Workshop on Quality Assurance and GMP of multisource HIV/AIDS medicines

1
Workshop on Quality Assurance and GMP of
multisource HIV/AIDS medicines
WHO Prequalification Project Dossier Assessment

• János Pogány, pharmacist, PhD,
• consultant to WHO
• Shanghai, 01 March 2005
• E-mail pogany_at_axelero.hu

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Abbreviations and notes

• API(s) Active pharmaceutical ingredient(s)
• ARV Antiretroviral
• EOI Expression of interest
• FPP(s) Finished pharmaceutical product(s)
• ICH International Conference on Harmonization
• MLEM Model List of Essential Medicines
• Ph.Eur. European Pharmacopoeia
• Ph.Int. International Pharmacopoeia
• USP United States Pharmacopeia
• Text in green refers to WHO guidelines or
  requirements
• Text in yellow indicates an assessment issue

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Subjects for discussion

• Which ARV FPPs are prequalified?
• Prequalification data and information
  requirements for quality
• WHO manuals, guides, EOI requirements
• Prequalification guides
• Assessment of product dossiers
• Change control
• ICH guides
• Closing remarks

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Which ARV FPPs are prequalified?

• 13th MODEL LIST OF ESSENTIAL MEDICINES and
  EXPRESSION OF INTEREST (January 2004)

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Nucleoside Reverse Transcriptase Inhibitors (NRTI)

• ABACAVIR
• DIDANOSINE (ddl)
• buffered chewable, dispersible tablets 25 mg, 50
  mg, 100 mg, 150 mg, 200 mg
• buffered powder for oral solution 100 mg, 167 mg,
  250 mg packets
• unbuffered enteric coated capsule 125 mg, 200 mg,
  250 mg, 400 mg
• LAMIVUDINE (3TC)
• tablet, 150mg,
• oral solution 50 mg/5ml

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Nucleoside Reverse Transcriptase Inhibitors (NRTI)

• STAVUDINE (d4T)
• capsule 15mg, 20mg, 30mg, 40mg
• powder for oral solution, 5mg/5ml
• TENOFOVIR
• ZIDOVUDINE (ZDV or AZT)
• tablet, 300mg
• capsule 100 mg, 250 mg
• oral solution or syrup, 50mg/5ml
• solution for IV infusion, injection 10 mg/ml in
  20-ml vial

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Non-nucleoside Reverse Transcriptase Inhibitors
(NNRTI)

• EFAVIRENZ (EFV or EFZ)
• capsule, 50 mg, 100 mg, 200 mg
• oral solution, 150 mg/5ml
• NEVIRAPINE (NVP)
• tablet 200 mg
• oral suspension 50 mg/5-ml

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Protease inhibitors (PI)

• INDINAVIR (IDV)
• capsule, 200 mg, 333 mg, 400 mg (as sulfate)
• LOPINAVIR RITONAVIR (LPV/r)
• capsule, 133.3 mg 33.3 mg
• oral solution, 400 mg 100 mg/5ml
• NELFINAVIR (NFV)
• tablet, 250mg (as mesilate)
• oral powder 50mg/g cont.

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Protease inhibitors (PI)

• RITONAVIR (r)
• capsule, 100 mg
• oral solution 400 mg/5ml
• SAQUINAVIR (SQV)
• capsule, 200mg
• Antibacterial and antimycobacterial agents,
  antiprotozoal agents, antiviral agents,
  antifungal agents and anti-cancer drugs listed in
  EOI5.

