Dr. Pogány - WHO, Bangkok 1/71 QUALITY MANAGEMENT OF ANTIMALARIAL MEDICINES János Pogány, Ph.D., WHO consultant Bangkok, 19 October Experience in prequalification of antimalarial medicines (product dossier assessment)

Dr. Pogány - WHO, Bangkok 2/71 ABBREVIATIONS and NOTES APIActive pharmaceutical ingredient BPBritish Pharmacopoeia EOIExpression of interest FDC(s)fixed-dose combination(s) FPP(s)Finished pharmaceutical product(s) Ph.Eur.European Pharmacopoeia Ph.Int.International Pharmacopoeia USPUnited States Pharmacopeia Text in green refers to WHO documents or requirements Text in light blue indicates a quality assessment issue

Dr. Pogány - WHO, Bangkok 3/71 SUBJECTS FOR DISCUSSION 1. Interchangeability of FPPs 2. Artemisinin-based antimalarials 3. Requirements for submission of pharmaceutical data 4. Main gaps observed in the evaluation of dossiers  Regulatory aspects  Correspondence with FPP manufacturers 5. A few conclusions

INTERCHANGEABILITY OF FPPs Pharmaceutical equivalence

Dr. Pogány - WHO, Bangkok 5/71 INTERCHANGEABILITY (IC) INTERCHANGEABILITY OF MULTISOURCE FPPs (IC) = (ESSENTIAL SIMILARITY WITH INNOVATOR) = PHARMACEUTICAL EQUIVALENCE ( PE ) + BIOEQUIVALENCE (BE) IC = PE + BE

Dr. Pogány - WHO, Bangkok 6/71 PHARMACEUTICAL EQUIVALENCE  FPPs MEET SAME OR COMPARABLE STANDARDS  SAME API (chemical and physical equivalence)  SAME DOSAGE FORM AND ROUTE OF ADMINISTRATION  SAME STRENGTH  COMPARABLE LABELING  WHO-GMP (batch-to-batch uniformity of quality)  STABILITY EQUIVALENCE

Dr. Pogány - WHO, Bangkok 7/71 INACTIVE INGREDIENTS ACTIVE INGREDIENTS PACKING MATERIALS FPP MANUFACTURER Manufacturin g authorization Marketing authorization GMP standards Pharmacopeia standards NATIONAL DRA1 NATIONAL DRA2 FACTORS INFLUENCING PE

ARTEMISININ-BASED FPPs EXPRESSION OF INTEREST (March 2003)

Dr. Pogány - WHO, Bangkok 9/71 ARTEMISININ-BASED FPPs  Artemether, oral preparations  Artemether, intramuscular preparations  Artemether + lumefantrine, oral preparations  Artemotil, injectable forms  Artenimol (dihydroartemisinin) tablets, capsules, paediatric granules, suppositories

Dr. Pogány - WHO, Bangkok 10/71 ARTEMISININ-BASED FPPs  Artesunate injection for IV and IM  Artesunate, oral preparations  Artesunate + amodiaquine, oral preparations  Artesunate + mefloquine, oral preparations  Artesunate + sulphadoxine/pyrimethamine (SP), oral preparations

PREQUALIFICATION PROJECT OF WHO Requirements for submission of pharmaceutical data

Dr. Pogány - WHO, Bangkok 12/71 PREQUALIFICATION GUIDES 1. manual-on-marketing/who-dmp-rgs-985.doc 1. /activities/qualityassurance/gmp/gmpcover.html 2. WHO/HTP/EDM/QSM/2001: Standard Operating Procedure: Assessing Product Files 3. International Conference on Harmonization (ICH) guidelines

Dr. Pogány - WHO, Bangkok 13/71 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.

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 SOP 020/00 - Assessing Product Files 8.4 Addendum D – Product Assessment Report – Generic FPPs

Dr. Pogány - WHO, Bangkok 15/71 SCOPE OF THE GUIDELINE  This guideline applies only to APIs manufactured by chemical synthesis or semi- synthetic processes and to FPPs containing such APIs.  APIs manufactured by fermentation and cell culture processes should comply with the general requirements and specific monographs of the Ph.Eur..or the USP. Corresponding FPPs should be assessed by the monographs of the BP or the USP; for non-compendial APIs and FPPs, the ICH-Q6B guide “Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products” should be used.

