Biowaivers Vinod P. Shah, Ph. D. Chair, Regulatory Science Special Interest Group, FIPInternational Workshop in Vietnam FIP-AAPS Workshop on Generic Pharmaceutical Equivalence HCM City, Vietnam March 19-21, 2012
BiowaiverThe term biowaiver is applied to a regulatory drugapproval process when the dossier (application) isapproved based on evidence of equivalence otherthan in vivo bioequivalence test.For solid oral dosage forms, Biowaiver(s) isgenerally based on a dissolution test.
Biowaivers Types of Products• Solutions• IV Products• Immediate Release (IR) Products – Lower Strengths – BCS Class 1 – BCS Class 2? – BCS Class 3?• Extended Release (ER) Products – Lower Strengths• Topical Dosage Forms – Solutions – Aerosols – Antifungals• Inhalation and Nasal Dosage Forms (Aerosols) – Solutions
BiowaiversPrinciples employed for assessing biowaiver• Biopharmaceutics Classification System• In vitro in vivo correlation (Level A, B, C and D)• Formulation proportionality and dissolution profile similarity (f2)• Quality by Design (QbD) Space• In vitro release profile• In vitro characterization
Waiver of in vivo BA & BE forIR drug products based on BCS• Criteria for biowaiver – Highly soluble: Highest dose soluble in 250 ml in pH 1.2 – 6.8 – Highly permeable: extent of absorption greater than 85% – Rapidly dissolving: 85% or greater by basket method 100 rpm or paddle method 50 rpm in 900 ml in pH 1.2, 4.5 and 6.8• For a waiver of BE, T and R products should exhibit similar dissolution profile FDA Guidance - Waiver for Class 1 Drugs
Guidance for IndustryWaiver of In Vivo Bioavailabilityand Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on aBiopharmaceutics Classification System http://www.fda.gov/cder/guidance/index.htm August 2000
BCS-based Biowaivers• BCS Class 1: HS/HP - VRD or RD in pH 1.2, 4.5 and 6.8• BCS Class 2: LS/HP/Weak Acids – Rapid dissolution in pH 6.8 and similar dissolution profile in pH 1.2, 4.5 and 6.8• BCS Class 3: HS/LP/VRD – contains no inactive ingredients that are known to alter GI motility and/or absorption For biowaivers Test (multisource) and Reference (comparator) products must have similar dissolution profile (f2) in all 3 media WHO Technical Report Series, No. 937, 2006, Annex 7, p 347 - 390
World Health Organization Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeabilityWHO Technical Report Series, No. 937, 2006 Annex 7, p 347 - 390
Guidance for Industry Bioavailability andBioequivalence Studies for Orally Administered Drug Products General Considerations http://www.fda.gov/cder/guidance/index.htm March 2003
Dissolution Based Biowaivers• Conventional Release Products - Lower strengths, proportional formulations, f2 - BCS Class 1: HS/HP/RD - BCS Class 2: LS/HP, Weak acids, HS in pH 6.8 - BCS Class 3: HS/LP/Very Rapidly dissolving• Extended Release Products - Lower strengths, proportional formulations and same release mechanism - Beads in a capsule - Profile comparison in one medium - Tablets - Profile comparison in pH 1.2, 4.5, 6.8
Quality by Design (QbD)• QbD is essential part of modern approach to pharmaceutical quality – it combines critical manufacturing process and operating parameters.• IVIVC, Concept of mapping, QbD – design space: developing product with acceptable quality and performance• QbD – Design space: Multi-dimensional space that encompasses combination of product design, manufacturing process parameters and component attributes that provide assurance of acceptable product quality and performance.
Topical Antifungal (Targeting SC)• If Q1 and Q2 equivalent – in vitro testing – in vivo testing waived based on in vitro results• If Q1 equivalent but Q2 difference – in vitro testing – in vivo tests if Q2 difference is potentially significant• If Q1 and Q2 differ – in vitro testing – in vivo tests required to demonstrate no formulation effect on absorption
ConclusionsBiowaiver• Lowering regulatory burden, provide regulatory relief without loss of drug product quality• Product approved based on in vitro data