world health organization's prequalification program for medicines

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Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services

World Health Organization's Prequalification Program for

medicines

Dr Lembit RägoCoordinator

Quality Assurance and Safety: MedicinesEssential Medicines and Pharmaceutical Policies

World Health OrganizationGeneva, Switzerland

E-mail: [email protected]

V Conference of the PANDRH17 – 19 November 2008Buenos Aires, Argentina

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Is quality and safety of medicines still a big problem nowadays?

Panama case in 2006. It turned out the cause

of death of more than forty five persons was simple. The cough syrup and potentially other medicines produced in the governmental pharmaceutical factory were contaminated.

The death were caused by diethylene glycol (DEG) found in medicines. DEG is a chemical cousin of antifreeze and used widely by various industries. It is toxic to the kidneys and can cause deadly renal failure.

Pictures. 1. Waiting for answer. 2. A popular medicine in Panama that turned to be a killer. 3. Medicines traced down and removed from supply chain

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Viracept (nelfinavir) saga

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Heparin "saga" 2008 – many countries affected

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What is WHO doing to help the countries?

Normative functions

Capacity building

Prequalification

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Normative functions

Nomenclatures and classifications International Nonproprietary (generic) Names –

INNs Anatomical Therapeutic Chemical (ATC)

classification and Daily Defined Doses (DDD) International guidelines, standards and norms, mostly

in the area of quality assurance International Pharmacopoeia WHO GMP, interchangeability, fixed dose

combinations, variations, stability guidelines etc.

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New Specifications adopted by 41st WHO Expert Committee - examples

Abacavir oral solution Abacavir sulfate tablets Didanosine tablets Didanosine oral solution (adult formulation) Lamivudine oral solution Lamivudine tablets Stavudine capsules Zidovudine capsules Zidovudine IV injection Zidovudine oral solution Zidovudine and Lamivudine tablets Zidovudine, Lamivudine and Abacavir tablets

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Prequalification of essential medicines

The UN prequalification program is an action plan for expanding

treatment access for patients with

HIV/AIDS

Tuberculosis

Malaria

… and includes also selected products for reproductive health

and Avian flu (oseltamivir)

by ensuring quality, efficacy and safety of medicines procured using

international organizations and funds (e.g. UNICEF, Global Fund,

UNITAID)

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Why the prequalification is needed?

Risks • Sourcing of poor quality products or even counterfeit medicines

risk to patients, toxic reactions, treatment failure, resistance

bad quality (generic) products undermine public confidence Problems

• Millions of people living with HIV/AIDS, tuberculosis and malaria, have no or limited access to treatment

• Substandard and counterfeit products in different countries • Weak or absent QA systems of medicines supply chain• Lot of money invested in procurement

products with very different quality sourced

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Prequalification basic principles

Legitimate - General procedure and standards approved through WHO Expert Committee system involving all WHO Member States and WHO Governing bodies

Voluntary for participating manufacturers Widely discussed

• FIP Congress, Nice 2002 • Supported by International Conference of Drug Regulatory

Authorities (ICDRA) in 2002, 2004 and 2006 representing more than 100 national drug regulatory authorities;

Transparent (all information available on the web site http://mednet3.who.int/prequal/ )

Open to both innovators and multisource/generic manufacturers No cost for applicants as per today (in future fees considered) Capacity building important part of it

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Expected outcomes of prequalification

Public lists of products and manufacturing sites • Meeting international standards on quality, safety, and efficacy

Capacity building and harmonization• National Drug Regulatory Authorities (DRAs), manufacturers,

WHO treatment programs, NGOs, procurement organizations Ongoing quality monitoring

• Ongoing monitoring of prequalified products Facilitate access to treatment

• Through fair procurement mechanisms (e.g. tender, competition based on the same quality standards)

• WHO commitment to developing better access to quality medicines

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How prequalification is organized?

Role of WHO: Managing and organizing the project on behalf of the UN • provides technical and scientific support and guarantee that

international norms and standards are applied all through the process including assessment, inspection (GMP, GCP, GLP) and quality control

Partners: • UNICEF, UN Population Fund (UNFPA), UNAIDS and with the

support of the World Bank• Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS

Department Actors: Qualified assessors and inspectors from National DRAs of

ICH and non-ICH countries, and inspectorates belonging to PIC/S

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Assessment procedure- Product dossiers

Innovator products• Abridged procedure if approved by stringent authorities like EMEA and

US FDA• Assessment reports from Drug Regulatory Authorities (DRSs), WHO

Certificate of Pharmaceutical Product (CPP), batch certificate, update on changes

