Introduction What is a Biowaiver? A biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (i.e. not considered necessary for product approval). Instead of conducting expensive and time-consuming in vivo studies, the physicochemical properties of the API, permeability data and a dissolution test can be adopted as the surrogate basis for the decision of product approval.

Observed 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.2 When the in vivo dissolution of an IR solid oral dosage form is rapid in relation to gastric emptying and the drug has high permeability, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastrointestinal transit time. Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing Class 1 drug substances, as long as the inactive ingredients used in the dosage form do not significantly affect absorption of the active ingredients. The BCS approach outlined in this guidance can be used to justify biowaivers for highly soluble and highly permeable drug substances (i.e., Class 1) in IR solid oral dosage forms that exhibit rapid in vitro dissolution using the recommended test methods (21 CFR 320.22(e)). The recommended methods for determining solubility, permeability, and in vitro dissolution are discussed below.

The Biopharmaceutical Classification System concept Created in 1995 by the US FDA (Department of Human Health). • First aim: granting biowaivers for Scale-Up and Post-Approval Changes (SUPAC). • Second aim: more recent, extension of the BCS concept for approval of oral generic products According to the BCS, drug substances are classified as follow: .

Class 3 Poorly permeable Highly soluble Class 2 Highly permeable Poorly soluble Class 4 Class 1

Solubility and Permeability Solubility is considered high when the ratio of the highest orally- administered dose to the solubility of the API (mg/ml) is 250 ml or lower at a pH range of 1-7.5. Methodology Stability Permeability is considered high when 90 % or more of the orally administered dose is absorbed in the small intestine. Methodology: Pharmacokinetic studies (bioavailability or mass balance studies), or Intestinal permeability (tissue culture models, in vitro permeability methods) Mechanism of API transport, addition of Internal standards, more than one method. Linearity

Determining Drug Product Dissolution Characteristics Dissolution testing: USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the following dissolution media: 0.1 N HCl or Simulated Gastric Fluid USP without enzymes. a pH 4.5 buffer. a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. A minimum of 12 dosage units of a drug product should be evaluated to support a biowaiver request. Samples should be collected at a sufficient number of intervals to characterize the dissolution profile of the drug product (e.g., 10, 15, 20, and 30 minutes) Rapidly dissolving, meaning it should release at least 85% of its content in 30 min

Eligibility Criteria for Biowaiver BCS classification of the API: solubility and permeability (Class I) Dissolution characteristics: rapidly dissolving Excipients: may influence motility and/or permeability in the gastrointestinal tract. Therapeutic index: must not be an API with a narrow TI Formulation: product not designed to be absorbed from the oral cavity

characteristics of API according to the WHO Eligibility for the biowaiver procedure based on solubility and permeability characteristics of API according to the WHO Class 1 Highly permeable Highly soluble Class 2 Highly permeable Poorly soluble A biowaiver can be granted, these waivers are considered on a case by case basis especially if the therapeutic window is narrow Class 3 Poorly permeable Highly soluble Class 4 Poorly permeable Poorly soluble

Class 1 Highly permeable Highly soluble Class 2 Highly permeable Poorly soluble Class 3 Poorly permeable Highly soluble Class 4 Poorly permeable Poorly soluble Eligible only if dose: solubility ratio of 250ml or lower at pH 6.8

Class 1 Highly permeable Highly soluble Class 2 Highly permeable Poorly soluble A biowaiver can be granted if the product is very rapidly dissolving Class 4 Poorly permeable Poorly soluble Class 3 Poorly permeable Highly soluble

Class 1 Highly permeable Highly soluble Class 2 Highly permeable Poorly soluble Class 4 API’s are not eligible for a biowaiver Class 3 Poorly permeable Highly soluble Class 4 Poorly permeable Poorly soluble

Literature search (physicochem., Solubility, Quantitation) Validation of the anlytical methodology, Stability indicting methods Solubility determination studies (Shake-flask method) Dissolution tests of the oral dosage form (pH 1.2 – 6.8) Literature search for permeability data (BA, amount excreted in urine, Caco-2, Intestinal permeability studies) Literature search for indication, therapeutic index and possible interactions wth food and excipeints, reported bioeq. studies

Evaluation of Data and Biowaiver Application BCS Class(II, III, IV) Narrow therapeutic range Critical indication Slow and incomplete dissolution Food effects or interaction with excipients BE- Studies BCS Class I (II, III) Wide therapeutic range Non critical indication Rapid or very rapid dissolution No interaction with food or excipients BE- Studies Biowaiver

References: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Note for Guidance on the investigation of bioavailability of bioequivalence Biopharmaceutics Classification System: The Scientific Basis for Biowaiver Extensions, Pharmaceutical Research, Vol. 19, No. 7, July 2002 Biowaiver Monographs,J Pharm Sci, Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ibuprofen (Journal of Pharmaceutical Sciences, Vol. 94, 2121–2131 (2005) Isoniazid (Journal of Pharmaceutical Sciences, Vol. 96, 522–531 (2007) Prednisolone (Journal of Pharmaceutical Sciences, Vol. 96, 27–37 (2007) Chloroquine phosphate, chloroquine sulfate and chloroquine hydrochloride (J Pharm Sci 94:1389–1395 (2005)