1. 1 TG Dekker – WHO, MalaysiaFeb 2005 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@puk.ac.za

2. 2 TG Dekker – WHO, MalaysiaFeb 2005 Some abbreviations APIActive pharmaceutical ingredient BPBritish Pharmacopoeia CEPEU certificate of suitability CPP WHO-type Certificate of a Pharmaceutical Product EOIExpression of interest FDCFixed dose combination FPPFinished pharmaceutical product ICHInternational Conference on Harmonization Int.Ph.International Pharmacopoeia JPJapanese Pharmacopoeia Ph.Eur.European Pharmacopoeia SmPCSummary of product characteristics TBTuberculosis USPUnited States Pharmacopeia

3. 3 TG Dekker – WHO, MalaysiaFeb 2005 5 th Invitation for EOI (July 2004) (1) First-line anti-TB products 1.Ethambutol hydrochloride (Eth) 400 mg tablets 2.Pyrazinamide (Py) 400 mg tablets 3.Isoniazid (INH) 300 mg tablets  Fixed dose combinations: 4.2FDC: Rif/INH 150/75 mg tablets 5.2FDC: Rif/INH 150/150 mg tablets 6.2FDC: Eth/INH 400/150 mg tablets 7.3FDC: Rif/INH/Eth 150/75/275 mg tablets 8.4FDC: Rif/INH/Py/Eth 150/75/400/275 mg tablets 9.Streptomycin Sulfate 1g vial (injection)

4. 4 TG Dekker – WHO, MalaysiaFeb 2005 5 th Invitation for EOI (July 2004) (2) Second-line anti-TB products 10.Water for injection 5ml vial (injection) 11.Amikacin 500mg/2 ml vial (injection) 12.Kanamycin 1g powder for injection, vial 13.Capreomycin 1g powder for injection, vial 14.Cycloserine 250mg tablets 15.Ethionamide 125 mg or 250mg tablets 16.Ofloxacin 200 mg tablets 17.Protionamide 125 mg or 250mg tablets 18.Para-Aminosalicylic Acid 100 g or 4 g granules or powder 19.Moxifloxacin 400 mg tablets

5. 5 TG Dekker – WHO, MalaysiaFeb 2005 5 th Invitation for EOI (July 2004) (3) Formulations for children  Dosage forms should be  soluble tablets,  tablets with break line, and or  sachets 1.Rifampicin 60 mg / Isoniazid 60mg / Pyrazinamide 150 mg (R60/H30/Z150) 2.Rifampicin 60 mg / Isoniazid 30mg (R60/H30) 3.Rifampicin 60 mg / Isoniazid 60 mg (R60/H60) Total number of products on current list: 22

6. 6 TG Dekker – WHO, MalaysiaFeb 2005 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

7. 7 TG Dekker – WHO, MalaysiaFeb 2005 Guideline (ICH registered products) Guideline on Submission of Documentation for 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. 8 TG Dekker – WHO, MalaysiaFeb 2005 ICH registered products - requirements 1.Certified copy of WHO-type CPP 2.Assessment report(s) issued by DRA 3.WHO-type batch certificate 4.Primary packaging differs from ICH approved?  Stability data in new packaging 5.Formulation, strength (??), specs., etc. differ?  Justification in favour of acceptability (BE?) 6.Submit sample(s) of FPP

9. 9 TG Dekker – WHO, MalaysiaFeb 2005 Guideline (Not ICH registered products) Guideline on Submission of Documentation for 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)

10. 10 TG Dekker – WHO, MalaysiaFeb 2005 Quality assessment - summary The quality assessment includes the following aspects: 1Characteristics of FPP 2/33 2API (impurities, stability, specifications, etc) 3/33 3Finished pharmaceutical product (FFP) 8/33 1.Pharmaceutical development 8/33 2.Formulation 9/33 3.Manufacturing process/validation 9/33 4.Excipients 12/33 5.Product specifications/control 12/33 6.Packaging 14/33 7.Stability testing (shelf-life) 14/33 8.Labelling/SmPC/PIL 19/33

11. 11 TG Dekker – WHO, MalaysiaFeb 2005 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

12. 12 TG Dekker – WHO, MalaysiaFeb 2005 Section 1. Characteristics of FPP 2/33 1Details of product 2Sample for visual inspection of product and packaging 3Regulatory 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

