Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities

Abstract

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities

“…Furthermore, the ICH M13A draft guideline also describes studies involving multiple comparator products, studies with multiple test products, endogenous compounds, and other IR dosage forms (e.g., orally disintegrating tablets, chewable tablets, suspensions, fixed dose combination products) that are not addressed in the current review publication. However, the current review publication, along with previous publications [ 3 , 29 ] from the IRPP BEWGG describe several topics that will be addressed under future ICH projects (e.g., ICH M13B and M13C guidelines). It is evident that the continued efforts of the IPRP BEWGG will have a notable impact with respect to promoting collaboration and achieving regulatory convergence and harmonization in the field of BE study performance.…”

“…By comparing and contrasting the requirements of the different regulatory agencies and sharing the regulatory information with the ICH EWG for M13A [ 54 ], it is evident that the persistent efforts of the IPRP BEWGG are instrumental in identifying and supporting topics for ICH harmonization. As the ICH EWG focus shifts towards the drafting of the ICH M13B guideline (BE for Immediate Release Solid Oral Dosage Forms: Additional Strengths), the prior work of the IPRP BEWGG regarding additional strength biowaivers [ 3 , 29 ] should benefit the ICH EWG.…”

“…The purpose of this work is to summarise the regulatory requirements for the design and analysis of BE studies of oral immediate-release (IR) products. The information and discussions generated from this survey have proven to be useful regarding the development of the ICH M13A guideline [ 3 ] and may continue to be useful to industry and regulatory agencies in understanding the scientific rationale and regulatory considerations pertaining to the standardization of BE study design and acceptance criteria for IR solid oral dosage forms.…”

Alternative Pharmacokinetic Metrics in Single-Dose Studies to Ensure Bioequivalence of Prolonged-Release Products at Steady State—A Case Study

“…For prolonged-release generic products, there is almost a worldwide consensus on the need for single-dose fasted and fed bioequivalence (BE) studies [ 1 ]. However, the need of BE studies at steady state for the approval of generic prolonged-release products that exhibit accumulation after repeated dosing is a controversial issue.…”