Dossier Requirements (quality part)

1
Dossier Requirements(quality part)

• Workshop on GMP and Quality Assurance of
• Multisource Tuberculosis Medicines
• Kuala Lumpur Malaysia
• 21-25 February 2005

Theo Dekker, D.Sc., consultant to WHO Research
Institute for Industrial Pharmacy North-West
University, Potchefstroom, South
Africa iiftgd_at_puk.ac.za
2
Some abbreviations

• API Active pharmaceutical ingredient
• BP British Pharmacopoeia
• CEP EU certificate of suitability
• CPP WHO-type Certificate of a Pharmaceutical
  Product
• EOI Expression of interest
• FDC Fixed dose combination
• FPP Finished pharmaceutical product
• ICH International Conference on Harmonization
• Int.Ph. International Pharmacopoeia
• JP Japanese Pharmacopoeia
• Ph.Eur. European Pharmacopoeia
• SmPC Summary of product characteristics
• TB Tuberculosis
• USP United States Pharmacopeia

3
5th Invitation for EOI (July 2004) (1)

• First-line anti-TB products
• Ethambutol hydrochloride (Eth) 400 mg tablets
• Pyrazinamide (Py) 400 mg tablets
• Isoniazid (INH) 300 mg tablets
• Fixed dose combinations
• 2FDC Rif/INH 150/75 mg tablets
• 2FDC Rif/INH 150/150 mg tablets
• 2FDC Eth/INH 400/150 mg tablets
• 3FDC Rif/INH/Eth 150/75/275 mg tablets
• 4FDC Rif/INH/Py/Eth 150/75/400/275 mg tablets
• Streptomycin Sulfate 1g vial (injection)

4
5th Invitation for EOI (July 2004) (2)

• Second-line anti-TB products
• Water for injection 5ml vial (injection)
• Amikacin 500mg/2 ml vial (injection)
• Kanamycin 1g powder for injection, vial
• Capreomycin 1g powder for injection, vial
• Cycloserine 250mg tablets
• Ethionamide 125 mg or 250mg tablets
• Ofloxacin 200 mg tablets
• Protionamide 125 mg or 250mg tablets
• Para-Aminosalicylic Acid 100 g or 4 g granules or
  powder
• Moxifloxacin 400 mg tablets

5
5th Invitation for EOI (July 2004) (3)

• Formulations for children
• Dosage forms should be
• soluble tablets,
• tablets with break line, and or
• sachets
• Rifampicin 60 mg / Isoniazid 60mg / Pyrazinamide
  150 mg (R60/H30/Z150)
• Rifampicin 60 mg / Isoniazid 30mg (R60/H30)
• Rifampicin 60 mg / Isoniazid 60 mg (R60/H60)
• Total number of products on current list 22

6
Product characteristics

• When developing, evaluating and considering
  finished pharmaceutical products (FPPs), the
  following are the main characteristics
• Safety
• Efficacy
• Quality
• These aspects are to some extent interrelated
• Quality (as part of GMP) must ensure consistency
  of safety and efficacy of all batches produced

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Guideline (ICH registered products)

• Guideline on Submission of Documentationfor
  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 inter alia the
  European Union, Japan and USA (handout)

8
ICH registered products - requirements

• Certified copy of WHO-type CPP
• Assessment report(s) issued by DRA
• WHO-type batch certificate
• Primary packaging differs from ICH approved?
• Stability data in new packaging
• Formulation, strength (??), specs., etc. differ?
• Justification in favour of acceptability (BE?)
• Submit sample(s) of FPP

9
Guideline (Not ICH registered products)

• Guideline on Submission of Documentationfor
  Prequalification of Multisource (Generic)
  Finished Pharmaceutical Products (FPPs)used in
  the Treatment of HIV/AIDS, Malaria and
  Tuberculosis (hand-out)
• Based on
• Marketing Authorization of Pharmaceutical
  Products with special Reference to Multisource
  (Generic) Products a Manual for a Drug
  Regulatory Authority (Blue Book)

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Quality assessment - summary