13. 13 TG Dekker – WHO, MalaysiaFeb 2005 Section 2. Active pharmaceutical ingredient (API) 3/33 separate topic 2.1Nomenclature (INN, Systematic, CAS, etc.) 2.2Properties (structure, stereochemistry, etc) 2.3Site of manufacture 2.4Route of synthesis (impurities, etc) 2.5Specifications (pharmacopoeia?) 2.6Container closure system 2.7Stability testing – re-test period & storage -  Open part of Drug Master File (DMF)  CEP

14. 14 TG Dekker – WHO, MalaysiaFeb 2005 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)

15. 15 TG Dekker – WHO, MalaysiaFeb 2005 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

16. 16 TG Dekker – WHO, MalaysiaFeb 2005 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

17. 17 TG Dekker – WHO, MalaysiaFeb 2005 Pharmaceutical development 1.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 2.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 3.Provide a development report

18. 18 TG Dekker – WHO, MalaysiaFeb 2005 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

19. 19 TG Dekker – WHO, MalaysiaFeb 2005 Formulation table example ٭Removed during process (not in total mass) Ingredient Quantity per tablet (mg) Quantity per batch (kg) Purpose Isoniazid300.0030.00Active ---------------- -------------- Mg Stearate2.000.20Lubricant Pur. Water٭60.06.00Solvent Total450.0045.00 100 000 tablets

20. 20 TG Dekker – WHO, MalaysiaFeb 2005 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

21. 21 TG Dekker – WHO, MalaysiaFeb 2005 3.5 Manufacturing process 9/33 a.Flow diagram  Indicate critical steps – in-process controls b.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.

22. 22 TG Dekker – WHO, MalaysiaFeb 2005 Manufacturing process (continued) c.Proposal for reprocessing – justified with data d.Copy of master formula e.Batch manufacturing record – real batch f.Sterile products – sterilisation steps &/or aseptic procedures g.Description of in-process tests h.Data for ≥ 3 full scale batches to support achievement of predetermined specifications

23. 23 TG Dekker – WHO, MalaysiaFeb 2005 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)

24. 24 TG Dekker – WHO, MalaysiaFeb 2005 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

25. 25 TG Dekker – WHO, MalaysiaFeb 2005 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 R&D and a valid process = reproducible product of good quality

26. 26 TG Dekker – WHO, MalaysiaFeb 2005 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. 27 TG Dekker – WHO, MalaysiaFeb 2005 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)

28. 28 TG Dekker – WHO, MalaysiaFeb 2005 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. 29 TG Dekker – WHO, MalaysiaFeb 2005 3.9 Control of FPP 12/33 Four subsections: 1.Specifications 2.Analytical procedures 3.Validation of analytical procedures 4.Batch analysis

30. 30 TG Dekker – WHO, MalaysiaFeb 2005 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)

31. 31 TG Dekker – WHO, MalaysiaFeb 2005 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

32. 32 TG Dekker – WHO, MalaysiaFeb 2005 3.9.1 FPP specifications – typical 1.Appearance 2.Identification of the following in FPP  APIs  Colorants (skip testing possible)  Preservatives 3.Physical tests appropriate to dosage form e.g.  LOD, friability, hardness (tabs), relative density 4.Uniformity of dosage units (mass / content) 5.Pharmaceutical tests, e.g. dissolution

33. 33 TG Dekker – WHO, MalaysiaFeb 2005 3.9.1 FPP specifications – typical (con.) 6.Purity tests  Degradation products (related substances)  Residual solvents (solvents used in process) 7.Microbial count / sterility / bacterial endotoxins 8.Content of APIs in FPP (assay)  Limits 95.0% – 105.0%, unless justified 9.Content of preservatives  Limits 90.0% – 110.0%, generally acceptable

34. 34 TG Dekker – WHO, MalaysiaFeb 2005 Example - FPP specs – uncoated tablets AttributeRelease limitsStability limits AppearanceFull descriptionSame as release IdentificationAt least 1 method Not required for stability studies. Not regarded as variables for product. DimensionsDiameter, etc Average massw.r.t. theoretical Mass uniformityPh.Eur/USP/Int.Ph Tablet hardness*product specificSame as release

35. 35 TG Dekker – WHO, MalaysiaFeb 2005 Example of FPP specs – uncoated tabs (con.) AttributeRelease limitsStability limits Friability*≤ 1 % (normally)Same as release DissolutionSet per productSame as release DisintegrationNot 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 limitsSkip-testing * Tests not necessary at release if done in-process