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Fixed-dose combinations (EOI)

• LAMIVUDINE STAVUDINE
• LAMIVUDINE ZIDOVUDINE
• LAMIVUDINE STAVUDINE EFAVIRENZ
• LAMIVUDINE STAVUDINE NEVIRAPINE
• LAMIVUDINE ZIDOVUDINE EFAVIRENZ
• LAMIVUDINE ZIDOVUDINE NEVIRAPINE

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Pillars of regulatory QA

• MANUFACTURING AUTHORIZATION
• DESIGN
• CONSTRUCTION
• AUTHORIZED PERSON
• OTHERS

• MARKETING AUTHORIZATION
• ANALYTICAL METHODS
• DEVELOPMENT PHARMACEUTICS
• COMPOSITION OF PIVOTAL BATCHES
• OTHERS

GMP INSPECTION QUALITY ASSURANCE
(QA) CONTAMINATION, ISSUES QUALIFICATION,
VALIDATION OTHERS
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Regulatory quality assurance

• The former slide emphasizes an integrated
  approach to QA based on scientific risk
  management of the
• manufacturing authorization based on GMP design
  and construction,
• marketing authorization (assessment of product
  dossiers), and
• inspections,

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http//mednet3.who.int/prequal/

• GMP main principles for pharmaceutical products
• GMP starting materials
• Active pharmaceutical ingredients (bulk drug
  substances)
• Pharmaceutical excipients
• GMP specific pharmaceutical products
• Sterile pharmaceutical products

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WHO GMP - General considerations

• Licensed pharmaceutical products (marketing
  authorization) should be manufactured only by
  licensed manufacturers (holders of a
  manufacturing authorization) whose activities are
  regularly inspected by competent national
  authorities, p.9.

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What data and information needs to be submitted
in a dossier for the assessment of a generic
product?

• MULTISOURCE (GENERIC) FPPs

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EOI criteria for quality assessment

• 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

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EOI criteria for quality assessment

• Certificate of Pharmaceutical Product exist in
  accordance with the WHO certification scheme on
  the quality of pharmaceutical products moving in
  international commerce
• Product dossiers of acceptable quality are to be
  submitted and assessed with regard to the
  pre-qualification requirements and approved
• Outcome of the GMP inspection performed by or on
  behalf of WHO, UNICEF, UNAIDS and UNFPA

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http//mednet3.who.int/prequal/

• Marketing Authorization of Pharmaceutical
  Products with Special Reference to Multisource
  (Generic) Products A Manual for a Drug
  Regulatory Authority (The so-called blue book)
• Regulatory Support Series, No. 5 WHO, Geneva, 1999

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Initial decisions on options for premarket
evaluation by a NDRA

• Blue book, p. 21
• Prepare its own reports
• Rely on evaluation reports prepared by other
  national authorities
• Rely on decisions made by other national
  authorities
• Use some permutation of these approaches.

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Domestically manufactured products

• If the FPP has been locally developed and
  manufactured, the national drug regulatory
  authority (NDRA) must evaluate the data set
  itself (Blue book, 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 (Blue book, p. 23).

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Blue book, Annex 7 Detailed Advice on Evaluation
of Data by the Drug Regulatory Authority

• Example Specifications for the finished product,
  p.153
• Provide a list of tests and limits for results
  for the finished product, including sufficient
  detail of test methods for them to be replicated
  by another laboratory. If the product is tested
  on the basis of a monograph in a pharmacopoeia,
  it is sufficient to provide a copy of the
  monograph together with any test methods
  referenced but not duplicated in the monograph.
  Provide details of any specifications additional
  to those in the pharmacopoeia. Provide both
  release and expiry limits for results. Provide
  the results of validation of the assay method for
  this formulation. For pharmacopoeial methods,
  provide data which demonstrate that the method is
  applicable to this formulation.

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http//mednet3.who.int/prequal/

1. 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
2. Guide on Requirements for Documentation of
   Quality pharmaceutical products manufactured in
   and approved by stringent drug regulatory
   authorities including inter alia EU, Japan and
   USA (not discussed in this presentation)
3. Other WHO guides
4. International Conference on Harmonization (ICH)
   guidelines

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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

• Assessors Guide Generic FPPs

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Section 1. CHARACTERISTICS OF THE FPP

• 1.1 Details of the product
• 1.1.1 Name, dosage form and strength of the
  product
• 1.1.2 Approved generic name(s) use International
  Non-proprietary Name (INN), if any
• 1.1.3 Visual description of the FPP
• 1.1.4 Visual description of the packaging
• 1.2 Sample
• 1.3 Regulatory situation in other countries

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Section 2. Active Pharmaceutical Ingredients

• Separate presentation on Tuesday, 1 March 2005
• Just one point ...

