Transcript Prequalification of essential medicines Technical Briefing Seminar Salle G, WHO Main building Geneva, 28 September 2004 Andre van Zyl, M.

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: +41.22.791.3598 Fax: +41.22.791.4730
World Health Organization
E-mail: [email protected]
Prequalification of essential medicines
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Layout:
 Introduction and background
 Quality Assurance (QA)
 Procedure for prequalification
 Product assessment
 Manufacturers
 Current status
 Quality control
 Ongoing monitoring and requalification
 Summary and conclusion
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Key questions to be addressed:
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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?
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1. Introduction and background
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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
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Is quality of pharmaceuticals a problem?
Substandard drugs is a big problem - antibiotics, antimalarials,
antituberculosis drugs included. What about antiretrovirals?
Incorrect
ingredient
16%
Percentage breakdown of
data on 325 cases of
substandard drugs reported from around the
world to WHO database
Incorrect
amount
17%
Other errors
7%
No active
ingredient
60%
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2. Quality Assurance (QA)
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Partners:
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Start a prequalification project as a Pilot: Objective
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Managing the project and provide technical support, norms and
standards on product assessment, GCP, GLP, GMP
Developed internal Quality Assurance system
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To ensure that products meet international safety, efficacy and quality
standards for purchasing and supply: Focus on HIV/AIDS
WHO role:
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UNICEF, UNFPA, UNAIDS, WHO, agreed and also supported by the
World Bank
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Quality Assurance and Safety: Medicines (QSM)
Standard Operating Procedures (SOPs)
Manuals and guidelines
General Procedure for Prequalification
WHO etc)
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Norms and standards (product dossiers, manufacturers
Expected outcome
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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
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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
50%
45%
48.0%
40%
35%
42.0%
30%
25%
20%
15%
10%
5%
10%
V. limited capacity
Basic capacity
Moderate capacity
0%
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WHO/HTP/EDM/QSM
Criteria for safety, efficacy and quality
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What is required for multisource products?
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Marketing Autghorization of Pharmaceutical Products with special reference to
multisource (generic) products (WHO/DMP/RGS/98.5)
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3.
3.1
3.2
3.3
3.4
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Details of the product
Regulatory situation in other countries
Active pharmaceutical ingredient (s) (API)
Properties of the active pharmaceutical ingredient(s)
Sites of manufacture
Route(s) of synthesis
Specifications
– API described in a pharmacopoeia:
– API not described in a pharmacopoeia:
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3.5
Stability testing
– WHO Expert Committee on Specifications for Pharmaceutical
Preparations, Thirty-fourth report. Geneva, World Health Organization,
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http://www.ifpma.org/ich5q.html#stability
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General procedure: Pre-qualification
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Required (2)?
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4.
4.1.
4.2.
4.4.
4.5
4.6
4.7
4.8
Finished product
Formulation
Sites of manufacture
Manufacturing procedure
Specifications for excipients
Specifications for the finished product
Container/closure system(s) and other packaging
Stability testing
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WHO/HTP/EDM/QSM
General procedure: Pre-qualification
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Required (3)?
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4.9
4.10
4.11
4.12
4.13
4.14
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)
Interchange-ability (bio-equivalence studies)
Summary of pharmacology, toxicology and efficacy of
the product
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WHO Projects in quality assurance
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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
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3. QA: Prequalification. www.who.int/medicines
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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
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Innovator products
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Multisource products
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Assessment report from DRA, CPP, Batch certificate, changes
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:
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DRA assessors from Brazil, Canada, Denmark, France, Germany,
Philippines, Sweden, Switzerland, Zimbabwe and others
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3. QA: Manufacturing sites and Contract Research
Organizations (CROs)
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Manufacturers: GMP compliance
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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
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Team of inspectors
Ethics, clinical, analytical
Product and site specific: as per dossier and includes data verification on
subject data, method validation, calculations etc)
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Current status
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Started March 2001
Five EOIs including ARVs, antibiotics, anticancer,
antifungal products have been published
Ongoing assessments and follow-up
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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
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Quality Control (QC) on Antiretrovirals (ARVs) and
problems experienced
Quality control:
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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
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Quality Control (QC) on Antiretrovirals (ARVs)
Monographs and specifications – International
Pharmacopoeia
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Draft monographs for ARVs
Discussion with manufacturers and other
pharmacopoeia
Internationally validated methods for monographs
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Preparation of official reference standards
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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:
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Batch manufacturing record,
Specifications and dossier information,
Raw data including quality control tests and results,
Validation protocol and report,
Changes and deviations,
OOS investigations,
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Bio-batch records
Quality Control (QC) on Antiretrovirals (ARVs)
Quality problems experienced (products and dossiers):
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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
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Quality Control (QC) on Antiretrovirals (ARVs)
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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
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Ongoing monitoring and requalification
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Samples taken after supply
Routine inspections and additional inspections
Changes and variations controlled
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Products and manufacturers
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Requalification (re- assessment) every 3 years
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World Health Assembly resolution: WHA57.14 of May
2004
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FDCs and policies
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FDCs:
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New guidelines:
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Essential Medicines List
Advantages and disadvantages of FDCs
Licensing of FDCs in USA and EU
FDA and WHO
Government roles and policies
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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
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Prequalification
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Tuberculosis:
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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)
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Others: Await additional data
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Prequalification
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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
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Prequalification
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Future?
Reproductive health products
Others?
Need capacity and resources including finance, staff
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Summary and conclusion
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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 requalification 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
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