1

Identification of CPPs basedon CQAs & Mechanistic Process & Product Understanding: A Case Study

Ajit S. Narang, Ph.D.Bristol-Myers Squibb, Co.

2nd FDA/PQRI Conference on Advancing Product Quality

Bethesda, MD

October 5-7, 2015

Overview

� Identification of Drug Product CQAs and CPPs:→Prior knowledge→Risk assessment→Product & process knowledge

� Correlational studies, e.g., DoE� Mechanistic studies, e.g., degradation kinetic modeling

� Case study: Brivanib Alaninate tablet development, wet granulation→Stability risk assessment: impact of residual water

� Control strategy during processing→Bioavailability risk assessment

� Drug-excipient binding interaction� Drug self-association

→Process monitoring and control strategy� PATs: FBRM probe, DFF sensor, & NIR

Pharmaceutical Development

Bioavailability

ManufacturabilityStability

4

Composition of Brivanib Alaninate Tablets

Ingredient % w/w

Intra-granular

Brivanib alaninate 50

Hydroxypropyl cellulose 4

Croscarmellose sodium 3

Microcrystalline cellulose 23.50

Water for Granulation 46

Extra-granular

Crospovidone 3

Microcrystalline cellulose 14.75

Colloidal silicon dioxide 0.5

Magnesium stearate 1.25

Opadry reddish brown or yellow 3% (weight gain)

Tablet strength: 400 mg (800 mg core tablet weight)

Mix

Add BMS-582664-02,

Intra-granular MCC,

HPC and CCSHigh Shear Mixer

25 L Fuji high

shear granulator

Granulation High Shear Mixer

Wet Mill

Fluid bed drying

Milling

Add EG MCC,

xPVP, Cab-O-Sil

Bin

Blender

Add Mg

Stearate

and blend

Compress

into Tablets

Manufacturing Process Flowchart

5

6

QbD Methodology

RA• Perform product risk analysis to identify CQAs

PPs & MAs

• List relevant material attributes and process parameters that can potentially impact CQAs

Unit Ops

• Perform process risk analysis to identify attributes and parameters to be studied

DoE etc.• Conduct development studies

CQAs & CPPs

• Identify critical attributes and parameters

CS• Establish control strategy

Formulation Ruggedness Study Design

23 split plot design

Center Point

1.5%

1.5%

4.5%

4.5%

HPC

CCS

Mg Stearate

1.5%

0.5%

2.5 kg batch size

Key Responses

Granulation: -Particle size -Flow-Compaction properties-Adhesion tendency

Tablets:-Visual defects -Dissolution-Friability -Disintegration

Design Space Studied During Process DoE

Impeller Tip Speed

44%

49%

Wat

er L

evel

10s 50s

3.6m/s 6m/s

Wet Massing Time

High Shear Granulation

Quality Attributes

� Potency

� Content uniformity

� Appearance

� Impurities

� Dissolution

Process Parameters

� Each unit operation

� Interactions

In-process material attributes

Mechanistic process understanding

Mechanistic product understanding

- Basis of effect of process parameters

10

RA: Tablet Potency & Content Uniformity

11

RA: Tablet Appearance

12

RA: Impurities

Water Content: Hydrolysis of Prodrug

• Moisture in core tablets posses long term stability risk� Brivanib Alaninate is moisture sensitive � Degradation rate increases when the moisture level is high� This poses a risk to stability over long periods of time

• Over short periods of time (~24h) Brivanib Alaninate is stable in the presence of water

• Control of tablet moisture before packaging is essential to slow degradation rate

00.020.040.060.080.1

0.120.140.160.180.2

0 0.2 0.4 0.6 0.8

Ra

te o

f hyd

roly

sis

% RH/100

13

Target Moisture Level

0

2

4

6

8

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

Moi

stur

e C

onte

nt

(%w

t. g

ain/

wt.

dry)

%RH/100

25°C

0

0.05

0.1

0.15

0.2

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

Rat

e of

form

atio

n of

P

aren

t (%

/day

)

% RH/100

Parent Formation RateAcceptable Degradation

Rate (Parent below limit for 2 years)

Final Moisture Target

Desorption Isotherm

14

Moisture control – option 1

• Humidity control method� Low humidity processing environment prevents moisture

pickup

High Shear Mixer

Water added for granulation

Granulation dried to <1.3%

Low humidity environment

Wet Granulation

Fluid Bed Drying

Blending and Compaction

Film Coating

Packaging

Alu bags

Low humidity environment

Low humidity environment

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Moisture control – option 2

• Coating control method� Uses coating step to remove moisture absorbed during previous

process steps� Does not require current facilities to be modified

High Shear Mixer

Water added for granulation

Granulation dried to <1.3%

Potential for moisture pickup

Moisture driven off

during coating

Low humidity environment

Wet Granulation

Fluid Bed Drying

Blending and Compaction

Film Coating

Packaging

Preheating: <1.6%Final: <1.8%

Alu bags

Limits:

16

17

RA: Dissolution

Effect of Material Attributes & Process Parameters

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RA: Dissolution

Impact of Material Attributes

� API particle size affects drug release rate.

19

RA: Dissolution: Wet Granulation Process Parameters

� DoE study enabled the identification of process parameters that impact product dissolution.

