US Food and Drug Administration: 2005-4137S2 02 Hussain

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Biopharmaceutics Classification

System (BCS): A RegulatoryRisk Management Tool

Ajaz S. Hussain, Ph.D.Deputy Director

Office of Pharmaceutical ScienceCDER, FDA

Uncertainty & Variability

2000



Ajaz Hussain, FDA

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

olutions

uspensions

hewable, etc.

onventionalablets

apsules

R Products

“Self-evident” - Biowaivers grantedCondition- excipients do not alter absorption

(historical data)

Pre-1962 DESI Drugs: In Vivoevaluation for “bio-problem”

drugs (TI, PK, P-Chem)Post-1962 Drugs: Generally

In Vivo - some exceptions

(IVIVC..)

SUPAC-IR(1995)

Dissolution-IRBCS

(pre-/post

approval)

In VIVOSUPAC-MR

IVIVC



Ajaz Hussain, FDA

Bioequivalence Hearing of 1986

• “..seems sensible to think that swallowingsomething that turns into a solution rapidlywould be difficult to lead to differences fromone product to the next……” – Bob Temple in response to Arnold Becketts

presentation

• “……I’ve learned that there is no support herefor attempting to provide such assurancesolely with in vitro data.”

– Milo Gibaldi



Ajaz Hussain, FDA

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 BEstudies

• Focus on prevention - “building quality into products” - “right first time”

• Time and cost of drug development andreview



Ajaz Hussain, FDA

Prior to SUPAC-IR/BCS

• in vivo bioequivalence (BE) assessments to justify (a majority of) manufacturingchanges

• preferred use of “prior approvalsupplement” process to implement changes



SUPAC-IR/BCS: For some

‘Level 2’ Changes HS/HP LS/HP HS/LP LS/LP

Critical Process Gastric

Emptying

Dissolution Permeability D/P

IVIVC Not likely Likely Not likely (?)

Method 0.1 N HCl pH 1 - 7.4 App/Comp In Vivo BE

AcceptanceCriteria

Single point85% in 15 min

Multiple profiles

(f2 > or = 50)

Single profile(f2 > or = 50)

AUC & Cmax90% CI

80-125%

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 anapproved Reference product when the followingconditions 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



Ajaz Hussain, FDA

BCS: Class Membership

• High Solubility – the highest dose strength is soluble in <250 mL

aqueous buffers over pH range of at 37 oC.

• 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

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 tomitigate the risk

• Acceptability of the Decision – is the decision acceptable to society?



Dissolution Test &Bioequivalence: Risk Assessment

Dissolutiongenerally

“over-

discriminating”

Dissolution failsto signal

bio-in-equi~ 30% (?)

NO YES

N O

Y E S

B i o e q u

i v a l e n

t

Dissolution Specification

Why?



Ajaz Hussain, FDA

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, 37 oC> 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:Typical Physiologic Parameters:SS ingle Dose Fasting BE Studyingle Dose Fasting BE Study

Volume = Gastric fluid + 8 oz water (~300 ml)pH of gastric fluid = 1-3Res. 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 hoursPermeability - high compared to other parts

Hydrodynamics?



Dissolution tests: Debates

• Dissolution tests are“over

discriminating”• Products thatdissolve about 70%in 45 minutes haveno medicallyrelevantbioequivalenceproblems

• Dissolution tests arenot sufficient to

assurebioequivalence• Demonstration of

IVIVC is necessary • IVIVC’s are

“Product Specific”



Dissolution Test Problems:False +ives and -ives

15 min 30 min 45 min AUC Cmax

Ref 95 96 98 100 100

B 96 97 97 104 95C 62 84 92 84 55D 82 94 95 88 87

E 103 103 103 112 120F 13 35 53 100 102

Test/Ref. Mean

I. J. MacGilvery. Bioequivalence: A Canadian RegulatoryPerspective. 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

