BSC Biowaiver: Components, Requirements and Criteria Abubakr O. Nur (B. Pharm.; M. Pharm.; PhD) Associate Professor of Pharmaceutical Technology Faculty of Pharmacy, University of Khartoum

6th medical and health sciences studies conference/2015 Bioavailability Drug Dosage Process patient Route Real Dose A.O. Nur 6th medical and health sciences studies conference/2015

Methods to assure Bioequivalence PK studies In vitro Studies PD studies Clinical studies A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 When BE is not required? "Bioequivalence study is not required when the in vivo bioavailability or bioequivalence of a drug product is self-evident"!!!! A.O. Nur 6th medical and health sciences studies conference/2015

Self-evident bioavailability!! Injectable, ophthalmic and otic solutions-conditional Oral and topical solutions-conditional Conventional drug products with a determination of efficacy Conventional oral solid products containing BCS class I and III drugs-conditional A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 Waiver of Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BCS A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 What is a biowaiver? It is when the in vivo bioavailability and/or bioequivalence studies are waived and not considered necessary for a product approval . A.O. Nur 6th medical and health sciences studies conference/2015

Quality built in products Reduction of time, cost and resources Why Biowaiver? Ethical Reasons 21 CFR 320.25(a) “… no unnecessary human research should be done.” Quality built in products Now industry practicing on “building quality into products from right first time” Reduction of time, cost and resources in vivo bioequivalence study cost up to $250,000 and require up to 2 months to complete A.O. Nur 6th medical and health sciences studies conference/2015

Biowaivers Supproting guidance -FDA guidance (USA) -EMA guidance (Europe) -PMDA guidance (Japan) -WHO guidance -TGA guidance (Australia) These guidance documents vary with respect to items definition, content and concept. A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 BCS Class I Low solubility High permeability Class II High solubility Low permeability Class III Class IV Definitions of High solubility and High permeability vary within different guidance?! High solubility High permeability A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 The Concept Drug Solubility Dosage dissolution Drug permeation Drug Absorption A.O. Nur 6th medical and health sciences studies conference/2015

Early stages of new drug development Implementation fields of BCS-based biowaiver Early stages of new drug development SUPAC (up to level 2) Line extension Drug product approval A.O. Nur 6th medical and health sciences studies conference/2015

Requirement of BCS-based biowaiver Biowaiver application is eligible for a solid oral Test product when satisfying the following attributes: API is BCS Class I (some guidance consider Class III and Class II drugs also) API is not considered to have a narrow therapeutic range The product exhibit a very rapid or rapid and similar in vitro drug dissolution under specified conditions to an approved Reference product. Reference and test products are pharmaceutical equivalent Excipients used are not likely to affect drug absorption A.O. Nur 6th medical and health sciences studies conference/2015

Components of BCS-based biowaiver study Comparative in vitro dissolution testing Comparator product suitability Batch type Type and amount of excipients A.O. Nur 6th medical and health sciences studies conference/2015

Comparative in vitro dissolution testing in BCS biowaiver Criteria for dissolution medium and pH range Criteria for dissolution apparatus Criteria for operating speed and test duration Criteria for number of tested units Criteria for reference product Criteria for dissolution sampling Criteria for dissolution samples analysis Criteria for comparison based on drug BCS class Criteria for dissolution similarity and dissimilarity Criteria for study reporting A.O. Nur 6th medical and health sciences studies conference/2015

Criteria to waive BCS class I drugs (FDA, EMA and WHO) Very rapid Dissolution (≥85% in 15 min) In vitro dissolution of comprator and test products in different medium Eligible for biowaiver Rapid Dissolution (≥85% in 30 min) Comparison of the dissolution profiles for similarity (f2 ≥50) A.O. Nur 6th medical and health sciences studies conference/2015

Criteria to waive BCS class III drugs (EMA and WHO) 3. Risk assessment for low permeability 1. Very rapid Dissolution (≥85% in 15 min) In vitro dissolution of comprator and test products in different medium 2. Identical Excipients Eligible for biowaiver A.O. Nur 6th medical and health sciences studies conference/2015