20

RA: Dissolution

Impact of Process Parameters w/Material Attributes

� Dissolution of tablets manufactured with worst case combination of API particle size & wet granulation process parameters

21

RA: Dissolution: Material Attributes

Mechanistic Basis of Effect of Process Parameters

� Identification of in-process MAs that impact DP Qas enables focus of control strategy development.

22

PAT Tools to Support Control Strategy

NIR for Granule Water Content during Fluid Bed Drying

� Real-time measurement of granule water content during drying.

Probe Tip Enlargement

• Rotating focused-laser measures chord length• Proven technology for particles suspended in liquids• Measures particles in contact with probe sapphire tip• Probe placed directly in solution or powder flow

Lasentech FBRM C35 Probe “Chord Length”

Chord Length Distribution by

FBRM

24

Test 1: 1% HPC batch

Test 3: 5% HPC batch

Test 2: 3% HPC batch

10

100

10000

5

10

15

0

200

400

600

800

Chord Length (um)

1% HPC-Dry A: Water - 40% HPC - 1% PH102

Time (minutes)

Sq

uar

e W

eig

hte

d (M

ass)

10

100

10000

5

10

15

0

200

400

600

800

Chord Length (um)

3% HPC-Dry B: Water - 40% HPC - 3% PH102

Time (minutes)S

qu

are

Wei

gh

ted

(Mas

s)

10

100

10000

5

10

15

0

200

400

600

800

Chord Length (um)

5% HPC-Dry C: Water - 40% HPC - 5% PH102

Time (minutes)

Sq

uar

e W

eig

hte

d (M

ass)

1% HPC

3% HPC

5% HPC

25

(i) (ii) (iii)

Drag Flow Force (DFF) Sensor

� Measures ‘wet mass consistency’ that correlated with granule densification/porosity

DFF Sensor Peak

distribution statistics

Test 1: 1% HPC batch

Test 3: 5% HPC batch

Test 2: 3% HPC batch

00.1

0.20.3

0.40.5

0.60

5

10

15

0

10

20

30

40

50

60

70

Force (N)

1% HPC-Dry A: Water - 40% HPC - 1% PH102

Time (minutes)

Nu

mb

er o

f Pea

ks

00.1

0.20.3

0.40.5

0.60

5

10

15

0

10

20

30

40

50

60

70

Force (N)

3% HPC-Dry B: Water - 40% HPC - 3% PH102

Time (minutes)N

um

ber

of P

eaks

00.1

0.20.3

0.40.5

0.60

5

10

15

0

10

20

30

40

50

60

70

Force (N)

5% HPC-Dry C: Water - 40% HPC - 5% PH102

Time (minutes)

Nu

mb

er o

f Pea

ks1% HPC

3% HPC

5% HPC

27

Control Strategy

Acknowledgements

� Sherif Badawy

� Kevin Macias

� Tim Stevens

� Sailesh Varia

� Dilbir Bindra

� Keirnan LaMarche

� Ganeshkumar Subramanian

� Judy Lin

� Pankaj Shah

� Valery Shevrev & Vadim Stepnaiuk, Lenterra, Inc.

Selected Publications and Acknowledgements• Panakanti R and Narang AS (2012) Impact of excipient interactions on drug bioavailability from solid dosage

forms. Pharm Res 29: 2639.

• Narang A, Yamniuk A, Zhang L, Comezoglu SN, Bindra DS, Varia S, Doyle M, and Badawy S (2012) Reversible and pH-dependent weak drug-excipient binding does not affect oral bioavailability of high dose drugs. J PharmPharmacol 64:553-65.

• Badawy SIF, Narang AS, LaMarche K, Subramanian G, and Varia SA (2012) Mecahnistic basis for the effects of process parameters on quality attributes in high shear wet granulation. Int J Pharm 439: 324-333.

• Narang AS, Badawy S, Ye Q, Patel D, Vincent M, Raghavan K, Huang Y, Yamniuk A, Vig B, Crison J, Derbin G, Xu Y, Ramirez A, Galella M, and Rinaldi F (2015) Role of self-association and supersaturation on oral absorption of a poorly soluble weakly basic drug. Pharm Res 32: 2579-2594.

• Badawy SIF, Narang AS, LaMarche KR, Subramanian G, Varia SA, Lin J, Stevens T, and Shah PA (2015) Integrated application of quality-by-design principles to drug product development: case study of brivanb alaniante film coated tablets. J Pharm Sci (under revision).

• Narang AS, Sheverev VA, Stepaniuk V, Badawy S, Stevens T, Macias K, Wolf A, Pandey P, Bindra D, and Varia S (2015) Real-time assessment of granule densification in high shear wet granulation and application to scale-up of a placebo and a Brivanib Alaninate formulation. J Pharm Sci 104: 1019-1034.

• Narang AS, Sheverev V, Freeman T, Both D, Stepaniuk V, Delancy M, Millington-Smith D, Macias K, and Subramanian G (2015) Process analytical technology for high shear wet granulation: wet mass consistency reported by in line drag flow force sensor is consistent with powder rheology measured by at line FT4 powder rheometer®. J Pharm Sci (under revision).