# Presentation: 285878

## Biopharmaceutics Classification System (BCS): A Regulatory Risk Management Tool

- Ajaz S. Hussain, Ph.D.
- Deputy Director
- Office of Pharmaceutical Science
- CDER, FDA

- Uncertainty & Variability

- 2000

## Next Steps

- New BCS Technical Committee
- Co-Chair: Lawrence Yu & Mehul Mehta
- Address implementation questions
- Database and prospective research for extensions (links to PQRI and FIP)
- Class III and Class II drugs
- Further research (FDA)
- Extension of BCS based biowaivers
- Waiver of “fed” bioequivalence studies
- Continuation of educational initiatives
- practitioners and public
- International harmonization

## Regulatory Bioequivalence: An Overview  

- Regulatory Bioequivalence: An Overview

- Solutions
- Suspensions
- Chewable, etc.
- Conventional
- Tablets
- Capsules
- MR Products

- “Self-evident” - Biowaivers granted
- 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
- BCS
- (pre-/post approval)

## Bioequivalence Hearing of 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

## Need to Reduce Our Reliance on In Vivo BE Studies: Why?

- Ethical reasons
- 21 CFR 320.25(a) “... no unnecessary human research should be done.”
- Science continues to provide new methods to identify and eliminate unnecessary *in vivo* BE studies
- Focus on prevention - “building quality into products” - “right first time”
- Time and cost of drug development and review

## Prior to SUPAC-IR/BCS

*in vivo* bioequivalence (BE) assessments to justify (a majority of) manufacturing changes
- preferred use of “prior approval supplement” process to implement changes

## SUPAC-IR/BCS: For some ‘Level 2’ Changes

- Note: NTI drugs excluded for some Level 2 Changes

## Waiver of in vivo BE studies based on BCS (8/30/2000)

- Recommended for a solid oral _Test_ product  that exhibit ***rapid*** (85% in 30 min) and ***similar*** *in vitro* dissolution under specified conditions to an approved _Reference_ product when the following conditions are satisfied:
- Products are ***pharmaceutical equivalent***
- Drug substance is ***highly soluble*** and ***highly permeable*** and is not considered have a ***narrow therapeutic range***
- Excipients used are not likely to effect drug absorption

## BCS: Class Membership

- High Solubility
- the highest dose strength is soluble in _<_250 mL aqueous buffers over pH range of at 37oC.
- High Permeability
- extent of absorption in humans is determined to be  90%
- Rapid Dissolution
-  85% dissolves within 30 minutes in 0.1 HCl (or SGF), pH 4.5, and pH 6.8 buffers (or SIF) using Apparatus I at 100 rpm or Apparatus II at 50 rpm.

## Risk of Bio-in-equivalence

- Risk factors
- Manufacturing changes pre/post approval
- minor - moderate - major changes
- Poor process capability
- high between and within batch variability
- Reliance on *in vitro* dissolution tests
- single point specification - sampling - predictability
- Other factors
- deficiencies in BE study design - Type II error

*Bioequivalence - one of the critical links between quality and S&E*

## BCS a tool for risk management

- 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?

## Dissolution Test & Bioequivalence: Risk Assessment

## Minimizing Risk of Bio-in-equivalence

- Does *in vitro* dissolution process emulates *in vivo* dissolution process?
- Dosage form disintegration, dissolution and stability
- Gastrointestinal fluid volume, composition, and hydrodynamic conditions
- Residence time (undissolved and dissolved drug) in stomach and small intestine
- Impact of excipients differences on GI physiology - drug bioavailability?

## Dissolution Test Methods

- > 900 ml, 37oC
- > Water, 0.1 N HCl, pH 6.8 buffer, or...
- > 50 rpm (paddle), 100 rpm (basket),...
- > Vessel geometry
- > Location of dosage unit

## Typical Physiologic Parameters:Single Dose Fasting BE Study

## 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”

## Dissolution Test Problems:False +ives and -ives

- Test/Ref. Mean

- I. J. MacGilvery.  Bioequivalence: A Canadian Regulatory
-  Perspective. In, Pharmaceutical Bioequivalence
- . Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc., New York,  (1992)).

## Failure to Discriminate Between Bio-in-equivalent Products: Inappropriate Acceptance Criteria

- 0

- 10

- 20

- 30

- 40

- 50

*% Drug Dissolved*

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 80

- 90

- 100

- 110

*USP Specification*

*Product A*

*Product B*

*Time in Minutes*

*Product B was not*
*bioequivalent to*
*Product A*

*Log(AUCinf): CI 94.6 - 123.6*

*Log(AUC): CI 89.1 - 130.0*

*Cmax: CI 105.3 - 164.2*

## Failure to Discriminate Between Bio-in-equivalent Products: Inappropriate Test Method?

## NDA #X: Bioequivalent?

- Drug X  (100 mg dose, volume required to dissolve the dose at pH 8, lowest solubility, is 230 ml, extent of absorption from a solution is 95%)
- Weak base exhibits a sharp decline in solubility with increasing pH above 3
- Clinical-trial formulation: Wet granulation, drug particle size (D50%) 80 microns, lactose MCC, starch, Mg-stearte, silicon dioxide. Tablet weight 250 mg. Dissolution in 0.1 N HCl 65% in 15 min and 100 % in 20 minutes. Disintegration time 10 minutes.

