Bioequivalence and Characterization of Generic Drugs

Xinyuan (Susie) Zhang

DQMM/ORS/OGD/CDER/FDA November 18, 2016

CERSI workshop: Substitutability of Generic Drugs: Perceptions

and Reality

Disclaimer: The views expressed in this presentation are those of the speaker and not necessarily those of the Food and Drug Administration (FDA).

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OGD General Procedures to Study Substitutability of Generic Drugs

In vivo performance evaluation

Conclusion and communication

GDUFA research studies

Absorption modeling for risk evaluation Conduct studies

Problem identification

Root cause analysis

Formulation In vitro performance

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Evaluate the impact of slow dissolution in a specific pH condition on BE (warfarin sodium tablets)

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Warfarin Case Background

Root cause analysis (OPQ,

2013-2014)

Modeling and simulation (OGD, 2014)

In vivo BE study (VACR, 2015)

Signals detection in FAERS (OSE, 2013-2014)

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In Vitro Studies

• Purpose – Identify an appropriate condition to stress the tablets

• Stress Conditions – 40 °C/75% RH for 1, 3, 4 hours, 1, 2, 4, 7, and 14 days – additional 2, 4, and 7 days, respectively, at 25 °C/60% RH

• In vitro performance test – Dissolution

• Two-stage (pH 1.0 -> pH 7.5) • pH 4.5 • Water

– Assay, Impurities, IPA – Crystallinity

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Slightly Change in Color

Top row: Coumadin Bottom row: Taro 40°C/75%RH

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Assay was within spec under the stress condition for less than 7 days

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80 85 90 95 100 105 110

untreated 1h 3h 4h 2d 4d 7d 7d

14d 2+7 4+77+7

Taro Coumadin

7+7 and 14 days conditions failed the assay specification.

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Isopropyl Alcohol (IPA) was not detected after the tablets were exposed in the

stressed condition for more than 4 hours

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sample condition warfarin sodium

weigh (mg/tablet) amount(%)

IPA content(%)

Coumadin

Untreated 5.15 103.06 8.63

40°C, 75%RH 1 d 4.89 97.81 Not

detectable 40°C, 75%RH 1 d and

shipping for one week

5.02 100.33 Not

detectable

Taro

Untreated 5.12 102.45 9.40

40°C, 75%RH 1 d 4.93 98.65 Not

detectable 40°C, 75%RH 1 d and

shipping for one week

5.01 100.20 Not

detectable

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XRPD: Excipients vs Fresh Tablets

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starch

Magnesium Stearate

Lactose Taro fresh

Coumadin fresh

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Crystallinity transformed to amorphous form after treatment

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Peak at 2-theta angle of approx 8 is warfarin Na crystal specific

Coumadin treated Taro untreated

Coumadin untreated Taro fresh

Coumadin fresh

Taro treated

WFS powder

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Dissolution in Water at 30 min

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Dissolution decreased in acidic conditions after being treated in stressed condition.

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0

20

40

60

80

100

120

0 50 100 150 200

% D

isso

lved

Time (min)

2-stage

Coumadinuntreated (C)

Taro untreated (A)

Coumadin 1day (D)

Taro 1day (B)

0

20

40

60

80

100

120

0 20 40 60 80

% D

isso

lved

Time (min)

pH 4.5

Coumadin untreated(C)

Taro untreated (A)

Coumadin 1day (D)

Taro 1day (B)

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Hypotheses

• The loss of isopropyl alcohol (IPA) will have impact on in vivo performance

• The slower dissolution in acidic media will have impact on BA/BE

Crystalline warfarin sodium is a clathrate with 8-8.5% isopropanol (IPA)

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Mechanistic Oral Absorption Modeling and Simulation

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Innovative Model for Future Product Development

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PBPK modeling for oral dosage forms

Zhang X. et al. (2014) Clinical Pharmacology & Therapeutics

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Simplified Absorption Process

Zhang X. et al. (2014) CPT

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Inputs and Outputs Drug substance and product information: •Dose and dose volume •Solubility vs. pH profiles •logP, pKa •Dissolution: MR: dissolution profiles; IR: particle size and density •Diffusion coefficient •Permeability •Metabolic kinetics

Physiological parameters •GI transit time •GI geometry •GI fluid properties •Enzymes/transporters distribution •Blood flow

PK parameters • Clearance, Vd • Tissue/organ parameters

for physiologically based distribution and elimination models

• Fa, Fg • In vivo dissolution • Drug in each cmpt

• Fh, BA • PK profiles

Metabolite Info

Parent and metabolite PK

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General Practice

Data collection

PBPK/absorption model building

Model validation

BE simulation

Zhang X. et al. (2011) The AAPS Journal Babiskin A. et al. (2015) J Pharm Sci.

