Download Waiver of In Vivo Bioavailability and Bioequivalence

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 1
Highly permeable
Highly soluble
Class 2
Highly permeable
Poorly soluble
Class 3
Poorly permeable
Highly soluble
Class 4
Poorly permeable
Poorly soluble
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:
(1)0.1 N HCl or Simulated Gastric Fluid USP without
enzymes.
(2)a pH 4.5 buffer.
(3)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
Eligibility for the biowaiver procedure based on solubility and permeability
characteristics of API according to the WHO
Class 1
Highly permeable
Highly soluble
A biowaiver can be
granted, these waivers are
considered on a case by
case basis especially if the
therapeutic window is
narrow
Class 2
Highly permeable
Poorly soluble
Class 3
Poorly permeable
Highly soluble
Class 4
Poorly permeable
Poorly soluble
Class 1
Highly permeable
Highly soluble
Class 3
Poorly permeable
Highly soluble
Class 2
Highly permeable
Poorly 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 3
Poorly permeable
Highly soluble
Class 4
Poorly permeable
Poorly 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
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)