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The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has enjoyed wide use since 1995 as a mechanism for waiving in vivo bioavailability and bioequivalence studies. In 2000, the US-FDA was the first regulatory agency to publish guidance for industry describing how to meet criteria for requesting a waiver of in vivo bioavailability and bioequivalence studies for highly soluble, highly permeable (BCS Class I) drugs. Subsequently, the World Health Organization (WHO) and European Medicines Agency (EMA) published guidelines recommending how to obtain BCS biowaivers for BCS Class III drugs (high solubility, low permeability), in addition to Class I drugs. In 2015, the US-FDA became better harmonized with the EMA and WHO following publication of two guidances for industry outlining criteria for obtaining BCS biowaivers for both Class I and Class III drugs. A detailed review and comparison of the BCS Class I and Class III criteria currently recommended by the US-FDA, EMA, and WHO revealed good convergence of the three agencies with respect to BCS biowaiver criteria. The comparison also suggested that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators. It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach.
Ideally, access and affordability to medicines for all patients can be facilitated by global pharmaceutical development programs (1). As a result, simultaneous filings to multiple regulatory agencies are common within both the innovator and generic pharmaceutical industries (2). Although, in theory, simultaneous dossier submissions can greatly streamline the drug approval process, in practice, worldwide drug marketing approvals may be delayed due to region-specific regulatory requirements or dissimilar regulatory review outcomes from agencies of different jurisdictions. As per established published regulations, regulatory agencies are tasked with ensuring the quality, safety, and efficacy of all medications that they approve for marketing within their respective countries. Thus, designing a regulatory strategy that would meet the diverse needs of regulators worldwide is a major challenge for drug developers who seek global markets.
One approach for which regulators have made great strides toward international harmonization is the application of the Biopharmaceutics Classification System (BCS). The BCS is an important tool for waiving the regulatory requirement for in vivo bioavailability (BA) and/or bioequivalence (BE) studies in both new and generic drug development. This review will explain the BCS-based biowaiver process and its role in drug development, describe how the BCS biowaiver approach evolved from its inception to its present state, and summarize the current state of the BCS biowaiver implementation in several jurisdictions throughout the world.
Regulatory agencies have long recognized that, for some drug products, in vivo BA/BE may be self-evident and, as such, can waive the requirement for in vivo evidence (3) in certain circumstances (to grant a biowaiver). The use of biowaivers is in the spirit of avoiding unnecessary human testing whenever possible and facilitates access to drugs in jurisdictions such as the USA, EU, Canada, Australia, and also emerging countries. Application of the BCS in waiving BA/BE requirements is based on premises that if (1) two immediate-release (IR) drug formulations/products behave as oral solutions within the GI tract due to high solubility and rapid dissolution, (ii) no precipitation occurs in the GI tract once the API is dissolved, and (iii) the two IR formulations have the same in vivo dissolution profile under all intestinal luminal conditions, then they should have the same rate and extent of absorption, and therefore be bioequivalent (4). Another premise underlying the development of the BCS is the recognition that the two key factors governing drug absorption are aqueous solubility and intestinal permeability (5). Thus, the BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability (6). As such, the BCS designates all drugs as belonging to one of four classes: Class I (high solubility, high permeability), Class II (low solubility, high permeability), Class III (high solubility, low permeability), and Class IV (low solubility, low permeability) (5).
Ability to waive in vivo BE requirements using the BCS biowaiver approach can be pivotal to a successful regulatory submission, because demonstrating that two drug formulations/products are bioequivalent is an essential drug approval requirement for both innovator and generic drug products (7). Two drug formulations/products are deemed bioequivalent when they do not differ significantly in the rate and extent to which the active ingredient or active moiety becomes available at the site of action when the two formulations/products are given at the same molar dose under similar experimental conditions in an appropriately designed study (8–10). In generic drug development, demonstration of BE between the generic and its corresponding reference product is required for approval. In new drug development, BE is used to link the commercialized, to-be-marketed formulation and the clinical-scale formulation that underwent Phase III safety and efficacy testing. BE evidence is also required when commercialized drug products (whether new or generic) undergo certain types of scale-up or post-approval changes. Thus, in any of these regulatory situations where BE studies are deemed necessary for an IR solid oral dosage form, the potential exists for a BCS-based biowaiver, provided that the appropriate BCS designation criteria are met.
