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Slide 1 of 16 Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es.

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Presentation on theme: "Slide 1 of 16 Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es."— Presentation transcript:

1 Slide 1 of 16 Dar Es Salaam Sept Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es Salaam, Tanzania Date: 10 to 14 September 2007 Evaluation of Quality and Interchangeability of Medicinal Products

2 Slide 2 of 16 Dar Es Salaam Sept Evaluation of Quality and Interchangeability of Medicinal Products Quality Evaluation Issues

3 Slide 3 of 16 Dar Es Salaam Sept General remarks (1) Concerns  Supportive literature information absent in most dossiers (other than compendial data) –Literature information not professionally analysed & discussed in terms of the situation –Photocopies and/or full reference particulars of literature used in dossier are not presented  Responses to assessment reports not comprehensive –Resulting in multiple assessment/responses

4 Slide 4 of 16 Dar Es Salaam Sept Administrative Poor organisation of the dossiers hampers the assessment. Examples: –Files are sometimes poorly bound (or not securely packed in the courier parcels) –Absence of table of contents –Absence of page numbers throughout dossier –It is recommended that sections be clearly indicted with securely fixed tags to assist cross-checking by assessors

5 Slide 5 of 16 Dar Es Salaam Sept Section 1. Characteristics of FPP  Samples of FPPs are not always submitted This is quite frustrating, since the samples are needed for instance: –To verify the description of the product –To inspect the packaging materials –To check correctness of the label –To check the data in the SmPC & PIL –For laboratory testing

6 Slide 6 of 16 Dar Es Salaam Sept Section 2. API deficiencies  Full description of the reactions/steps used in the API synthesis not presented, including the purification step. Specifications of chemicals, catalysts & solvents used also absent. –Possible impurities cannot be established –Benzene (class 1 solvent, ≤ 2 ppm) in toluene  1,2-dichloroethane used in the synthesis of ethambutol 2HCl not specified in API specs. –This is a class 1 solvent, ≤ 5 ppm (ICH) –Class 1 solvents acceptable only when unavoidable

7 Slide 7 of 16 Dar Es Salaam Sept Section 2. API deficiencies (2)  The open part of the DMF of the API is often incomplete and lacks information such as –Solubility properties (solubility in water, buffers at different pH values & organic solvents and partition coefficient) –Solid state properties (existence/absence of polymorphism, hygroscopicity, particle size, flowability, etc.)  API specifications lack attributes additional to compendial monograph, e.g. –Residual solvents (OVIs), particle size –USP OVIs (organic volatile impurities) not always covering specific synthesis OVIs

8 Slide 8 of 16 Dar Es Salaam Sept Section 2. API deficiencies (3)  The limits for assay in the API specifications not given to one decimal place, e.g. –Must be % (instead of %) –The same applies for the FPP specifications  Potency determination & CoAs not presented for secondary/working standards –Applies to both API and FPP manufacturer –Official standards available  Copies of API CoAs and stability data sheets not QA certified, signed or dated

9 Slide 9 of 16 Dar Es Salaam Sept Section 2. API deficiencies (4)  Degradation information not presented - through forced degradation studies and/or - from relevant literature / CEP –To identify possible degradants for stability studies –To verify specificity of stability assay method - Diode array detection for API peak purity not demonstrated in stability indicating assay validation!

10 Slide 10 of 16 Dar Es Salaam Sept Section 3. FPP deficiencies  Pharmaceutical development reports are seldom included (done?) – a major problem –When provided often incomplete –Result: changes requested during assessment, for instance due to stability problems  Pivotal batches (BE, validation, stability) –Lack of table for comparison of formulas & discussion –Lack of comparative dissolution testing (f 2 similarity calculations)

11 Slide 11 of 16 Dar Es Salaam Sept Section 3. FPP deficiencies (2)  The purpose of excipients not indicated in the unit and batch formula table  Overages not justified –Especially in case of rifampicin containing FPPs  Commercial colorant mixtures (e.g. Opadry) –Composition not indicated –Test methods not included  Microbial limit and colorants (skip-testing) not included in FPP specifications

12 Slide 12 of 16 Dar Es Salaam Sept Section 3. FPP deficiencies (3)  Documentation not in English, e.g. in –Manufacturing process documentation –Validation reports  Statements on adventitious agents not presented, e.g. –TSE/BSE (e.g. Mg-stearate from animal origin) –Asbestos in talc  Lack of validation data/reports on pilot and first 3 commercial batches

13 Slide 13 of 16 Dar Es Salaam Sept Section 3. FPP deficiencies (5)  Stability specifications lack parameters that may be variables, e.g. –Tablet strength, friability & water content –These variables are interrelated, also with dissolution, and may show meaningful trends –Testing of these variables is inexpensive  Stability data presented in tables lack e.g. –Discussion of each parameter –Statistical analysis where required –Full details of batches tested

14 Slide 14 of 16 Dar Es Salaam Sept Section 3. FPP deficiencies (6)  Real-time stability studies carried out under Zone II conditions (25ºC / 60% RH) 1.Yet storage requirements indicated on labels, in SmPC & PIL often 30ºC !! 2.Storage requirements must be supported by stability studies 3.Zone IV strongly recommended for procurement purposes (currently: 30ºC / 65% RH). - A large portion of medicines distributed to Zone IV areas

15 Slide 15 of 16 Dar Es Salaam Sept Section 3. FPP deficiencies (7)  Summary of product characteristics (SmPC): –Not included –Essential for FPP –Essential for WHOPAR  (1) Identification of dosage form and (2) presentation (packaging description) not given in detail in SmPC and PIL –Important in fighting counterfeit

16 Slide 16 of 16 Dar Es Salaam Sept THANK YOU


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