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Biopharmaceutics Classification System (BCS): A Regulatory Risk Management Tool. Uncertainty & Variability. Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA. 2000. Next Steps. New BCS Technical Committee Co-Chair: Lawrence Yu & Mehul Mehta

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biopharmaceutics classification system bcs a regulatory risk management tool

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

Uncertainty & Variability

Ajaz S. Hussain, Ph.D.

Deputy Director

Office of Pharmaceutical Science

CDER, FDA

2000

next steps
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

Ajaz Hussain, FDA

regulatory bioequivalence an overview

In VIVO

SUPAC-MR

IVIVC

Regulatory Bioequivalence: An Overview

“Self-evident” - Biowaivers granted

Condition- excipients do not alter absorption

(historical data)

Solutions

Suspensions

Chewable, etc.

Conventional

Tablets

Capsules

MR Products

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
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

Ajaz Hussain, FDA

need to reduce our reliance on in vivo be studies why
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

Ajaz Hussain, FDA

prior to supac ir bcs
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

Ajaz Hussain, FDA

supac ir bcs for some level 2 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
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 similarin 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
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.

Ajaz Hussain, FDA

risk of bio in equivalence
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

Ajaz Hussain, FDA

bcs a tool for risk management
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?

Ajaz Hussain, FDA

dissolution test bioequivalence risk assessment

Dissolution

generally

“over-

discriminating”

NO YES

Bioequivalent

Why?

Dissolution fails

to signal

bio-in-equi

~ 30% (?)

NO YES

Dissolution Specification

Dissolution Test & Bioequivalence: Risk Assessment
minimizing risk of bio in equivalence
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?

Ajaz Hussain, FDA

dissolution test methods
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 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, ….

Hydrodynamics?

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

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 tests: Debates
dissolution test problems false ives and ives
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
Failure to Discriminate Between Bio-in-equivalent Products: Inappropriate Acceptance Criteria

Product B

110

Product B was not

bioequivalent to

Product A

100

90

Product A

80

70

60

% Drug Dissolved

50

40

Log(AUCinf): CI 94.6 - 123.6

30

USP Specification

20

Log(AUC): CI 89.1 - 130.0

10

0

0

10

20

30

40

50

Cmax: CI 105.3 - 164.2

Time in Minutes

failure to discriminate between bio in equivalent products inappropriate test method

(weak acid, rapid dissolution in SIF)

Capsule (Ref.)

1800

1600

Tablet 1

(wet-granulation - starch)

1400

1200

Tablet 2

(direct compression -

calcium phosphate)

1000

Drug Concentration in Plasma (ng/ml)

800

600

400

200

USP Paddle 50rpm, Q 70% in 30 min

0

0

1

2

3

4

5

6

Time in Hours

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.

NDA #X: Bioequivalent?
in vitro in vivo dissolution
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

Ajaz Hussain, FDA

in vitro in vivo correlations
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)

Ajaz Hussain, FDA

formulation specific ivivc

Peak Concentration Vs. % Dissolved in vitro

Clarke et al. J. Pharm. Sci. 66: 1429, 1977

30

I

28

H

26

B

24

E

22

Peak Concentration (ug/100ml)

D

20

G

18

F

C

16

J

14

A

12

20

40

60

80

100

% Dissolved in 40 minutes

“Formulation Specific” IVIVC
reliance on current dissolution practice can poses an unacceptable level of risk
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

Ajaz Hussain, FDA

metoprolol ir tablets in vitro in vivo relationship

110

1.2

100

Rapid

1.1

90

AUC

80

Slow

1.0

70

Cmax

60

0.9

AUC, AND Cmax RATIOS (T/R)

50

0.8

% DRUG RELEASED

40

30

0.7

SOLUTION

20

FDA-UMAB

(931011)

0.6

10

0

0.5

0

5

10

15

20

25

30

35

0.2

0.4

0.6

0.8

1.0

1.2

RATIO (T/R) OF % DISSOLVED AT

10 MINUTES

TIME IN MINUTES

Metoprolol IR Tablets:In Vitro - In Vivo Relationship

FDA-UMAB

(931011)

metoprolol ir tablets experimental simulation data

Mean Intestinal Transit Time = 1.67 h

2.0

85%

D

I

S

S

O

L

U

T

I

O

N

T

I

M

E

(h)

