Stability Studies : Regulatory evaluation and most frequently observed Sultan Ghani

 Incomplete stability to meet the requirements as stimulated in the regulations & guidelines  Identification and testing of degradation products not performed.  Stability testing protocol is inappropriate and not followed.  Inappropriate selection of test parameters for stability study samples (0, 6, 12, 18,..)  Sampling procedures and frequency of testing incomplete

 Hold time testing at various stages of manufacturing not properly performed and validated ◦ Hold time for bulk granulation ◦ Hold time for bulk solutions  Reconstitution and dilution studies are insufficient ◦ Do not cover the proposed claims. ◦ Do not include in-use studies (Parenteral, Ophthalmic, etc.)

 Incomplete information on reference standards ◦ Primary reference standard (compendial) ◦ Secondary reference standard  Incomplete methods of analysis and method validation ◦ House Methods (Full validation studies) ◦ Compendial methods (suitability of compendial methods, etc.)  Insufficient demonstration of method equivalency ◦ Compendial vs. House methods

 Analytical method transfer studies not performed ◦ Same business establishments ◦ Different business establishments ◦ API supplier vs. Dosage form manufacturer methods  Variation in analytical results  Lack of investigation of the Out of Specification (OOS) results.

 Lack of investigation of known/unknown degradation products ◦ Toxic degradation products (Doxorubicin cardio- toxicity may be caused by its metabolite doxorubicinol) ◦ Metabolites (metabolite of imipenem, Thienamycin M1 causes cleavage of the molecule)

 Incomplete results of antimicrobial testing ◦ Microbial testing as per compendial monograph  Changes in analytical methods from development to commercial production ◦ Most regulatory authorities prefer complete dissolution profile rather than single time point testing of stability samples.  Assay results are not reported as absolute values ◦ Should be reported as % of initial

 Formulation  Formulation differences ◦ Pilot vs. commercial (stability study batches)  Batch numbers and the quality part of the report are not the same as the batch number in the bioequivalence report

 Specifications  Lack of justification of stability specifications ◦ Tests and Acceptance criteria, etc.  Lack of stability the tests, acceptance criteria  S tudies not conducted on comparable samples (age of the samples) to get a meaningful comparison of the degradation profiles

 Container Closure System:  Interaction between the material and the actual product are not properly studied  No control of moisture level in the container if product is moisture sensitive  Change of the container closure is not justified  Information on reproducibility and accuracy of dosing device is missing  Compatibility on aged samples are not performed