Multiple Choices by mikesanye

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									Evaluation of Quality and Interchangeability of
              Medicinal Products

  Training Workshop for Evaluators
 from National Medicines Regulatory
      Authorities in East African
            Community

                  Dar Es Salaam, Tanzania
            Date: 10 to 14 September 2007

          Slide 1 of 16   Dar Es Salaam Sept. 2007
Evaluation of Quality and Interchangeability of
              Medicinal Products




               Quality Evaluation Issues




         Slide 2 of 16   Dar Es Salaam Sept. 2007
                         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


                Slide 3 of 16   Dar Es Salaam Sept. 2007
                          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




          Slide 4 of 16      Dar Es Salaam Sept. 2007
        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




               Slide 5 of 16   Dar Es Salaam Sept. 2007
             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



               Slide 6 of 16   Dar Es Salaam Sept. 2007
             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




                 Slide 7 of 16     Dar Es Salaam Sept. 2007
           Section 2. API deficiencies (3)
 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


               Slide 8 of 16   Dar Es Salaam Sept. 2007
          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!




              Slide 9 of 16   Dar Es Salaam Sept. 2007
                 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
      (f2 similarity calculations)




               Slide 10 of 16   Dar Es Salaam Sept. 2007
          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
              Slide 11 of 16   Dar Es Salaam Sept. 2007
          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


              Slide 12 of 16   Dar Es Salaam Sept. 2007
           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



               Slide 13 of 16   Dar Es Salaam Sept. 2007
          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




              Slide 14 of 16   Dar Es Salaam Sept. 2007
         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




             Slide 15 of 16   Dar Es Salaam Sept. 2007
                 THANK YOU




Slide 16 of 16     Dar Es Salaam Sept. 2007

								
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