Since being introduced in 1995, the Biopharmaceutics Classification System (BCS) has had a major impact on the regulation and development of immediate release (IR) oral drug products. Fundamentally, the BCS is a scientific framework for classifying drug substances (i.e., active pharmaceutical ingredients) based on the factors that determine rate and extent of absorption for the purpose of establishing equivalence in quality between test and reference products. The system has been formally adopted by regulatory authorities worldwide as a means to establish technical standards for waiving bioavailability (BA) and bioequivalence (BE) testing requirements for oral drugs. By providing a basis for avoiding unnecessary in vivo studies, BCS helps significantly reduce the cost and time of developing drug products. BCS is used to establish equivalence in applications for brand and generic medicinal products, variations, fixed combinations, extensions, and hybrids. However, despite its recognized value and increasing application, it remains an underutilized tool for drug development and international regulation. Moreover, as a decade-old example of a science-driven, standard-setting approach to streamline, harmonize and improve regulatory review, its fate going forward could signal the likely prospects for FDA’s regulatory science initiative.
To gain a better understanding of the issues that surround the BCS, the Center for the Study of Drug Development at Tufts University Medical School (Tufts CSDD) conducted interviews with 20 key opinion leaders from academic, generic and brand-name drug firms, as well as government representatives (see Figure 1):
How does the Biopharmaceutics Classification System work?
Developed by Amidon and colleagues, the BCS classifies immediate releases solid oral dosage forms on the basis of solubility and permeability parameters (when combined with dissolution testing) [1]. According to this schema, drug substances are categorized as having either rapid or slow in vitro dissolution, and then classified based on aqueous solubility and intestinal permeability of the active pharmaceutical ingredient (API):
Amidon posited that human outcomes can be accurately determined based on the evaluation of two intrinsic properties of the API (permeability and solubility) and one property of the drug product (dissolution). The evaluation of these properties can be performed in vitro, therefore avoiding expensive and time-consuming testing in humans.
Interview Respondents: Generally-speaking, respondents believe that the BCS continues to be a very relevant tool that is credible, based in sound science, reliably predictive, and defensible scientifically. The BCS put everybody on the same page in terms of understanding absorption from a mechanistic standpoint, showing the importance of dissolution as a predictor of absorption, and removing the veil of mystery from the evaluation of formulations. General criticisms of the BCS are that it is too conservative, misses some significant interactions such as those determined by transporters, and lacks clinical relevance for some special patients groups (e.g., short gut in kids).
How is the Biopharmaceutics Classification System used for Regulatory Purposes?
The FDA pioneered efforts to establish BCS as a regulatory tool in the drug approval process. In 2000, the US Food and Drug Administration (FDA) published a guideline that allowed sponsors to justify requests to waive in vivo BA and/or BE study requirements for IR solid oral dosage forms based on BCS criteria, so-called biowaivers [2]. The guidance provides recommended approaches for classifying an IR oral drug product and determining its dissolution characteristics. According to FDA, demonstration of BA or BE may not be necessary for substances that are highly soluble and highly permeable (i.e., fall into Class I) and exhibit rapid dissolution. The BCS has been extolled as an exemplar of FDA’s Critical Path Initiative efforts to employ more science-driven approaches to streamlining clinical trials, [3] and more recently by the American Association of Pharmaceutical Scientists as an example of regulatory science.
Interview Respondents – It was generally agreed, even among Government respondents, that more information should be made publicly available about biowaiver application results to avoid redundant testing as well as to reduce detrimental reliance on information in the scientific literature that can be conflicting, when available at all. The data released by FDA do not have to identify the particular applicant or other proprietary data, but could be aggregated to serve an educational purpose, advance open science, as well as to promote the BCS in the same way that public release of data did for the FDA’s Voluntary Genomics Data Submissions program.
How is the Biopharmaceutics Classification System used by Industry?
