In Vitro Biowaiver Studies

Rapid and Cost Effective establishment of Bioequivalence for Generic, Branded solid dosage Immediate Release (IR) BCS Class I and Class III formulations by FDA / EMEA approved In vitro methods

Bio waiver means in vivo bioavailability (BA) and/or bioequivalence (BE) studies are replaced with in vitro studies to classify the equivalence of two pharmaceutical products for product approval. Bio waiver is initially applied for scale up and post approval changes (SUPAC) of generic product 1. and later extended to approval of orally administered BCS class I (high solubility and high permeability) and class III (high solubility and low permeability) generic drugs. BCS class I and class III molecules with a similar in vivo dissolution profile under all luminal conditions will have the same extent of drug absorption (Amidon et al.1995). Characterizing solid dosage immediate release (IR) formulation of BCS class I and III for bioequivalence by establishing the in vitro dissolution, and solubility and permeability for the active pharmaceutical ingredient (API) waives-off the requirement of expensive and time consuming clinical BA-BE studies there by reducing the time and cost of bringing the product to market.

A drug product is considered RAPIDLY DISSOLVING when > 85% of the labelled amount of drug substance dissolves within 30 minutes in three different media (pH 1.2, 4.5 and 6.8) in a paddle (50 rpm) or basket (100 rpm) apparatus at 37 °C in a volume of 900 mL.

The aqueous solubility of the drug is considered to be high when the highest single unit dose is COMPLETELY SOLUBLE in 250 mL or less of aqueous solution at (pH 1.2, 4.5 and 6.8) at 37 °C.

A drug substance is considered HIGHLY PERMEABLE when extent of absorption in humans is determined to be > 85% of an administered dose, based on a mass balance determination or in comparison to an intravenous reference dose, in the absence of evidence suggesting instability in the gastrointestinal tract. Intestinal permeability is assessed by validated in vitro permeability models such as Caco-2.

The pharmaceutical product is considered for Biowaiver upon following criteria:

  • Should be BCS class I and III.
  • Should be rapidly dissolving.
  • Should not contain excipients which can influence the intestinal absorption.
  • Should not be a narrow therapeutic index.
  • Should not be absorbed from the buccal cavity.

www.fda.gov/cder/guidance/cmc5.pdf

www.fda.gov/cder/guidance/3618fnl.htm

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