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Tablet Manufacturing Starts with the
Purification/Crystallization of API
Isolation and purification of API Physical processing and packaging of API Granulation Compression
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Tablet Manufacturing Starts with the
Purification/Crystallization of API

• Attributes with potential impact on
  processability
• existence/absence of polymorphs and water/solvent
  of crystallization/solvatation
• particle size
• bulk density (tapped and untapped)
• flowability (flowing properties)
• hygroscopicity

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Section 3. Finished Pharmaceutical Products

• ILLUSTRATIVE EXAMPLES OF REQUIREMENTS

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Section 3. FPP(s)

• 3.1 Manufacturing and marketing authorization
• 3.2 Pharmaceutical development
• 3.2.1 Company research and development
• 3.2.2 Information from literature
• 3.3 Formulation
• 3.4 Sites of manufacture

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Pharmaceutical development

• This section should contain information on the
  development studies conducted to establish that
  the dosage form, the formulation, manufacturing
  process, container closure system,
  microbiological attributes and usage instructions
  are appropriate for the purpose specified in the
  application. The studies described here are
  distinguished from routine control tests
  conducted according to specifications.

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Pharmaceutical development

• Illustrative examples
• Compatibility of APIs with each other fixed-dose
  combinations (FDCs)
• A discriminating (in the case of FDCs)
  dissolution method should be developed and
  integrated in the quality control and stability
  programs
• Packaging should be selected to ensure the
  quality of the FPP throughout its shelf life.

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Part 3. FPP(s)

• 3.5 Manufacturing process
• 3.6 Manufacturing Process Controls of Critical
  Steps and Intermediates
• 3.7 Process Validation and Evaluation
• 3.7.1 New generic FPPs
• 3.7.2 Established generic FPPs

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Validation - new generic FPPs

• The progress from pre-formulation ? formulation ?
  pilot manufacture ? industrial scale manufacture
  should be shown in the dossier submitted for
  prequalification to be logical, reasoned and
  continuous.
• Full validation studies should be completed for
  each FPP at the production scale.

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Validation - new generic FPPs

• Short description of the process with a summary
  of the critical processing steps or critical
  parameters to be monitored during validation.
• Interim in-process controls proposed with
  acceptance criteria.

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Validation - new generic FPPs

• Additional testing, e.g., failure mode analysis,
  intended to be carried out
• Sampling plan where, when and how the samples
  are taken.
• Details of methods for recording and evaluation
  of results.
• Proposed timeframe.

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Validation established generics

• Annual quality review data and analysis 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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Part 3. FPP(s)

• 3.8 Specifications for excipients
• 3.8.1 Excipients not described in Int.Ph., JP,
  BP, Ph.Eur., or USP
• 3.8.2 Excipients described in Int.Ph., JP, BP,
  Ph.Eur., or USP
• 3.9 Control of the FPP
• 3.9.1 Specifications for the FPP
• 3.9.2 Analytical procedures
• 3.9.3 Validation of analytical procedures
• 3.9.4 Batch analysed
• 3.10 Container/closure system(s) and other
  packaging

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Specifications for the FPP

• Illustrative issues
• The maximum acceptable deviation in the API
  content of the FPP shall not exceed 5 of the
  label claim at batch release.
• Degradation products, synthesis impurities
  (typically not applicable) and residual solvents
  (rarely applicable).
• Dissolution versus disintegration time.
• All analytical methods should be validated or
  verified (system suitability).