Dr. Pogány - WHO, Bangkok 16/71 Section 1. CHARACTERISTICS OF THE FPP 1.1 Details of the product Name, dosage form and strength of the product Approved generic name(s) [use International Non- proprietary Name (INN), if any] Visual description of the FPP Visual description of the packaging 1.2 Sample 1.3 Regulatory situation in other countries

Section 2. API quality issues Illustrative examples of requirements

Dr. Pogány - WHO, Bangkok 18/71 APIs UNDER DISCUSSION NON-COMPENDIAL APIs LumefantrineSulfamethoxypyrazine INTERNATIONAL PHARMACOPOEIA ArtemetherArtemisinin ArtemotilArtenimol ArtesunateMefloquine hydrochloride Proguanil HCl INTERNATIONALLY USED PHARMACOPOEIAE Amodiaquine HCl (USP)Pyrimethamine (Ph.Eur., USP) Proguanil HCl (BP)Sulfadoxine (Ph.Eur.)

Dr. Pogány - WHO, Bangkok 19/71 LOW-RISK APIs 1. CERTIFICATE OF SUITABILITY (DRA) 2. DRUG MASTER FILE  OPEN PART (APPLICANT)  CLOSED PART (DRA) 3. PHARMACOPEIA MONOGRAPH  LITERATURE EVIDENCE OF STABILITY  SYNTHESIS IMPURITIES ARE CONTROLLED BY MONOGRAPH (toxicology of additional impurities)  CLASS1 SOLVENTS EXCLUDED, CLASS2 SOLVENTS CONTROLLED 4. FPP IS REGISTERED IN THE ICH REGION

Dr. Pogány - WHO, Bangkok 20/71 HIGH-RISK, ARTEMISININ-BASED APIs  NO INNOVATOR API/FPP IN THE ICH REGION.  NO REFERENCE STANDARD/COMPARATOR IS AVAILABLE FOR:  PHARMACEUTICAL EQUIVALENCE STUDIES  BIOEQUIVALENCE STUDIES  THE APIs and FPPs ARE NOT OFFICIAL IN THE INTERNATIONALLY USED MAJOR PHARMACOPOEIAS  WHO GUIDES/SOPs APPLY TO MULTISOURCE FPPs. ICH GUIDES SHOULD BE USED FOR EVALUATION.

Dr. Pogány - WHO, Bangkok 21/71 Section 2. APIs 2.1Nomenclature International Nonproprietary Name (INN) Compendial name if relevant Chemical name(s) Company or laboratory code, if applicable Other non-proprietary name(s), e.g., national name, United States Adopted Name (USAN), Japanese Accepted Name (JAN); British Approved Name (BAN) Chemical Abstracts Service (CAS) registry number

Dr. Pogány - WHO, Bangkok 22/71 CHEMICAL NAME(s)  ARTESUNATE (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro- 3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]1,2- benzodioxepin-10-ol, hydrogen succinate; therefore eight (8) stereogenic centres exist, or 128 pairs of enantiomers and 256 diastereo- isomers are possible. Only one used in therapy.  CAS Reg. No:

Dr. Pogány - WHO, Bangkok 23/71 Section 2. APIs 2.2 Properties of API(s) API not described in BP, Int.Ph., JP, Ph.Eur., or USP API described in BP, Int.Ph., JP, Ph.Eur., or USP Information from literature.

Dr. Pogány - WHO, Bangkok 24/71 NON-COMPENDIAL APIs No reference standard/spectrum. Documented evidence of structure and stereochemistry - such as clearly visible, quality assurance (QA)-certified copies of infrared, nuclear magnetic resonance (proton and C-13), ultraviolet and mass spectra - should be submitted together with professional interpretation of the relevant parts of spectra, X- ray diffractograms, thermograms, and so on.

Dr. Pogány - WHO, Bangkok 25/71 (NON)-COMPENDIAL API(s) No/insufficient information from pharmacopoeia and manuals. Physicochemical and other relevant properties of the API, such as solubility in water, other solvents and buffers of different pH; partition coefficient; existence/absence of polymorphs and water/solvent of crystallization; results of hygroscopicity testing; particle size and so on.

Dr. Pogány - WHO, Bangkok 26/71 Section 2. APIs 2.3 Site(s) of manufacture 2.4Route(s) of synthesis 2.4.1API not described in BP, Int.Ph., JP, Ph.Eur., or USP API described in BP, Int.Ph., JP, Ph.Eur., or USP Specifications of starting materials and intermediates used in the synthesis

Dr. Pogány - WHO, Bangkok 27/71 COMPENDIAL API(s) The official monograph of an API in a pharmacopoeia does not necessarily control the quality of the API. Impurities, including residual solvents, depend on the synthesis route (steps, conditions, catalysts, by- products, batch size, process control, etc.) and this may differ from manufacturer to manufacturer.

