Prequalification and Quality Monitoring of anti-malaria products Andre van Zyl, M. Pharm. Project Manager Health Technology and Pharmaceuticals Cluster,

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%

40%

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