisource (generic)
finished pharmaceutical product for the WHO Prequalification of
Medicines Programmed: Quality part

 All the relevant guidelines and forms published on WHO PQP

web site (http://www.who.int/prequal/)

 Maintenance (variations, requalification) done in-house and during

assessment sessions
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 Administration of dossier assessments
 Assessors
 In-house and external (90%), mostly from SRAs (subject to availability).
Total assessor pool 50+.
 Assessment sessions every 2 months in Copenhagen for 5 days
 Dossiers are assessed by at least 2 assessors (Q and BE separate), each
report is reviewed by a more senior assessor.
 Assessors from developing countries constitute ≈ 40%
 A unique opportunity for assessors from all over the world to work
together
 Frequent manufacturer meetings and Teleconferences
 Assessments in-between sessions done (WHO HQ)

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 Prequalification of SRA approved products
(innovator or generic)
 Assessments and inspections by a stringent regulatory authority
(SRA) are recognised by PQP
 SRAs are 1) ICH member, 2) ICH observer or 3) RA associated with an
ICH member through a legally binding, mutual recognition agreement.

 Abbreviated process for prequalifying medicines approved by an

SRA (no duplication)

 Variations handled by the SRA

 Also limited to defined priority medicines (listed on the EOIs)

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 Paths for inclusion of a product in the list of
prequalified products
 Prequalification of multisource generic products
 Full review of dossier and inspection of sites by PQP
 Prequalification of innovators
 Approval based on marketing authorization issued by an NMRA in
ICH region and associated countries
 Prequalification of generic products approved by SRA
 Approval based on SRA marketing authorization
 Recognition of temporary approvals / scientific opinions
 USFDA PEPFAR approval/tentative approval
 EMA article 58
 Health Canada Access programme

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 Products prequalified 2007- 2013

70
60
NTD
50 Diarrhea
40 Influenza
30 RH
20 Malaria
10 TB
0 HIV

2013
2007

2008

2009

2010

2011

2012
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 Variations
 Applies to changes to prequalified products.
 The changes are classified into the following categories:
 Notifications : have minimal or no adverse effects on the overall quality, efficacy
and safety of the FPP.
• IN (Immediate notification): do and tell immediately
• AN (Annual notification): do and tell within 12 months following implementation
 Minor variations: may have minor effects on the overall quality, efficacy and
safety of the FPP.
• can be implemented if no objection letter has been issued within 60 days of
acknowledgment of receipt of the application
 Major variations: could have major effects on the overall quality, efficacy and
safety of the FPP.
• Prior acceptance by WHO-PQP is required before the changes can be implemented.

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 Requalification

 Quality review after five years from the date of prequalification of

the product, or when requested to do so by PQP (whichever date is
earlier)

 Procedure applicable to products fully assessed and prequalified

by WHO.

 Purpose of requalification:
 Ensure that the listed products conform to current norms and standards.
 Follow up on commitments made at time of prequalification
 Assessment of consistency of the quality of the prequalified FPP and its
manufacturing process(es) over the identified period.

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 API Prequalification

 Started as a pilot project in October 2010.

 It is part of the WHO Prequalification of Medicines Programme.

 It is a scheme for manufacturers of APIs that are used in invited

medicinal products (current 6th EOI).

 It seeks to verify and identify APIs that are of good quality and
manufactured in compliance with GMP.

 Involves assessment of the APIMF and inspection of

manufacturing sites.

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 API prequalification

 Applicants with prequalified APIs are issued with a WHO

Confirmation of API Prequalification document.

 Assessment process abbreviated if APIMF is already accepted.

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 Benefits to API manufacturers
 APIs can be prequalified independent of an FPP application.
 Public recognition as a source of quality API, manufactured in
compliance with GMP.
 Opportunities to verify compliance with GMP.
 Opportunities to compile, revise and refine regulatory
documentation, leading to quicker acceptance by other national
regulatory agencies.

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 Benefits to FPP manufacturers

 Ease of identifying potential sources of quality API.

 Identifying API manufacturers with robust quality systems in

place.

 Identifying API manufacturers that maintain good regulatory

documentation, which may be used in regulatory submissions.

 Reduced API assessment requirements (PQP)

 Reduced post-prequalification variation (changes)

requirements.

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 How are APIs Prequalified
Invitation

Application

GMP Assessment
(Inspection/desk review) (Quality)

Decision

Listing

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 Publishing

List of PQ APIs
+ WHOPIRs
Website (Public)
Website (Public)

Confirmation Document (Private)

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 Confirmation of API PQ document

 Provided to the API manufacturer for distribution at their

discretion
 Contains:
 The assigned WHO application number.
 The INN name of the active pharmaceutical ingredient.
 API manufacturer company name.
 The API specification version number.
 A copy of the API specifications.
 The assigned re-test period.
 The recommended storage conditions.
 A copy of the assay and related substances test methods.

 Intended for: UN agencies, NMRAs, FPP manufacturers

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 Future of API Prequalification

Dec 2011 Dec 2012 Dec 2013 May 2014

Total number of 36 69 100 108

applications
Number of PQ 8 28 51 61
APIs

 There is very positive feedback from FPP manufacturers

whenever PQ of APIs is discussed.

 The number of applications and prequalified APIs continues to

increase.

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 WHO Public Assessment Report (WHOPAR)

 Aims to make assessment outcomes publicly available

 Report summarizes assessment of the product data and

information submitted in the product dossier (excluding
confidential/proprietary information).

 Published by WHO PQP on the web site

 Composed of 8 parts, including those for SmPC, PIL &

Labelling

 Updated regularly

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 Technical assistance

 Provision of expert consultants to

 Manufacturers
 Quality control laboratories

 Assistance focuses on
 GMP, GCP or GLP compliance
 Data development and compilation of dossier

 Technical assistance is separated from the assessments and

inspections

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Conditions for provision of technical assistance
Manufacturers:

 Participation in the Prequalification of Medicines Programme

 Capable and willing to improve

 Located in a developing country

Products:

 Inclusion in the EOIs

 High public health value

 Poorly represented in the prequalified list.

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 Benefits of PQ to manufacturers

 Access to international funds (participation in tenders)

 Facilitated registration in some recipient countries

 Capacity building (within the process)

 Possibility for technical assistance

 Recognition as a WHO listed company (better image, more

trust from procurement agencies and regulators)

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 Prequalification Statistics

 1st product prequalified in 2002.

 Total of 388 products currently prequalified (06 May 2014).

 Majority of the prequalified products are for HIV/AIDS (244

out of 388).

 61 APIs currently prequalified (07 May 2014).

 137 FPPs currently under assessment (07 May 2014)

 48 APIs currently under assessment (07 May 2014)

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 Web site: http://www.who.int/prequal/

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 Products under assessment (on website)

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 Further information:

Further information: http://www.who.int/prequal/

Email: prequalassessment@who.int or
stahlm@who.int (Dr. Matthias Stahl)

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 Thank you!

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