The Biopharmaceutical Classification System (BCS) was developed by a collaboration of academic, industrial and government scientists in order to provide guidelines for the development of oral dosage forms (Yu et al., 2002).  The basic principle behind the classification system is that the absorption of immediate-release, orally administered drugs is driven by two properties, the solubility of the drug in the gastrointestinal tract and the permeability of the drug across the intestinal epithelial cell barrier.  Proper in vitro surrogates for these two properties should allow prediction of a drug’s absorption in vivo from in vitro assays.

A drug’s solubility classification in the BCS is a function of the intended human dose. Drugs whose solubility under appropriate conditions exceeds the highest dose strength dissolved in 250 ml are classified as “soluble”, i.e., Class I or III according to the BCS scheme. Drugs not meeting these criteria are classified as Class II or IV. Class I and Class II drugs have high permeability in an appropriate permeability assay system that has been validated with compounds of known in vivo human fractional absorption after oral administration. Drugs not meeting these criteria are class III, if they have high solubility, or class IV, if their solubility is low.

The in vitro tests needed to characterize a drug candidate’s BCS classification include: 

• determination of the pK_a value(s) of the compound,
• its solubility at low and neutral pH—as well as above and below the pK_a for weak acids
• the permeability of the compound across an in vitro biological test system such as Caco-2 or MDCK cell monolayers or intestinal strips.

The in vitro permeability system must be validated using reference compounds with known human fractional absorption and each assay must include one or more suitable internal standard compounds to verify the assay’s performance with the test compound present. Absorption Systems uses a rigorously validated, FDA-audited Caco-2 system for BCS permeability testing. The system has been validated at two different pH values to maximize your compound's chances of being classified as "high permeability." In addition, we have introduced a new high-permeability internal reference compound that gives us a wider dynamic range of permeability classification.

The FDA published its position on biowaivers in an August 2000 Guidance for Industry, Waiver of In Vivo Bioavailablity and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.  The regulatory requirements are addressed in 21 CFR 320.  The Guidance details the conditions under which a drug may be eligible for a waiver of in vivo bioavailability and bioequivalence studies, i.e., a biowaiver.  Such studies are required in order to demonstrate equivalent bioavailability in case of changes in formulation during clinical trials or prior to launch, in ANDAs (to demonstrate bioequivalence of a generic form of a drug), or, in some cases, when the manufacturing site or process is changed.  The biowaiver provision only applies to immediate-release, solid oral dosage forms for which the active ingredient does not have a narrow therapeutic index.

In our experience, in many cases the FDA is now asking for data documenting the BCS classification of new drugs early in the approval process, regardless of whether or not the sponsor has requested a biowaiver.  In terms of development time and cost, it makes sense to have Absorption Systems classify your new drug candidate within the BCS as early as possible.  Then, if it falls into Class I, you will already have the data in hand to demonstrate to the FDA that it should be granted a biowaiver later in development or post-approval .  We recommend, first, non-GLP BCS solubility and permeability studies (see the flow chart below under Attachments).  If the results indicate that the test compound falls into BCS Class I, then you would proceed with definitive BCS solubility and permeability studies in compliance with GLP requirements

Currently,  only  Class I  (highly  soluble  and highly permeable) drugs that dissolve rapidly are eligible for a biowaiver.  This policy is based on research showing that systemic exposure to a drug, which is proportional to its rate and extent of absorption, is in turn related to its solubility and permeability, especially when the rate of dissolution is rapid in relation to gastric emptying.  There is currently an ongoing dialogue regarding the idea that Class III (high-solubility, low-permeability) compounds should also be eligible for a biowaiver.  The rationale is that, once a compound is in solution, its systemic bioavailability is  then dependent only on its permeability.  If  you can demonstrate comparable solubilities and rates of dissolution in two different formulations, the bioavailabilities will be comparable.  Permeability is based on the chemical structure of a compound and is less dependent than, e.g., the rate of dissolution or stability, on the excipients in a given formulation.  Thus, a compound that has low permeability (Class III) will not have a much different permeability in one formulation than another. Absorption Systems is an active participant in this dialogue, with the FDA and members of the pharmaceutical industry, to extend eligibility for biowaivers beyond Class I to include Class III compounds.