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  1. Dossier Requirements for Generics: Quality (Part I) EMRO 1st workshop on WHO Prequalification Programme of Priority Essential Medicines6-7 June 2007, Cairo, EGYPT Maryam MEHMANDOUST, PhD Pre-qualification programme: Priority Essential MedicinesWHO- HTP/ PSM/ QSM mehmandoustm@who.int

  2. Glossary • API Active Pharmaceutical Ingredient • APIMF Active Pharmaceutical Ingredient Master File • ARV Antiretroviral • CoS Certificate of Suitability • EDQM European Directorate for Quality of Medicines and HealthCare • EoI Expression of Interest • FPP Finished Pharmaceutical Product • GMP Good Manufacturing Practices • ICH International Conference on Harmonization • Int. Ph. International Pharmacopoeia • JP Japanese Pharmacopoeia • Ph. Eur. European Pharmacopoeia • PIL Patient Information Leaflet • PQ Prequalification • PQIF Pharmaceutical Quality Information form • SPC Summary of Product Characteristics • TB Tuberculosis • USP United States Pharmacopoeia

  3. WHO Reference text for Multisource (Generic) products WHO/DMP/RGS/98.5 - Marketing Authorisation of Pharmaceutical Products with Special Reference to Multisource (Generic) Products - A Manual for a Drug Regulatory Authority (Blue Book) (1999). [under revision] available on WHO web-site: http://www.who.int/prequal/

  4. WHO Reference text for Multisource (Generic) products / Definitions Active Pharmaceutical Ingredient (API) A substance or compound that is intended to be used in the manufactureof a pharmaceutical product as a therapeutically active compound (ingredient) Pharmaceutical Product Any preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient. Finished Pharmaceutical Product (FPP) A product that has undergone all stages of production, including packaging in its final container and labelling.

  5. Multisource (Generic) product Multisources are Pharmaceutically equivalent (WHO definition) • same amount of the same API • same dosage form • meet the same or comparable standards • intended to be administered by the same route Multisourceswhich are therapeutically equivalent are interchangeable

  6. Quality of a Generic product Multisource products must be of good quality and at least as safe and efficacious as existing products (WHO Manual, Blue Book, P. 29, chapter H., Interchangeability)) Equal quality with the comparator ora quality shown and assessed to be as acceptable Same Safety – Same efficacy Demonstration of pharmaceutical equivalenceof the FPP including that of the API

  7. Reference textsPrequalification quality guidelines for dossier submission • Guideline on submission of documentation for prequalification of multi-source (Generic) Finished Pharmaceutical Products (FPPs) used in treatment of HIV/AIDS, Malaria and Tuberculosis (Main Generic guide with 8 annexes) [under revision] • Supplement 1 : Dissolution testing • Supplement 2 : Extension of the WHO list of stable APIs (not easily degradable) • Guidance on variations to a prequalified dossier • Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure • ICH notes for guidance (when applicable) These documents are available on WHO website:http://www.who.int/prequal/

  8. Documentation on Quality Partto be submitted to the WHO PQ team • Covering letter • Product dossier on part Quality • PQIF (annex 8 to the main generic guide): properly filled out in WinWord format, See mock-up PQIF on www.who.int/prequal/ under training material and workshops, Hanoi, Vietnam, January 2006

  9. Documentation on Quality Partto be submitted to the WHO PQ team /PQIF

  10. Documentation on Quality Partto be submitted to the WHO PQ team /PQIF

  11. Documentation on Quality Partto be submitted to the WHO PQ team / PQIF

  12. Quality dossier / Section 1 Information on the Finished Pharmaceutical Product (FPP) 1.1. Details of the Product- Name, dosage form and strength of the product- Approved generic name (INN)- Visual description of the FPP- Visual description of the packaging 1.2. Samples (visual examination and comparison with the SPC and PIL 1.3. Regulatory situation in Member States / list countries- Countries where a MA has been issued- Countries where a MA has been withdrawn- Countries where a Marketing Application has been rejected, deferred

  13. Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

  14. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) Scientific data on the API can be submitted in the following order of preference • A valid Certificate of Suitability (CoS) or CEP, latest version, with all its annexes issued by EDQM • An APIMF (Active Pharmaceutical Ingredient Master File) submitted by the API manufacturer, containing the whole information requested in section 2 • Complete submission of data requested in Section 2

