WHO Prequalification of Medicines Programme

Raul Kiivet, MD, PhD

Manager, Prequalification of Medicines ProgrammeQuality Assurance and Safety: Medicines (QSM)

Department of Essential Medicines and Pharmaceutical Policies (EMP)

18 November 2008

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Web site updated constantly – www.who.int/prequal

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Prequalification of Medicines ProgrammePrequalification of Medicines Programme

The UN Prequalification Programme is ensuring that medicines procured with international funds are of assessed and inspected quality, efficacy and safety.

The Prequalification Programme is an action plan for expanding access to priority essential medicines in the following four areas:- HIV/AIDS - Tuberculosis- Malaria- Reproductive Health

A UN Prequalification Program of Quality Control Laboratories exists to facilitate the quality control of the prequalified products.

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Prequalification of Medicinal Products: ObjectivesPrequalification of Medicinal Products: Objectives

- Propose a list of prequalified products and manufacturers meeting international norms and standards of which the quality, efficacy and safety has been assessed, inspected and controlled

- Ensure that international norms and standards are applied at all the steps of the Prequalification Programme.

- Make sure re-evaluation and maintenance of the list are performed and that variations and changes are correctly controlled.

- Help the national drug regulatory authorities to build up capacity in assessment, inspection and control meeting international norms and standards.

- Develop the local possibilities of production and clinical studies by offering customized technical assistance.

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Assessment of the product dossier i.e. quality specifications, pharmaceutical development, stability, bioequivalence…

Copenhagen assessment week- 15 to 20 assessors during one week at least every two months - Every dossier is assessed by at least two assessors including one senior assessor for the second assessment

- An assessment report is issued- Letter summarizing the findings and asking for clarification and additional data if necessary; sent first by e-mail to the applicant followed by surface mail

Handling of variations of already prequalified products

- Done in house and during Copenhagen-week

Prequalification of Priority Essential Medicines Organisation (1) Prequalification of Priority Essential Medicines Organisation (1)

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Inspections of manufacturers of Finished Products (FP) Active Pharmaceutical Ingredient (API) and also Contract Research Organizations (CRO, which carry out bioequivalence studies)

Team of inspectors - WHO representative (qualified GMP inspector)

- Inspector from well-established inspectorate - National inspectors invited to be part of the team but have no

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

- Inspector of developing countries as observer, for capacity building purpose.

Prequalification of Priority Essential Medicines Organisation (2)Prequalification of Priority Essential Medicines Organisation (2)

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

1. Artemisinin-based fixed dose oral combination formulationsArtemether + Lumefantrine, tablet 20 mg + 120 mg; tablet 40 mg + 240 mg

tablet 60 mg + 360 mg; tablet 80 mg + 480 mg 2. Artemisinin-based fixed dose combination or co-blistered oral

formulations Artesunate + Amodiaquine, tablet 25 mg + 76.5 mg; tablet 50 mg + 153 mg

tablet 100 mg + 306 mg Artesunate + Mefloquine, tablet 25 mg + 250 mg; tablet 50 mg + 250 mg

tablet 100 mg + 250 mg Artesunate + Sulfadoxine + Pyrimethamine, tablet 25 mg + 500 mg + 25 mg

tablet 50 mg + 500 mg + 25 mg; tablet 100 mg + 500 mg + 25 mg 3. Artemisinin-based fixed dose combination or co-blistered oral

paediatric formulations, preferably dispersible

August 2008 - 6th Invitation to manufacturers of anti-malarial medicines

August 2008 - 6th Invitation to manufacturers of anti-malarial medicines

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Assessment & Inspections

Key numbers for 2007 21 products prequalified (28 in 2008*), 90 dossiers submitted (66 in 2008*) 463 assessment reports (487 in 2008*) 46 inspections (43 in 2008*)

* (8 months)

For each prequalified product in 2007 there were: 5-15 assessment reports 3-7 inspections it took 2 years in average to be prequalified

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Currently prequalifed (15 November 2008):

162 for treatment of HIV/AIDS and related diseases

18 for treatment of tuberculosis (10 prequalified in 2007-08)

13 for treatment of malaria (8 prequalified in 2007-08)

List of WHO Prequalified Medicinal ProductsList of WHO Prequalified Medicinal Products

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

2005 2006 2007 2008 * (8 months)

HIV 67 42 25 39

TB 17 9 17 13

Malaria 3 5 7 11

Repr Health - - 10 3

New submissions to prequalification

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

As of 1 November 2008:

120 products for treatment of HIV/AIDS and related diseases

48 products for treatment of tuberculosis

23 products for treatment of malaria

11 reproductive health products

Currently under evaluation in WHO Prequalification ProgrammeCurrently under evaluation in WHO Prequalification Programme

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Transparency – dossier status information on the web

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Anti-malaria medicines under evaluation

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Inspections - statistics in 2007 vs 2006

A total of 45 (2006 – 42) inspections were carried out in 2007:

