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
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
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)

In VIVO
SUPAC-MR
IVIVC
Ajaz Hussain, FDA
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
Ive 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


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
Acceptance
Criteria
Single point
85% in 15 min
Multiple
profiles
(f2 > or = 50)
Single profile
(f2 > or = 50)
AUC & Cmax
90% 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 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
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
o
C.
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?
Dissolution Test &
Bioequivalence: Risk Assessment
Dissolution
generally
over-
discriminating
Dissolution fails
to signal
bio-in-equi
~ 30% (?)
NO YES
N
O










Y
E
S

B
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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
o
C
> 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, .
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?
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
IVIVCs 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 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
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
%

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10
20
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40
50
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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
(weak acid, rapid dissolution in SIF)
Time in Hours
0 1 2 3 4 5 6
D
r
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C
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i
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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, 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.
Ajaz Hussain, FDA
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)
Formulation Specific IVIVC
Peak Concentration Vs. % Dissolved in vitro
Clarke et al. J. Pharm. Sci. 66: 1429, 1977
% Dissolved in 40 minutes
20 40 60 80 100
P
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0
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12
14
16
18
20
22
24
26
28
30
A
B
H
I
D
F
J
C
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 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
TIME IN MINUTES
0
5 10 15 20 25 30 35
%

D
R
U
G

R
E
L
E
A
S
E
D

0
10
20
30
40
50
60
70
80
90
100
110
Rapid
Slow
FDA-UMAB
(931011)
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

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m
a
x

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(
T
/
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)

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
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
AUC
Cmax
Plot 1 Regr
S
O
L
U
T
I
O
N

T

8
5
%


~

3
0

m
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i
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v
i
t
r
o

0.1 0.2 0.3 0.4 0.5
0.0
0.5
1.0
1.5
2.0
0.0
0.5
1.0
1.5
2.0
0.75
0.80
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 h
85%

D
I
S
S
O
L
U
T
I
O
N

T
I
M
E

(h)

Gastric Emptying Half-Time (h)
Ajaz Hussain, FDA
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
FDAs 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
Formulation
BCS
Permeability
Ranitidine or
Metoprolol
0.15 g
0.1 g
0.15 g
0.1 g
Low
High
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 Lower
90% CI
Upper
90%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)
Time(hours)
0 2 4 6 81012
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. (n
g
/m
L
)
0
100
200
300
400
500
Sucrose
Sorbitol
Ranitidine: 150 mg
Sucrose: 5 g
Sorbitol: 5 g
Polysorbate 80: AcPhe(N-MePhe)
2
NH
2

Permeability (CACO-2)
0
5
10
15
20
25
30
35
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
AP - BL BL - AP
Nerurkar, Burton and Borchardt. Pharm. Res. 13: 528-534 (1996)
P
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Common Excipients in IR Tablets
COMMON EXCIPIENTS IN TABLETS
(The Inactive Ingredient Guide: More than 100 submissions)
Number of Submissions
0 500 1000 1500 2000
2500
0
5
10
15
20
25
Methyl cellulose
Gelatin
Propylene glycol
Acacia
Ethyl cellulose
Polysorbate 80
Crosspovidon
Carnuba wax
Hydroxy propyl cellulose
Sucrose*
Talc
Calcium phosphate*
Sodium lauryl sulfate
Polyethylene glycol*
Crosscarmellose sodium
Titanium dioxide
Hydoxy propyl methyl cellulose*
Povidone
Stearic acid
Sodium starch glycolate
Silicon dioxide
Lactose*
Micorcrystaline cellulose
Starch*
Mg-stearate
List does not include colors
* Several types combined
Impact of Polysorbate 80* on BE
INACTIVE INGREDIENTS IN
5 VERAPAMIL "AB" RATED TABLETS
# of Products
0 1 2 3 4 5
5
10
15
20
25
Colloidal silicon dioxide
Corn starch
Croscarmellose sodium
D&C Yellow #10
Dibasic calcium phosphate
FD&C Blue
Gelatin
Hydoxypropylmethyl cellulose
Hydoxy propyl cellulose
Iron oxide
Lactose
Mg. stearate
Microcrystalline cellulose
Opadry white
Opaspray bright yellow
Polacrilin potassium
Polyethylene glycol
Polysorbate 80
Propylene glycol
Sodium starch glycolate
Sodium carboxymethyl cellulose
Stearic acid
Talc
Titanium dioxide
Triacetin
* Used as a plasticizer
Ajaz Hussain, FDA
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
Volume (ml) of water required to dissolve the highest dose
strength at the lowest solubility on the pH 1-7.5 range
J
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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

Ajaz Hussain, FDA
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)


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 FDAs Knowledge space
Drug-excipient interactions (chemistry & clinical pharmacology)
Drug substance and formulation variable and clinical performance
PK, Pk/PD, biomarkers,..