Training Workshop on Pharmaceutical Quality and Bioequivalence, 17-19 January 2006

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Training Workshop on Pharmaceutical Quality and
Bioequivalence, 17-19 January 2006
Procedures for Participation in the
Prequalification Project

• János Pogány, pharmacist, Ph.D.
• consultant to WHO
• Hanoi, Vietnam, 17 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 of WHO
• ICH International Conference on Harmonization
• MA Marketing Authorization
• PQ Prequalification

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Subjects for discussion

1. Expectations of participants
2. Interchangeability of FPPs
3. EoI
4. Global quality issues
5. Illustrative PQ Requirements for Quality of APIs
   and FPPs
6. Pharmaceutical Quality Information Form
7. Main points again

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Expectations of participants

• Procedures for participation in the PQ project
• Expression of Interest
• Documentation to be discussed
• Guidelines for drafting a Site Master File (SMF)
• Guidelines on submission of documentation for
  multi-source (generic) FPPs
• Quality part
• Bioequivalence part
• The workshop should be interactive with
  questions and answers after each major point of
  the guidelines.

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Interchangeability (IC)

• Interchangeability (IC) of multisource FPPs
  (Essential similarity with innovator FPP)
• Pharmaceutical equivalence (PE) Bioequivalence
  (BE)
• IC PE BE

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Pharmaceutical equivalence

• FPPs meet same or comparable standards
  (pharmacopoeia, marketing authorization)
• Same API (chemical and physical equivalence of
  specifications)
• Same dosage form and route of administration
• Same strength
• Comparable labeling
• WHO-GMP (batch-to-batch uniformity of quality)
• Stability equivalence

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High-risk APIs and FPPs

• Reference standard/comparator is not available
  for
• Pharmaceutical (dissolution) equivalence studies
• Bioequivalence studies
• APIs and FPPs are not official in the
  internationally used major pharmacopoeias
• WHO guides/SOPs apply to multisource FPPs. ICH
  guides should be used for evaluation.
• Require particular attention by national DRA as
  regards assessment of applications for MA

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Low-risk APIs

• Certificate of suitability (DRA)
• Drug Master File
• Open part (Applicant)
• Closed part (DRA)
• Pharmacopeia monograph
• Literature evidence of stability
• Synthesis impurities are controlled by monograph
  (toxicology of additional impurities)
• Class1 solvents excluded, class2 solvents
  controlled
• FPP is registered in the ICH region

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SIXTH EXPRESSION OF INTERESTOctober 2005

• HIV and related diseases
• Illustrative examples

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EOI Oral Preparations

• Antiretrovirals as single-ingredient formulations
  for use in adults and adolescents
• Anti-retrovirals as fixed-dose combinations
• Anti-infective drugs
• Antibacterial and antimycobacterial agents
• Antiprotozoal and antifungal agents
• Antiviral agents
• Anti-cancer drugs
• Palliative care drugs

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Antiretrovirals

• Nucleoside/Nucleotide Reverse Transcriptase
  Inhibitors
• Abacavir
• Didanosine
• Lamivudine
• Stavudine
• Tenofovir
• Zidovudine
• Only FPPs listed in the EOI are assessed.

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Antiretrovirals

• Non-Nucleoside Reverse Transcriptase Inhibitors
• Efavirenz
• Nevirapine
• Protease Inhibitors
• Indinavir
• Nelfinavir
• Saquinavir
• Ritonavir

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Antiretrovirals - paediatric FPPs

• Reduced and/or scored solid dosage formulations
  of
• Abacavir
• Efavirenz
• Lamivudine
• Nevirapine
• Zidovudine
• http//www.who.int/3by5/paediatric/en/

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Anti-retrovirals as FDCs

• Reverse Transcriptase Inhibitors
• Lamivudine Stavudine
• Lamivudine Zidovudine (Combivir)
• Lamivudine Stavudine Efavirenz
• Lamivudine Stavudine Nevirapine
• Lamivudine Zidovudine Efavirenz
• Lamivudine Zidovudine Nevirapine
• Lamivudine Zidovudine Abacavir (Trizivir)
• Tenofovir Emtricitabine
• Protease Inhibitors
• Lopinavir Ritonavir
• http//webitpreview.who.int/entity/3by5/publicatio
  ns/documents/arv_guidelines/en/

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Paediatric FDCs

• Reduced and/or scored solid dosage formulations
  of
• Reverse Transcriptase Inhibitors
• Lamivudine Stavudine
• Lamivudine Zidovudine
• Lamivudine Stavudine Nevirapine
• Lamivudine Zidovudine Nevirapine
• Lamivudine Zidovudine Abacavir
• Protease Inhibitors
• Lopinavir Ritonavir

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Co-packaged FPPs
Co-packaged preparations of the standard ARV
combinations, for adult, adolescent and
paediatric use are also sought
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EOI requirements

• The medicines listed in this Invitation for
  Expression of Interest are those for which a need
  has been identified by the HIV/AIDS department,
  WHO. The submitted products should be of assured
  pharmaceutical quality and relevant data to
  support efficacy should be provided. Procedure
  for submission of EOI
• Submit a covering letter expressing the interest
  to participate in the project, confirming that
  the information submitted in the product dossiers
  is correct.