Dr. Pogány - WHO, Bangkok 28/ ROUTE(S) OF SYNTHESIS  European certificate of suitability (CEP) together with annexes.  Flow diagram of the synthetic process(es) that includes batch size, molecular formulae, chemical structures; description of operating conditions, purification steps, catalysts and solvents.  Sequential procedural narrative of the manufacturing process with detailed description of purification and crystallization.

Dr. Pogány - WHO, Bangkok 29/71 ARTESUNATE SYNTHESIS – Step 1

Dr. Pogány - WHO, Bangkok 30/71 ARTESUNATE SYNTHESIS – Step 2 Dihydroartemisinine

Dr. Pogány - WHO, Bangkok 31/71 Section 2. APIs 2.5Specifications 2.5.1API not described in BP, Int.Ph., JP, Ph.Eur., or USP 2.5.2API described in BP, Int.Ph., JP, Ph.Eur., or USP 2.6 Container closure system

Dr. Pogány - WHO, Bangkok 32/71 CHEMICAL EQUIVALENCE  OFFICIAL COMPENDIA  BATCH-TO-BATCH UNIFORMITY  IMPURITY PROFILE  RESIDUAL SOLVENTS  ASSAY  PHYSICOCHEMICAL PROPERTIES  GMP and STABILITY EQUIVALENCE

Dr. Pogány - WHO, Bangkok 33/71 IMPURITIES Concept of impurities has changed with time and the development of analytical methods.  IDENTIFIED IMPURITY  UNIDENTIFIED IMPURITY  SPECIFIED IMPURITY  UNSPECIFIED IMPURITY

Dr. Pogány - WHO, Bangkok 34/71 IMPURITY EQUIVALENCE  NO NEW IMPURITY IS OBSERVED IN THE KEY INTERMEDIATE ABOVE 0.1%  NO NEW IMPURITY IS OBSERVED IN API ABOVE THE QUALIFICATION THRESHOLD  EACH EXISTING IMPURITY IS WITHIN ITS STATED LIMIT  TOTAL IMPURITIES ARE WITHIN THE STATED LIMIT

Dr. Pogány - WHO, Bangkok 35/71 POTENTIAL SYNTHESIS IMPURITIES OF ARTESUNATE STARTING MATERIALS and REACTANTS  Potential impurities of artemisinin (pesticides)  Unreacted artemisinin  Unreacted artenimol (dihydroartemisinin), mixture of α- and β-epimers  Unreacted succinic acid (POTENTIAL) BY-PRODUCTS  Deoxy-artemisin  Dimers of artesunate  β-Artesunate

Dr. Pogány - WHO, Bangkok 36/71 RESIDUAL SOLVENTS  EACH EXISTING RESIDUAL SOLVENT (methanol, methylene chloride and heptane) IS WITHIN ITS STATED LIMIT  NEW RESIDUAL SOLVENTS, IN EITHER AN INTERMEDIATE OR THE API, ARE AT OR BELOW THE LEVELS RECOMMENDED IN THE ICH GUIDE  SKIP TESTING IS PERMITTED IF DOCUMENTED EVIDENCE HAS BEEN PROVIDED ON ABSENCE OF NOT LESS THAN ??? BATCHES

Dr. Pogány - WHO, Bangkok 37/71 ASSAY BY TITRATION During stability studies, the assay was increasing. The hydrolysis may yield artenimol and succinic acid. The latter can justify the increase in assay. +

Dr. Pogány - WHO, Bangkok 38/71 Artesunate – identification, impurities and assay

Dr. Pogány - WHO, Bangkok 39/71 CRITICAL DEFICIENCIES  Synthesis impurities, including residual solvents, which may be present in API, have not been characterised and analysed.  Analytical validation information - including experimental data for the analytical procedures used for testing the API and impurities - have not been provided.  The preparation and quality specification of primary (absolute) and secondary (working) standards has not been described.

Dr. Pogány - WHO, Bangkok 40/71 Section 2. APIs 2.7Stability testing Stress testing (forced degradation) 2.7.2Regulatory stability testing

Dr. Pogány - WHO, Bangkok 41/71 FORCED DEGRADATION STUDIES 1. Intrinsic stability of the molecule ( sensitivity of the API to potential effects of the external environment – selection of containers ) 2. Identification of likely degradants  Stability-indicating power of assay method  Stability studies of the FPP 3. No standard method, 10-30% degradation, stress factors, conditions and time 4. Solid state degradation ( supporting information )

Dr. Pogány - WHO, Bangkok 42/71 REGULATORY STABILITY TESTING 1. It is not necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed at o C under moderate stress conditions. 2. Photostability ( ICH Q1B, non-compendial APIs ) 3. Stability protocol, report with professional evaluation of data is required. 4. A re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label.