• The quality assessment includes the following
  aspects
• 1 Characteristics of FPP 2/33
• 2 API (impurities, stability, specifications,
  etc) 3/33
• 3 Finished pharmaceutical product (FFP) 8/33
• Pharmaceutical development 8/33
• Formulation 9/33
• Manufacturing process/validation 9/33
• Excipients 12/33
• Product specifications/control 12/33
• Packaging 14/33
• Stability testing (shelf-life) 14/33
• Labelling/SmPC/PIL 19/33

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Administrative 1/33

• A Covering letter
• Statement information is true and correct
• B Application (FPP dossier)
• Four main sections (with subsections)
• Stick to the sections prescribed
• Sections should be clearly marked (preferably
  with securely fixed tags)
• Number all pages
• Table of contents

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Section 1. Characteristics of FPP 2/33

• Details of product
• Sample for visual inspection of product and
  packaging
• Regulatory status in other countries. List
  countries in which
• This product has been granted a marketing
  authorization
• this product has been withdrawn from the market
• the application for marketing has been rejected,
  deferred or withdrawn

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Section 2. Active pharmaceutical ingredient (API)
3/33 separate topic

• 2.1 Nomenclature (INN, Systematic, CAS, etc.)
• 2.2 Properties (structure, stereochemistry, etc)
• 2.3 Site of manufacture
• 2.4 Route of synthesis (impurities, etc)
• 2.5 Specifications (pharmacopoeia?)
• 2.6 Container closure system
• 2.7 Stability testing re-test period storage
• -
• Open part of Drug Master File (DMF)
• CEP

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Section 2. API 3/33

• The API (name) strength per unit dose can be
  considered the only constants when starting to
  development the dosage form and to chose primary
  packaging materials. Thus, it is important to
  understand
• The physical properties, which should be well
  studied and dealt with (e.g. flowability,
  particle size, polymorphism, hygroscopicity,
  solubility)
• The chemical properties, especially aspects such
  as- stability (mainly hydrolysis, oxidation
  photolysis)- possible API-excipient
  interactions- API-API interactions in FDCs
• (API details will be dealt with in separate
  session)

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Section 3. Finished pharmaceutical product (FPP)
8/33

• 3.1 Authorisation 8/33
• Submit valid manufacturing authorisation for
  pharmaceutical production
• Submit marketing authorisation
• To demonstrate that product is registered or
  licensed according to national requirements

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3.2 Pharmaceutical development 8/33 separate topic

• Pharmaceutical R D provides the foundation of
  the activities aimed at ensuring that the patient
  receives an FPP (product) that consistently meets
  established standards specifications of
• Safety
• Efficacy
• Quality, including stability
• Typical aspects covered in development studies
• Choice of dosage form, excipients packaging
• Compatibilities of API with excipients, primary
  packaging materials, and other APIs (in FDCs)
• Development/validation of analytical methods

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Pharmaceutical development

• Learn about the product through desk research
• Collect analyse available information on e.g.
  APIs, formulas, excipients, compatibility,
  stability, dosage form, strength, packaging
  analysis.
• Compile a Product Profile Report
• Development according to plan, including
• Preformulation studies
• Formula / dosage form development packaging
• Development/validation of analytical techniques
• Comparative dissolution studies
• (Accelerated) stability
• Final formula / manufacturing process
• Provide a development report

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3.3 Formulation 9/33

• Formula in tabulated form for
• Administration unit (e.g. one tablet)
• Typical batch
• Excipients
• State function (e.g. lubricant, disintegrant)
• Special technical grade (e.g. micronised,
  purified water)
• Also those removed during process (e.g. water)
• Also those not always added (e.g. acid alkali)
• Capsule shells, inked imprints on dosage form

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Formulation table example

• ? Removed during process (not in total mass)

Ingredient Quantity per tablet (mg) Quantity per batch (kg) Purpose
Isoniazid 300.00 30.00 Active
---------------- ---------------- ---------------- --------------
Mg Stearate 2.00 0.20 Lubricant
Pur. Water? 60.0 6.00 Solvent
Total 450.00 45.00
100 000 tablets 100 000 tablets
20
3.4 Sites of manufacture 9/33

• For each facility where all/part of manufacturing
  occurs, including production, packaging QC
• Name of manufacturer
• Street address
• Phone fax numbers
• E-mail addresses
• For major production sites submit
• WHO type of CPP
• Valid GMP certificate

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3.5 Manufacturing process 9/33

• Flow diagram
• Indicate critical steps in-process controls
• Description of manufacturing/packaging
• Scale
• Equipment by type (e.g. tumble dryer) capacity
• Process parameters for steps, e.g. time, temp, pH
• Environmental conditions, e.g. rel. humidity for
  hygroscopic FPPs.

