1. Prequalification of essential medicines
Technical Briefing Seminar
Salle G, WHO Main building
Geneva, 28 September 2004
Andre van Zyl, M. Pharm. Project Manager
Health Technology and Pharmaceuticals Cluster, Essential Drugs and Medicines Policy, Quality Assurance and Safety: Medicines
Tel: Fax:
World Health Organization

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

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

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

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

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

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

8. 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. Criteria for safety, efficacy and quality
WHO/HTP/EDM/QSM
Criteria for safety, efficacy and quality
What is required for multisource products?
Marketing Autghorization of Pharmaceutical Products with special reference to multisource (generic) products (WHO/DMP/RGS/98.5)
1. Details of the product
2. Regulatory situation in other countries
3. Active pharmaceutical ingredient (s) (API)
3.1 Properties of the active pharmaceutical ingredient(s)
3.2 Sites of manufacture
3.3 Route(s) of synthesis
3.4 Specifications
API described in a pharmacopoeia:
API 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)

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

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

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

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

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

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

16. Ongoing assessments and follow-up
Current status
Started March 2001
Five EOIs including ARVs, antibiotics, anticancer, antifungal products have been published
Ongoing assessments and follow-up
Products, manufacturing sites and CROs
June 2004: 277 product dossiers for innovator and multi-source products
Samples tested
15th edition of the List of prequalified products and manufacturers published
Second tender published

17. Quality Control (QC) on Antiretrovirals (ARVs) and problems experienced
Assessment: Samples selected for analysis
Three independent laboratories used
Standard Test Procedures (STP) and methods as well as specifications used (dossiers)
Lack of monographs in pharmacopoeia until recently
Lack of official reference standards
All products tested met specifications
After purchasing:
Samples selected – comparative dissolution study
Protocol prepared, independent laboratory used

18. Quality Control (QC) on Antiretrovirals (ARVs)
Monographs and specifications – International Pharmacopoeia
Draft monographs for ARVs
Discussion with manufacturers and other pharmacopoeia
Internationally validated methods for monographs
Preparation of official reference standards

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

20. Quality Control (QC) on Antiretrovirals (ARVs)
Quality problems experienced (products and dossiers):
Non prequalified products (although under assessment) supplied to several countries where it is known that these products do not meet international standards
Product dossiers lacking data and information including
API: source of API, synthesis, specifications, method validation, stability
Pharmaceutical development data
Formulation and manufacturing process
Validation (consistency)
Stability
No bio-equivalence studies or incomplete study reports

21. Quality Control (QC) on Antiretrovirals (ARVs)
Manufacturing sites and CROs (GMP, GCP, GLP)
Poor design, layout and construction
Lack of validation (process, utilities, equipment etc)
Hormones, antibiotics such as penicillin, in same areas
Lack of raw data
Cross-contamination and mix-ups
Lack of quality control on materials
Time to take corrective action needed as manufacturers have to perform studies to generate data e.g. stability
Validation of manufacturing processes
Upgrading of manufacturing facilities
Perform (new) bio-equivalence studies
Different requirements and standards: local market versus export

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

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

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

25. Prequalification
Malaria:
41 product dossiers
Four cancelled or withdrawn
Mainly ACTs
Only 2 prequalified to date: Coartem and Artesunate
Problems: Lack of quality specifications
Lack of clinical data being presented
Lack of GMP compliance

26. Prequalification
Future?
Reproductive health products
Others?
Need capacity and resources including finance, staff

27. Summary and conclusion
Several lists published (HIV: 15th edition)
QA and prequalification continue to facilitate access to a wide range of products meeting international standards
Ongoing quality control, monitoring, assessment and re-qualification is needed
Mechanisms should be in place to prevent the supply of counterfeit and substandard medicines
Harmonization in assessments and increased capacity building
Ensure safe, effective, quality products are purchased and supplied