The first regulatory guidances encouraging the use of the BCS for biowaivers of Class I immediate-release (IR) solid oral dosage forms were issued by the US Food and Drug Administration (US-FDA) in 2000 (6, 11) and by the European Medicines Agency (EMA) in 2001 (12). Later, the World Health Organization (WHO) and EMA published guidelines allowing the granting of BCS biowaivers for both Class I and Class III drugs (9, 10). Initially, the WHO also considered granting biowaivers for some drugs of weak acids in Class II (13) but presently grants biowaivers for only Class I and Class III drugs. In May 2015, the US-FDA revised its BCS Guidance to expand the biowaiver provision to Class III drugs (14). Subsequently, in July 2015, the US-FDA posted a new draft Guidance for Industry which provided recommendations for in vitro dissolution testing and specification criteria for immediate-release solid oral dosage forms containing BCS Class I and Class III drugs (15). The EMA and US-FDA publish individual BE or product-specific guidances advocating the use of BCS biowaivers (16, 17), and the International Pharmaceutical Federation (FIP) has published 44 monographs on the subject (18). Presently, many emerging markets are implementing the BCS biowaiver approach based on jurisdiction-specific guidelines or the WHO guidelines.
Thus, the BCS is now widely established in the academic, industrial, and regulatory world for waiving the regulatory requirements of conducting comparative bioavailability studies to demonstrate in vivo BA/BE of immediate-release (IR) solid oral dosage forms containing BCS Class I and Class III drugs (5, 6). However, although great advances have been made recently in harmonizing some aspects of BCS biowaiver implementation among major regulatory jurisdictions, there remain a number of dissimilarities among them (notably, in Japan, the BCS biowaiver has not been implemented at all), presenting a challenge for innovator and generic companies that seek to utilize a BCS biowaiver approach for global registration of a drug product.
The criteria, published in regulatory guidelines available in the public domain, which must be satisfied for consideration of granting a BCS-based biowaiver, for the US-FDA (14, 15), the EMA (9, 19), and the WHO (10), were compared. The selection of agencies for comparison is based on information presented at a Regulatory Sciences Open Forum (Proposals for Regulatory Harmonization of a Global BCS Framework – Challenges and Opportunities) during the 2014 American Association of Pharmaceutical Sciences (AAPS) Annual Meeting (13).
Table TableII compares the BCS biowaiver approaches currently used by the US-FDA, the EMA, and the WHO. The last column provides recommendations for what studies could be undertaken or what criteria/conditions to be met for a single regulatory filing that would satisfy the criteria of all three agencies.
With the posting of the Draft BCS Guidance in May 2015 and a Draft Dissolution Guidance in July 2015, the US-FDA moved into better convergence with the EMA and WHO with respect to the criteria necessary for granting a BCS-based biowaiver (the 2015 US-FDA Draft BCS Guidance replaced the original 2000 US-FDA BCS Guidance). Until the posting of the 2015 Draft BCS Guidance, the US-FDA would only grant biowaivers for Class I pharmaceutically equivalent IR oral dosage forms and would not consider biowaivers for Class III IR drug products. Notably, during the period from 2000 until 2015, to support granting a BCS biowaiver of a Class I drug, the US-FDA expected to see solubility determinations over the pH range of 1.0 to 7.5, considered in vivo evidence of high permeability to be in vivo Fa ≥90%, and would only accept in vitro dissolution testing via USP Apparatus 1 at 100 rpm or USP Apparatus 2 at 50 rpm (no exceptions). Aspects of the US-FDA BCS biowaiver approach until the 2015 posting of the Draft Guidance contrasted dramatically with the approaches of the EMA and WHO. Beginning in 2006 (WHO) and 2010 (EMA), both the EMA and WHO considered biowaivers for both Class I and Class III IR drug products (either pharmaceutical equivalents or alternatives), expected solubility determinations over the pH range of 1.2 to 6.8, considered evidence of high permeability to be in vivo BA ≥85%, and would consider using paddle speeds of 75 rpm in rare (EMA) or all (WHO) circumstances. The low rate of BCS-biowaiver submissions from 2000 to 2015 may have been due in part to these differences (11); for example, from 2000 to 2015, the number of BCS biowaiver requests submitted to the US-FDA averaged approximately two per year (Mehta M. Applicability of BCS-Based Biowaiver: Requirements and Conditions – US-FDA Perspective. European Federation for Pharmaceutical Sciences Global Bioequivalence Harmonisation Initiative. Amsterdam, 2015).
