Formulation Selection Experiments and Bioequivalence

Formulation Selection Experiments and Bioequivalence and Dissolution Studies:

2.2.3 Formulation Selection Experiments:

Based on the outcome of the desk research and the national requirements for marketing authorization, formulation experiments will be conducted to develop the Quality Target Product Profile (QTPP) of the FPP.

Experiments may include determining the qualitative and quantitative composition of the comparator product. The qualitative information on the comparator product may be available in the public domain, e.g. in its summary of product characteristics (SmPC) or package leaflet. Screening different formulations to match the comparator dissolution profile is the best method to select the final formula for scale-up from laboratory to pilot batch.

Selected formulations may be stress-tested to challenge CQAs and to establish tentative acceptance limits for their control.

Any special design features of the pharmaceutical product (e.g. tablet score-line, overfill, or anti-counterfeiting measure) should be identified as such features affect the pharmaceutical product and a rationale for their use should be provided in the Product Dossier (PD).

2.2.4 Bioequivalence and Dissolution Studies:

Bioequivalence and comparative dissolution studies should be conducted with samples from a batch of the FPP of at least pilot size. The dissolution conditions and acceptance criteria should be derived from the dissolution profiles obtained for the biobatch.

Where an in vivo bioequivalence study could be waived, similarity of the formulations may be required, in particular with respect to excipients that may have an influence on the extent and rate of absorption, e.g. sorbitol in liquid formulations or mannitol in solid dosage forms. For instance, when considering a biowaiver for an immediate-release solid oral dosage form containing a BCS class 3 API, the risk of reaching an inappropriate biowaiver decision needs to be critically evaluated, especially when the extent of absorption (f_abs) is less than 50%. As part of the risk assessment the excipients used will also need to be scrutinized carefully in terms of both qualitative and quantitative composition – the greater the deviation from the comparator composition, the greater the risk of an inappropriate biowaiver decision.

Inclusion of summaries of all bioequivalence studies (passed and failed) on the final formulation in the PD may be required.

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

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