prequalification and quality monitoring of anti-malaria products andre van zyl, m. pharm. project...
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Prequalification and Quality Monitoring of anti-malaria
products
Andre van Zyl, M. Pharm. Project ManagerHealth 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 OrganizationE-mail: [email protected]
Workshop on GMPBangkok
Thailand, 18 – 22 October 2004
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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
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Key questions:
Why is WHO doing prequalification? What are the WHO criteria for safety, efficacy and quality? What are the WHO projects related to QA and prequalification? Which countries apply acceptable standards? How does WHO ensure GMP, GCP, GPPQCL 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
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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Substandard drugs is a big problem - antibiotics, antimalarials, antituberculosis drugs included. What about antiretrovirals?
Incorrect amount
17%
No active ingredient
60%Other errors7%
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?
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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)
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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
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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
48.0%
42.0%
10%
0%
5%
10%
15%
20%
25%
30%
35%
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45%
50%
V. limited capacity Basic capacity Moderate capacity
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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) http://www.ifpma.org/ich5q.html#stability
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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
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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
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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, GPPQCL
Training workshops and seminars, DRA capacity building Counterfeit monitoring
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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
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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
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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 GPPQCL 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)
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Current status Started March 2001 – malaria in 2002 EOIs published – mainly ACT Ongoing assessments and follow-up
Products, manufacturing sites (APIs and FP) CROs
Now 42 dossiers (malaria only) under assessment 2 products prequalified Several manufacturing sites inspected Interim process
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Current status 14 Sites inspected to date
3 for APIs 11 for FP (including contract activities such as packing)
APIs: All in Asia All 3 at first non-compliant 2 accepted after corrective action, 3rd under review (await
corrective action plan)
Problems mainly validation, qualification, HVAC
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Current status Finished products:
11 sites (including contract activities such as packing)
Asia: 5 sites – 3 accepted 3 After corrective action, await corrective action plan from 2
Europe: 5 sites – 2 accepted (with corrective actions) Await corrective action 1, under review 1, 1 re-assess)
Africa: 1 site – 1 accepted
Problems mainly mix-ups, validation, qualification, HVAC, cross-contamination, contamination, documentation
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Quality Control (QC) and problems experienced
Quality control: Assessment: Samples checked Not yet selected for analysis
Four independent laboratories used for ARVs Standard Test Procedures (STP) and methods as well as specifications used
(dossiers) Lack of monographs in pharmacopoeia until recently Lack of official reference standards
After purchasing: ARVs Samples selected – comparative dissolution study Protocol prepared, independent laboratory used
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Quality Control (QC)
Monographs and specifications
International Pharmacopoeia Chinese Pharmacopoeia Discussion with manufacturers – review and update
Internationally validated methods for monographs Preparation of official reference standards
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Quality Control (QC)
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
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Quality Control (QC)
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 Lack of study reports for safety and efficacy
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Quality Control (QC)
Manufacturing sites and CROs (GMP, GCP, GLP) Poor design, layout and construction Lack of validation and qualification (process, utilities, equipment etc) Lack of raw data Cross-contamination and mix-ups Lack of quality control on materials HVAC
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 Different requirements and standards: local market versus export
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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 Public reports
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FDCs and policies
FDCs: 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
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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
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Summary and conclusion
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