Thus, the present BCS biowaiver approaches of the US-FDA, EMA, and WHO are in reasonably good agreement with respect to BCS Classes and IR dosage forms for which biowaivers are considered, definition of high in vivo permeability, and definition of highly soluble drug substance. There remain some notable differences among these three jurisdictions. With respect to establishing high solubility, the US-FDA appears to have the most stringent recommendations for which pH values to test. By contrast, the US-FDA asks that the highest strength be used for establishing high solubility, whereas the EMA and WHO ask that the highest therapeutic dose be used. With respect to establishing high permeability, the US-FDA will consider in vivo and in situ animal models and in vitro methods, such as those using cultured monolayers of animal or human epithelial cells—for passively absorbed drugs only—as pivotal methods, whereas the EMA and WHO consider these methods to be supportive only. With respect to establishing rapid or very rapid dissolution, the US-FDA now requests that dissolution testing use a volume of 500 mL, whereas the EMA and WHO request using the [typical] compendial volume of 900 mL or less.
In addition to posting its new draft guidance that recommends how to design solubility, permeability, and dissolution studies to establish that a drug is BCS Class I or III (14), the US-FDA also recently posted a draft guidance that provides recommendations on how to set dissolution specification criteria for IR Class I and Class III drug formulations (15). The two different draft guidances distinguish between dissolution testing to establish BCS Class versus dissolution testing that, together with chemistry, manufacturing, and controls (CMC) data, characterizes the quality and performance of the drug product to be marketed (20, 21). Thus, to establish BCS Class I or III, the US FDA presently recommends that applicants use the following: media of three pH values as noted in Table TableI;I; media volume of 500 mL: USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm or 75 rpm when justified; appropriate sampling times for dissolution profile generation; and statistical methods for comparing dissolution profiles.
By contrast, for stability and quality controls dissolution testing of Class I and III drugs, the US-FDA presently recommends that applicants use 500 mL of 0.01 M HCl aqueous media, USP Apparatus I at 100 rpm or USP Apparatus II at 75 rpm, a single point dissolution specification of Q=80% in 30 min for BCS Class I drugs, and a single point dissolution specification of Q=80% in 15 min for BCS Class III drugs. In addition, the US-FDA now recommends that, for drug products in both BCS Class I and III, USP disintegration testing can be used in lieu of the dissolution test if the product is shown to meet a dissolution specification of Q=80% in 15 min.
The BCS is well established as a valid approach for waiving the requirements for in vivo BA and BE studies of Class I and Class III IR solid oral dosage forms in both new and generic drug development. The US-FDA, EMA, and WHO presently show good convergence with respect to the types of studies and documentation needed to establish that a drug is Class I or Class III. The US-FDA still differs somewhat from the other two jurisdictions with respect to criteria considered necessary to show high solubility, high permeability, and rapid dissolution, the latter to be performed in a smaller volume, 500 mL, compared to the EMA and WHO requirements which specify a volume of 900 mL. Nonetheless, these differences are such that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators.
The authors thank Alfredo García Arieta, Paulo Paixao, and Ivana Taševská for reviewing and providing helpful comments on this paper.