High Throughput and Predictive Stability Approaches for Parallel Drug Product

Development

Pharmaceutical Development and Manufacturing Sciences, PDMS, Janssen pharmaceutica NV

Likun Wang, Sabine Thielges, Maarten van der Wielen, Stefan Taylor

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Disclaimer

The opinions expressed in this presentation are those of the presenter only and do

not necessarily reflect the positions or opinions of Janssen Research &

Development, LLC. (“Janssen”) or any other individuals or affiliates of Janssen. The

presenter makes no warranties with respect to the accuracy or completeness of the

data or materials presented. All information is provided for informational purposes

only and does not constitute advice or endorsement of any products or processes.

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Janssen Pharmaceutica NV

• A Global Pharmaceutical Company

• A pharmaceutical company of Johnson & Johnson

• HQ in Beerse, Belgium

• Multiple R&D sites in Europe, US, China and India

Janssen, Beerse, Belgium

Janssen, Geel, Belgium

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Outline

Background & Challenges in Pharmaceutical R&D

Overview of LEA platform in Janssen Pharmaceutical Research & Development

Case Studies: • Excipient Compatibility

• Accelerated Stability Assessment Program (ASAP)

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Our challenge in pharmaceutical R&D

• More complex products (the easy ones are gone)

• Constantly increasing regulatory and patient expectations

• Cost of drug development is rising exponentially, and timelines are expanding

• We need more shots on goal due to high attrition

• Need more killer experiments

The solution???

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Drug Product Development

Drug Product

Bioavailability

StabilityProcessability

• Can be developed only if• Bioavailability• Processability• Stability

are achieved simultaneously

• Parallel concept development is the major approach to accelerate drug product development process

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Parallel concept development – a design space perspective

• Need systematic experimentation, e.g.DoE

• Parallel concept development

• Need higher throughput

• Down-scaling and automation is the key

Entire design space

Narrowed design space

Good bioavailability subspace

Good processability subspace

Good stability subspace

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Challenges with down-scaled, automatic experiments

Central information

storage

DoE

Material handling

Analysis

Reporting

DoE (Minitab, Design expert, etc.)

Material handling(different softwares)

Analysis (different software)

Reporting (Excel ?)

Smaller scale and more automation

Am

ou

nt

of

info

rmati

on

Progress of experiment

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LEA: centralized information handling platform

Database RAS

Library Studio

Automation Studio

CM3 Hamilton UPLC …

DoE

Execution & analysis

Symyx data browser

LEA data viewerData query & processing

Report generation

Pipeline Pilot

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Integrating Hardware and software: SM Development labs example

Product Design and Developability Workflows

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• Support to Drug substance and drug product development

• 16 active screening workflows implemented and used as part of our platform-based development approach

API workflows DP workflows

1. Polymorph screen 1. Thermodynamic solubility screen

2. Salt screen 2. Excipient compatibility

3. Re-crystallization screen 3. Solid Dispersion

4. Morphology screen 4. Aqueous solution formulation

5. Forced degradation 5. IV formulation screen

6. Accelerated Stability Assessment Program (DS)

6. Accelerated Stability Assessment Program (DP)

7. Miniaturized powder flowability 6. Precipitation Inhibition

7. Nano-milling & physical stability

8. Co-solvent & lipid formulation screen

9. Powder blend segregation

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PART I. Excipient Compatibility – The Dynamics of Drug Product Stability

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Excipient Compatibility

•Study chemical compatibility behavior between API and excipients

•Closely related to drug safety and efficacy

•Normally carried out in early development phase

•Sometimes included in the preformulation package

•Solid state form selection need to be done before excipient compatibility

•Final morphology, particle size are preferred

•Final synthesis route is best in place

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Different Approaches Towards Excipient Compatibility

1:1 mixtures • Easy to set-up• May overestimate (Not the actual ratio)• May underestimate (Synthetic effect)

Full Blend then N-1 method (remove one excipients per time)• Gives more information• 2-step method• More time consuming

DoE approach – Mixture Design

• Able to predict the dynamics of mixture• Much more samples need to be prepared

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Challenges to conquer before getting the benefits of mixture DoE

•Powder dispensing

•Mixing powder homogeneously in small scale

Component 1 Component 2 Component 3 Component 4 Component 5 Component 6 Component 7

Run A:MCC B:Mannitol C:Lactose D:Aerosil 200 Pharma E:Croscarmellose sodium F:SLS G:Magnesium stearate% % % % % % %

1.00 12.89 12.89 12.89 4.43 4.43 3.00 2.482.00 0.00 0.00 32.00 10.00 0.00 6.00 5.003.00 12.89 12.89 12.89 4.43 4.43 3.00 2.484.00 45.00 0.00 0.00 0.00 0.00 6.00 2.005.00 12.89 12.89 12.89 4.43 4.43 3.00 2.486.00 38.00 0.00 0.00 10.00 0.00 0.00 5.007.00 0.00 38.00 0.00 0.00 10.00 0.00 5.008.00 0.00 32.00 0.00 0.00 10.00 6.00 5.009.00 0.00 0.00 45.00 0.00 3.00 0.00 5.00

