János Pogány, pharmacist, Ph.D.
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János Pogány, pharmacist, Ph.D. consultant to WHO Guilin, China , 9 January 2006 E-mail: [email protected] WHO Training Workshop on Pharmaceutical Quality, G MP and Bioequivalence with a focus on artemisinines. Expression of Interest and

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János Pogány, pharmacist, Ph.D.

consultant to WHO

Guilin, China, 9 January 2006

E-mail: [email protected]

WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalencewith a focus on artemisinines

Expression of Interest and

Guidelines on Assessment of Applications for Prequalification

Pogány - Guilin

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APIActive Pharmaceutical Ingredient

DRADrug Regulatory Authority

EoIExpression of Interest

FDCFixed-Dose Combination

FPPFinished Pharmaceutical Product

GMP Good Manufacturing Practices

ICH International Conference on Harmonization

MA Marketing Authorization


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Subjects for discussion

  • Theme of the Workshop

  • EoI for Antimalarial Drugs

  • Global quality issues

  • Prequalification Experience–Illustrative deficiencies

  • Pharmaceutical Quality Information Form

  • Main points again

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Expectations of participants

Chinesemalaria (and also some TB)pharmaceutical manufacturers expressed interestof applyingfor WHO prequalification, and some are already inthe process ofpreparing dossiers. What they expect to learn from the training is a kind of case study, they want to learn practical lessons from a pilot dossier assessment or site inpection process with one or two specific products (like artesunate, etc.).


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EoI – Oral Preparations

  • Artesunate*+ Amodiaquine

  • Artemether*+Lumefantrine*

  • Artesunate*+ Mefloquine

  • Artesunate*+ SP (sulphadoxine / pyrimethamine)

    * Assessed originally by ICH guidelines*High risk API

    + ... FDC or co-blistered (co-packaged) FPPs

    All oral FPPs include paediatric formulations.

    (EOI is included in the Notes Page of this and the subsequent slides)

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Co-blistered FPP

Two (or more) tablets different APIs (one marked with red arrow and the other one with green arrow) are packed together.

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EoI – Other dosage forms

  • Artemether Injection and rectal FPPs

  • Artemotil (arteether) Injection

  • Artesunate Injection and rectal FPPs

    Only FPPs listed in the EOI are assessed.

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EoI requirements

Submit a product dossier in the recommended format as specified in the Guideline for submission of a product file which can be obtained by electronic mail [email protected] or [email protected] also available on the web page http://mednet3.who.int/prequal. The dossier should be accompanied by a sample of the product to enable analyses (e.g. 1 x 100 Tablets).

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History and Current Status

  • First EOI published on 8 May 2002

  • Assessment of dossiers started in July 2002

  • FPPs[48 applications (2 cancelled) - three approvalsas at 1 January 2006]

  • Problems delaying prequalification are discussed in forthcoming slides

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Global regulatory issues

  • If the product has been locally developed and manufactured, the NDRA mustevaluate the data set itself (p. 23).

  • If an evaluation report—critical summary and interpretation of the data, with conclusions—is not available it is not possible to seek a WHO-type certificate (p. 23).

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Global regulatory issues

API or FPP originate „legally” from countries where:

  • Manufacture of APIsisnot regulated

  • Pharmaceutical exports and importsare not regulated

  • MA of FPPs is issued without evaluation or with a check-list assessment by the national NDRA

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Global regulatory issues

  • Formal stability studies are not required for MA

  • Biostudiesare not requiredfor MA

  • NationalGood Manufacturing Practices (GMP) do not comply with WHO-GMP requirements

  • API was not official in internationally used major pharmacopoeias

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Artemisin-derivative issues

  • No innovator FPP is registered in the ICH region. No comparator is available for:

    • Pharmaceutical equivalence studies

    • Bioequivalence studies

  • The APIs and FPPs were not official inthe internationally used major pharmacopoeias

  • WHO guides/SOPsapply to multisource FPPs. ICH guideshad to be used.

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At start of history of PQ

Excerpts from a letter to the manufacturer: Please note that we do not assess documentation and samples not listed in the EOI. We also do not evaluate FPPs, which have not been granted a marketing authorization in any country of the world. Efficacy, safety and quality cannot be based on conclusions of the Applicant drawn from the report of a consulting company and definitely not from the assessment report of a DRA.

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Synthesis deficiencies

  • Potential synthesis by-products,solvents and representative batch scalewere not provided.

  • The final purification, crystallizationand subsequent operations were not described in details.

  • Existence/absence of polymorphs, particlesize, bulk and tapped density and hygroscopicitywere not submitted.

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  • Stress stability (forced degradation) tests were not submitted to identifyexistence or absence degradants and to substantiate specificity of the impurity test method.

  • “Room temperature and accelerated tests are in progress.” Results were not submitted.

