Pharmaceutical Development - Additional Considerations

Pharmaceutical Development - Additional Considerations:

2.2 Additional Considerations

2.2.1 Selection and Characterization Of Comparator Finished Pharmaceutical Product(s):

In many countries the NMRA provides a list of comparator products. Alternatively, references are available from WHO (Prequalification of Medicines Programme), and in international lists of comparator products. Note that for a dossier to be submitted to the Prequalification of Medicines Programme the comparator must be selected from the published lists. Guidance regarding Prequalification of Medicines Programme comparator products is available under Guidance on bioequivalence studies on the Prequalification of Medicines Programme web site (    

In the case of fixed-dose combination (FDC) FPPs, there will be instances when a combination of APIs is recommended for clinical use but an innovator FDC FPP containing these APIs, whose approval was based on clinical trial data, will not be available as a comparator product. FDCs approved based on data such as bioequivalence data are not typically used as comparators, as the original safety and efficacy data are linked to the monocomponent products and not the FDC FPP. For FDC FPPs, the development strategy should take into account the formulas of the individual component comparator FPPs. If the innovator FDC exists this should be the target product for the FDC multisource product development – even if the individual comparator tablets could also be used in the bioequivalence study (see also WHO Guidelines for registration of fixed-dose combination medicinal products (6)).

The comparator product batch may be selected by dissolution profile testing (see WHO’s Multi source (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (7). Ideally a batch which shows intermediate dissolution under the most discriminative condition (where the difference in dissolution between the fastest and slowest batches studied is the largest) should be selected as the reference product for pharmaceutical equivalence studies and bioequivalence studies. 

2.2.2 Benchmarking For Formulation Experiments and Stability Studies:

The comparator sample should be thoroughly examined for parameters such as physical properties, shelf-life, including in-use stability information, storage instructions and details of the container-closure system in comparison to the outcome of the desk research and the requirements for marketing the new multi source product in the intended market.

All the relevant quality attributes of the dosage form should be analysed, e.g. assay, related substances, dissolution rate, pH, preservative concentrations, water content, total mass, mass variation, resistance to crushing, friability and disintegration of tablets.

The information obtained forms the basis for the development of the new multi source FPP. 

Pharmaceutical Development of multi source (generic) Finished Pharmaceutical Products - points to consider,  (Annex 3, WHO Technical Report Series 970, 2012)

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