1. 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

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

3. Methods to assure Bioequivalence
PK studies
In vitro
Studies
PD studies
Clinical
studies
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When BE is not required?
"Bioequivalence study is not required when the in vivo bioavailability or bioequivalence of a drug product is self-evident"!!!!
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6th medical and health sciences studies conference/2015

5. 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
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Waiver of Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BCS
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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 .
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6th medical and health sciences studies conference/2015

8. Quality built in products Reduction of time, cost and resources
Why Biowaiver?
Ethical Reasons
21 CFR (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
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6th medical and health sciences studies conference/2015

9. 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.
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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
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The Concept
Drug Solubility
Dosage dissolution
Drug permeation
Drug Absorption
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12. 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
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13. 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
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14. Components of BCS-based biowaiver study
Comparative in vitro dissolution testing
Comparator product suitability
Batch type
Type and amount of excipients
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15. 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
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6th medical and health sciences studies conference/2015

16. 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)
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6th medical and health sciences studies conference/2015

17. 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
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6th medical and health sciences studies conference/2015

18. 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 !!
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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.
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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.
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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.
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References
US, Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research (CDER) 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) Guideline on the Investigation of Bioequivalence.
US, Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research (CDER) 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) 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).
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Amidon GL, Lennernäs H, Shah VP, Crison JR A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12(3):
Yu LX, et al Biopharmaceutics Classification System: The scientific basis for biowaiver extensions. Pharm Res 19:921–925.
Moore JW, Flanner HH Mathematical comparison of curves with an emphasis on in vitro dissolution profiles. Pharmaceutical Technology 20:64–74.
Shah VP, et al In vitro dissolution profile comparison – statistics and analysis of the similarity factor, f2. Pharm Res 15:889–896.
Medicines Evaluation Board, The Netherlands, 2012 (
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.
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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,
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
General notes on Biopharmaceutics Classification System (BCS)-based biowaiver applications. WHO Prequalification of Medicines Programme, Guidance Document October 2012
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WHO Prequalification of Medicines Programme, 2012 (
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 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):
Seema R., Ankur R., Arun N. Biowaivers: Criteria and Requirements. Int. J. Pharm. Biol. Arch. 2012; 3(4):
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26. Thank you for your attention
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6th medical and health sciences studies conference/2015