1. Prequalification and Quality Monitoring of anti-malaria products Andre van Zyl, M. Pharm. Project Manager Health Technology and Pharmaceuticals Cluster, Essential Drugs and Medicines Policy, Quality Assurance and Safety: Medicines Tel: +41.22.791.3598 Fax: +41.22.791.4730 World Health Organization E-mail: vanzyla@who.int Workshop on GMP Bangkok Thailand, 18 – 22 October 2004

2. 2 WHO - EDM Prequalification of essential medicines n Layout: ä Introduction and background ä Quality Assurance (QA) l Procedure for prequalification l Product assessment l Manufacturers l Current status l Quality control l Ongoing monitoring and requalification l Summary and conclusion

3. 3 WHO - EDM Key questions: n Why is WHO doing prequalification? n What are the WHO criteria for safety, efficacy and quality? n What are the WHO projects related to QA and prequalification? n Which countries apply acceptable standards? n How does WHO ensure GMP, GCP, GPPQCL compliance? n Does WHO have a role in surveillance of counterfeit medicines? n What is the WHO role on FDCs? n What is the impact of the roles and policies of governments on WHO's potential for support and intervention?

4. 4 WHO - EDM 1. Introduction and background n What are the problems? l Millions of people living with HIV/AIDS, TB and malaria, have no or limited access to treatment l Procurement and supply of substandard and counterfeit products in different countries l Weak/absent QA systems l Money invested – lost n Risk: Sourcing of poor quality products, risk to patients, treatment failure, resistance

5. 5 WHO - EDM Substandard drugs is a big problem - antibiotics, antimalarials, antituberculosis drugs included. What about antiretrovirals? Incorrect amount 17% No active ingredient 60% Other errors 7% Incorrect ingredient 16% Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database Is quality of pharmaceuticals a problem?

6. 6 WHO - EDM 2. Quality Assurance (QA) n Partners: ä UNICEF, UNFPA, UNAIDS, WHO, agreed and also supported by the World Bank n Start a prequalification project as a Pilot: Objective ä To ensure that products meet international safety, efficacy and quality standards for purchasing and supply: Focus on HIV/AIDS n WHO role: ä Managing the project and provide technical support, norms and standards on product assessment, GCP, GLP, GMP n Developed internal Quality Assurance system ä Quality Assurance and Safety: Medicines (QSM) ä Standard Operating Procedures (SOPs) ä Manuals and guidelines ä General Procedure for Prequalification ä Norms and standards (product dossiers, manufacturers etc)

7. 7 WHO - EDM Expected outcome n List of products and manufacturers: ä Meeting international norms and standards on safety, efficacy and quality (S, E, Q) n Harmonization: ä Co-operation, training, capacity building – NDRAs, WHO, PAs, NGOs n Facilitate access to treatment: ä Procurement mechanisms (e.g. tender, competition) ä Ongoing monitoring of S, E, Q

8. 8 WHO - EDM About 50% of the countries in sub-Saharan Africa have very limited/no capacity to control the market-where regulatory authorities exist enforcement is weak

9. 9 WHO - EDM WHO/HTP/EDM/QSM Criteria for safety, efficacy and quality n What is required for multisource products? ä Marketing Autghorization of Pharmaceutical Products with special reference to multisource (generic) products (WHO/DMP/RGS/98.5) ä 1. Details of the product ä 2.Regulatory situation in other countries ä 3. Active pharmaceutical ingredient (s) (API) ä 3.1 Properties of the active pharmaceutical ingredient(s) ä 3.2 Sites of manufacture ä 3.3 Route(s) of synthesis ä 3.4 Specifications –API described in a pharmacopoeia: –API not described in a pharmacopoeia: ä 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

10. 10 WHO - EDM WHO/HTP/EDM/QSM General procedure: Pre-qualification n Required (2)? ä 4. Finished product ä 4.1.Formulation ä 4.2. Sites of manufacture ä 4.4. Manufacturing procedure ä 4.5Specifications for excipients ä 4.6Specifications for the finished product ä 4.7Container/closure system(s) and other packaging ä 4.8Stability testing

11. 11 WHO - EDM WHO/HTP/EDM/QSM General procedure: Pre-qualification n Required (3)? ä 4.9Container labelling ä 4.10Product information ä 4.11Patient information and package inserts ä 4.12Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s) ä 4.13Interchange-ability (bio-equivalence studies) ä 4.14Summary of pharmacology, toxicology and efficacy of the product

12. 12 WHO - EDM WHO Projects in quality assurance n Prequalification ä HIV/AIDS, tuberculosis, malaria (and others ??) n Norms and standards ä Guidelines for products including FDCs ä GMP, GCP etc n International Pharmacopoeia ä Monographs ä Specifications ä Reference substances n Quality control ä Sampling and testing ä Comparative dissolution n Inspections ä GMP, GCP, GPPQCL n Training workshops and seminars, DRA capacity building n Counterfeit monitoring

13. 13 WHO - EDM 3. QA: Prequalification. www.who.int/medicines n Invitation for EOI – voluntary participation n Guidelines for product dossier compilation (data and information on S, E, Q) n Screening and assessment of dossiers and product samples n SMF and manufacturing site inspection n Reports on outcome of assessments n Assessment of additional data and information n Follow up inspection n Quality control (testing of samples) n Listing the outcome (compliance) n Ongoing assessment n Ongoing monitoring n Requalification

