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.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Molecular Anatomy of the Class I Ligase Ribozyme for Elucidation of the Activity-Generating Unit.

The class I ligase ribozyme consists of 121 nucleotides and shows a high catalytic rate comparable to that found in natural proteinaceous polymerases. In this study, we aimed to identify the smaller active unit of the class I ligase ribozyme comprising ~50 nucleotides, comparable to the estimated length of prebiotically synthesized RNA. Based on the three-dimensional structure of the class I ligase ribozyme, mutants were prepared and their ligation activities were analyzed. Sufficient ligation activity was maintained even when shortening to 94 nucleotides. However, because it would be difficult to approach the target of ~50 nucleotides by removing only the partial structure, the class I ligase ribozyme was then split into two molecules. The ligation activity was maintained even when splitting into two molecules of 55 and 39 nucleotides. Using a system with similar split ribozymes, we analyzed the ligation activity of mutants C30, C47, and A71, which have been previously identified as the positions that contribute to catalytic activity, and discussed the structural basis of the activity of these bases. Our findings suggest the rationale for the class I ligase ribozyme's assembling from multiple fragments that would be achievable with prebiotic synthesis.

First Approval of Generic Mometasone Furoate Nasal Suspension Spray in Japan: Similarities and Differences Between Japan and the USA.

The Ministry of Health, Labour and Welfare (MHLW) in Japan approved the first generic version of Nasonex in February 2018. The Pharmaceuticals and Medical Devices Agency requires in vitro, pharmacokinetic, and pharmacodynamic or clinical endpoint data to approve generic nasal spray drug products. However, the MHLW has not published basic principle for approving nasal generic drug products. Therefore, this article summarizes the data used for the approval of the first generic Nasonex based on publicly available data. Additionally, we compare the bioequivalence evaluations regarding the human studies based on the generic version of Nasonex between Japan and the USA.

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

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.

Generic Drug Product Development in Japan: Regulatory Updates During 2014-2019 and the Future.

The growth of healthcare cost is a serious issue in many countries. Generic drug products play an essential role in reducing healthcare costs because they are less costly than the innovator drug products. The regulatory review of generic drug products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). This report introduces the activities of the PMDA from fiscal years 2014-2019. The number of approvals of new generic drug products and partial changes was trending downward. Alternatively, the PMDA conducted six types of consultation meetings to advise on development and application; the number of consultation meetings was increasing. Moreover, during this period, the Ministry of Health, Labour and Welfare issued two basic principles for ophthalmic dosage forms and dry powder inhaler drug products and revised the guidelines for bioequivalence. Finally, the future of generic drug product development and considerations to improve their regulation were discussed. More efforts will continue to enable a more efficient and rational generic drug product development and shortening of the review period for partial change approval.