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

Abstract

In relation to the registration of generic products, waivers of in vivo bioequivalence studies (biowaivers) are considered in three main cases: certain dosage forms for which bioequivalence is self-evident (e.g. intravenous solutions), biowaivers based on the Biopharmaceutics Classification System and biowaivers for additional strengths with respect to the strength for which in vivo bioequivalence has been shown. The objective of this article is to describe the differences and commonalities in biowaivers for additional strengths of immediate release solid oral dosage forms between the participating members of the International Pharmaceutical Regulators Program (IPRP). The requirements are based on five main aspects; the pharmacokinetics of the drug substance, the manufacturing process, the qualitative and quantitative composition of the different strengths, and the comparative dissolution profiles. For the pharmacokinetic aspects, many regulators/agencies have the same requirements. All strengths must be manufactured with the same process, although a few regulators/agencies accept small differences. In relation to the formulation aspects, the data required breaks down into three major approaches based initially on one of those of the EU, the USA or Japan, but there are some differences in these three major approaches with some country specific interpretations. Most regulators/agencies also have the same requirements for the dissolution data, though there are some notable exceptions.

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

“…Identifying the most sensitive strength(s) to be used in vivo is basically dependent on the pharmacokinetics of the drug in the modified release dosage form. The waiver thus depends on the degree of similarity of the manufacturing process, the qualitative and quantitative composition of the different strengths of the test drug product and the in vitro dissolution behaviour of the different strengths of the test drug product (4). Additional factors that may affect bioavailability and the requirements for obtaining a waiver specific to modified release dosage forms include the release mechanism, product shape and whether it constitutes a multiple unit or single unit dosage form.…”

“…3 Optional. 4 Multiple dose studies may be considered for extended-release dosage forms with a tendency to accumulate. 5 These are "recommendations", but applicants can use alternative approaches if the alternative approach complies with applicable statutes and regulations.…”

“…3 Multimedia testing (pH 1.2, 6.0 and 6.8) are required (see text above for details). 4 Duration may exceed the specified time of 45 minutes. QC Method 2 100 rpm in the paddle apparatus pH 6.8 to 7.5 1 -200 rpm in the paddle apparatus pH 6.8 to 7.5 1 -100 rpm in the basket method 3 pH 6.8 to 7.5 1 pH 6.8 200 rpm in the basket method 3 pH 6.8 to 7.5 1 -30 strokes/min in the basket-rack assembly 3 pH 6.8 to 7.5 1 with and without disk -…”

“…The IPRP BEWGG has previously described the BCS-based biowaiver criteria used by the IPRP BEWGG's participating regulators and organisations in 2018 (3). Their requirements for additional strength biowaivers specific to immediate release solid oral dosage forms with systemic action were presented in a further publication in 2019 (4). Recently, the biowaiver requirements for oral and injectable dosage forms were published (5).…”

A Survey of the Regulatory Requirements for the Waiver of In Vivo Bioequivalence Studies of Generic Products in Certain Dosage Forms by Participating Regulators and Organisations of the International Pharmaceutical Regulators Programme

“…The requirements to waive in vivo bioequivalence studies for immediate release (IR) solid oral dosage forms based on the Biopharmaceutics Classification System (i.e., BCS biowaivers) in IPRP jurisdictions have been previously described (2) and are now harmonised by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (3). In addition, waivers of in vivo bioequivalence studies may be applied to additional strengths of IR solid oral dosage forms with respect to the strength for which in vivo bioequivalence has been shown (4). Furthermore, waivers of in vivo bioequivalence studies may also apply to certain dosage forms irrespective of the BCS waiver criteria.…”