In early drug development, BCS helps guide the selection of drug candidates through quantitative and predictive models; it enables pharmaceutical companies to streamline formulation strategies and discover better compounds. Most pharmaceutical companies have integrated consideration of profiling data, including solubility and permeability, into high throughput screening and lead optimization processes. Upon consideration of BCS parameters, if a new compound is categorized as Class II, III, or IV, it indicates to Discovery the need to improve solubility and/or permeability for subsequent compounds; it indicates to Manufacturing that there may be greater formulation risks during development; and it indicates to clinicians that there is a potential for large variability in exposure and a significant food effect [4].
The proceedings of a recent international workshop with participants from 17 countries emphasized the critical function of quality-by-design (Qbd), and in turn the supporting role of the BCS, in the assurance of product quality and meeting user needs. QbD challenges pharmaceutical scientists to link product manufacturing parameters to clinical performance. Traditional methods for measuring clinical quality (i.e. clinical pharmacokinetic studies) are not sustainable, however, due to the expansive and expensive amount of testing they require. Among the new methods being utilized is in vitro dissolution testing. BA/BE guidelines, such as the BCS, provide a regulatory platform for in vitro dissolution to serve as a surrogate for clinical quality with respect to drug exposure in the body and serve as an important contributor to Quality-by-Design implementation [3].
In later stages of drug development, BCS helps sponsors determine what actions are needed to demonstrate the bioequivalence of a new formulation. Sponsor companies can potentially save hundreds of thousands of dollars in costs, and several months of time in development, if bioequivalence studies are avoided. It has been estimated that the application of BCS can result in annual savings of $35 million for the pharmaceutical industry [5].
Interview Respondents: It was generally considered that BCS was a useful tool routinely employed among brand companies for molecule characterization regarding drug-ability, go/no go develop-ability decisions, and considerations for possible formulation modifications. The BCS, however, is also being used to characterize the formulations used at different stages of development, for scale-up and post-approval changes (SUPAC), and now increasingly for postmarket problem-solving and drug re-positioning. Respondents also indicated that the BCS was useful for helping companies to build in QbD earlier in development, to ensure that it is maintained throughout the process, and to bolster confidence in the quality of the final product.Generics, especially ones withglobal markets, and experience with FDA, EMA and WHO biowaiver regimes, use BCS routinely to apply for biowaivers from human BA/BE testing.
Barriers to Use in Industry
The practice of submitting BCS-based biowaivers has become more routine as industry has realized the benefits of the system. However, despite the recognized value of BCS in reducing cost and time expended in the development of IR solid dosage forms, BCS is currently underutilized by sponsor companies to forego in vivo regulatory BE requirements for a wide variety of reasons. Modeling and simulation to assess BE in general is underused “… due to lack of confidence in the fundamentals of this approach and lack of experience with regulatory acceptance” [6]. Specifically regarding BCS, reluctance among sponsors to apply for BCS-based biowaivers has been attributed to perceived lack of certainty of acceptance by the regulatory agencies [7]. Therefore, greater certainty in regulatory decision making would presumably increase and enhance the application of BCS in industry.
Sponsors may also be reluctant to apply for biowaivers due to the existence of unnecessary barriers in current guidelines, implementation barriers within companies (e.g. perception of project delay risk), [3] compartmentalization of company resources, and a general lack of knowledge about BCS or the biowaiver process. Finally, lack of global harmonization has been identified as a major impediment to the employment of BCS by sponsor companies.
Interview Respondents: For Brands the growing body of knowledge regarding the importance of transporters and their linkage to drug-drug, food-drug, and other interactions, has exacerbated concerns about the limits of BCS predictive power for clinical relevance. Similarly, the fact that fewer and fewer drugs in a company pipeline are likely to be categorized as BCS I limits the applicability of the BCS under the current FDA regulatory regime. Generic companies that are on the fence regarding use of the BCS say that it is a competitive disadvantage for being listed on formularies not to have human BA/BE data. In addition, if companies apply for biowaivers and are rejected (see Figure 3), their route to market has thus been delayed (and made more costly) instead of streamlined.