- The company wants to manufacture the product using direct compression.
- To-Be-Marketed formulation: Direct compression, drug particle size (D50%) 300 microns, dicalcium phosphate, MCC, Mg-stearate, silicon dioxide. Tablet weight 500 mg. Dissolution in 0.1 N HCl - 85% in 15 min., and 95% in 20 min. Disintegration 1 min.
- Clincal product exhibits poor dissolution in pH 7.4 media (about 30% in 60 minutes). Data for T-b-M not available.

## In Vitro & In Vivo Dissolution

- Dissolution methods evolved over last thirty years - reproducible test method for lot-lot quality assurance
- Dissolution media volume and composition selected to maintain “sink” conditions
*In vivo* dissolution is a complex process (e.g., pH profile, bile concentration, motility patterns)
*In vivo* “sink” condition created due to intestinal permeability

## In Vitro - In Vivo Correlations

- When dissolution is slow (rate limiting) *IVIVC* have been demonstrated, however such a correlation may not hold when certain formulation changes are introduced
- For ER products a change in release mechanism
- For IR products of low solubility drugs (e.g., spirinolactone and carbamezapine)

## “Formulation Specific” IVIVC

## Reliance on current dissolution practice can poses an unacceptable level of risk

- Compared to high solubility drugs, risk is higher for low solubility drugs
- Products with slow or extended dissolution profiles pose a higher risk (dissolution rate limiting)
-  Need for a rapid dissolution criteria
- Potential for significant differences between *in vivo* and *in vitro* “sink” conditions higher for low permeability drugs

## Metoprolol IR Tablets:In Vitro - In Vivo Relationship

**FDA-UMAB **
**(931011)**

## Metoprolol IR Tablets: Experimental & Simulation Data

## Risk Factor: Excipients

- Is the [current] approach of evaluating excipients for decisions related to biowaiver of oral solutions sufficient?

## Sorbitol/Mannitol: Impact on Bioavailability

- 2.3 grams of mannitol in a chewable tablet reduced bioavailability of cimetidine (a _low permeability_ drug, per FDA’s BCS Guidance) compared to a tablet containing the same amount of sucrose
-  AUC, Cmax , and Tmax ratios of the mean values were 71%, 46%, and 167%, respectively
- Sparrow et al. J. Pharm. Sci. 84: 1405-1409, (1995)
- About 10 grams of sorbitol had no (minimal) effect on bioavailability (Cmax and AUC) of theophylline (a _high permeability_ drug)
- Fassihi et al. Int. J. Pharm. 72: 175-178, (1991)

## Experimental Formulations

- * Rapidly metabolized at/in the intestinal wall to glucose and fructose, both exhibit complete absorption

## Bioequivalence Assessment

- Note: Solution containing sucrose was used as the reference

## Excipient Effect for a Class III Drug (Hussain et al. AAPS Annual Meeting, 2000)

- Ranitidine: 150 mg
- Sucrose: 5 g
- Sorbitol: 5 g

## Polysorbate 80: AcPhe(N-MePhe)2NH2 Permeability  (CACO-2)

- Nerurkar, Burton and Borchardt. Pharm. Res. 13: 528-534 (1996)

**Pe X 10****6**** (cm/sec)**

## Common Excipients in IR Tablets

## Impact of Polysorbate 80* on BE  

- * Used as a plasticizer

## Risk Factor: Excipients

- Is the [current] approach of evaluating excipients for decisions related to biowaiver of oral solutions sufficient?
-  For BCS based biowaivers a higher standard was adopted (by limiting biowaivers to *highly permeable* drugs)
- excipients used in solid oral products less likely to impact drug absorption compared to liquid oral product
*High permeability* attribute reduces the risk of bio-in-equivalence
- decreased small intestinal residence time by osmotic ingredients
- enhanced intestinal permeability (potentially by surfactants)

## Slide 36

## 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**

**1**

**10**

**100**

**1000**

**10000**

**100000**

**0.01**

**0.1**

**1**

**10**

**I**

**III**

** ****II**

**IV**

**Rapid Dissolution (in vivo & in vitro)**
**Likely****	****	****	****	****Unlikely**

**Dissolution likely **
**to be “rate determining.”**
**Complex in vivo disso. And**
**solubilization process.**

**Dissolution *****in vivo***
**not likely to be rate**
**limiting -  well**
**characterized excipients**

**Some hesitation with **
**the use of current **
**dissolution test **
**and concerns**
**with respect to**
**excipients.**

**Generally “problem” drugs**
**in vitro dissolution may**
**not be reliable **

## Bioequivalence: IR Products

- Reference

- Test

- 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.)

- Normal healthy subjects
- Crossover design
- Overnight fast
- Glass of water
- 90% CI within 80-125%
- of Ref. (Cmax & AUC)

## Recommendations on Exploring Extension of BCS?

- BCS a key tool in QbD (pre-formulation)
- Part of the QbD Decision Tree
- QbD – Design Space
- Pre/post approval BE “bridging studies” -Waivers of *in vivo* studies based on design space concept (consider all BCS classes)
- Eliminate the concern of generic drugs (initial approval)
- Developing FDA’s Knowledge space
- Drug-excipient interactions (chemistry & clinical pharmacology)
- Drug substance and formulation variable and clinical performance
- PK, Pk/PD, biomarkers,..