Slide 1 of 16 Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines...

of 16 Dar Es Salaam Sept. 2007

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





Quality Evaluation Issues


General remarks (1) 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


AdministrativeAdministrative

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


Section 1. Characteristics of FPPSection 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


Section 2. API deficienciesSection 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


Section 2. API deficiencies (2)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



The limits for assay in the API specifications not given to one decimal place, e.g.– Must be 98.0-101.0% (instead of 98-101%)– 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



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!


Section 3. FPP deficienciesSection 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

(f2 similarity calculations)


Section 3. FPP deficiencies (2)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



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



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



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 studies3. Zone IV strongly recommended for procurement purposes

(currently: 30ºC / 65% RH).- A large portion of medicines distributed to Zone IV areas



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


THANK YOUTHANK YOU

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