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

1
WHO Training Workshop on Pharmaceutical Quality,
GMP and Bioequivalence with a focus on
artemisinines
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

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Abbreviations

• 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

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Subjects for discussion

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

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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/

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EXPRESSION of INTEREST

• ANTIMALARIAL FPPs

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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 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).

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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
  approvals as at 1 January 2006
• Problems delaying prequalification are discussed
  in forthcoming slides

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GLOBAL QUALITY ISSUES

• ANTIMALARIAL FPPs

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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).

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Global regulatory issues

• API or FPP originate legally from countries
  where
• Manufacture of APIs is not regulated
• Pharmaceutical exports and imports are 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
• 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

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

• ILLUSTRATIVE DEFICIENCIES

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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
  details.
• Existence/absence of polymorphs, particle size,
  bulk and tapped density and hygroscopicity were
  not submitted.

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Stability

• 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.

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

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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.

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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 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.

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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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PREQUALIFICATION QUALITY REQUIREMENTS

• STANDARDS, GUIDELINES and TEMPLATES

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International Pharmacopoeia

• Artemether
• Artemisinin (Extracted from ???)
• 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

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

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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
   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

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.

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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.

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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
  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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THANK YOU
??!