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Warfarin Sodium Parameters API Warfarin sodium

pKa 5.28

Solubility vs. pH: Various solubility values were reported

logP 2.6

Permeability High

T1/2 (hr) Average 40 hrs, range 20-60 hrs

pH 4.5 pH 6.8 pH 7.5aa 0.005 0.279 1.11b 0.0001 0.279 1.11c 1.11 1.11 1.11d 0.0001 0.005 0.005e 0.0001 0.01 0.01f 0.0001 0.02 0.02

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Solubility profile does not impact PK significantly

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Particle size and density do not impact PK significantly

0 100 200 3000.99

1

1.01

1.02

particle diameter (µm)

Cm

ax r

atio

0 100 200 3000.99

1

1.01

1.02

particle diameter (µm)

AU

Ct r

atio

0 1 2 30.99

1

1.01

1.02

particle density (g/mL)

Cm

ax r

atio

0 1 2 30.99

1

1.01

1.02

particle density (g/mL)

AU

Ct r

atio

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Effect of Dose on PK (under single dose condition)

0.9 1 1.1 1.2 1.30.9

1

1.1

1.2

1.3

dose ratio

PK r

atio

CmaxAUCt

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Warfarin dissolution profiles

40°C/75% RH One Day plus 25°C/60% RH for 7 Days

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Simulation based on the Z factor predicts BE

Cmax AUC0-72Pred. Pred.

RLD untreated Test treated 1.0000 1.0181RLD untreated RLD treated 0.9996 1.0181RLD untreated Test untreated 0.9998 1.0081RLD treated Test treated 1.0004 1.0000Test untreated Test treated 1.0002 1.0100RLD treated Test untreated 1.0002 0.9901

Reference Test

σWR = 0.1

(0.955, 80%)

(0.5, 30%)

(0.5, 80%)

Mapping the Dissolution Space for BE

Based on the RSABE criteria, if the PE of Cmax was 0.955 and the passing rate was 80%, it required minimum 30% release at 30 min in pH 4.5 and 80% release at 30 min in pH 6.8.

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BE study design

• Four treatments – A: Taro 5 mg tablets stored at room temperature. – B: Taro 5 mg tablets 40 °C/75% RH for 1 day. – C: Coumadin 5 mg tablets stored at room temperature. – D: Coumadin 5 mg tablets 40 °C/75% RH for 1 day.

• Four sequences – ABCD, BCDA, DCAB, DABC

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Average BE Analysis (2016)

A: Test 5 mg tablets stored at room temperature. B: Test 5 mg tablets 40°C/75% RH for 1 day. C: RLD 5 mg tablets stored at room temperature. D: RLD 5 mg tablets 40°C/75% RH for 1 day.

AUC0-72 Cmax

Geometric Mean Ratio

90% Confidence Limits

Geometric Mean Ratio

90% Confidence Limits

Primary Comparisons

B vs. C 0.998 (0.968, 1.030) 1.007 (0.957, 1.059) C vs. D 0.996 (0.965, 1.028) 1.009 (0.941, 1.082)

Secondary Comparisons

A vs. C 1.017 (0.979, 1.056) 0.990 (0.906, 1.082)

B vs. D 1.014 (0.974, 1.056) 1.014 (0.974, 1.056)

A vs. B 1.015 (0.990, 1.041) 0.979 (0.916, 1.048)

A vs. D 1.014 (0.974, 1.056) 1.007 (0.909, 1.116)

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Results

• Solubility in low pH, particle size, and particle density did not have significant impact on bioavailability.

• Dose (potency) impacted PK proportionally. • Dissolution rate at pH 6.8 was the most relevant

condition to bioavailability. • An in vivo BE study confirmed the prediction. • M&S helped map the post-market risk assessment

space where it’s infeasible to conduct in vivo studies for all scenarios.

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Summary • OGD conducts both internal and external

research activities to address the substitutability of generic drug products issues.

• Modeling and simulation plays a significant role in the studies of substitutability of generic drug products.

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Acknowledgements • Hong Wen, Ph.D. • Jianghong Fan, Ph.D. • Minori Kinjo, Ph.D. • Jill Brown, B.S., R.N. • Wanjie Sun, Ph.D. • Wenlei Jiang, Ph.D. • Myong-Jin Kim, Pharm.D. • Liang Zhao, Ph.D. • Robert Lionberger, Ph.D. • Purdue University: Prof. Tonglei Li, Ph.D. • VACR