0.70

0.75

0.90

AUC

1.5

1.2

Cmax

0.95

0.80

Plot 1 Regr

0.85

1.0

1.1

1.0

0.5

AUC, AND Cmax RATIOS (T/R)

0.9

0.0

Mean Intestinal Transit Time = 3.33 h

2.0

0.75

0.8

0.80

SOLUTION

T 85%

~ 30 min

in vitro

1.5

0.95

0.7

0.85

FDA-UMAB (931011)

0.90

1.0

0.6

0.5

0.5

0.2

0.4

0.6

0.8

1.0

1.2

RATIO (T/R) OF % DISSOLVED AT 10 MINUTES

0.0

0.1

0.2

0.3

0.4

0.5

Gastric Emptying Half-Time (h)

Metoprolol IR Tablets: Experimental & Simulation Data
risk factor excipients
Risk Factor: Excipients
  • Is the [current] approach of evaluating excipients for decisions related to biowaiver of oral solutions sufficient?

Ajaz Hussain, FDA

sorbitol mannitol impact on bioavailability
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
Experimental Formulations

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

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

Ranitidine: 150 mg

Sucrose: 5 g

Sorbitol: 5 g

Ajaz Hussain, FDA

polysorbate 80 acphe n mephe 2 nh 2 permeability caco 2
Polysorbate 80: AcPhe(N-MePhe)2NH2 Permeability (CACO-2)

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

Pe X 106 (cm/sec)

common excipients in ir tablets

COMMON EXCIPIENTS IN TABLETS

(The Inactive Ingredient Guide: More than 100 submissions)

Methyl cellulose

25

Acacia

Gelatin

Propylene glycol

Ethyl cellulose

20

Polysorbate 80

Crosspovidon

Carnuba wax

Hydroxy propyl cellulose

Sucrose*

Excipient

Talc

15

Calcium phosphate*

Sodium lauryl sulfate

Polyethylene glycol*

Crosscarmellose sodium

Titanium dioxide

10

Hydoxy propyl methyl cellulose*

Povidone

Stearic acid

Sodium starch glycolate

Silicon dioxide

5

Lactose*

Micorcrystaline cellulose

Starch*

Mg-stearate

0

0

500

1000

1500

2000

2500

Number of Submissions

List does not include colors

* Several types combined

Common Excipients in IR Tablets
impact of polysorbate 80 on be

INACTIVE INGREDIENTS IN

5 VERAPAMIL "AB" RATED TABLETS

Colloidal silicon dioxide

Corn starch

25

Croscarmellose sodium

D&C Yellow #10

Dibasic calcium phosphate

FD&C Blue

Gelatin

20

Hydoxypropylmethyl cellulose

Hydoxy propyl cellulose

Iron oxide

Lactose

Inactive ingredients

15

Mg. stearate

Microcrystalline cellulose

Opadry white

Opaspray bright yellow

Polacrilin potassium

10

Polyethylene glycol

Polysorbate 80

Propylene glycol

Sodium starch glycolate

Sodium carboxymethyl cellulose

5

Stearic acid

Talc

Titanium dioxide

Triacetin

0

1

2

3

4

5

# of Products

Impact of Polysorbate 80* on BE

* Used as a plasticizer

risk factor excipients35
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)

Ajaz Hussain, FDA

bcs class membership risk management
BCS Class Membership: Risk Management

Rapid Dissolution (in vivo & in vitro)

Likely Unlikely

10

I

II

Dissolution in vivo

not likely to be rate

limiting - well

characterized excipients

Dissolution likely

to be “rate determining.”

Complex in vivo disso. And

solubilization process.

1

III

IV

Jejunal Permeability

Peff (x10 -4) cm/sec

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

0.1

0.01

1

10

100

1000

10000

100000

Volume (ml) of water required to dissolve the highest dose

strength at the lowest solubility on the pH 1-7.5 range

bioequivalence ir products
Bioequivalence: IR Products

Pharmaceutical Equivalent

Products

Reference

Test

Possible Differences

Drug particle size, ..

Excipients

Manufacturing process

Equipment

Site of manufacture

Batch size ….

Normal healthy subjects

Crossover design

Overnight fast

Glass of water

90% CI within 80-125%

of Ref. (Cmax & AUC)

Documented Bioequivalence

= Therapeutic Equivalence

(Note: Generally, same dissolution spec.)

Ajaz Hussain, FDA

recommendations on exploring extension of bcs
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,..

Ajaz Hussain, FDA