Prequalification of HIV/AIDS Drugs - UN joint activity

 Partners* –

UNAIDS

– – – –

UNICEF UNFPA WHO With the support of World Bank

 WHO – Manages, provides technical support/assistance based on WHO norms and standards, plus ICH and other standards, where applicable. PQ team independent.

Prequalification basic principles

• Voluntary for participating manufacturers • Legitimate - General procedure and standards approved through WHO Expert Committee system • Widely discussed in many fora – FIP Congress, Nice 2002 – Supported by ICDRA in 2002 and 2004, representing more than 100 national drug regulatory authorities – WHA resolution 57.14 (May 2004) • Transparent (information on the web site http://www.who.int/medicines/) • Open to both innovators and multisource/generic manufacturers • No cost for applicants so far

General procedure: Pre-qualification

Steps of the Procedure – 1. Invitation for EOI (public, drug lists) – 2. Guidelines for product dossier compilation – 3. Receiving submissions (dossiers) – 4. Screening of dossiers – 5. Dossier evaluation (WHO Manual+guidelines) – 6. Site inspection (GMP, GCP, GLP) – 7. Reports and outcome (compliance/add info?) – 8. Pre-qualification results (web) – 9. Testing of samples Re-qualification (3 years)

EOI HIV and related diseases • NNRTIs • NRTIs • PIs • Anti-infectives (antibacterial, antimycobacterial, antiprotozoal, antiviral, antifungal) • Anticancer • FDCs (Lam/Stav, Lam/Zid, Lam/Stav/Efavir, Lam/Stav/Nevir, Lam/Zid/Efavir, Lam/Zid/Nevir)

General procedure: Pre-qualification • What will be required (1) ?

– 1. – 2.

– 3. – 3.1 Details of the product Regulatory situation in other countries Active pharmaceutical ingredient (s) (API) Properties of the API – 3.2 – 3.3 – 3.4 Sites of manufacture Route(s) of synthesis Specifications (API described/not described in a pharmacopoeia) – 3.5 Stability testing – WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-fourth report. Geneva, World Health Organization, 1996: 65 79(WHO TRS, No 863) http://www.ifpma.org/ich5q.html#stability

General procedure: Pre-qualification • What will be required (2)?

– 4. – 4.1.

– 4.2. – 4.4. Finished product Formulation Sites of manufacture Manufacturing procedure – 4.5

– 4.6

– 4.7

– 4.8

Specifications for excipients Specifications for the finished product Container/closure system(s) and other packaging Stability testing

General procedure: Pre-qualification • What will be required (3)?

– 4.9

– 4.10

– 4.11

– 4.12

Container labelling Product information Patient information and package inserts Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s) – 4.13

– 4.14

Interchangeability (bio-equivalence studies) Summary of pharmacology, toxicology and efficacy of the product

Access to HIV/AIDS Drugs of Acceptable Quality • What are the technical difficulties and problems experienced or revealed as a result of pre-qualification?

• Quality of product dossiers varied - Lack of information regarding API, validation, specifications, bio-equivalence - DRAs not applying same standards as recommended by WHO, yet products are registered and used - Very few substances and products have Pharmacopoeia monographs - What standards to apply? If standards not available - full assessment necessary

Access to HIV/AIDS Drugs of Acceptable Quality • Difficulties and problems (cont) Manufacturing site inspections - Manufacturers not ready - Upgrading of facilities to comply with WHO GMP - DRAs issued CPP – yet non-compliance - Inspections reveal non-compliance, e.g. antibiotics (penicillin), hormones and other products manufactured in the same site - No validation

The prequalification part of the project has two major activities: countries are providing expertise • • I. Assessment of products dossiers i.e. quality specifications, pharmaceutical development, bioequivalence etc. :

Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Zimbabwe ...

• II. Manufacturing site inspections: teamwork of inspectors: WHO representative (qualified GMP inspector), inspector from well established inspectorate (Pharmaceutical Inspection Convention Scheme countries) and national inspector(s):

Canada, France, Italy, Switzerland, The Netherlands … Quality control analysis -

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