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Manufacturing process (continued)

1. Proposal for reprocessing justified with data
2. Copy of master formula
3. Batch manufacturing record real batch
4. Sterile products sterilisation steps /or
   aseptic procedures
5. Description of in-process tests
6. Data for 3 full scale batches to support
   achievement of predetermined specifications

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3.6 Process controls 10/33

• Critical steps
• Acceptance criteria (justified)
• Tests (cross reference)
• Intermediates isolated during process
• Acceptance criteria (justified if not compendial)
• Tests (cross reference)

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3.7 Process validation evaluation 10/33

• Differentiate between the following generics
• 3.7.1 New FPPs (new for manufacturer)
• FPPs that have been newly developed by the
  manufacturer, though it will be a generic
• Full validation required
• 3.7.2 Established FPPs
• The manufacturer has manufactured marketed this
  FPP for quite some time and now wishes to
  prequalify the FPP
• 10 recent consecutive batches
  result/trend/statistical analysis discussion

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3.7.1 Validation new product 10/33

• Demonstrate validity of the process
• Report for 3 production batches, including
• Batch analytical data
• CoAs
• Batch production records
• Conclusions
• Otherwise validation protocol with commitment
• See guidelines for protocol requirements (page
  11/33)
• Report will be available for inspection
• Validation report to be submitted (page 11/33)
• Sound pharmaceutical RD and a valid process
  reproducible product of good quality

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3.8 Excipients - specifications 12/33

• Of natural origin?
• Microbial limits (skip-testing)
• Of human or animal origin? Info on adventitious
  agents, such as
• TSE/BSE (e.g. Mg-stearate from animal origin)
• Asbestos in talc (test included in current
  BP/Ph.Eur. IR and XRPD)
• Colours permitted by
• EU, FDA, Japan (references bottom p. 12/33)

27
3.8.1 Excipients not in compendia 12/33

• Such excipients not recommended
• See guideline for requirements
• Some standard mixtures comprising excipients in
  pharmacopoeia, e.g. Opadry colours
• Table with composition of such mixture
• Specifications with tests (normally from
  supplier)
• Compendia (pharmacopoeias) considered
• International Pharmacopoeia (Int.Ph.)
• BP, JP, Ph.Eur, USP (ICH region)

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3.8.2 Excipients described in compendia 12/33

• Provide a copy of monograph
• Also copies of methods referred to in monograph
  but not appearing in monograph
• Current pharmacopoeial monograph always
  applicable
• If monograph change, new monograph valid
• Details of any specifications additional to
  monograph
• E.g. particle size, residual solvents

29
3.9 Control of FPP 12/33

• Four subsections
• Specifications
• Analytical procedures
• Validation of analytical procedures
• Batch analysis

30
3.9.1 Specifications for the FPP 12/33

• Specifications are one part of a total control
  strategy for the FPP designed to ensure product
  quality and consistency (ICH Q6A).
• Others include adherence to GMP e.g., suitable
  facilities, a validated manufacturing process,
  in-process testing, stability testing, API
  testing, etc.
• Product specifications (as in pharmacopoeia) or
  split into
• Release specifications
• Shelf-life specifications (may differ if
  justified)

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3.9.1 FPP specifications continued

• Important reading for setting specifications
• ICH guideline Q6A (also good for generics)
• Specifications Test Procedures and Acceptance
  Criteria for New Drug Substances and New Drug
  Products Chemical Substances.
• Specifications based on pharmacopoeia
• Additional product related specifications, e.g.
• Those standard for the dosage form (e.g.
  friability, tablet hardness, mass uniformity)
• ID of (coating) colorants, microbial limits (skip
  testing?)
• Related substances in USP monograph for TB 4FDC

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3.9.1 FPP specifications typical

• Appearance
• Identification of the following in FPP
• APIs
• Colorants (skip testing possible)
• Preservatives
• Physical tests appropriate to dosage form e.g.
• LOD, friability, hardness (tabs), relative
  density
• Uniformity of dosage units (mass / content)
• Pharmaceutical tests, e.g. dissolution

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3.9.1 FPP specifications typical (con.)

