Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

First revision of the "Guideline on the Investigation of bioequivalence": BCS-based Biowaiver - opportunities and limitations

Dr. Alexander Vuia (Abschlußjahr: 2011)

Proving of in vivo bioequivalence between a test and reference product is of great importance in the context of different steps of product development and several types of applications. Applying for a BCS-based Biowaiver by providing a justification regarding evidence of bioequivalence based on appropriate in vitro data may be attractive for the applicant due to cost reduction and timesaving. The revision of the "Guideline on the Investigation of Bioequivalence" coming into force on 1 August 2010 has replaced the former Note for Guidance. The aim of this master thesis is to present the revised and expanded requirements and reflecting the resulting new opportunities and limitations for application of a BCS-based Biowaiver.
 
The revised version of the BE-Guideline provides clear and detailed Guidance in Appendix III regarding the basic requirements for applying a BCS-based Biowaiver in the EU. Application to Appendix III is restricted to highly soluble substances with known human absorption and having no narrow therapeutic index. The BCS-based Biowaiver approach applies for immediate release, solid pharmaceutical products for oral use and systemic action having the same pharmaceutical form. Consequently, as defined for bioequivalence studies, the comparability of the formulation of test and reference product is required in principle. Beside the applicability to BCS class I substances, a BCS-based Biowaiver are generally eligible for highly soluble substances with limited absorption (BCS class III) based on defined additional restrictive requirements. This provides the opportunity to apply a biowaiver for a considerable range of substances which were generally excluded in the past. Basic requirements and detailed experimental conditions for appropriate classification of a drug substance in the BCS have been provided. Hence, the basis for a clear interpretation of the requirements for applying a BCS-based Biowaiver within several procedures has been established avoiding future divergent interpretation as occurred in the past based on the former NfG. Elimination of former uncertainties will facilitate the estimation whether a BCS-based Biowaiver can successfully applied and in addition provide the opportunity to reduce in vivo bioequivalence testing.
 
On the other hand it should be recognized that applying for a BCS-based Biowaiver based on the requirements of the Appendix III of the Guideline can only be applied as in vitro surrogate for in vivo bioequivalence studies. It is only applicable to address the question of bioequivalence. Thus, a BCS-based Biowaiver is not applicable to relative bioavailability studies. The concept of the BCS-based Biowaiver is designed only to detect the potential influence of the formulation of the product on bioavailability. Conclusions or discussions with respect of an in vivo relevance of differences in the dissolution profile of test and reference product are therefore inappropriate and not accepted.
 
In case of an intended biowaiver application, involvement of the regulatory affairs department in the early project steps is recommended to ensure the opportunity to address the revised and current requirements in due time. Regarding a planned application outside the EU, reference to Guidance of the respective region is recommended, since BCS-based Biowaiver requirements are still not harmonised on a global level.

A further extension to the BCS-based Biowaiver approach to pH-dependant soluble, highly permeable, weak acidic, ionisable drug compounds based on further experience and scientific discussions leading in adapted requirements regarding the drug substance classification into the BCS would be appreciated in the future. It may be feasible, if sufficient experimental data will be available justifying the proof of bioequivalence by applying a BCS-based Biowaiver in this case.

Pages: 40