  15. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.1. Nomenclature 2.2. Properties of the API** 2.3. Site(s) of manufacture 2.4. Route(s) of synthesis** 2.5. Specifications** 2.6. Container- closure system 2.7. Stability testing ** The requirements may differ depending on if the API is pharmacopoeial or non-pharmacopoeial

  16. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) TB drugs / 6th EoI • Rifampicin (rifampin) Ph. Eur., USP, BP, Ph. Int. • Ethambutol 2HCl Ph. Eur., USP, BP, Ph. Int., JP • Pyrazinamide Ph. Eur., USP, BP, Ph. Int., JP • Isoniazid Ph. Eur., USP, BP, Ph. Int., JP • Streptomycin sulfate Ph. Eur., USP, BP, Ph. Int. • Amikacin Ph. Eur., USP, BP, Ph. Int., JP • Kanamycin Ph. Eur., USP, BP • Capreomycin USP, Ph. Int. • Cycloserine USP, JP • Ethionamide Ph. Eur., USP, BP, Ph. Int., JP • Ofloxacin Ph. Eur., USP, BP • Prothionamide Ph. Int., JP • p-Aminosalicylic acid (and sodium salt) Ph. Eur., USP

  17. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) Artemisinin based antimalarial drugs / EoI May 2005 • Artesunate Ph. Int. • Artemether Ph. Int. • Artemotil (arte-ether) Ph. Int. • Amodiaquine Ph. API • mefloquine • Sulphadoxine • Pyrimethamine • Lumefantrine Non-pharmacopoeial

  18. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) Antiretrovirals • Abacavir Ph. Int. • Didanosine Ph. Int. • Efavirenz Ph. Int. • Indinavir Ph. Int., USP • lamivudine Ph. Eur., USP, BP, Ph. Int. • Nelfinavir Ph. Int. • Nevirapine Ph. Int., USP, Ph. Int. • Stavudine Ph. Eur., USP, BP, Ph. Int. • Saquinavir Ph. Int., USP • Ritonavir Ph. Int., USP • Zidovudine Ph.Int., USP, Ph. Eur., BP • Tenofovir and Emtricitabine Non-pharmacopoeial

  19. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.1. Nomenclature (INN, chemical name, CAS No.) 2.2. Properties of the API (pharmacopoeial substances)- Properties which are not described in a monograph such as solubilities in water and different buffer solutions, existence/absence of polymorphs, Particle size - Verification of structure by Infra-red (IR) comparison to an official Reference standard

  20. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.2. Properties of the API (non-pharmacopoeial substances)- Chemical structure, stereochemistry, molecular mass- Isomeric nature including stereo-chemical configuration - Proof of the structure: interpreted spectra such as IR, NMR, UV, RX, thermograms…- Physico-chemical properties such as solubilities in water and different buffer solutions, existence/absence of polymorphs,…

  21. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.3. Site(s) of manufactureName and address of each facility /alternative facility + valid manufacturing authorization for production of API 2.4. Route(s) of synthesis (Pharmacopoeial substance)Brief outline of the manufacturing process i.e.- flow chart and brief description of the manufacturing of API- name of solvents, reagents and catalysts used in the process- emphasis on final steps specifically those of purification and crystallization

  22. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.4. Route(s) of synthesis (non-pharmacopoeial substance)- flow chart and detailed description of the manufacturing of API, operating conditions and materials used, typical batch size- list of materials used: solvents, reagents and catalysts used in the process and their specifications- specifications of starting key raw material and intermediates - emphasis on final steps specifically those of purification and crystallization- in-process controls, identification of critical steps and their validation- description of alternative processes while showing that the final impurity profile remains the same as that of the main process- Reprocessing- Declaration on use/non use of TSE risk materials

  23. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.5. Specifications (Pharmacopoeial substance)-Copy of the pharmacopoeial monograph used + additional tests not mentioned in the monograph- Specifications of the API (analytical procedures and associated limits) should comply with the requirements of a specific monograph + those of the general monograph (if applicable) + controls on residual solventse.g. Ph. Eur. General monograph on substances for pharmaceutical use (2034)- If the API is prepared by a different method of synthesis liable to leave impurities other than those mentioned in the monograh- impurities to be characterized - demonstrate that the pharmacopoeial analytical procedure is suitable to control these new impurities - if not, develop and propose a new validated method with an acceptable limit for that impurity