36. 36 TG Dekker – WHO, MalaysiaFeb 2005 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. 37 TG Dekker – WHO, MalaysiaFeb 2005 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. 38 TG Dekker – WHO, MalaysiaFeb 2005 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. 39 TG Dekker – WHO, MalaysiaFeb 2005 ICH (Q2A) table - validation parameters 13/33 TestIDimpuritiesAssay Incl. diss. quantitativelimit Accuracy++ Precision Repeatability++ Iterm. precision++ Specificity++++ Detection limit+ ?+ Quantitation limit+ Linearity++ Range++

40. 40 TG Dekker – WHO, MalaysiaFeb 2005 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

41. 41 TG Dekker – WHO, MalaysiaFeb 2005 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. 42 TG Dekker – WHO, MalaysiaFeb 2005 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. 43 TG Dekker – WHO, MalaysiaFeb 2005 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. 44 TG Dekker – WHO, MalaysiaFeb 2005 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. 45 TG Dekker – WHO, MalaysiaFeb 2005 Stability report See Annex 2 (Guidelines) 1.Info on batches tested 2.Unit composition (or cross-reference) 3.Container closure system (commercial!!) 4.Literature and/or supporting data 5.Methods – stability indicating (cross-reference) 6.Stability plan (schedule) 7.Tabulated test data (including specifications) 8.Analysis/discussion of data (statistical if negative trend) 9.Shelf-life proposal (including storage condition) 10.Post approval commitments

46. 46 TG Dekker – WHO, MalaysiaFeb 2005 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►036912182436 30ºC / 65% RH (zone IV)XXXXXXXX 40ºC / 75% RH (accel) XX 25ºC / 60% RH (zone II)XXXXXXX

47. 47 TG Dekker – WHO, MalaysiaFeb 2005 3.12 Container labelling 19/33 1.Outer packaging (where no outer packaging, on immediate packaging – e.g.securitainer) 2.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. 48 TG Dekker – WHO, MalaysiaFeb 2005 SmPC and PIL 20/33 3.13Summary 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. 49 TG Dekker – WHO, MalaysiaFeb 2005 Variations Draft guidance on variations with respect to the dossier submitted and accepted in the Prequalification 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. 50 TG Dekker – WHO, MalaysiaFeb 2005 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. 51 TG Dekker – WHO, MalaysiaFeb 2005 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. 52 TG Dekker – WHO, MalaysiaFeb 2005 9. Minor change in the manufacturing process of the active substance Conditions 1.No change in qualitative and quantitative impurity profile or in physico-chemical properties 2.The synthesis route remains the same, i.e. intermediates remain the same Documentation 1.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 2.Batch analysis data (in comparative tabular format) of at least two batches (minimum pilot scale) manufactured according to the currently approved and proposed process 3.Copy of approved specifications of the API

53. 53 TG Dekker – WHO, MalaysiaFeb 2005 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) 1.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 2.Appropriate (re-)validation studies have been performed in accordance with relevant guidelines 3.Results of method validation show new test procedure to be at least equivalent to the former procedure. 4.Any new test method does not concern a novel non- standard technique or a standard technique used in a novel way

54. 54 TG Dekker – WHO, MalaysiaFeb 2005 12. Change in test procedure for API, etc. (cont.) Documentation (depending on change, not all applicable) 1.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) 2.Comparative validation results showing that the current test and the proposed one are equivalent

55. 55 TG Dekker – WHO, MalaysiaFeb 2005 31. Minor change in the manufacture of the finished product Conditions 1.The overall manufacturing principle remains the same 2.The new process must lead to an identical product regarding all aspects of quality, safety and efficacy 3.In case of a change in the sterilisation process, the change is to a standard pharmacopoeial cycle only 4.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. 56 TG Dekker – WHO, MalaysiaFeb 2005 31. Minor change in the manufacture of the finished product (cont.) Documentation 1.Amended relevant sections of the part 4: Finished product of the product dossier 2.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 3.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. 57 TG Dekker – WHO, MalaysiaFeb 2005 31. Minor change in the manufacture of the finished product (cont.) Documentation (cont.) 4.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 5.Copy of approved release and end-of-shelf life specifications 6.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) 7.The batch numbers of stability batches

58. 58 TG Dekker – WHO, MalaysiaFeb 2005 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. 59 TG Dekker – WHO, MalaysiaFeb 2005 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. 1.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. 60 TG Dekker – WHO, MalaysiaFeb 2005 New dossier (2) 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 3.Changes in the route of administration

61. 61 TG Dekker – WHO, MalaysiaFeb 2005 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