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Specifications of API and FPP manufacturers

  • The melting point is 143-145oC (p.4) as opposed to 131-134oC± 1.5oC in the DMF.

  • Individual impurity limits were not based on batch analysis results and they were not in line with the ICH guidelines (e.g., NMT 1.0% instead of NMT 0.1%).

  • Residual solventswere included in the in-house monograph but not in the DMF.

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Specifications of API and FPP manufacturers

  • Noadequate information was provided on the preparation and quality specification of primary (absolute) and secondary (working) standards. (For instance, lack of complete CoA, assay by two different validated methods, detailed information on storage, etc.).

  • HPLC method is described as an alternative assay to titration but acceptance limits are 97-103% as opposed to 98-102% in the DMF.

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Development pharmaceutics

  • A report was not submitted to identify and describe the formulation and process attributes that can influence batch reproducibility, product performance and FPP quality, including stability.

  • A tabulated summary of the compositions of the FPP used in clinical trials or stability studies and a presentation of dissolution profiles was not provided..Dissolution time was not studied at all.

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Concurrent validation

  • The progress from pre-formulation → formulation → pilot manufacture → production scale manufacture was not shown in the submission.

  • There wasno validation report on the first three (3) production scale batches to establish the nature and specifications of subsequent in-process and final tests as well as provide assurance that the manufacturing process met expected results.

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Retrospective validation

Annual quality review data and analysis were not submitted to prove that the manufacturing processes —including equipment, buildings, personnel and materials— are capable of achieving the intended results on a consistent and continuous basis.

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Stability of FPP and SmPC

  • Degradants, dissolution rate and profile, water content, hardness, microbiological attributes, etc. were not tested or quantified.

  • A national DRA-approved Summary of Product Characteristics (SmPC) type information for health professionals was not submitted.

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Correspondence with manufacturers

  • Substantial degradation was observed at high temperature and under intensive light.

  • Class2 solvents: pyridine and chloroform are used in the synthesis.

  • Impurities:“Further efforts are made to improve the process.”

  • The currently available stability data reveal possible decomposition and justify only a one (1) year re-test date.

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Correspondence with manufacturers

  • The stress data show that the blister pack does not protect the tablets even if overwrapped by additional protective packing.Supplier reduced expiry date.

  • Analysis of the tests for microbiological purity on„two (2) batches showed contamination with an invading yeast.”

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International Pharmacopoeia

  • Artemether

  • Artemisinin (Extracted from青蒿素)

  • Artemotil

  • Artenimol

  • Artesunate

  • Mefloquine Hydrochloride

  • Proguanil Hydrochloride BP

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International quality standards

  • Amodiaquine USP

  • Amodiaquine Hydrochloride USP

  • Lumefantrine

  • Pyrimethamine BP, PhEur, PhInt, USP

  • Sulphadoxine BP, PhEur, PhInt, USP

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Prequalification guidelines

  • Guide on Submission of Documentation for Prequalification of innovator Finished Pharmaceutical Products (FPPs) used in the treatment of HIV/AIDS, malaria and tuberculosis and approved by Drug Regulatory Authorities (DRAs) in the International Conference on Harmonization (ICH) region and associated countries, including among others the EU, Japan and USA

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Prequalification quality guidelines

  • WHO/DMP/RGS/98.5 Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities(The Blue Book)

  • Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis.

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Prequalification quality guidelines

  • Supplement 1 [for use from July 2005 (CPH25)] - Dissolution testing

  • Supplement 2 [for use from July 2005 (CPH25)] - Extension of the WHO List of Stable (not easily degradable ARV) APIs1

    1World Health Organization, WHO Technical Report Series, No. 863, 1996. Annex 5 Guidelines for stability testing of pharmaceutical products containing well-established drug substances in conventional dosage forms.

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Prequalification quality guidelines

  • Guidance on Variations to a Prequalified Dossier

  • Pharmaceutical Quality Information FormThe PQIFcontainssummary information provided by the applicanton critical pharmaceutical quality attributes–chemistry, pharmaceutical formulation, manufacturing process and product performance– and their relevance to safety and efficacy, following the structure of the Generic Guideline and frequently in tabulated forms.

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Main points again

  • The workshop deals with practical aspectsof preparing dossiers for prequalification, with illustrative examples from artemisinin derivative antimalaria FPPs.

  • The EoI limits the number of FPPs.

  • DRA did not assessgeneric FPPs –used in the treatment of HIV/AIDS, malaria and tuberculosis– and most manufacurers did not have dossiers for MA, at the beginning of PQ.

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Main points again

  • Artemisinin-derived APIs and FPPswere marketed at global level for decades without meetingbasic standards of quality.

  • It takes time to get into prequalification compliance

    • Develop new formulation

    • Data to be generated, tests carried out

    • GMP upgrade needed

  • Increase in the number of prequalified Artesunate Tablets is expected because there has been an official comparator since 2005.

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    Pogány - Guilin