Dr. Pogány - WHO, Bangkok 43/71 DATA OF STABILITY BATCHES Batch numbers Date of manufacture Site of manufacture Batch size (kg) Date of initial analysis The batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates.

Dr. Pogány - WHO, Bangkok 44/71 TEST PARAMETERS  CHEMICAL CHARACTERISTICS (ASSAY AND IMPURITIES INCLUDING DEGRADANTS)  PHYSICAL CHARACTERISTICS (PHOTOSTABILITY, APPEARANCE AND WATER)  MICROBIOLOGICAL ATTRIBUTES (STERILE APIS AS A RULE)

Dr. Pogány - WHO, Bangkok 45/71 GENERAL CONDITIONS  REAL TIME 25 ± 2 o C and 60 ± 5 % RH, 12 months  INTERMEDIATE 30 ± 2 o C 65 ± 5% RH, 6-12 months  ACCELERATED 40 o ± 2 o C 75 ± 5% RH, 3-6 months (There may be justified exceptions with grandfathered drugs.)

Dr. Pogány - WHO, Bangkok 46/71 OBJECTIVE: RETEST PERIOD Regulatory stability studies provide documented evidence that an API remains within specification during the re-test period if stored in the original container under prescribed conditions.  An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 ± 2 o C / 65 ± 5 % RH for 2 years and at 40 ± 2 o C / 75 ± 5 % RH for 6 months.

Dr. Pogány - WHO, Bangkok 47/71 STABILITY and LABELING NOTE FOR GUIDANCE ON DECLARATION OF STORAGE CONDITIONS IN THE PRODUCT PARTICULARS. (LABELING OF PRODUCTS SENSITIVE TO TEMPERATURE, LIGHT AND HUMIDITY).

FPP quality issues Illustrative examples of requirements

Dr. Pogány - WHO, Bangkok 49/71 Part 3. FPP(s) 3.1Manufacturing and marketing authorization 3.2 Pharmaceutical development 3.2.1Company research and development Information from literature 3.3Formulation 3.4Sites of manufacture

Dr. Pogány - WHO, Bangkok 50/71 MARKETING AUTHORIZATION  If the FPP has been locally developed and manufactured, the national drug regulatory authority (NDRA) must evaluate the data set itself (p. 23).  If an evaluation report —critical summary and interpretation of the data, with conclusions— is not available, it is not possible to seek a WHO- type certificate (p. 23).

Dr. Pogány - WHO, Bangkok 51/71 Part 3. FPP(s) 3.5Manufacturing process 3.6Manufacturing Process Controls of Critical Steps and Intermediates 3.7Process Validation and Evaluation 3.7.1New generic FPPs 3.7.2Established generic FPPs

Dr. Pogány - WHO, Bangkok 52/71 CONCURRENT VALIDATION NEW GENERIC FPPs  Full validation studies should be completed for each FPP at the production scale.  Short description of the process with a summary of the critical processing steps or critical parameters to be monitored during validation.  FPP specification (release) including IPC acceptance criteria should be derived from validation batches

Dr. Pogány - WHO, Bangkok 53/71 RETROSPECTIVE VALIDATION ESTABLISHED GENERIC FPPs Annual quality review data and analysis were not submitted to prove that the manufacturing processes —including equipment, buildings, personnel and materials— are capable of achieving the intended results on a consistent and continuous basis.

Dr. Pogány - WHO, Bangkok 54/71 Part 3. FPP(s) 3.8Specifications for excipients 3.8.1Excipients not described in Int.Ph., JP, BP, Ph.Eur., or USP 3.8.2Excipients described in Int.Ph., JP, BP, Ph.Eur., or USP 3.9Control of the FPP Specifications for the FPP Analytical procedures Validation of analytical procedures Batch analyses 3.10Container/closure system(s) and other packaging

Dr. Pogány - WHO, Bangkok 55/71 SPECIFICATIONS FOR THE FPP  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 against disintegration time.  All analytical methods should be validated or verified (compendial methods).  Microbiological purity (skip testing)

Dr. Pogány - WHO, Bangkok 56/71 Part 3. FPP(s) 3.11Stability testing Stability-indicating quality parameters Photostability Testing Selection of Batches Container Closure System Testing Frequency Storage Conditions General case Finished products packaged in impermeable containers Finished products packaged in semi-permeable containers Evaluation Extrapolation of data Core Storage Statements

Dr. Pogány - WHO, Bangkok 57/71 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.  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.