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Part 3. FPP(s)

• 3.11 Stability testing
• 3.11.1 Stability-indicating quality parameters
• 3.11.2 Photostability Testing
• 3.11.3 Selection of Batches
• 3.11.4 Container Closure System
• 3.11.5 Testing Frequency
• 3.11.6 Storage Conditions
• 3.11.7 General case
• 3.11.8 Finished products packaged in impermeable
  containers
• 2.11.9 Finished products packaged in
  semi-permeable containers
• 2.11.10 Evaluation
• 2.11.11 Extrapolation of data
• 2.11.12 Core Storage Statements

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Stability of FPPs

• Characteristics studied should be those in the
  FPP specification that are likely to be affected
  by storage and/or not monitored routinely at the
  time of manufacture.
• Analytical procedures should be fully validated
  and stability indicating. Whether and to what
  extent replication should be performed will
  depend on the results of validation studies.
• It may be appropriate to have justifiable
  differences between the shelf life and release
  acceptance criteria based on the stability
  evaluation and the changes observed on storage.

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Stability of FPPs

• A systematic approach should be adopted in the
  presentation and evaluation of the stability
  information, which should include, as
  appropriate, results from the physical, chemical,
  biological and microbiological tests, including
  particular attributes of the dosage form (for
  example, dissolution rate for solid oral dosage
  forms, hardness, LOD, etc.).
• An API is considered as stable if it is within
  the defined/regulatory specifications when stored
  at 30 2 oC / 60 5 RH (2 years) and 40 2
  oC / 75 5 RH (6 months).

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Part 3. FPP(s)

• 3.12 Container labelling
• 3.12.1 Outer packaging or, where there is no
  outer packaging, on the immediate packaging
• 3.12.2 Blisters and strips
• 3.13 Product information for health professionals
• 3.14 Patient information and package leaflet
• 3.15 Justification for any differences to the
  product in the country or countries issuing the
  submitted WHO-type certificate(s).

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Labelling - blisters and strips

• Name, strength and pharmaceutical form of the FPP
  
• Name of the manufacturer, company or person
  responsible for placing the product on the
  market.
• The batch number assigned by the manufacturer.
• The expiry date in an uncoded form.

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WHOPAR

• Propose a copy of the Summary of Product
  Characteristics (SmPC) aimed at medical
  practitioners and other health professionals and
  approved by the competent authority at the time
  of licensing. The SmPC is an essential part of
  pre-qualification and it can only be changed with
  the consent of WHO.
• Provide copies of all package inserts distributed
  to the patients. The package leaflet should be
  in conformity with the SmPC. It should be written
  in English, should be legible and comprehensible.

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Other WHO guides on quality of FPPs

• AN ILLUSTRATIVE EXAMPLE

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Animal Spongiform Encephalopathy Agents

• Products with risk of transmitting agents of
  animal spongiform encephalopathies are those
  derived from tissues or secretions of animals
  susceptible to transmissible spongiform
  encephalopathies. This definition applies to all
  substances or preparations obtained from such
  animals and to all substances or preparations
  where products obtained from such animals are
  included as active substances or excipients or
  have been used during production, e.g. as raw or
  source materials, starting materials or reagents.
• WHO Technical Report Series, No. 908, 2003

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International Conference on Harmonization guides

• AN ILLUSTRATIVE EXAMPLE

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Impurities in New Drug Products -Q3B(R)

• Illustrative excerpts
• This guideline addresses only those impurities in
  new drug products classified as degradation
  products of the API or reaction products of the
  API with an excipient and/or immediate container.
• Generally, impurities present in the API need not
  be monitored or specified in the FPP unless they
  are also degradation products.
• The specification for a FPP should include a list
  of degradation products expected to occur during
  manufacture of the commercial product and under
  recommended storage conditions.

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Guidance on variations in a dossier submitted
within the prequalification program

• GENERAL OVERVIEW

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Minor changes

• MINOR CHANGE is a change concerning an amendment
  to the contents of the documents such as they
  existed at the time when the product was listed
  as prequalified.
• PRIOR EVALUATION of the submitted documentation
  amended as a result of the variation is required
  for minor changes.
• 41 minor changes are listed in the document.

