The use of computational tools in development and manufacture in the pharmaceutical industry

Richard Storey

Materials Scientist, AstraZeneca Pharmaceuticals Macclesfield14/12/16

Contents• Overview of Pharmaceutical formulation development• Our vision for Pharmaceutical Sciences• Importance of Materials Sciences to product design and how it

has inspired our vision • Case studies highlighting our scientific ecosystem • Future perspective and how ADDoPT will catalyse our vision

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Developing a new medicine takes a long time and is risky

Patent life is 20 years

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Discovery

Preclinical Testing $335mPhase 1 20‐100 healthy volunteers $142m

Phase 2 100‐500 patients  $137mPhase 3 1000‐5000 patients $174m

Regulatory review $14mTesting/post marketing Total $802m

5000-10000 chemical compounds screened250 enter preclinical testing

5 enter clinical testing1 approved by regulators

Only 1 in 5 recoups development costs

Why do we need a pharmaceutical dosage form?• Dosage forms (e.g. tablet, solution, injection) are required to achieve:

– Control of dose on a per unit basis– Reproducible delivery to the site of action at the correct rate (immediate/modified)– Acceptability to the patient/health practitioner (eg ease of handling)– Ability to be produced reproducibly on a large scale– Sufficient shelf-life for a commercially viable product– Delivery via different routes of administration eg oral, parenteral, inhaled etc.

• Every time!

Pharmaceutical Development has a diverse set of deliverables

Develop Analytical Methods

Develop Formulations and Device

Develop Manufacturing Methods

Product care;knowledge transfer;processing options,exploratory work

Expert evaluation of potential drug compounds from iMeds

Develop Synthetic Route, Drug Substance

Manufacturing, packing and logistics of pre clinical and clinical materials

Develop Packaging

CMC Documentation, and Quality Assurance

Handover to Manufacturing

1. Weighing out excipients 2. Weigh out Bulk Drug 3.Dry mix excipients and drug 4. High shear wet granulation 5. Fluidised Bed Drying

6. Moisture content7. Milling10. Compression

11. De-dusting 12. In process tests 13. Coating dispersion preparation 14.Coating 15. Appearance check

9. Blending 8.Addition of lubricant

Example Tablet Manufacturing Process

Variable materials can provide significant challenges!the same particles

as last time

the right

particles

Particles

we cant

make

now

Moving towards design

Trial and error making and testing, leading to extensive consumption of material and time.

Risk of correlation driven understanding.

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Make

TestSelect

Design Test Refine

Predictive design, followed by prototype testing and refinement. The better the prediction, the fewer the prototypes.

Hypothesis driven understanding.

Reduced experiments

Increased understanding

Use of data to help understand risk of development

• An understanding of previous experiences can help assess the risk of material properties and the process

• Can allow early assessment of risk of successful formulation

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#1 download paper from this journal in 2015

Crystal Structure LandscapeThe power of the community coming together

“One of the continuous scandals in the physical sciences is that it remains impossible to predict the structure of even the simplest crystalline solids”

J. Maddox Nature 1988

• Conformational assessment

• Force field improvements

• Sophisticated search algorithms

• Structural similarity clustering

Pharmaceutical Materials Science Our Evolution -Shaped by Academia

1. Crystal Engineering ~ The design of organic solids. Desiraju 19892. Crystal engineering ~ The design and application of functional solids

Seddon and Zaworotko 19993. Beyond the molecular frontier 20034. EPSRC Direct Assembly Network 20105. MRS Bulletin ~ Pharmaceutical Materials Science 20116. International school of crystallography 48th course ~ Engineering

crystallography from molecule to functional form 20157. Crystal growth & design ~ Molecules, Materials, Medicines (M3): Linking

Molecules to Medicines through Pharmaceutical Material Science 20158. ADDoPT (Advanced Digital Design of Pharmaceutical Therapeutics) project

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12Pfizer Confidential

• An unprecedented structural perspective of product design– Design products from the molecular structure upwards which assists troubleshooting and

importantly allows us to build quality design concepts in de novo.• Enhanced relationships at the academic/industry interface

– We are developing a sophisticated scientific support ecosystem which complements our internal capabilities

• Towards a digital definition of drug product design – We are evolving to use a digital framework for product design and process development

which will revolutionise product realisation in terms of speed and quality.