• Trusting scientific expertise of well-established DRAs Multisource products

• Full dossier with all data and information requested• Quality : information on starting materials and finished product

including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc

• Efficacy and safety: Bio-equivalence study or clinical study report• US FDA tentative approvals for ARVs – recognition scientific assessment

based on information exchange (Confidentiality agreement between US FDA and WHO); the same approach apply for EU Art 58 and Canadian access procedure)

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Inspections and QA analysis

Inspections Manufacturing site (final product, packaging) Active pharmaceutical ingredient (API) Research laboratory or Contract Research Organization (CRO) Teamwork of inspectors

• WHO representative (qualified GMP inspector)• Inspector from well-established inspectorate (Pharmaceutical Inspection

Cooperation Scheme countries – PIC/S)• National inspector/s invited to be part of the team but have NO decision

making power (different GMP standards, potential conflict of interest)

Quality control analysis - upon need, but not always necessarily before prequalification and supply, increasingly as part of proactive follow-up

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Prequalification: the technical documents are WHO normative documents

The Expert Committee documents pass wide international consultation and are finally adopted by the Committee composed of outstanding international technical experts

In case WHO standards are "silent" other applicable standards such as ICH and national standards are used

New TRS No 943 with 41st Report from 2007 Updated PQ general procedure PQ of QC labs procedure

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Current status

Started with HIV/AIDS products in 2001 – malaria and TB products joined later

Prequalified products " Active" dossiers in pipeline • 171 HIV related medicines 65• 17 anti-tuberculosis medicines 25• 10 anti-malarial medicines 32• 184 115+

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Transparency: WHO Public Inspection Reports (WHOPIR) and WHO Public Assessment Reports (WHOPAR) on web

*WHOPAR – structure and amount of information the same as in European Public Assessment Report (EPAR)

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News example: latest 9 products listed

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Inspections 2005-2007

Inspections of finished products (FP) manufacturers in 2007 reaching 26

Active pharmaceutical ingredients (API) manufacturers in 2007 – 6

Contract Research Organizations (CRO) for BE studies in 2007 - 13

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5

10

15

20

25

30

FP API CRO

2005

2006

2007

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Dossier assessment – number of assessment reports generated for different product groups

In 2007 total 511 assessment reports were generated

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50

100

150

200

250

300

350

400

HIV TB Malaria

2005

2006

2007

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Publications 2005-2007

Prequalification of medicines. WHO Drug Information, 2005, 19:1.

WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2.

Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalifi cation Programme. Journal of Generic Medicines, 2006, 3(2):96–105

Survey of the Quality of Antiretroviral Medicines Circulating in Selected African Countries, WHO/PSM/QSM/2007.9 (September 2007)

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Capacity building: Examples of trainings organized by in 2007Capacity building: Examples of trainings organized by in 2007

Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines Cape Town, South Africa, 16 - 20 April 2007

Training Workshop on Dissolution, Pharmaceutical Product interchangeability and Biopharmaceuticals Classification System (BCS) Kiev, Ukraine, 25 - 27 June 2007

Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence with a Focus on TB products Jiaxing, China , 5 - 9 November 2007

Training Seminar for Quality Control Laboratories on Quality Assurance, Prequalification and Development of Standards Rabat, Morocco, 27 - 29 November 2007

Training Workshop on WHO Good Manufacturing Practices Dakar, Senegal, 11 - 14 December 2007

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Pharmaceutical Development with Focus on Paediatric formulationsPharmaceutical Development with Focus on Paediatric formulations

WHO/FIP/IUPHAR Training Workshop

Hyatt Regency Hotel

Sahar Airport Road

Andheri East, Mumbai, India

28 April 2008 – 2 May 2008

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Participants of trainings organized and supported by WHO Medicines Prequalification Progarmme 2007

100

145

10200

QCLs Regulators Manufacturers Procurers

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Other specific regulatory pathways for products of public health needs

EU Article 58 US FDA tentative approvals linked to PEPFAR Canadian Access to medicines scheme

WHO cooperates with all the above mentioned Confidentiality agreement with US FDA in place and

working; CA with Health Canada in progress MoU (including confidentiality arrangements) under

developemnt with European Commission

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Summary Not so good news

Only limited number of products have met the required standards (especially malaria and TB products)

Takes time to get into compliance• Data to be generated, tests to be carried out …• GMP upgrade needed

Quality has its price Good news

Relatively large number of products and suppliers comply with the standards (mostly ARVs so far)

Many potential suppliers appreciating feedback and willing to improve Unique technical knowledge obtained about products, especially about

generic antiretrovirals and antimalarials Capacity building component appreciated a lot Working together – way to learn to recognize each others work and work for

reducing duplicative efforts

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Prequalification - a good engine to pull quality of medicines into international agenda

It challenges the still existing reality - "poor quality medicines for poor"

How best keep it going as huge unfinished agenda is ahead?

world health organization's prequalification program for medicines

Documents