Dr. Pogány - WHO, Bangkok 58/71 DATA OF STABILITY BATCHES Batch number Date of manufacture Site of manufacture Batch size (kg) Batch size (number of units) Date of initial analysis Batch number of the (API)

Dr. Pogány - WHO, Bangkok 59/71 STABILITY OF FPPs  A systematic approach should be adopted in the presentation and evaluation of the stability information.  Organize data for all attributes separately and evaluate each attribute in the report.  Shelf life acceptance criteria should be derived from consideration of all available stability information.  Unless otherwise justified, 30°C ± 2°C / 65% ± 5% RH is the preferred real-time condition for the prequalification project.

Dr. Pogány - WHO, Bangkok 60/71 EVALUATION OF STABILITY DATA – BEST CASE 1. Tabulate and plot stability data on all attributes at all storage conditions and evaluate each attribute separately. 2. No significant change at accelerated conditions within six (6) months. 3. Long-term data show little or no variability and little or no change over time.

Dr. Pogány - WHO, Bangkok 61/71 EVALUATION OF STABILITY DATA – BEST CASE 4. Long-term data show little or no variability and little or no change over time. 5. Statistical analysis is normally unnecessary. 6. Proposed retest period = period covered by long-tem data + 12 months

Dr. Pogány - WHO, Bangkok 62/71 Part 3. FPP(s) 3.12Container labelling Outer packaging or, where there is no outer packaging, on the immediate packaging Blisters and strips 3.13Product information for health professionals 3.14Patient information and package leaflet 3.15Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s).

Dr. Pogány - WHO, Bangkok 63/71 WHOPAR  Propose a copy of the Summary of Product Characteristics (SmPC) aimed at medical practitioners and other health professionals and preferably 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.

Main gaps observed in the evaluation of dossiers Regulatory aspects and correspondence with manufacturers

Dr. Pogány - WHO, Bangkok 65/71 GLOBAL REGULATORY ISSUES API or FPP originate „LEGALLY” from countries where:  Manufacture of APIs is not regulated  Pharmaceutical exports and imports are not regulated

Dr. Pogány - WHO, Bangkok 66/71 GLOBAL REGULATORY ISSUES  National requirements for MA do not meet WHO requirements. E.g., stability and biostudies are/were not required  MA of FPPs is issued without evaluation by the national drug regulatory authority (NDRA)  Certificate of Pharmaceutical Product (CPP) is issued by the NDRA without assessment of the FPP quality.

Dr. Pogány - WHO, Bangkok 67/71 CORRESPONDENCE WITH MANUFACTURERS  Impurities: “Further efforts are made to improve the process.”  Individual impurity limits were not based on batch analysis results and they were not in line with the ICH guidelines (e.g., NMT 1.0% instead of NMT 0.1%).  Residual solvents were included in the monograph but not in the DMF.  Class2 solvents: pyridine and chloroform are used in the synthesis and not tested in the API.

Dr. Pogány - WHO, Bangkok 68/71 CORRESPONDENCE WITH MANUFACTURERS  The melting point is o C (p.4) as opposed to o C ± 1.5 o C in the DMF.  No adequate information was provided on the preparation and quality specification of primary (absolute) and secondary (working) standards. (For instance, lack of complete CoA, assay by two different validated methods, detailed information on storage, etc.).

Dr. Pogány - WHO, Bangkok 69/71 CORRESPONDENCE WITH MANUFACTURERS  FPP - HPLC method is described as an alternative assay to titration but acceptance limits are % as opposed to % in the DMF.  FPP - Analysis of the tests for microbiological purity on „two (2) batches showed contamination with an invading yeast.”  Stress stability (forced degradation) tests on the API were not submitted.  Substantial degradation was observed at high temperature and under intensive light.

Dr. Pogány - WHO, Bangkok 70/71 CORRESPONDENCE WITH MANUFACTURERS  “Room temperature and accelerated tests are in progress.” Results were not submitted.  The stress data on FPP show that the blister pack does not protect the tablets even if overwrapped by additional protective packing. Supplier reduced expiry date.  The currently available stability data reveal possible decomposition and justify only a one (1) year re-test date.

Dr. Pogány - WHO, Bangkok 71/71 A FEW CONCLUSIONS 1. Artemisinin-derived FPPs had been on the market for decades but most of them did not meet basic standards of quality at the beginning of the project. 2. It takes time to get into compliance  Develop new formulations  Data to be generated, tests carried out  GMP upgrade needed 3. One FPP is prequalified from a DC; another one is registered in the ICH region. 4. Evaluation of dossiers is still free of charge.