Our vision - towards a digital definition of drug product design

Pharmaceutical Materials Sciences at Cambridge

Building our vision Towards a national ecosystem for the digital design of products. Leveraging our UK R&D

ecosystem {100} binding

Computational Product and Process Development

Diamond Light Source Unprecedented structural definition

Hartree Centre (STFC Daresbury)Digital frame work

Cambridge Crystallographic Data Centre - Informatics

Particle design at the active ingredient /drug product interface

CrystallisAbilityMolecules that are designed not to crystallise

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‘Anarchy in the solid state: structural dependence on glass-forming ability in triazine-based molecular glasses’ Wuest, J.D & Lebel, O; Tetrahedron 2009 65 7393-7402

N

N

N

NH NH

A B

R1

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Solid form informatics and frequency analysis – Cryptic Crystallography

Mary Queen of Scots

Acc. Chem. Res. 23, 120-126, 1990

The Adventure of the Dancing Men Sir Arthur Conan Doyle

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1998 — Abbott Laboratories announced that it was experiencing manufacturing difficulties with the capsule formulation of its HIV protease inhibitor, Norvir.

"We have encountered an undesired formation of a Norvir (Ritonavir) crystalline structure (Form II) that affects how the capsule form of Norvirdissolves”

“In Form II all of the strong hydrogen bond donors and acceptors have been satisfied and are strong….Since the strength and completeness of the hydrogen bonding has attained the maximum possible in the Form II lattice, it is not thought possible that another undiscovered polymorph of ritonavir would exist with equivalent or lower solubility than that of form II’’

2000 crystallisations identifies two solvates plus an anhydrous form (2003).

[1] Chemburkar et al Org. Process Res. Dev. (2000), 4(5), 413.[2] Bauer et al Pharmaceutical Research (2001), 18(6), 859.[3] Morissette et al PNAS (2003) 100 2180

Norvir Case – Important we build on the learnings NORVIR

Prediction is an important part of process understanding

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Colour Particle size

10 µm20 µm50 µm75 µm

100 µm

• 10 and 20 µm particles seen to exit at the start of the simulation

CFD/DEM modelling of spiral jet mill

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10 μm 9 μm 8 μm 7 μm 6 μm

5 μm 4 μm 3 μm 2 μm 1 μm

• Particle trajectories gradually change with decrease in particle size• Classification only seen with 1 μm particles

Results:Simulation

Molecular Basis of Crystal Morphology-Dependent Adhesion Behaviour of Mefenamic Acid During TabletingVrushali Waknis & Elza Chu & Roxana Schlam & Alexander Sidorenko & Sherif Badawy & Shawn Yin & Ajit S. Narang Pharm Res (2014) 31:160–172

• Sticking of material to punch surfaces during tabletting

• Linked to the slip planes present in the crystal lattice• Different habits produced different levels of sticking• Potential for predicting “right particle” to help control

performance

Cryst. Growth Des., 2013, 13 (7), pp 2824–283

Building the particle passport perspective

Face Specific PropertiesComputable Difficult to measure

Average Surface Properties

= sum of contribution face property Readily measured

Drug Product

Performance Manufacturability Stability

Part

icle

Pas

spor

t Con

cept

(Inte

rnat

iona

l Sch

ool o

f Cry

stal

lora

phy,

Eric

e20

15)

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Synthonic Engineering

Formulation Design Product Performance

Active Ingredient Final Step

Solid FormFormation

A B

a)

c)

Mechanical Properties

Cry

stal

Sha

pe &

Sen

sitiv

ity to

Sol

vent

Surface Energy

Dissolution & Crystal ShapeEffect

Surface-Surface Interactions

Surface Chemistry

Dissolution & Surface ChemistryEffect

Wet

tabi

lity

Building the particle passport

A £20.4m UK Government‐Industry‐Academia collaboration 

“This project has the potential to propel the UK to the forefront of medicinal product design and manufacture”