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Example of minor change Replacement or addition
of a manufacturing site for part or all of the
manufacturing process of the FPP cont.

• Conditions
• Site appropriately authorised by the relevant
  competent authority for the packaging or
  manufacturing of the pharmaceutical form and
  product concerned.
• New site must be approved by WHO as complying
  with WHO GMP, a satisfactory inspection of the
  manufacturing site has been performed in the last
  three years by WHO or a competent authority of a
  ICH region country.
• Product concerned is not a sterile product.
• Validation scheme is available or validation of
  the manufacture at the new site has been
  successfully carried out according to the current
  protocol with at least three production scale
  batches.

52
Example of minor change Replacement or addition
of a manufacturing site for part or all of the
manufacturing process of the FPP cont.

• Documentation
• Proof that the proposed site is authorised by the
  relevant competent authority as complying with
  WHO GMP within the prequalification project for
  the packaging or manufacturing of the
  pharmaceutical form and product concerned.
• The batch numbers of not less than 3 batches used
  in the validation study should be indicated and
  related validation protocol (scheme) to be
  submitted.
• The variation application should clearly outline
  the present and proposed finished product
  manufacturers.

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Example of minor change Replacement or addition
of a manufacturing site for part or all of the
manufacturing process of the FPP cont.

• Documentation
• Copy of approved release and end-of-shelf life
  specifications.
• Batch analysis data on three production batches
  and comparative data on the last three batches
  from the previous site.
• For semisolid and liquid formulations in which
  the API is present in non-dissolved form,
  appropriate validation data including microscopic
  imaging of particle size distribution and
  morphology.

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Example of minor change Replacement or addition
of a manufacturing site for part or all of the
manufacturing process of the FPP

• Documentation
• For solid dosage forms a comparative dissolution
  test data on the last 3 batches from the previous
  site and the 3 first batches for the new site
  including not less than 6 time points should be
  provided.
• Statement as when the change will be effective
  should be submitted.
• Submit updated section 3.4 of the product
  dossier.

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Major change

• A MAJOR CHANGE is a change to the documentation
  which can neither be deemed to be a minor
  variation within the meaning of preceding
  definition (therefore exceeding the frame of a
  minor change) nor to be a change for which the
  submission of a new application would be
  necessary.

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Major changes

• Change in the manufacturing process of the API
• Change in the composition of the finished product
• Change of immediate packaging of the FPP

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New dossier

• Certain changes are so major that they are
  considered to fundamentally alter the terms of a
  prequalification and consequently cannot be
  considered as a change. For these changes a new
  dossier must be submitted.

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New dossier

• Changes to the API (self-evident examples)
• Change of the API to a different API
• Inclusion of an additional API to a
  multi-component product
• Removal of one API from a multi-component product
• Change in the dose of one or more APIs

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New dossier

• Changes to the pharmaceutical dosage form
• Change from an immediate release product to a
  slow- or delayed-release dosage form and vice
  versa
• Change from a liquid to a powder for
  reconstitution, or vice versa
• Changes in the route of administration

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Additional stability studies

• In all cases of changes the supplier of the
  dossier has to investigate whether or not the
  intended change will have an impact or not on the
  quality of the API and the FPP and consequently
  on their stability.
• For all changes that require the generation of
  stability data, the first three production scale
  batches manufactured following notification/approv
  al of the change should be placed on long term
  stability testing using the same stability
  testing protocols as described in the assessment
  guide. The results of the stability studies when
  available should be submitted within the
  prequalification program.

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Main points again

1. Only ARV FPPs included in MLEM and EOI are
   prequalified.
2. WHO manuals and guides were prepared with
   well-established, compendial, multisource FPPs in
   mind but ARV FPPs rarely meet these criteria.
3. Prequalification guides permit the assessment of
   non-compendial, multisource FPPs, as well.
4. ICH guidelines are used, when a quality issue
   cannot assessed by WHO guides.
5. Changes to prequalified FPPs are also controlled
   in the evaluation process.

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THANK YOU
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