Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Biopharmaceutics Classification System - State of the Art in Development and Practice ***

Maren Seip (Abschlußjahr: 2003)

The Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98) states, that the biopharmaceutics classification system (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability - the main parameters for influencing rate and extent of absorption of a drug substance through gastrointestinal membranes and having significant influence on its bioavailability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from immediate release solid oral dosage forms:

• Solubility
• Intestinal permeability
• In vitro dissolution

Based on this realisation, Amidon et al developed a system basing on solubility and permeability of the drug substance creating four classes:

Class I: High solubility, high permeability
Class II: Low solubility, high permeability
Class III: High solubility low permeability
Class IV: Low solubility, low permeability.

In addition, immediate release solid oral dosage forms are categorised as having rapid or slow dissolution.

High solubility according to the BCS means that the highest single dose of the drug substance is soluble in not more than 250 ml aqueous solution over the physiological pH range. Solubility includes stability of the drug substance at physiological important pH values: one hour at pH 1 and three hours at pH 6.8.

High permeability according to the BCS corresponds with an absorption rate of more than 90 %. Minimum requirements for pH values are the following buffer solutions: at or about pH 1.0, 4.6, 6.8. A drug product is considered to be rapidly dissolving when at least 85 % of the labelled amount of drug substance dissolves within 30 minutes at standardised conditions.

Content of documentation to submit to the FDA as well to the European Authorities is mentioned.

At the moment, the FDA and European guidelines allow applicants the request for a waiver of bioequivalence studies explicitly for oral immediate release forms with systemic action containing BCS class I drug substances (highly soluble and highly permeable) provided that the drug substance has a non-critical therapeutic range and the drug product shows a high dissolution rate. As this fact is stated in official guidelines, this can be considered as state of scientific knowledge.

Additionally, the CPMP Note for Guidance states that for active substances which are highly water soluble (BCS class I and III), the product could be in general exempted from bioequivalence studies unless this exemption could entail a potential risk (e.g. narrow therapeutic range, risk of therapeutic failure). This statement includes BCS class I as well as BCS class III substances, as both are characterised by high solubility. Further research is needed to establish more criteria to expand the regular use of BCS for class III substances.

For medicinal products containing BCS class II substances, the situation is different. In general, bioequivalence has to be shown by an in vivo study, unless an IVIVC could be established. From a biopharmaceutical point of view, drug substances belonging to this BCS class are most critical and most interesting. Some examples for drug products containing BCS class II substances to propose a biowaiver request are discussed in this work. Further research is still needed to expand the regulated use for class II substances with certain criteria.

For drug products containing class IV substances, bioequivalence studies should generally be conducted, a request for a biowaiver is not possible using the biopharmaceutics classification scheme.

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