ABPI & BIA

Part‐funded under the Advanced Manufacturing Supply Chain 

Initiative (AMSCI*)*A BIS initiative delivered by Finance Birmingham and Birmingham City Council

Instigated by the Medicines Manufacturing Innovation 

Partnership (MMIP) 

ADDoPT Project

Project Consortium• Pharma

Primes:

SMEs: 

Research:

Digital Design: Molecules to Medicine

Design and control of optimised development & manufacturing processes through data analysis and first principle models

Processes Products Performance

Quality systems

Release profilesMaterials properties

Particle attributes

Surface chemistry

FormulationProcessing rules

Manufacturing classification

Improve / optimise for impact

DownstreamUpstream

Product and Process Design

Product Performance

CrystallisationFiltrationWashingDrying

ActiveIngredient

(API)

MillingBlending

CompactionCoating

Primary Manufacturing  ‐ Secondary Manufacturing 

Work Packages

WP1

System Framework for Manufacture

WP2 

Case Studies: AstraZeneca, Bristol‐Myers Squibb, GlaxoSmithKline, Pfizer

WP3

Curation and integration of clinical and commercial  manufacturing data

WP4

Constitutive models for manufacturing processes and 

product performance

WP5

Integrated Chemical Supply Chain:  Solid form design to optimize primary and secondary manufacturing 

with product performance

WP6

Process Control & Optimization

WP7

Dissemination, exploitation and training

Flow of informationData may refer to molecules, particles, manufacturing processes, etc.

All Primes Consortium

Data on“dead” compounds/anonymised data

Data on “in pipeline”compoundsBig Data tools:

databases & statistical models correlating data

Each Prime individually

Data on “in manufacture”

compounds

Mechanisticmodelling

tools

Consortium(and beyond)

Non-confidential

Feedback asto how welltools work

to update tool

Publicly availabledata (not limited to

Primes’ compounds),e.g. from

patents, Googlesearches

Public domain

Data sharing with STFC• Creation of models/linkages between physical properties using Hartree

supercomputing facility• Focus topics

1. Modelling of solubility from lattice energy (polymorph changes, single crystal structure, etc.)

2. Prediction of physical bulk properties (density, compressibility, flow, etc) from fundamental properties (shape, size)

• Cross company sharing of analytical data to assist development of big data models to help direct development– Harmonised methodologies/data format

gPROMS FormulatedProductsTracking of material structure across the system

Crystallization

Reaction

Blending

Dry Granulation

Tabletting

Oral Absorption

In‐vitro dissolution

Unit operations effect  transformations of complex materials

Material description reflectsearlier processing

DevelopDevelop

DesignDesign

Fundamental Science

Fundamental Science

SupplySupply

EvaluateEvaluate

Pharma Personal Care

FoodAgrochem

NFCCPI

EPSRC Centres for Doctoral Training / Innovative Manufacture

Platform facilities offering unprecedented structural perspective

DiamondDiamond

CMACCMACStructure

Properties

Processing

Performance

Other high value products…

Catapults

MMIP

EPSRC Research Themes

NPLNPLHartreeHartreeCLFCLF

Engineering

ISISISIS

FormulationComplex

ParticulatesSoft Matter: Polymers

Synthetic Biology Sensors,

Instrumentation

Catalysis

Healthcare

Process Systems

ICTInformation

Systems

Soft Matter: Functional Interfaces

Artificial Intelligence

Distributed Systems

Future Manufacturing

Manufacturing Technologies

Process Systems

Infrastructure

Chemical Structure

Condensed Matter

Computational Modelling

Scientific Computing

Therapeutics

AMSCI

ADDoPTReMediES

HVMDigitalPrec. Med.

Future Formulation

Future FormulationH2020 IMIH2020 IMI Other H2020, SPIRE etc.Other H2020, SPIRE etc.

PMTCPMTC

PSE

SSPCSSPC

InnovateUK ProgrammesHealth

Manufacturing Enabling Tech.

CCDC

PELBritest

Digital Design – An Emerging Cross Sector Ecosystem

Acknowledgements to Simon Black (AZ) and Robert Docherty (Pfizer)

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Formation Solid Form Formulation

Summary