  24. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.5. Specifications (Pharmacopoeial substance) (cont.) • If existence of polymorphs, discuss the need for having or not a specification for polymorphs • if substance insoluble in water, discuss the need for a particle size specifications these aspects are not covered by the pharmacopoeial monograph - Batch analyses for at least 2 batches manufactured on each site and from each route of synthesis

  25. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.5. Specifications (non-pharmacopoeial substance)- Requirements of the note for guidance ICH Q6A apply - Characterize organic impurities, inorganic impurities, residual solvents, catalysts residues which may be potentially present in the final substance - Propose acceptable limits according to ICH Q3A (impurities) and ICH Q3C (residual solvents) - Propose appropriate analytical procedures suitable for the intended use, correctly validated + full detailed description of the method in order to be replicated by a control laboratories - Batch analyses for at least 2 batches manufactured on each site and from each route of synthesis - Description on how the reference standard used in analytical procedures is prepared, how its identity, its purity and its assay have been set + 1 certificate of analysis

  26. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.6. Container-closure system • Description of the packaging • Identification of materials and components of the packaging • Specifications of these materials • Justification for choice of these materials, e.g. - protection against light, humidity - compatibility of the used materials with the API, interactions between the API and the closure such as sorption, leaching (mainly in case of a liquid API)

  27. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.6. Stability of the API • Stress study • to know different degradation pathways of an API and degradation products formed • to demonstrate the intrinsic stability of the API The above information is useful further for development pharmaceutics of the FPP • To demonstrate the stability indicating power of the analytical procedure used Reference can be done to the literature or to pharmacopoeiae, if the above information is there available

  28. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.6. Stability of the API • Formal stability study necessary to establish a re-test period and a precaution for storage / labelling statement Definition of the re-test period Period of time during which the API is expected to remain within its specifications and can be used in the manufacture of a given product (without control prior to manufacture of Drug Product) in condition that the API has been stored under defined storage conditions

  29. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.6. Stability of the API • Formal stability study • 3 lots of API: 1 production scale and 2 of pilot size • Parameters susceptible to change during storage should be followed: assay, related substances and degradation products, isomeric nature,… • Minimum of data at submission of the dossier • 12 months long term ICH condition 25°C/60% RH, • 12 months intermediate ICH condition 30°C/65% RH, • 6 months accelerated ICH 40°C/75% RH Unless otherwise justified, the long term storage condition for Prequalification is 30°C/ 65% RH

  30. Submission of data on API – section 2Certification of Suitability (CoS) / CEP Option • Issued by EDQM for substances described in the Ph. Eur. www.edqm.eu • 2 types of CEPs: quality CEP and TSE CEP • Information which can be found on a quality CEPCEP reference, CEP holder, site of manufacture of the substance, monograph according to which the dossier is evaluated, additional impurities and residual solvents not mentioned in the monograph, additional methods to those of the monograph are appended, re-test period with packaging system and storage condition (if applicable), date of validity of the CEP A quality CEP certifies that the quality of the substance can be checked according to the Ph. Eur. by applying the analytical methods described in the Ph. Eur. monograph supplemented by those appended to the CEP.

  31. Submission of data on API – section 2APIMF Option • Procedure implemented since January 2007, www.who.int/prequal • To protect the "know-how" of the manufacturer of the API • While giving the whole information on manufacture of the API to the WHO PQ team of assessors • While giving a part of the information to the applicant to Prequalification/ manufacturer of the finished product • An APIMF is composed of: Applicant's /Open part + Restricted / Closed part • Manufacturer of the API should make available to the applicant to Prequalification the Applicant's part + Letter of access

  32. Submission of data on API – section 2APIMF Option • Manufacturer of the API should submit on the other hand the Applicant's part + Restricted + Letter of access to WHO team An APIMF is to be submitted only in support of a FPP dossier • An APIMF is not an independent dossier of API • Scope open to pharmacopoeial and non-pharmacopoeial APIs • Scope of APIMF only open to APIs≠ US and Canadian master file procedures • See annex 1 of the APIMF guide for the content of an APIMF • Content of APIMF corresponds to data required in section 2 of the prequalification quality dossier without difference between pharmacopoeial and non-pharmacopoeial APIs

  33. Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

  34. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.1. Manufacturing and marketing authorization 3.2. Pharmaceutical development 3.3. Formulation 3.4. Sites of manufacture 3.5. Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7. Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

  35. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.12. Container labelling 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)

  36. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.1. Manufacturing and Marketing Authorization • Valid manufacturing authorization for pharmaceutical production including the pharmaceutical form applied for • Marketing authorization to demonstrate the product is registered / licensed in accordance with national requirements 3.2. Pharmaceutical development The aim is to build a quality product by design.