26 (17) inspections of the manufacturing sites of finished product manufacturers

6 (10) inspections of the manufacturing sites of active pharmaceutical ingredients (APIs)

13 (15) inspections of contract research organizations (CROs)

In 2006 two inspectors in house, four in 2008

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Transparency – Inspection outcomes on the web

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Problems

Antimalarials and antituberculosis products – old problems but few new solutions

No new innovator products Generic products with no innovator

…or problem "new" products

GMP (both for finished dosage form and API)

Quality part of the dossier – specifications, stability data etc

Safety and efficacy – poor clinical and safety data, poor quality information

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Training activities in 2008

In total 13 training courses of 3 to 5 days: ten courses organized and 3 co-organized

In Belgium, Brazil, China, India, Iran, Jordan, Morocco, Nicaragua, Pakistan, Tanzania

More than 500 participants - staff of regulatory authorities and pharmaceutical manufacturers

Topics: Development of diossiers for submission Asssessment of Interchangeable medicines Pharmaceutical Development of Paediatric Formulations GMP, Quality and Bioequivalence of malaria ATC products GMP, Quality and Bioequivalence of Reproductive Health products Pharmaceutical Development of Paediatric Formulations

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Prequalification of Quality Control Laboratories

So far mainly for AFRO region, now wider scope 6 QC Labs prequalified

RIIP, South Africa – 07/2005 LNCPP, Algeria – 10/2005 Adcock, South Africa – 01/2008 National QCL, Kenya – 07/2008 National QCL, Marocco – 07/2008 Vimta Labs, India – 07/2008

13 QC Labs audited, corrective measures proposed Cameroon, Mali, Madagascar, Niger, Senegal Ghana, Etiopia, Kenya NQCL, Kenya MEDS, Uganda, Tanzania

8 QC Labs expressed interest, but not send LIF yet Benin, Burkina Faso, Cote d'Ivoire, Guinea

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Technical Assistance - Policy

Criteria for the products in relation to which technical assistance is considered: Inclusion in the list of expression of interest High value for Public Health purposes Poor representation on the Prequalification list Manufacture has applied for PQ (exemptions can be made upon justified

requests for technical assistance from regional offices) danger

Criteria for the experts: Excellent qualifications and long standing experience in the area where

expertise is required Absence of conflict of interest Total intellectual independence from the prequalification programme, no

participation in inspections or assessments.

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Technical Assistance - Examples 2007

Manufacture of oral solid dosage forms anti TB Ukraine

Technical Assistance on stability studies

06-09 February 2007

Manufacturer of sterile anti malarial API China

TA on manufacture of a sterile API under aseptic conditions

05-10 March 2007

Manufacture of oral solid dosage forms anti malarial Cambodia TA on packaging of co-blisters 26 March – 02 April 2007

Manufacture of oral solid dosage forms ARV Zimbabwe TA on GMP compliance 01-05 May 07

Manufacturer of anti TB API IndiaTA on manufacturing process validation and GMP

20-26 May 2007

Manufacture of oral solid dosage forms anti malarial Cambodia TA on packaging of co-blisters 17-29 July 2007

Manufacture of oral solid dosage forms ARV. Bangladesh TA on GMP and engineering 23–29 August 2007

Manufacture of oral solid dosage forms ARV Zimbabwe TA on GMP compliance 04-09 November 2007

Manufacturer of anti TB API IndiaTA on manufacturing process validation and GMP

17-21 December 2007

Manufacturer of sterile anti malarial API China

TA on manufacture of a sterile API under aseptic conditions

17-22 December 2007

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Revision of PQ procedure in 2008

Reasons for revision 5 years experience from implementation discrepancies between rules and practices unclear responsibilities of parties

Aims of revision increase transparency of PQ activities publish more details of prequalified products harmonize terminology and clarify procedures better define responsibilities confidentiality agreement with applicants

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

New PQ procedure for APIs in 2009

until now the qualification of API source and manufacturer is the responsibility of finished product manufacturer => API manufacturer seldom inspected and API dossier commonly not evaluated

API source considered "confidential" information Oct 2008 WHO Expert Committee on Specifications for

Pharmaceutical Preparations will discuss Procedure for API Master File in Prequalification Programme PQ procedure for active pharmaceutical ingredients (APIs) – new

"regulatory" approach

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Summary remarks The purpose of the prequalification programme is to list good quality, safe and

effective medicinal products in the interest of public health in resource-limited countries.

The products should be submitted with technical data proving the quality of API and finished product together with necessary data on safety and efficacy

Manufacturing sites of API s and finished products should operate according to GMP principles in order to deliver consistent quality products

Technical assistance for promising manufacturers/products can be made available to achieve the goal and speed up the prequalification process.

Close cooperation with international procurement and financial institutions quality as prerequisite for procurement decision instruments to support quality production

Encourage manufacturers to invest into quality, and to apply for independent evaluation

Main aim of PQ – to increase choice and access to quality products