Global Harmonization
Under the FDA, drug substance is considered highly soluble if its highest strength is soluble in 250 ml or less of aqueous media in the pH range of 1.0 to 7.5, and rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolves in 30 min using prescribed protocols and USP apparatus. A drug substance is considered to be highly permeable if it exhibits 90% or higher human intestinal absorption by in vitro permeation studies in excised tissue or across epithelial cells (e.g., Caco-2 cells) [8].
Introduced in 2001, the European Medicines Agency (EMA) guidance on the technical standards for biowaiver submission is slightly less stringent than that of the FDA. Under the latest version of EMA guidance (issued in 2010), IR oral dosage forms that demonstrate rapid dissolution and are highly soluble (i.e. fall into Class I or III) may be eligible to waive the in vivo BE requirement [9]. In considering biowaiver applications, EMA places more importance on solubility than permeability; in vitro permeability data is accepted only in support of clinical data [10].
Based on the FDA and EMA guidelines, the World Health Organization (WHO) set forth a guidance document for regulatory agencies around the world on the use of BCS-based biowaiver applications in 2005 [11]. Under WHO’s guidance document, BCS-based biowaivers apply to Class I and Class III drugs products; more specifically, highly soluble active pharmaceutical ingredients with known human absorption/permeability characteristics, are eligible for the BCS-based biowaiver approach for establishing the safety and efficacy of generic products. In addition, the WHO document also recognizes the potential for biowaivers of Class II drugs that are weak acids. The WHO is less conservative than the FDA documents in terms of definition of high permeability of a drug, but a bit more stringent regarding solubility requirements.
There are certainly benefits to be garnered from the global harmonization of biowaiver criteria as some 3% of international trade is in biopharmaceuticals. Almost 3/4 of the drugs on the WHO essential medicines list fall into BCS classes I and III, as do 60% of drugs on a list of the 200 top selling drugs in the US, Great Britain, Japan, and Spain making them suitable for BE testing based on in vitro dissolution procedures [12]. However, BCS is not currently implemented by all regulatory authorities worldwide, nor is it uniformly applied among those nations that have chosen to base biowaiver guidelines on BCS criteria. Waiver of expensive human BA/BE testing can benefit healthcare budgets in cash-strapped countries, as would access to an internationally valid, in silico repository of BCS determinations. Such a task is not as overwhelming as it might first appear. The Pan American Network for Drug Regulatory Harmonization (PANDRH) published an examination of a reference list of 96 drugs common to 8 countries in Latin America as well as Canada and the U.S., and found that only 4 drugs required BE studies in all 10 countries [13]. Furthermore, such a system would be an important step for evaluating product quality of traditional medicines from countries, such as South Africa, that are looking for export opportunities.
Interview Respondents: Respondents identified FDA’s conservative application of BCS relative to other regulatory authorities as an impediment to international harmonization; FDA typically grants biowaivers only for BCS Class I drugs, while other regulatory authorities are increasingly granting biowaivers for BCS Class III, and occasionally even Class II, drugs. Another challenge identified was the fact that many important countries among both the emerging markets (e.g., Russia only has a draft guidance on biowaivers) and mature markets (e.g., in Japan no biowaiver is accepted for the first generic approval) are still at odds with developing international consensus on biowaiver policy. Lack of central databases, language barriers, and trademark certificates have also been identified as challenges to global harmonization.
Conclusion
Respondents in general considered BCS to be a simple, inexpensive, and reliable tool routinely employed among companies in a variety of settings such as biowaivers of human BA/BE testing, molecule characterization regarding drug-ability, go/no go develop-ability decisions, and considerations for possible formulation modifications. Interviews with key experts in industry, government and academia, suggest the need to address a number of issues such as global harmonization of the parameters and processes used by major regulatory bodies, making more information about biowaiver decisions publicly available, and updating the FDA guidance for industry. Such actions would enable the the BCS to evolve as an exemplar of regulatory science that could facilitate solutions across a range of present-day problems , such as pediatric formulations, as well as future challenges like nanosuspensions, rather than to devolve into another lost opportunity for reducing costs and de-risking compounds due to lack of communication, coordination and leadership.
References
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