  37. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development The section should contain information on the development studies conducted to establish that • the dosage form, • the formulation, • the manufacturing process, • the container closure system, • microbiological attributes and • storage and usage instructions are appropriate for the purpose specified in the dossier.

  38. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (pre-formulation) • Physico-chemical characteristics of the APIs • solubility (composition) • water content (stability) • hygroscopicity (stability) • particle size (solubility, bioavailability, suspension properties, stability …) • polymorphism (solubility, bioavailability, stability) • Data obtained from literature : Books, Journals, International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts, Internet …… • Experimental data (if necessary)

  39. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of excipients) • Intended function of each excipient • Criteria • compatibility of excipients with API(s), • characteristics of the excipients (water content, particle size, flowability, density, rheological behavior…) • Particularly : other non active constituents (lowest acceptable concentration to be chosen e.g. concentration of parabens as preservatives) • Experimental data needed.

  40. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of the manufacturing process) • Parameters : characteristics of the APIs, dosage form, composition…. . • Rational behind the choice (e.g. why a non over kill process as a sterilisation process?) • Justification of the overage (if any) • Identification of the critical steps • In Process Control (IPC) • Selection and optimisation of manufacturing process

  41. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (dissolution testing) • To study dissolution operating conditions (media, pH, rotation, …) • To develop a discriminatory dissolution method • Comparative dissolution testing is a tool, mandatory in development pharmaceutics section of the dossier in PQ, See Supplement 1 • Help in selection of the formulation - compare formulation(s) with innovator product, - a basic strategy in development to maximize the chances of bioequivalence • Comparison of pivotal batches to commercial batches/ post-approval changes • Setting of dissolution specifications

  42. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (details of batches studied) • Provide a summary of development of the FPP from pre-formulation to production scale. • Provide a comparison of formulas (tabulated form) of : • bio-batche(s) (clinical/bioequivalence), • development batches, • stability batches, • batches for validation/production

  43. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of formulation and compatibility) • Compatibility of APIs with the excipients • Compatibility of APIs between each other in case of fixed dose combinations See example of 4FDC for TB products

  44. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of formulation and compatibility) • Each tablet contains 4 APIs . Rifampicin ………………. 150 mg . Isoniazid …………………. 75 mg . Pyrazinamid …………….. 400 mg . Ethambutol 2HCl…………275 mg . Excipients ………………..

  45. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of formulation and compatibility) • Rifampicin Oxidation (quinone & N-oxide) • Protect from air exposure Hydrolysis (3-formylrifamycin & 25-desacetyl) • Wet granulation/drying a potential problem ? Reaction with Isoniazid • Produces 3-(isonicotinylhydrazinomethyl) rifamycin or more commonly known as isonicotinyl hydrazone. Light sensitive • Product to be protected from light exposure

  46. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of formulation and compatibility) • Isoniazid Reacts with aldehydes/reducing sugars • Sugar & lactose to be avoided in formulation !! • 3-formylrifamycin (from rifampicin) • Ethambutol hydrochloride (2HCl) Hygroscopic • Absorbs water reactions in tablets. Creates slightly acidic conditions • The acidic conditions enhance reaction between rifampicin and isoniazid (isonicotinyl hydrazone formation)

  47. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (preventive/protective measures) • Formulation – no sugar/lactose (isoniazid) • Separate granulation of rifampicin & isoniazid (limit contact) • Rifampicin as powder (not granulate) ? • Prevent oxidation & hydrolysis • Low water content of tablet • Protect product from moisture and oxygen • Film coating, • Non-permeable packaging • Light protection

  48. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.3. Formulation • Formula in tabulated form for : • Administration unit (e.g. one tablet), • Typical batch - Precise any overage, - Precise quantity adjustment of the API, - Precise q.s. for excipient. • Excipients : • State function (e.g.lubricant, disintegrant), • Precise technical grade (e.g. micronised, purified water), • Also those removed during process (e.g. water), • Also those not always added (e.g. acid & alkali) : pH adjustment, • Capsule shells, inked imprints on dosage form, • Also gas (inert atmosphere).

  49. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.4. Manufacturing sites • Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control • Include any alternative manufacturers • Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed • Submit a valid GMP certificate