10.00 43.00 0.00 0.00 0.00 10.00 0.00 0.0011.00 12.89 12.89 12.89 4.43 4.43 3.00 2.4812.00 12.89 12.89 12.89 4.43 4.43 3.00 2.4813.00 12.89 12.89 12.89 4.43 4.43 3.00 2.4814.00 45.00 0.00 0.00 2.00 0.00 6.00 0.0015.00 0.00 0.00 27.00 10.00 10.00 6.00 0.0016.00 0.00 45.00 0.00 0.00 0.00 6.00 2.0017.00 0.00 0.00 43.00 0.00 10.00 0.00 0.0018.00 0.00 43.00 0.00 10.00 0.00 0.00 0.0019.00 0.00 0.00 45.00 0.00 0.00 3.00 5.0020.00 28.00 0.00 0.00 10.00 10.00 0.00 5.0021.00 12.89 12.89 12.89 4.43 4.43 3.00 2.4822.00 0.00 43.00 0.00 10.00 0.00 0.00 0.0023.00 0.00 0.00 27.00 10.00 10.00 6.00 0.0024.00 0.00 32.00 0.00 0.00 10.00 6.00 5.00

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Powder dispensing

Right Arm Z2Vial Plate gripper

SV hopper

LEADatabase

RAS

•Chemical Maps•Dispensing Tags•Processing Tags

•Chemical Maps•Dispensing Tags•Processing Tags

•Time Stamp•Actual Dispenses

Automation Studio

•Time Stamp•Actual Dispenses

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Powder dispensingLEA

DatabaseRAS

Automation Studio

Symyx data browser

LEA data viewer

Pipeline PilotRAS

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Mixing in Small Scale

• Vortex MixingParticle size/morphology not affectedMixing efficiency depends on loadGentle mixing

• Magnetic stirrer bar/diskParticle size/morphology may affectedLonger mixing time

• Turbula MixerParticle size/morphology may affectedGood mixing efficiencyGentle mixing

-0.0499999999999997

2.91433543964104E-16

0.0500000000000003

0.1

0.15

0.2

0.25

0.3

30mg load

100mg load

RSD

of

blen

d ho

mog

enit

y

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

1000 rpm1400 rpm2000 rpm

RSD

of

ble

nd h

om

ogenit

iy

Blend Load (mg)

Vortex mixing speed (rpm)

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Case Study I: Compound X formulation challenge

•Standard capsule formulation•Poor flowability (formulator suggested to add more silicon dioxide)•High Dose (around 50% API load)

No silicon dioxide Medium silicon dioxide High silicon dioxide

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Case Study I: Compound X formulation challenge

• Silicon dioxide could cause degradation

• Interactions between silicon dioxide with fillers were revealed

• Optical formulation ranges can be suggested from stability perspective

• The amount of silicon dioxide need to be carefully controlled

• Mixture DoE and small-scale experiments can be used for excipient compatibility studies

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PART II. Accelerated Stability Assessment Program– The Kinetics of Drug Product Stability

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The concept of Accelerated Stability Assessment Program (ASAP)

• Relative Humidity corrected Arrhenius equation

• Isoconversion

• Monte-Carlo simulation

• Packaging

KC Waterman, AAPS PharmSciTech Vol 12 No.3, September 2011

)(lnln RHBRT

EAk a

% D

egra

dant

Time

70°C

50°C

25°C

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Case Study II: Bench Mark the Stability Behavior of Compound Y concepts

•Compound Y is under BCS Class II (Low solubility, high permeability)

•Need amorphous solid dispersion to boost bioavailabiilty

•28 amorphous solid dispersion concepts were investigated

•Need to predict/compare shelf life for each concepts

• 12 samples need to be prepared for each concept according to ASAP

• 336 samples in total prepared by CM3

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Case Study II: Bench Mark the Stability Behavior of Compound Y concepts

…

The samples preparation is finished within 2 days on CM3

Concepts Y/PVPVA 64 Y/HPMC-AS Y/HPMC E5 Y/Eudragit L100-55

…

Predicted Shelf-Life (year)Based on worst degradant

<1 2.4 2.3 2.6 …

•Automation enabled timely stability study for parallel drug product development •Shelf-life can be predicted via ASAP approach

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Conclusion & Challenges• With DoE and ASAP, down-scale and automation has added-on value for stability studies

• Parallel drug product development could benefit from down-scale and automation

• CM3 is not GMP certified yet

• Combine dynamics and kinetics studies

• Data handling challenge (HPLC peak identification)

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Thank for your attention!

Questions ?

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ASAP isoconversion: % degradant fixed at specification limit, time adjusted

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