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EOI requirements

• Submit a product dossier in the recommended
  format as specified in the 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. The dossier
  should be accompanied by a sample of the product
  to enable analysis (e.g. 1 x 100 Tablets).
• Submit a Site Master File for each manufacturing
  site as listed in the product dossier, in the
  recommended format.
• http//mednet3.who.int/prequal/

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EOI assessment criteria

• Valid manufacturers license for production
• Product registered or licensed in accordance with
  national requirements
• Products manufactured in compliance with GMP as
  certified by the national regulatory authority
  and/or certified GMP inspectors
• Product certificates exist in accordance with the
  WHO certification scheme on the quality of
  pharmaceutical products moving in international
  commerce
• Product dossiers of acceptable quality submitted
  and outcome of the assessment in respect of the
  pre-qualification procedure
• Outcome of the inspection performed by or on
  behalf of the above-mentioned agencies
• Manufacturer demonstrates sound financial
  standing

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History and current status

• First EOI published and assessment of dossiers
  started in 2001
• ARV FPPs 316 applications (15 cancelled) - many
  approvals as at January 2006
• Generic ARV FPPs were scarcely available at the
  beginning of the project, while there are many
  suppliers today
• Problems delaying prequalification

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GLOBAL QUALITY ISSUES

• FPPs in general

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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 DRA

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Global regulatory issues

• Formal stability studies were not required for MA
• Biostudies were not required for MA
• National Good Manufacturing Practices (GMP) do
  not comply with WHO-GMP requirements

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Illustrative Prequalification Requirements for
Qualityof APIs and FPPs

• ILLUSTRATIVE EXAMPLES

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WHO general requirements

• 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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General evaluation issues

• 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. This is still the
  situation today for example
• Efavirenz
• Emtricitabine
• Tenofovir
• and new monographs are continuously improved
• New evaluation issues surfaced with FDC.

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Synthesis deficiencies

• Potential synthesis impurities (e.g.,
  by-products, solvents) were not tested 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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Specifications

• Stress stability (forced degradation) tests were
  not submitted to identify existence or absence
  degradants and to substantiate specificity of the
  impurity test method.
• Degradants, dissolution rate and profile, water
  content, hardness, microbiological attributes,
  etc. of FPPs were not tested or quantified.
• No adequate information was provided on the
  preparation and quality specification of primary
  (absolute) and secondary (working) analytical
  standards. (For instance, lack of complete CoA,
  assay by two different validated methods,
  detailed information on storage, etc.).

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Development pharmaceutics

• A report was not submitted to identify and
  describe the critical product 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 (bioequivalence), stability
  and validation studies was not presented and, in
  case of formulation changes, dissolution profiles
  was not provided..

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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 not less the
  than first three (3) production scale batches to
  establish the nature and specifications of
  subsequent in-process acceptance criteria 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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SmPC and PIL

• A national DRA-approved Summary of Product
  Characteristics (SmPC) type information for
  health professionals was not submitted or it was
  not based on documented facts and figures.
• Patient Information Leaflet (PIL) was not based
  on the SmPC

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PREQUALIFICATION QUALITY REQUIREMENTS

• FPPs in general

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Prequalification guidelines (1)

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 guidelines (2)

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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Annexes to Generic Guide

1. Model Certificate of a Pharmaceutical Product
2. Model Batch Certificate of a Pharmaceutical
   Product
3. Model Stability Report of Active Pharmaceutical
   Ingredient (API)
4. Model Stability Report of Capsules/Tablets
5. Suggested Structure of the Summary of Product
   Characteristics
6. Suggested Structure of the Package Information
   Leaflet
7. Presentation of bioequivalence trial information
8. Presentation of pharmaceutical quality
   information

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Prequalification guidelines (3)

• 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 guidelines (4)

• Guidance on Variations to a Prequalified Dossier
• 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

• The workshop deals with selected aspects of
  procedures of prequalification
• The EoI limits the number of FPPs to the list
• National DRA have not assessed generic FPPs used
  in the treatment of HIV/AIDS, malaria and
  tuberculosis and most manufacurers have not had
  dossiers for MA, at the beginning of PQ.
• It has taken time to get into prequalification
  compliance
• Develop new formulation
• Data to be generated, tests carried out
• GMP upgrade needed
• Generic ARV FPPs are widely available as a result
  of PQ.

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THANK YOU