14. 14 WHO - EDM 3 QA: Product data and information n Innovator products ä Assessment report from DRA, CPP, Batch certificate, changes n Multisource products ä Full dossier with data and information ä Quality - including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc ä Bio-equivalence study report n Sample for verification and possible analysis n Assessment teams: ä DRA assessors from Brazil, Canada, Denmark, France, Germany, Philippines, Sweden, Switzerland, Zimbabwe and others

15. 15 WHO - EDM 3. QA: Manufacturing sites and Contract Research Organizations (CROs) n Manufacturers: GMP compliance ä Team of inspectors: WHO plus PIC/S member DRA plus local DRA inspector(s) ä QM, premises, equipment, materials, validation, QC, documentation ä Product and site specific and includes data verification (BMR, specifications, stability data, validation report, dossier etc) n CRO: GCP and GPPQCL compliance ä Team of inspectors ä Ethics, clinical, analytical ä Product and site specific: as per dossier and includes data verification on subject data, method validation, calculations etc)

16. 16 WHO - EDM Current status n Started March 2001 – malaria in 2002 n EOIs published – mainly ACT n Ongoing assessments and follow-up ä Products, manufacturing sites (APIs and FP) ä CROs n Now 42 dossiers (malaria only) under assessment n 2 products prequalified n Several manufacturing sites inspected n Interim process

17. 17 WHO - EDM Current status n 14 Sites inspected to date ä 3 for APIs ä 11 for FP (including contract activities such as packing) n APIs: All in Asia ä All 3 at first non-compliant ä 2 accepted after corrective action, 3 rd under review (await corrective action plan) n Problems mainly validation, qualification, HVAC

18. 18 WHO - EDM Current status n Finished products: ä 11 sites (including contract activities such as packing) n Asia: 5 sites – 3 accepted ä 3 After corrective action, await corrective action plan from 2 n Europe: 5 sites – 2 accepted (with corrective actions) ä Await corrective action 1, under review 1, 1 re-assess) n Africa: 1 site – 1 accepted n Problems mainly mix-ups, validation, qualification, HVAC, cross-contamination, contamination, documentation

19. 19 WHO - EDM Quality Control (QC) and problems experienced Quality control: n Assessment: Samples checked n Not yet selected for analysis n Four independent laboratories used for ARVs n Standard Test Procedures (STP) and methods as well as specifications used (dossiers) n Lack of monographs in pharmacopoeia until recently n Lack of official reference standards n After purchasing: ARVs n Samples selected – comparative dissolution study n Protocol prepared, independent laboratory used

20. 20 WHO - EDM Quality Control (QC) Monographs and specifications n International Pharmacopoeia n Chinese Pharmacopoeia n Discussion with manufacturers – review and update n Internationally validated methods for monographs n Preparation of official reference standards

21. 21 WHO - EDM Quality Control (QC) Post purchase inspections: n Assess GMP compliance at the manufacturing site for the batches supplied n Assess records and data for the batches including comparison of: ä Batch manufacturing record, ä Specifications and dossier information, ä Raw data including quality control tests and results, ä Validation protocol and report, ä Changes and deviations, ä OOS investigations, ä Bio-batch records

22. 22 WHO - EDM Quality Control (QC) Quality problems experienced (products and dossiers): n Non prequalified products (although under assessment) supplied to several countries where it is known that these products do not meet international standards n Product dossiers lacking data and information including ä API: source of API, synthesis, specifications, method validation, stability ä Pharmaceutical development data ä Formulation and manufacturing process ä Validation (consistency) ä Stability ä Lack of study reports for safety and efficacy

23. 23 WHO - EDM Quality Control (QC) n Manufacturing sites and CROs (GMP, GCP, GLP) ä Poor design, layout and construction ä Lack of validation and qualification (process, utilities, equipment etc) ä Lack of raw data ä Cross-contamination and mix-ups ä Lack of quality control on materials ä HVAC n Time to take corrective action needed as manufacturers have to perform studies to generate data e.g. stability n Validation of manufacturing processes n Upgrading of manufacturing facilities n Different requirements and standards: local market versus export

24. 24 WHO - EDM Ongoing monitoring and requalification n Samples taken after supply n Routine inspections and additional inspections n Changes and variations controlled ä Products and manufacturers n Requalification (re- assessment) every 3 years n World Health Assembly resolution: WHA57.14 of May 2004 ä Public reports

25. 25 WHO - EDM FDCs and policies n FDCs: ä Essential Medicines List ä Advantages and disadvantages of FDCs ä Licensing of FDCs in USA and EU n New guidelines: ä FDA and WHO n Government roles and policies ä Treatment plans and policies ä Recommended treatments ä Licensing – prequalification ä Different standards applied e.g. no bio-equivalence required in some countries, differences in GMP legislation and requirements

26. 26 WHO - EDM Prequalification n T uberculosis: n First line as well as second line TB drugs n About 150 product dossiers n All assessed, 8 products prequalified n Including 3 x 4 FDC (Pakistan, India and South Africa) n Others: Await additional data

27. 27 WHO - EDM Summary and conclusion n QA and prequalification continue to facilitate access to a wide range of products meeting international standards n Ongoing quality control, monitoring, assessment and re- qualification is needed n Mechanisms should be in place to prevent the supply of counterfeit and substandard medicines n Harmonization in assessments and increased capacity building n Ensure safe, effective, quality products are purchased and supplied