• Purity tests
• Degradation products (related substances)
• Residual solvents (solvents used in process)
• Microbial count / sterility / bacterial
  endotoxins
• Content of APIs in FPP (assay)
• Limits 95.0 105.0, unless justified
• Content of preservatives
• Limits 90.0 110.0, generally acceptable

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Example - FPP specs uncoated tablets
Attribute Release limits Stability limits
Appearance Full description Same as release
Identification At least 1 method Not required for stability studies. Not regarded as variables for product.
Dimensions Diameter, etc Not required for stability studies. Not regarded as variables for product.
Average mass w.r.t. theoretical Not required for stability studies. Not regarded as variables for product.
Mass uniformity Ph.Eur/USP/Int.Ph Not required for stability studies. Not regarded as variables for product.
Tablet hardness product specific Same as release
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Example of FPP specs uncoated tabs (con.)
Attribute Release limits Stability limits
Friability 1 (normally) Same as release
Dissolution Set per product Same as release
Disintegration Not required if dissolution is done Not required if dissolution is done
Rel. substances (degradants) Only if formed during production Required. Limits to one decimal
Assay (content) 95.0-105.0, unless justified May be 90.0-105.0, justified
Microbial limits Skip-testing
Tests not necessary at release if done in-process Tests not necessary at release if done in-process Tests not necessary at release if done in-process
36
FPP specifications special for FDCs

• Degradants (related substances) must be stated
  calculated in with reference to the parent API,
  not the sum of the APIs, e.g.
• Rifampicin / isoniazid tablets. Rifampicin
  quinone (degradant) as of rifampicin.
• If 2 APIs react with each other, then the
  degradant to be stated with respect to worst
  case, e.g.
• Rifampicin / isoniazid tablets. A Hydrazone
  forms from the 2 APIs. Specification
  hydrazone with respect to rifampicin (worst case
  in mass balance).
• Unknown degradants with respect to worst case
• Dissolution include all APIs (e.g. FDCs in the
  USP)

37
3.9.2 Analytical procedures 13/33

• Methods to be described in detail
• Copy of standard monograph tests (e.g.
  friability)
• System suitability included in HPLC methods
• Pharmacopoeial based control
• Copy of monograph (latest edition)
• Methods of additional tests (e.g. ID of coating
  colorants)

38
3.9.3 Validation analytical methods 13/33

• Non-pharmacopoeial methods
• All methods should be validated
• Validation reports, including data conclusions
• Stability of sample/standard solutions
• Pharmacopoeial methods
• Partial validation (to show validity for this
  formulation specificity important)
• Validation study - ICH guidelines
• Q2A Q2B

39
ICH (Q2A) table - validation parameters 13/33
Test ID impurities impurities Assay Incl. diss.
Test ID quantitative limit Assay Incl. diss.
Accuracy
Precision Precision Precision Precision Precision
Repeatability
Iterm. precision
Specificity
Detection limit ?
Quantitation limit
Linearity
Range
40
3.9.4 Batch analysis 14/33

• Results of at least 3 batches
• Testing against for full set of specifications
• Test date
• QA certified
• Batch number
• Date of batch manufacture
• Place of manufacture
• Batch size (kg units)
• Primary packaging materials
• Purpose of batches (stability, commercial, etc.)
• API batch number

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3.10 Packaging 14/33

• Container/closure system
• Suitability for storage, transport, compatibility
• Detailed description, including liner/wadding
• Specifications - Description- Identification
  (Typical IR - specific)- Drawings and critical
  dimensions
• Outer packaging
• Description, material

42
3.11 Stability testing 14/33 separate topic

• The purpose of stability testing is to provide
  evidence on how the quality of a FPP varies with
  time under the influence of a variety of
  environmental conditions such as temperature,
  humidity and light and to establish a shelf-life
  for the FPP (from current EMEA guidance
  CPMP/QWP/122/02).
• Stability studies should be performed- on each
  individual strength- each type of commercial
  container and- each container size (unless
  bracketing/matrixing)

