Revised Bioequivalence Guidance on BE Classification System to Extend Waiver Provisions for Class 3 Drugs

FDA today released a draft Guidance document entitled, “Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.”  This document is a revision of an August 2000 Guidance document of the same name.  However, in the revised version, FDA is proposing to permit waivers of in vivo bioequivalence testing for not only Class 1 (highly soluble and highly permeable drugs) that was permitted in the older Guidance, but also Class 3 drugs (those that are highly soluble, but have low permeability).  FDA has hinted about this change for years and now there is a draft Guidance that outlines the requirements for granting a waiver of in vivo bioequivalence requirements for Class 3 products.

The Guidance provides direction relative to both the solubility and dissolution testing requirements and also describes methods to assess permeability.  The Guidance also clearly states that these recommendations are relevant to solid oral immediate release dosage forms.  (Also please remember that this Guidance is a draft, and as such, is not for implementation until after finalization.)

FDA states that “[O]bserved in vivo differences in the rate and extent of absorption of a drug from two pharmaceutically equivalent solid oral products may be due to differences in drug dissolution in vivo.  However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid in relation to gastric emptying and the drug has high solubility, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastrointestinal (GI) transit time.  Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing class 1 and class 3 drug substances, as long as the inactive ingredients used in the dosage form do not significantly affect absorption of the active ingredients.”

For solubility, the FDA indicates that “[T]he solubility class boundary is based on the highest strength of an (immediate release [sic]) IR product that is the subject of a biowaiver request. A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media over the pH range of 1-6.8. The volume estimate of 250 mL is derived from typical BE study protocols that prescribe administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water.”  In addition, relative to dissolution, FDA expectations are that , 85% of the drug is dissolved within a specified period of time.  FDA will be looking for at least 3 replicate determinations at various pH conditions over the pH range of 1-6.8.

As far as permeability is concerned, if the absolute in vivo bioavailability is 85% or greater, then other means many not be necessary.  However, the FDA is recommending that in vivo or in situ animal models or in vitro testing may be used.  FDA recommends the following four methods to determine permeability:

(1) in vivo intestinal perfusion studies in humans;

(2) in vivo or in situ intestinal perfusion studies using suitable animal models;

(3) in vitro permeation studies using excised human or animal intestinal tissues; or

(4) in vitro permeation studies across a monolayer of cultured epithelial cells.

The Guidance document should be read carefully and its contents studied when determining how to apply its principles to practice.  And, in summary

For BCS class 1 drug products, the following should be demonstrated:

• the drug substance is highly soluble

• the drug substance is highly permeable

• the drug product (test and reference) is rapidly dissolving, and

• the product does not contain any excipients that will affect the rate or extent of absorption of the drug.

For BCS class 3 drug products, the following should be demonstrated:

• the drug substance is highly soluble

• the drug product (test and reference) is very rapidly dissolving (see section II.C.), and

• the test product formulation is qualitatively the same and quantitatively very similar, e.g., falls within scale-up and post-approval changes (SUPAC) IR Level 1 and Level 2 changes, in composition to the reference.

The Guidance document provides additional considerations that will be useful in establishing the data to support waivers of in vivo bioequivalence testing and should be considered by each applicant.  The full guidance can be found here.

FDA has determined that in vivo BE testing may not be needed in instances of BCS Class 1 and Class 3 drugs.  When the Agency will actually permit reliance on this Guidance to support approval for Class 3 drugs is not clear, but it is suggested that firms contact the FDA and gain permission to explore the use of the provisions of this guidance prior to actually implementing its contents, because, if FDA is not prepared to accept what appears to be its current thinking prior to finalizing the document, OGD might refuse-to-file an ANDA based on reliance on the draft Guidance.