1. Waiver of In Vivo Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Ajaz S. Hussain, Ph.D. Chair, BCS Working Group Biopharmaceutics Coordinating Committee OPS, CDER, FDA 16 November 2000 Advisory Committee for Pharmaceutical Science An Update on the BCS Guidance

2. Timeline Research (FDA, MPA,Univ. Michigan, Uppsala, and Maryland) Application in SUPAC-IR Guidance BCS Working Group formed to develop a guidance ACPS Discussion AAPS/CRS/FDA Workshop EUFEPS 4th Int. Conference on Drug Absorption “Expert Panel” Meeting ACPS Discussion AAPS Workshop on Permeability Methods ACPS Discussion Draft Guidance Published Internal Training Final Guidance Published External Training Next Steps 1990 11/1995 4/1996 8/1996 4/1997 6/1997 10/1997 12/1997 8/1998 10/1998 2/1999 6/2000 8/2000 9/2000

3. BCS Guidance 2000 Methods for classifying a drug based on solubility and intestinal permeability Rapid dissolution criteria Biowaiver for –rapidly dissolving solid oral dosage forms containing drugs that exhibit high solubility, high permeability, and wide therapeutic index established excipients

4. BCS a tool for risk management (discussion on risk management is based on R.F. Griffith. Dealing with risk. 1981) Assessment of risk –What is the risk of bio-in-equivalence between two pharmaceutical equivalent products when in vitro dissolution test comparisons are used for regulatory decisions? Likelihood of occurrence and the severity of the consequences? Regulatory Decision –whether or not the risks are such that the project can be persued with or without additional arrangements to mitigate the risk Acceptability of the Decision –is the decision acceptable to society?

5. Differences in Drug Dissolution: Primary Reason for Bio-in-equivalence(?) Solutions Suspensions Chewable, etc. Conventional Tablets Capsules MR Products “Self-evident” - Biowaiver possible Condition- excipients do not alter absorption (historical data) Pre-1962 DESI Drugs: In Vivo evaluation for “bio-problem” drugs (TI, PK, P-Chem) Post-1962 Drugs: Generally In Vivo - some exceptions (IVIVC..) SUPAC-IR (1995) Dissolution-IR Draft BCS (pre-/post approval) In VIVO SUPAC-MR IVIVC

6. FDA’s Bioequivalence Hearing (1986) “..seems sensible to think that swallowing something that turns into a solution rapidly would be difficult to lead to differences from one product to the next……” –Bob Temple in response to Arnold Becketts presentation “……I’ve learned that there is no support here for attempting to provide such assurance solely with in vitro data.” –Milo Gibaldi

7. Bioequivalence: IR Products ReferenceTest Pharmaceutical Equivalent Products Possible Differences Drug particle size,.. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution spec.)

8. Dissolution specifications and Bioequivalence Dissolution generally “over- discriminating” Dissolution fails to signal bio-in-equi ~ 20-30% (?) NO YES Bioequivalent Dissolution Specification Why?

9. Dissolution tests: Debates Dissolution tests are “over discriminating” Products that dissolve about 70% in 45 minutes have no medically relevant bioequivalence problems Dissolution tests are not sufficient to assure bioequivalence Demonstration of IVIVC is necessary IVIVC’s are “Product Specific”

10. Failure of Dissolution Tests to Signal Bio-in-equivalence Inappropriate “acceptance criteria” –single point criterion Inappropriate test method –media composition (pH,..) –media volume –hydrodynamics Excipients affect drug absorption Other reasons (type II error)

11. Typical Physiologic Parameters: S ingle Dose Fasting BE Study Volume = Gastric fluid + 8 oz water (~300 ml) pH of gastric fluid = 1-3 Res. time (fasting) = variable; T50%=15 min. Permeability - Low, compared to Small Intestine. Surface tension lower than water, …. Volume (fasting) = what gets emptied + SI vol.(500 ml?) pH = 3-8, surface tension low,... Res. time (fasting) : 2-4 hours Permeability - high compared to other parts Hydrodynamics?

12. BCS Class Boundaries: Objectives Dissolution (Product) Solubility (Drug) Permeability (Drug) Rapid dissolution - ensure that in vivo dissolution is not likely to be the “rate determining” step High solubility- ensure that solubility is not likely to limit dissolution and, therefore, absorption High permeability - ensure that drug is completely absorbed during the limited transit time through the small intestine

13. BCS Class Membership: Risk Management Volume (ml) of water required to dissolve the highest dose strength at the lowest solubility on the pH 1-7.5 range Jejunal Permeability Peff (x10 -4) cm/sec 110100100010000100000 0.01 0.1 1 10 I III II IV Rapid Dissolution (in vivo & in vitro) LikelyUnlikely Dissolution likely to be “rate determining” IVIVC possible (and would need to be demonstrated) When dissolution rate > gastric emptying dissolution not likely to be rate determining Same as above, however, need to establish why absorption is incomplete -sensitive to certain excipients? Generally “problem” drugs in vitro dissolution may not be reliable IVIVC may be possible

14. Acceptance of BCS based biowaivers Strong support from scientific community –ACPS, Experts, FDA staff, Public workshops Some concerns expressed at public workshops and comments on draft guidance “overly conservative” - should also apply to Class III and some class II drugs application for Generics impact of excipients

15. Next Steps Further research –Extension of BCS based biowaivers –Application for waiver of “fed” bioequivalence studies Continuation of educational initiatives –practitioners and public International harmonization