Criteria to waive BCS class II drugs (WHO) 1. Rapid Dissolution (≥85% in 30 min) at pH 6.8 2. Similar dissolution profiles in the three medium (f2 ≥50) In vitro dissolution of comparator and test products in different medium 3. Identical Excipients Eligible for biowaiver !! A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 Summary BCS based biowaiver has major advantage of cost, time and resource reduction in addition to ethical problems avoidance Many leading regulatory authorities have issued certain guidelines for supporting and carrying out biowaiver studies. Many new or generic drug formulations has been approved worldwide based on waived bioequivalence applications. A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 Compared to the FDA, which recognizes BCS Class I drugs as eligible for biowaivers and the EMA which recognizes BCS Class I and III drugs as eligible for biowaivers, the WHO suggests that for BCS Class I, II (weak acids) and III biowaivers may be possible, whereas the Prequalification of Medicines Programme (PQP) only allows biowaivers for BCS Class I and III drugs. A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 Biowaiver can be considered as trending regulatory issue for generic industry. Variation in criteria specifications and test conditions observed in different biowaiver guidance is the main hindrance for issuing a globally harmonized biowaiver guidance. It is expected in upcoming time that regulatory authorities will consider other classes of BCS for biowaiver study based on risk assessment. A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 References US, Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research (CDER). 2000 Guidance for industry: Bioavailability and bioequivalence studies for orally administered drug products-general considerations. European Medicines Evaluation Agency (EMA), Committee for Medicinal Products or Human Use (CHMP). 2010 Guideline on the Investigation of Bioequivalence. US, Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research (CDER). 2000 Guidance for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System. European Medicines Evaluation Agency (EMA), Committee for Medicinal Products or Human Use (CHMP). 2001 Guideline on the Investigation of Bioavailability and Bioequivalence. Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Fortieth Report. Geneva, World Health Organization, 2006 (WHO Technical Report Series, No. 937). A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 Amidon GL, Lennernäs H, Shah VP, Crison JR. 1995. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12(3):413-420. Yu LX, et al. 2002. Biopharmaceutics Classification System: The scientific basis for biowaiver extensions. Pharm Res 19:921–925. Moore JW, Flanner HH. 1996. Mathematical comparison of curves with an emphasis on in vitro dissolution profiles. Pharmaceutical Technology 20:64–74. Shah VP, et al. 1998. In vitro dissolution profile comparison – statistics and analysis of the similarity factor, f2. Pharm Res 15:889–896. Medicines Evaluation Board, The Netherlands, 2012 (http://www.cbg-meb.nl). Proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines immediate release, solid oral dosage forms. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006 (WHO Technical Report Series, No. 937), Annex 8. A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Fortieth Report. Geneva, World Health Organization. WHO Technical Report Series, No. 937, Annex 7: 2000, 347-390. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: Fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization. WHO Technical Report Series, No. 937, 2006, Annex 7. Australian regulatory guidelines for prescription medicines, Appendix 15: Biopharmaceutic studies, Australian Government, Department of Health and Ageing, Therapeutic Goods Administration, June 2004. http://www.tga.gov.au/pdf/pm-argpm-ap15.pdf. General notes on Biopharmaceutics Classification System (BCS)-based biowaiver applications. WHO Prequalification of Medicines Programme, Guidance Document October 2012 A.O. Nur 6th medical and health sciences studies conference/2015

6th medical and health sciences studies conference/2015 WHO Prequalification of Medicines Programme, 2012 (http://apps.who.int/prequal/). Reddy SK, Jamadar LD, Vasantharaju SG, Sreedhar D. Biowaivers for Immediate Release Solid Oral Dosage Forms. Pharma Times 2011; 43: 9-11. Kelly G. Biowaivers in the United States, European Union, and Japan. Accessed on April 2012 at http://american pharmaceuticalreview.com/ViewArticle.aspx? Content ID=4155. Akshay M., Neeraj K.F., Swapnil P. and Kailash B. BCS based biowaivers and their current regulatory issues, Indo American Journal of Pharm Research.2013; 3(6): 4617-4629. Seema R., Ankur R., Arun N. Biowaivers: Criteria and Requirements. Int. J. Pharm. Biol. Arch. 2012; 3(4):727-731 A.O. Nur 6th medical and health sciences studies conference/2015

Thank you for your attention A.O. Nur 6th medical and health sciences studies conference/2015