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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
– 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

“Self-evident” - Biowaivers granted
Solutions
Condition- excipients do not alter absorption
(historical data)
Suspensions

Pre-1962 DESI Drugs: In Vivo SUPAC-IR
Chewable, etc.
evaluation for “bio-problem” (1995)
drugs (TI, PK, P-Chem) Dissolution-IR
Conventional Post-1962 Drugs: Generally BCS
Tablets In Vivo - some exceptions (pre-/post
Capsules (IVIVC..) approval)

SUPAC-MR
MR Products In VIVO
IVIVC
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?
• 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
• 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

HS/HP LS/HP HS/LP LS/LP
Critical Process Gastric Dissolution Permeability D/P
Emptying
IVIVC Not likely Likely Not likely (?)

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

Acceptance Single point Multiple Single profile AUC & Cmax
Criteria 85% in 15 min profiles (f2 > or = 50) 90% CI
(f2 > or = 50) 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 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.
Ajaz Hussain, FDA
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
• 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
YES generally
Bioequivalent

“over-
discriminating”

Dissolution fails Why?
NO

to signal
bio-in-equi
~ 30% (?)

NO YES
Dissolution Specification
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

> 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

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
Dissolution tests: Debates
• Dissolution tests are • Dissolution tests are
“over not sufficient to
discriminating” assure
• Products that bioequivalence
dissolve about 70% • Demonstration of
in 45 minutes have IVIVC is necessary
no medically • IVIVC’s are
relevant “Product Specific”
bioequivalence
problems
Dissolution Test Problems:
False +ives and -ives
Test/Ref. Mean
15 min 30 min 45 min AUC Cmax
Ref 95 96 98 100 100
B 96 97 97 104 95
C 62 84 92 84 55
D 82 94 95 88 87
E 103 103 103 112 120
F 13 35 53 100 102
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
110 Product B
100 Product B was not
% Drug Dissolved

90
80 Product A bioequivalent to
70
60 Product A
50
40 Log(AUCinf): CI 94.6 - 123.6
30
20 USP Specification
10 Log(AUC): CI 89.1 - 130.0
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.)
Drug Concentration in Plasma (ng/ml)

1800
1600
Tablet 1
1400 (wet-granulation - starch)
1200 Tablet 2
1000 (direct compression -
calcium phosphate)
800
600

400

200
USP Paddle 50rpm, Q 70% in 30 min
0
0 1 2 3 4 5 6
Time in Hours
NDA #X: Bioequivalent?
• Drug X (100 mg dose, volume • The company wants to
required to dissolve the dose at manufacture the product using
pH 8, lowest solubility, is 230 direct compression.
ml, extent of absorption from a • To-Be-Marketed formulation:
solution is 95%) Direct compression, drug
• Weak base exhibits a sharp particle size (D50%) 300
decline in solubility with microns, dicalcium phosphate,
increasing pH above 3 MCC, Mg-stearate, silicon
• Clinical-trial formulation: Wet dioxide. Tablet weight 500 mg.
granulation, drug particle size Dissolution in 0.1 N HCl - 85%
(D50%) 80 microns, lactose in 15 min., and 95% in 20 min.
MCC, starch, Mg-stearte, Disintegration 1 min.
silicon dioxide. Tablet weight • Clincal product exhibits poor
250 mg. Dissolution in 0.1 N dissolution in pH 7.4 media
HCl 65% in 15 min and 100 % (about 30% in 60 minutes).
in 20 minutes. Disintegration Data for T-b-M not available.
time 10 minutes.
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
• 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
Peak Concentration (ug/100ml)

28 H
26
B
24
E
22

20 D
G
18 F
16 C
J
14 A
12
20 40 60 80 100

% Dissolved in 40 minutes
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

AUC, AND Cmax RATIOS (T/R)
100 Rapid
90 1.1
AUC
80 Slow 1.0
% DRUG RELEASED

70
Cmax
60 0.9
50
40 0.8

SOLUTION
30 0.7
FDA-UMAB
20 (931011) FDA-UMAB
(931011)
10 0.6
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
TIME IN MINUTES 10 MINUTES
Metoprolol IR Tablets: Experimental &
Simulation Data
Mean Intestinal Transit Time = 1.67 h
85% 2.0
0.70
0.75
AUC 0.90
D 1.5
1.2 Cmax
AUC, AND Cmax RATIOS (T/R)

I 0.95
Plot 1 Regr 0.80 0.85
S 1.0
1.1 S
O
1.0 L 0.5
U
0.9 T 0.0
Mean Intestinal Transit Time = 3.33 h
SOLUTION
I
2.0 0.75
0.8
FDA-UMAB (931011)

O
~ 30 min

0.80
N
in vitro

1.5
T 85%

0.7 0.95
0.85
T
0.6 I 1.0 0.90
M
0.5 E 0.5
0.2 0.4 0.6 0.8 1.0 1.2
(h)
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)
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
• 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
Ingredient Test Formulation Reference BCS
Formulation Permeability

Ranitidine or 0.15 g 0.15 g Low
Metoprolol 0.1 g 0.1 g High

Sucrose - 5g High*

Sorbitol 5g - 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 Lower Upper
90% CI 90%CI
Ln (Cmax) Ran: 44% Ran: 54%
Met: 71% Met: 85%
Ln(AUCi) Ran: 52% Ran: 62%
Met: 86% Met: 100%

Note: Solution containing sucrose was used as the reference
Plas
0

Excipient Effect for a Class III Drug
0 2 4 6
Time (hours)
8 10 12

(Hussain et al. AAPS Annual Meeting, 2000)

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

Ajaz Hussain, FDA
Polysorbate 80: AcPhe(N-MePhe)2NH2
Permeability (CACO-2)
Nerurkar, Burton and Borchardt. Pharm. Res. 13: 528-534 (1996)
35

Pe X 106 (cm/sec)
30
25
20
15
10
5
0
AP - BL BL - AP
None 3.85 34.31
5X10(-4) % W/V 5.62 26.52
5X10(-3) % W/V 8.58 20.11
5X10(-2) % W/V 9.44 15.82
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
Excipient

Hydroxy propyl cellulose
Sucrose*
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
List does not include colors
* Several types combined
Number of Submissions
Impact of Polysorbate 80* on BE
INACTIVE INGREDIENTS IN
5 VERAPAMIL "AB" RATED TABLETS
Colloidal silicon dioxide
Corn starch
25 Croscarmellose sodium
Inactive ingredients

D&C Yellow #10
Dibasic calcium phosphate
FD&C Blue
Gelatin
20 Hydoxypropylmethyl cellulose
Hydoxy propyl cellulose
Iron oxide
Lactose
Mg. stearate
15 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
* 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)
Ajaz Hussain, FDA
Ajaz Hussain, FDA
BCS Class Membership: Risk
Management
Rapid Dissolution (in vivo & in vitro)
Likely Unlikely
10
I Dissolution in vivo II
Dissolution likely
not likely to be rate to be “rate determining.”
Peff (x10 -4) cm/sec
Jejunal Permeability

limiting - well Complex in vivo disso. And
characterized excipients solubilization process.
1

III IV
Some hesitation with
the use of current Generally “problem” drugs
0.1 dissolution test in vitro dissolution may
and concerns not be reliable
with respect to
excipients.
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
Pharmaceutical
Equivalent
Products
Reference Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process Normal healthy subjects
Crossover design
Equipment Overnight fast
Glass of water
Site of manufacture
90% CI within 80-125%
Batch size …. of Ref. (Cmax & AUC)

Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution spec.)
Ajaz Hussain, FDA
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