BCS Classification of Drugs for Biowaiver
Oral bioavailability of a small molecule drug depends on the rate and extent of its absorption. These, in turn, are determined by drug properties such as solubility, permeability, and formulation (i.e., presence of excipients or nano formulation). Determination of in vitro solubility and permeability is a good basis for predicting and understanding in vivo absorption, by the classification of a drug into four different classes according to the Biopharmaceutics Classification System (BCS):
- Class 1: High Solubility – High Permeability
- Class 2: Low Solubility – High Permeability
- Class 3: High Solubility – Low Permeability
- Class 4: Low Solubility – Low Permeability
Potential practical applications of the BCS have been studied extensively over the past decades, and it was adopted by regulatory agencies globally as a guiding principle for developing test requirements for specific drug classes. The system currently has two major applications in the regulatory environment:
- It can be used to justify inclusion or omission of certain assays (e.g., efflux transporter substrate assessment assays) as part of drug approval processes
- It can serve as reference for granting a waiver of clinical bioequivalence studies (biowaiver)
BCS biowaivers are most commonly submitted as part of generic product development, when the drug is well-characterized and has already been approved. For generics, the possibility to waive clinical studies based on proven in vitro bioequivalence results in a significant reduction in both development time and costs. It can, however, also have important applications for new drug development where formulations may be changed even at late clinical stages, and demonstrating bioequivalence between the new and previous versions of the drug product offer the possibility of using previously generated clinical data.
In either case, the experimental setups for in vitro BCS drug class determination should strictly adhere to the latest international ICH M9 guidance and be run using characterized assay systems in order to be used in biowaiver applications.
2020 ICH M9 guideline on BCS-based biowaivers
This guidance focuses on biopharmaceutics classification system-based biowaivers, including recommendations for assay systems and setups, data interpretation, and eligibility criteria for filing.
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What steps go into the BCS classification of drugs?
Oral dosage is the most commonly employed and convenient route of drug delivery. While this approach provides relatively easy handling and administration as well as flexibility in the design of dosage form, poor bioavailability is often a challenge. Low oral drug bioavailability usually correlates with poor solubility and low permeability. These characteristics mostly concern the API in a drug product. However, the formulation and dosage form can also highly affect overall bioavailability. Therefore, in addition to the BCS drug classification of the API itself, dissolution assays also need to be conducted, and stability of the API in the gastrointestinal tract has to be demonstrated for biowaiver eligibility.
A complete BCS drug classification and biowaiver package consists of:
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BCS Solubility classification
To achieve the concentration of drug in systemic circulation needed for the proper pharmacological response, solubility is one of the most important characteristics to consider. Poorly water-soluble drugs often require high doses to reach therapeutic plasma concentrations upon oral administration. Drugs with poor aqueous solubility are also absorbed more slowly, which may lead to inadequate and variable bioavailability, and render the drug ineffective. Tackling low aqueous solubility is a major challenge encountered upon formulation development of both new chemical entities and generic development. Essentially, any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption.
To be eligible for a biowaiver, according to the latest international ICH M9 guidance, it needs to be demonstrated that the drug substance in the highest single therapeutic dose is completely soluble in 250 mL or less of aqueous media over the pH range of 1.2 – 6.8 at 37 ± 1 °C. This is achieved by determining experimentally the solubility of the drug substance over the pH range.
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BCS Permeability classification
The other main driver of drug oral bioavailability is its permeability via various tissue barriers, most importantly the intestinal epithelium, the site of initial absorption. For low permeability compounds, usually additional strategies need to be devised to improve bioavailability, such as targeting active uptake pathways, applying a prodrug-driven approach, or opting for more sophisticated delivery strategies, all of which lengthen and complicate the development pipeline. While in vitro assays are often used to predict in vivo permeability and bioavailability (fraction absorbed) of a compound, most systems, such as a PAMPA assay or non-validated cellular setups only provide system-specific permeability values that are not reproducible across systems or correlated to in vivo outcomes, thus cannot be used for regulatory purposes.
To overcome this, we apply a Caco-2-based assay system, in which in vitro permeability of a set of internal permeability standard drugs has been characterized and shows reliable correlation to their in vivo fraction absorbed. As part of system characterization and validation, in vitro permeability of these internal standards was plotted against the known human in vivo fraction absorbed to separate high- and low permeability groups and defined the class boundary reference compound. In the permeability class determination assay, the test compound is tested in parallel with a selection of these previously characterized permeability standards, which allows its classification as either high- or low permeable based on direct comparison to the high-low permeability boundary cut-off compound.
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In vitro Dissolution
Dissolution of a drug is defined as the extent and rate of solution formation from a dosage form, such as tablet, capsule, ointment, etc., which affect its bioavailability and therapeutic effectiveness. Dissolution testing is used to predict in vivo drug release profiles. For in vitro dissolution tests, the drug product is generally placed in a vessel filled with the appropriate medium which is kept at 37±1 °C for the experiment, and a dissolution apparatus is operated. The dissolution medium can range from degassed or sonicated deionized water to pH-adjusted chemically prepared solutions. Sample solutions collected from dissolution testing are analyzed by a validated analytical method for the active substance to trace product dissolution and release of the active substance.
When applying the BCS-based biowaiver approach, comparative in vitro dissolution tests should be conducted in a paddle (see figure) or basket type of apparatus at volume of 900 mL or less, at three different pH levels: pH 1.2, pH 4.5, and pH 6.8, while pharmacopeial buffers should be employed. To qualify for a BCS-based biowaiver for BCS Class I drug substances based on bioequivalence, both the test product and reference product should display either “very rapid” in vitro dissolution characteristics or “rapid” and similar in vitro dissolution characteristics under all the defined conditions. In cases where one product has rapid dissolution and the other has very rapid dissolution, similarity of the profiles should be demonstrated. To qualify for a BCS-based biowaiver for BCS Class III drug substances, both the test product and reference product should display very rapid in vitro dissolution characteristics under the defined conditions.
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Stability in the Gastrointestinal Tract
Stability of the drug in the GI tract is an important factor when considering oral bioavailability. As per the ICH M9 guidelines, demonstration of stability in the gastrointestinal tract is required if high permeability of the compound is demonstrated via in vitro Caco-2 studies. In vivo, drug loss from the GI tract can arise both from intestinal membrane permeation and thus absorption into the systemic circulation or due to degradation processes. Distinguishing between these effects and identifying the contribution of degradation to this effect, if any, helps establish permeability. Stability in the GI tract should be documented using simulated gastric and intestinal fluids. Drug solutions are incubated at 37 ºC for a period that is representative of the in vivo contact of the drug substance with these fluids, i.e., one hour in gastric fluid and three hours in intestinal fluid, at the end of which, remaining drug concentrations are determined. Significant degradation (>10%) of a drug precludes BCS high permeability classification.
A full package as well as individual BSC classification studies for a single element are also available at Charles River.