% D

r u g

D i s s o l v e d

010

2030405060708090

100110

USP Specification

Product A

Product B

Time in Minutes

Product B was notbioequivalent to

Product A

Log(AUCinf): CI 94.6 - 123.6

Log(AUC): CI 89.1 - 130.0

Cmax: CI 105.3 - 164.2



(weak acid, rapid dissolution in SIF)

Time in Hours0 1 2 3 4 5 6

D r u g

C o n c e n t r a

t i o n

i n P l a s m a

( n g

/ m l )

0

200

400

600

800

1000

1200

1400

1600

1800 Capsule (Ref.)

Tablet 1(wet-granulation - starch)

Tablet 2(direct compression -calcium phosphate)

USP Paddle 50rpm, Q 70% in 30 min

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



NDA #X: Bioequivalent?

• Drug X (100 mg dose, volumerequired to dissolve the dose atpH 8, lowest solubility, is 230ml, extent of absorption from asolution is 95%)

• Weak base exhibits a sharpdecline in solubility withincreasing pH above 3

• Clinical-trial formulation: Wetgranulation, drug particle size

(D50%) 80 microns, lactoseMCC, starch, Mg-stearte,silicon dioxide. Tablet weight250 mg. Dissolution in 0.1 NHCl 65% in 15 min and 100 %in 20 minutes. Disintegrationtime 10 minutes.

• The company wants tomanufacture the product usingdirect compression.

• To-Be-Marketed formulation:Direct compression, drug

particle size (D50%) 300microns, dicalcium phosphate,MCC, Mg-stearate, silicondioxide. 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.



Ajaz Hussain, FDA

In Vitro & In Vivo Dissolution

• Dissolution methods evolved over last thirtyyears - reproducible test method for lot-lotquality 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

• When dissolution is slow (rate limiting) IVIVC have been demonstrated, however

such a correlation may not hold whencertain 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” IVIVCPeak Concentration Vs. % Dissolved in vitro

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

% Dissolved in 40 minutes

20 40 60 80 100

P e a

k C o n c e n

t r a t i o n

( u g / 1 0 0 m

l )

12

14

16

18

20

22

24

26

28

30

A

B

H

I

D

F

JC

G

E



Ajaz Hussain, FDA

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 ratelimiting)

– 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

TIME IN MINUTES

0 5 10 15 20 25 30 35

% D

R U G R E L E A S E D

0102030405060

708090

100110

Rapid

Slow

FDA-UMAB(931011)

RATIO (T/R) OF % DISSOLVED AT10 MINUTES

0.2 0.4 0.6 0.8 1.0 1.2 A U C

, A N D C m a x R

A T I O S ( T / R )

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

S O L U T I O N

FDA-UMAB(931011)

AUC

Cmax



Metoprolol IR Tablets: Experimental &Simulation Data

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

0.2 0.4 0.6 0.8 1.0 1.2

A U C

, A N D C m a x

R A T I O S ( T / R )

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2AUC

Cmax

Plot 1 Regr

F D A - U

M A B ( 9 3 1 0 1 1 )

S O L U T I O N

T 8 5 %

~ 3 0 m

i n

i n v i t r o

0.1 0.2 0.3 0.4 0.50.0

0.5

1.0

1.5

2.00.0

0.5

1.0

1.5

2.0

0.750.80

0.85

0.90

0. 95

0.70 0.75

0.80 0.85

0.90

0. 95

Mean Intestinal Transit Time = 3.33 h

Mean Intestinal Transit Time = 1.67 h85%

DISSOL

U TION

TI

ME

(h)

Gastric Emptying Half-Time (h)



Ajaz Hussain, FDA

Risk Factor: Excipients

• Is the [current] approach of evaluatingexcipients 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 thesame 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 FormulationsIngredient Test Formulation Reference