43
Stability parameters (attributes)

• Stability studies should include testing of
  those attributes of the FPP that are
• susceptible to change during storage and are
• likely to influence quality, safety, and/or
  efficacy.
• The testing should cover, as appropriate, the
  physical, chemical, biological, and
  microbiological attributes, preservative content
  (e.g., antioxidant, antimicrobial preservative),
  and functionality tests (e.g., for a dose
  delivery system)
• From ICH Q1A(R2)

44
Tablets stability parameters

• Parameters specifically for tablets (often
  omitted)
• Tablet strength, friability and moisture can
  change with time if not in release specs,
  include in stability these are interrelated,
  also with dissolution
• Microbial limit at release and end-of-shelf
• Dissolution specification must be same as for
  release

45
Stability report

• See Annex 2 (Guidelines)
• Info on batches tested
• Unit composition (or cross-reference)
• Container closure system (commercial!!)
• Literature and/or supporting data
• Methods stability indicating (cross-reference)
• Stability plan (schedule)
• Tabulated test data (including specifications)
• Analysis/discussion of data (statistical if
  negative trend)
• Shelf-life proposal (including storage condition)
• Post approval commitments

46
Testing frequency storage conditions

• Solid oral dosage forms (tablets, capsules)
• Zone IV is real-time condition for
  prequalification project unless otherwise
  justified
• Zone II only if justified (may be fall-back for
  zone IV)
• ASEAN proposal for zone IV 30ºC / 75 RH

Condition? Month? 0 3 6 9 12 18 24 36
30ºC / 65 RH (zone IV) X X X X X X X X
40ºC / 75 RH (accel) X X
25ºC / 60 RH (zone II) X X X X X X X
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3.12 Container labelling 19/33

• Outer packaging (where no outer packaging, on
  immediate packaging e.g.securitainer)
• Blisters and strips
• All the elements as listed on pages 19-20 of
• Guideline on Submission of Documentation for
  Prequalification of Multisource (Generic)
  Finished Pharmaceutical Products (FPPs) Used in
  the Treatment of HIV/AIDS, Malaria and
  Tuberculosis.

48
SmPC and PIL 20/33

• 3.13 Summary of product characteristics (SmPC)
• To appear in WHOPAR
• Changes to SmPC to be approved by WHO
• See Annex 3 of guideline
• 3.14 Patient information leaflet (PIL)
• To appear in WHOPAR
• In conformance with SmPC
• From quality side, include in SmPC PIL
• Identification of dosage form in detail
• Presentation in detail
• Storage requirements and approved shelf-life

49
Variations

• Draft guidance on variations with respect tothe
  dossier submitted and accepted in
  thePrequalification Programme
• (Handout)
• ANNEX I (p. 3) - minor changes
• ANNEX II (p. 27) - major changes in general
• ANNEX III (p. 29) - types of changes requiring
• a new
  application

50
Minor changes

• A minor change is a change concerning an
  amendment to the contents of the documents such
  as they existed at the time of listing as
  prequalified
• The request, with documentation, for a minor
  change must be submitted for approval
• The minor changes in the guideline are listed in
  numerical order, with the conditions to meet and
  documentation required
• Currently 41 minor type of changes listed
• A few examples to follow (follow guideline
  numbers)

51
4. Change in the name and/or address of a
manufacturer of the API (where no CEP is
available)

• Condition
• The manufacturing site shall remain the same
• Documentation
• A formal document from a relevant official body
  in which the new name and/or address is mentioned
• Replacement page(s) of Section 3.2 (A new name
  and or a new address of the sites of
  manufacture) in the product dossier

52
9. Minor change in the manufacturing process of
the active substance

• Conditions
• No change in qualitative and quantitative
  impurity profile or in physico-chemical
  properties
• The synthesis route remains the same, i.e.
  intermediates remain the same
• Documentation
• Amendment to the relevant sections 3.4-3.5 of the
  product dossier and of the approved DMF (where
  applicable), including a direct comparison of the
  present process and the new process
• Batch analysis data (in comparative tabular
  format) of at least two batches (minimum pilot
  scale) manufactured according to the currently
  approved and proposed process
• Copy of approved specifications of the API

