In vitro testing and the Biopharmaceutics Classifi cation System Biopharmaceutics Classifi cation System

　　The Biopharmaceutics Classifi cation System (BCS) is based on aqueous solubility and intestinal permeability of the drug substance. It classifi es the API into one of four classes:

　　— Class 1: high solubility, high permeability

　　— Class 2: low solubility, high permeability

　　— Class 3: high solubility, low permeability

　　— Class 4: low solubility, low permeability

　　Combining the dissolution of the pharmaceutical product with these two properties of the API, takes the three major factors that govern the rate and extent of drug absorption from immediate-release solid dosage forms into account. On the basis of their dissolution properties, immediaterelease dosage forms can be categorized as having “very rapid”, “rapid”, or“not rapid” dissolution characteristics.

　　On the basis of solubility and permeability of the API, and dissolution characteristics of the dosage form, the BCS approach provides an opportunity to waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediate-release drug products (28). Oral drug products not eligible for a so-called “biowaiver” based on the BCS approach are described under section.

　　High solubility

　　An API is considered highly soluble when the highest dose recommended by WHO (if the API appears on the WHO Model List of Essential Medicines)or highest dose strength available on the market as a oral solid dosage form (if the API does not appear on the WHO Model List of Essential Medicines) is soluble in 250 ml or less of aqueous media over the pH range of 1.2–6.8.The pH-solubility profi le of the API should be determined at 37±1℃ in aqueous media. A minimum of three replicate determinations of solubility at each pH condition is recommended. Initial recommendations in the BCS Guidance suggested that the solubility should be measured over a pH range of 1.2–7.5. But successive scientifi c discussions and publications suggest that a pH range of 1.2–6.8 is more appropriate.

　　High permeability

　　An API is considered highly permeable when the extent of absorption in humans is 85% or more based on a mass balance determination or in comparison with an intravenous comparator dose. The initial recommendation in the BCS Guidance suggested an absorption value of 90% as a prerequisite for classifi cation as highly permeable. However, successive scientific discussions and scientifi c publications have suggested relaxing the criterion to 85% absorption for classifying an API as highly permeable. An acceptable alternative test method for permeability determination of the API could be in vivo intestinal perfusion in humans(i).

　　When this method is used for permeation studies,suitability of the methodology should be demonstrated, including determination of permeability relative to that of a reference compound whose fraction of dose absorbed has been documented to be at least 85%, as well as use of a negative control.

　　Supportive data can be provided by the following additional test methods:

　　(ii) in vivo or in situ intestinal perfusion using animal models; or

　　(iii) in vitro permeation across a monolayer of cultured epithelial cells (e.g.Caco-2) using a method validated using APIs with known permeabilities,although data from neither method (ii) nor (iii) would be considered acceptable on a stand-alone basis. In these experiments high permeability is assessed with respect to the high permeability of a series of reference compounds with documented permeabilities and fraction absorbed values,including some for which fraction of dose absorbed is at least 85%.

　　Determination of dissolution characteristics of multisource products in consideration of a biowaiver based on the Biopharmaceutics Classifi cation System

　　For exemption from an in vivo pharmacokinetic bioequivalence study, an immediate-release multisource product should exhibit very rapid or rapid in vitro dissolution characteristics (see below), depending on the BCS properties of the API. In vitro data should also demonstrate the similarity of dissolution profi les between the test and comparator products.

　　Very rapidly dissolving

　　A multisource product is considered to be very rapidly dissolving when no less than 85% of the labelled amount of the drug substance dissolves in 15 minutes using a paddle apparatus at 75 rpm or a basket apparatus at 100 rpm in a volume of 900 ml or less in each of the following media:

　　— pH 1.2 HCl solution;

　　— a pH 4.5 acetate buffer; and

　　— a pH 6.8 phosphate buffer.

　　(See also section 9.2, dissolution profi le comparison.)

　　Rapidly dissolving

　　A multisource product is considered to be rapidly dissolving when no less than 85% of the labelled amount of the drug substance dissolves in 30 minutes using a paddle apparatus at 75 rpm or a basket apparatus at 100 rpm in a volume of 900 ml or less in each of the following media:

　　— pH 1.2 HCl solution;

　　— a pH 4.5 acetate buffer; and

　　— a pH 6.8 phosphate buffer.

　　Qualifi cation for a biowaiver based on the Biopharmaceutics Classifi cation System

　　A biowaiver based on the BCS considers:

　　(a) the solubility and permeability of the API (see section 9.1);

　　(b) the similarity of the dissolution profi les of the multisource and comparator products in pH 1.2, 4.5 and 6.8 media (see below);

　　(c) the excipients used in the formulation (see below); and

　　(d) the risks of an incorrect biowaiver decision in terms of the therapeutic index of, and clinical indications for, the API (see section 5.1 for cases where an in vivo study would be required to demonstrate bioequivalence).

　　Only when there is an acceptable benefi trisk balance in terms of public health and risk to the individual patient should bioequivalence testing according to the guidelines given in this section be permitted.