Formulation

BCS

Permeability

Ranitidine orMetoprolol

0.15 g0.1 g

0.15 g0.1 g

LowHigh

Sucrose - 5 g High*

Sorbitol 5 g - Low

Water 15 ml 15 ml High

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

complete absorption



Bioequivalence Assessment

Parameter Lower90% CI

Upper90%CI

Ln (Cmax) Ran: 44%Met: 71%

Ran: 54%Met: 85%

Ln(AUCi) Ran: 52%Met: 86%

Ran: 62%Met: 100%

Note: Solution containing sucrose was used as the reference



Ajaz Hussain, FDA

Excipient Effect for a Class III Drug

(Hussain et al. AAPS Annual Meeting, 2000)

Ranitidine: 150 mgSucrose: 5 gSorbitol: 5 g



Common Excipients in IR TabletsCOMMON EXCIPIENTS IN TABLETS

(The Inactive Ingredient Guide: More than 100 submissions)

Number of Submissions

0 500 1000 1500 2000 2500

E x c i p i e n t

0

5

10

15

20

25Methyl cellulose

GelatinPropylene glycol

Acacia

Ethyl cellulosePolysorbate 80

CrosspovidonCarnuba wax

Hydroxy propyl celluloseSucrose*

TalcCalcium phosphate*

Sodium lauryl sulfatePolyethylene glycol*

Crosscarmellose sodiumTitanium dioxide

Hydoxy propyl methyl cellulose*Povidone

Stearic acidSodium starch glycolate

Silicon dioxideLactose*Micorcrystaline cellulose

Starch*Mg-stearate

List does not include colors* Several types combined



Impact of Polysorbate 80* on BEINACTIVE INGREDIENTS IN

5 VERAPAMIL "AB" RATED TABLETS

# of Products

0 1 2 3 4 5

5

10

15

20

25Colloidal silicon dioxideCorn starchCroscarmellose sodiumD&C Yellow #10Dibasic calcium phosphateFD&C Blue

GelatinHydoxypropylmethyl celluloseHydoxy propyl celluloseIron oxideLactoseMg. stearateMicrocrystalline celluloseOpadry whiteOpaspray bright yellowPolacrilin potassiumPolyethylene glycolPolysorbate 80Propylene glycolSodium starch glycolateSodium carboxymethyl celluloseStearic acidTalcTitanium dioxideTriacetin

* Used as a plasticizer



Ajaz Hussain, FDA

Risk Factor: Excipients

• Is the [current] approach of evaluating excipientsfor decisions related to biowaiver of oral solutionssufficient? – 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 drugabsorption compared to liquid oral product

– High permeability attribute reduces the risk of bio-in-equivalence

• decreased small intestinal residence time by osmoticingredients

• enhanced intestinal permeability (potentially by surfactants)



Ajaz Hussain, FDA



BCS Class Membership: Risk BCS Class Membership: Risk ManagementManagement

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

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

J e j u n a

l P e r m e a

b i l i t y

P e f f ( x 1 0 - 4

) c m

/ s e c

1 10 100 1000 10000 1000000.01

0.1

1

10I

III

II

IV

Rapid Dissolution (in vivo & in vitro)Likely Unlikely

Dissolution likelyto be “rate determining.”

Complex in vivo disso. Andsolubilization process.

Dissolution in vivo

not likely to be ratelimiting - well

characterized excipients

Some hesitation withthe use of current

dissolution test

and concernswith respect toexcipients.

Generally “problem” drugsin vitro dissolution may

not be reliable



Ajaz Hussain, FDA

Bioequivalence: IR Products

Reference Test

PharmaceuticalEquivalentProducts

Possible Differences

Drug particle size, ..

ExcipientsManufacturing process

Equipment

Site of manufacture

Batch size ….

Documented Bioequivalence= Therapeutic Equivalence

(Note: Generally, same dissolution spec.)

Normal healthy subjectsCrossover design

Overnight fastGlass 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,..

US Food and Drug Administration: 2005-4137S2 02 Hussain

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