What is the Biopharmaceutics Classification System and why does it matter?

The pharmaceutical industry is feeling the acute effects of disruption caused by the COVID-19 pandemic. With most human trials on hold, drug developers and generics companies will be looking for new ways to progress product portfolios. This series of blog posts aims to highlight BCS and BCS-based biowaiver applications as such an opportunity. This first blog will cover what the  Biopharmaceutics Classification System (BCS) is and how it relates to in vivo bioequivalence and bioavailability studies.

The Biopharmaceutics Classification System (BCS) is a method of classifying orally dosed drugs based on a few fundamental physical properties. Estimating oral drug absorption can be complex if absorption is impacted by in vivo factors like gastric emptying and fed/fasted state. However, for drugs that rapidly dissolve and readily permeate through the intestinal mucosa, their in vivo pharmacokinetics can be more easily predicted. BCS provides the basis to know for which drugs these assumptions can be made.

Classification under BCS is based on three simple measurements and defined by the FDA as:

• Solubility: drug is considered highly soluble when the highest therapeutic dose is soluble in 250 mL or less of aqueous media within the pH range of 1-6.8 at 37±1°C
• Intestinal permeability: drug is considered to be highly permeable when the systemic BA or the extent of absorption in humans is determined to be 85% or more of an administered dose.
• Dissolution: drug substance is considered rapidly dissolving when a mean of >85% of the labeled amount of the drug substance dissolves within 30 minutes

The first two of these are properties of the active pharmaceutical ingredient (API), whereas dissolution depends on the formulated drug product. Figure 1 shows how different drugs group into BCS classes based on these measurements. Importantly, immediate-release drugs that are classified as Class I and III have in vivo bioavailability that can be accurately predicted. This makes the need for in vivo bioavailability and bioequivalence studies for these compounds less critical.

Figure 1: Illustration of BCS classification of different compounds based on permeability and solubility

A significant advantage of the BCS is that classification can be accurately and quickly assessed via in vitro experiments. This leads to several key benefits, including:

• Reduced need for human studies. Limiting unnecessary research on human subjects should always be a top priority for drug developers and regulatory bodies alike
• Shortened development time + costs. Replacement of in vivo BA/BE studies could save between $50-150 million is lost earning potential per drug product
• Robust results for difficult compounds. Drugs with a highly variable API (due to, e.g., complex metabolism, enterohepatic recirculation) are vulnerable to in vivo BE failures due to the low sample size of these studies. Established in vitro protocols are more robust and can accommodate variability in drug behavior.

How can we help?

Absorption Systems has been involved in the development and delivery of BCS since its formation two decades ago. We have conducted hundreds of BCS studies, including for 8 of the 10 largest generics companies. Our pipeline for BCS includes a preliminary permeability screen that provides a quick indication as to whether a full BCS study is suitable for your product, saving you time and money.

Classification of permeability is based on comparison with a co-dosed internal reference compound. Absorption Systems’ High Permeability Internal Standard (HPIS), minoxidil, has the lowest available threshold for defining high permeability while having >95% fraction absorbed in humans (see Fig.2). This helps identify highly permeable novel compounds and improves in vivo correlation.

Figure 2: Apparent permeability (Papp) in Caco-2 system correlates with fraction absorbed in humans

Additionally, our In vitro Dissolution Absorption System (IDAS™) allows the evaluation of dissolution, solubility, and permeability simultaneously. This offers improved accuracy and in vivo correlation, particularly with non-Class I drugs. To find out more about how we can assist your BCS requirements, get in touch, or view our full range of small molecule capabilities.

Knowing the BCS class of your drug can provide a huge amount of useful information to inform its development pipeline. Most commonly, BCS is used as a regulatory mechanism for drug developers to avoid costly and time-consuming human BA/BE studies based on a novel product’s BCS classification. This mechanism, called a biowaiver, is the topic of the next post.

References

1.     Cook, JA, et al. Impact of Biopharmaceutics Classification System-Based Biowaivers, Mol Pharm 2010

2.     Food and Drug Administration, 2017. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Guidance for Industry. https://www.fda.gov/media/70963/download