53
12. Change in test procedure for API, starting
chemicals, intermediate, or reagent used in the
manufacturing process of an API

• Conditions (depending on change, not all
  applicable)
• The method of analysis should remain the same
  (e.g. a change in column length or temperature,
  but not a different type of column or method) no
  new impurities are detected
• Appropriate (re-)validation studies have been
  performed in accordance with relevant guidelines
• Results of method validation show new test
  procedure to be at least equivalent to the former
  procedure.
• Any new test method does not concern a novel
  non-standard technique or a standard technique
  used in a novel way

54
12. Change in test procedure for API, etc. (cont.)

• Documentation (depending on change, not all
  applicable)
• Amendment to the section 3.4 of the product
  dossier, which includes a description of the
  analytical methodology, a summary of validation
  data, revised specifications for impurities (if
  applicable) amendment to the section 3.5 of the
  product dossier if applicable)
• Comparative validation results showing that the
  current test and the proposed one are equivalent

55
31. Minor change in the manufacture of the
finished product

• Conditions
• The overall manufacturing principle remains the
  same
• The new process must lead to an identical product
  regarding all aspects of quality, safety and
  efficacy
• In case of a change in the sterilisation process,
  the change is to a standard pharmacopoeial cycle
  only
• Relevant stability studies in accordance with the
  relevant guidelines have been started with at
  least three production batches and at least three
  months stability data are at the disposal of the
  applicant. Assurance is given that these studies
  will be finalised and that the data will be
  provided immediately to the competent authorities
  if outside specifications or potentially outside
  specifications at the end of the approved shelf
  life (with proposed action)

56
31. Minor change in the manufacture of the
finished product (cont.)

• Documentation
• Amended relevant sections of the part 4
  Finished product of the product dossier
• For semi-solid and liquid products in which the
  API is present in non-dissolved form appropriate
  validation of the change including microscopic
  imaging of particles to check for visible changes
  in morphology comparative size distribution data
  by appropriate method
• For solid dosage forms dissolution profile data
  of one representative production batch and
  comparative data of the last three batches from
  the previous process data on the next two full
  production batches should be available on request
  or reported if outside specification (with
  proposed action)

57
31. Minor change in the manufacture of the
finished product (cont.)

• Documentation (cont.)
• Justification for not submitting a new BE study
  according to the current WHO guideline (WHO TRS,
  No.863). In case of a change to the sterilisation
  process, validation data should be provided
• Copy of approved release and end-of-shelf life
  specifications
• Batch analysis data (in a comparative tabulated
  format) on a minimum of three batches
  manufactured to both the currently approved and
  the proposed process. Batch data on the next two
  full production batches should be made available
  upon request and reported by the applicant if
  outside specification (with proposed action)
• The batch numbers of stability batches

58
Major changes

• A major change is a change to the documentation
  which can neither be deemed to be a minor change
  within the meaning of preceding definition
  (therefore exceeding the frame of a minor change)
  nor to be a change for which a new application
  would be necessary
• Most likely
• Change in the manufacturing process of the API
• Change in the composition of the finished product
• Change of immediate packaging of the finished
  product

59
New dossier

• Certain changes to a prequalified FPP are so
  major that they are considered to fundamentally
  alter the terms of prequalification and
  consequently cannot be considered as a change.
  For these changes a new dossier must be
  submitted.
• Changes to the API
• Change of the API to a different API
• Inclusion of an additional API to a
  multi-component product (FDC)
• Removal of one API from a multi-component product
• Change in the dose of one or more APIs

60
New dossier (2)

• Changes to the pharmaceutical form/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

61
Conclusion from PQ objective

• The objective of the prequalification project,
  is to assess the acceptability in principle of TB
  drugs for procurement by UN Agencies. The
  assessment procedure is aimed at identifying
  products and suppliers meeting WHO standards.
  Thus, the project facilitates the procurement of
  TB related drugs of acceptable quality
  Prequalification website
• The quality assessment includes changes to
  prequalified products
• ICH guidelines are used when a quality aspect
  cannot be assessed by the WHO guidelines