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


WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence with a focus on artemisinines Expression of Interest and Guidelines on Assessment of ... – PowerPoint PPT presentation

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Title: WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence with a focus on artemisinines

WHO Training Workshop on Pharmaceutical Quality,
GMP and Bioequivalence with a focus on
Expression of Interest and Guidelines on
Assessment of Applications for Prequalification
  • János Pogány, pharmacist, Ph.D.
  • consultant to WHO
  • Guilin, China, 9 January 2006
  • E-mail pogany_at_t-online.hu

  • API Active Pharmaceutical Ingredient
  • DRA Drug Regulatory Authority
  • EoI Expression of Interest
  • FDC Fixed-Dose Combination
  • FPP Finished Pharmaceutical Product
  • GMP Good Manufacturing Practices
  • ICH International Conference on Harmonization
  • MA Marketing Authorization
  • PQ Prequalification

Subjects for discussion
  1. Theme of the Workshop
  2. EoI for Antimalarial Drugs
  3. Global quality issues
  4. Prequalification Experience Illustrative
  5. Pharmaceutical Quality Information Form
  6. Main points again

Expectations of participants
  • Chinese malaria (and also some TB) pharmaceutical
    manufacturers expressed interest of applying for
    WHO prequalification, and some are already in the
    process of preparing 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.).
  • http//mednet3.who.int/prequal/


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)

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

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 from
    douceline_at_who.int or griffing_at_who.int also
    available on the web page http//mednet3.who.int/p
    requal. The dossier should be accompanied by a
    sample of the product to enable analyses (e.g. 1
    x 100 Tablets).

History and Current Status
  • First EOI published on 8 May 2002
  • Assessment of dossiers started in July 2002
  • FPPs 48 applications (2 cancelled) - three
    approvals as at 1 January 2006
  • Problems delaying prequalification are discussed
    in forthcoming slides


Global regulatory issues
  • If the product has been locally developed and
    manufactured, the NDRA must evaluate 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).

Global regulatory issues
  • API or FPP originate legally from countries
  • Manufacture of APIs is not regulated
  • Pharmaceutical exports and imports are not
  • MA of FPPs is issued without evaluation or with a
    check-list assessment by the national NDRA

Global regulatory issues
  • Formal stability studies are not required for MA
  • Biostudies are not required for MA
  • National Good Manufacturing Practices (GMP) do
    not comply with WHO-GMP requirements
  • API was not official in internationally used
    major pharmacopoeias

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 in the
    internationally used major pharmacopoeias
  • WHO guides/SOPs apply to multisource FPPs. ICH
    guides had to be used.

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.


Synthesis deficiencies
  • Potential synthesis by-products, solvents and
    representative batch scale were not provided.
  • The final purification, crystallization and
    subsequent operations were not described in
  • Existence/absence of polymorphs, particle size,
    bulk and tapped density and hygroscopicity were
    not submitted.

  • Stress stability (forced degradation) tests were
    not submitted to identify existence or absence
    degradants and to substantiate specificity of the
    impurity test method.
  • Room temperature and accelerated tests are in
    progress. Results were not submitted.

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 solvents were included in the in-house
    monograph but not in the DMF.

Specifications of API and FPP manufacturers
  • No adequate 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.

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.

Concurrent validation
  • The progress from pre-formulation ? formulation ?
    pilot manufacture ? production scale manufacture
    was not shown in the submission.
  • There was no 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.

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.

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.

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.

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.


International Pharmacopoeia
  • Artemether
  • Artemisinin (Extracted from ???)
  • Artemotil
  • Artenimol
  • Artesunate
  • Mefloquine Hydrochloride
  • Proguanil Hydrochloride BP

International quality standards
  • Amodiaquine USP
  • Amodiaquine Hydrochloride USP
  • Lumefantrine
  • Pyrimethamine BP, PhEur, PhInt, USP
  • Sulphadoxine BP, PhEur, PhInt, USP

Prequalification guidelines
  1. 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

Prequalification quality guidelines
  1. 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)
  2. Guideline on Submission of Documentation for
    Prequalification of Multi-source (Generic)
    Finished Pharmaceutical Products (FPPs) Used in
    the Treatment of HIV/AIDS, Malaria and

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.

Prequalification quality guidelines
  1. Guidance on Variations to a Prequalified Dossier
  2. Pharmaceutical Quality Information Form The PQIF
    contains summary information provided by the
    applicant on 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.

Main points again
  1. The workshop deals with practical aspects of
    preparing dossiers for prequalification, with
    illustrative examples from artemisinin derivative
    antimalaria FPPs.
  2. The EoI limits the number of FPPs.
  3. DRA did not assess generic 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.

Main points again
  • Artemisinin-derived APIs and FPPs were marketed
    at global level for decades without meeting
    basic standards of quality.
  • It takes time to get into prequalification
  • 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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