PDA: A Global Association

Innovation in Medicines

and Manufacturing

David Tainsh, GSK

Keith Pugh, MHRA

Joint Regulators/Industry QbD Workshop28-29 January 2014 London, UK

Introduction

• Current State

– We have heard a lot about the challenges and

successes of applying QbD

– Aside from Biopharms which we know are complex,

Immediate Release Products are just the tip of the

iceberg and we need to be more innovative if we are to

be successful in delivering consistent and reliable

quality for all products.

• Future State

– So before we close this workshop we just wanted to

reflect on some of the new challenges facing us, what

could be different and to ask how do you see it?

2

Challenges to Innovation

• Current Levels of Technical Capability

• Availability of New Skillsets

• Unwillingness to Deploy New Technology

• Large Investment in the Current State

• Perceptions of High Regulatory Hurdles

• Lack of Process to Manage Complex LCM

Changes

• Lack of an Overall Vision on How to Modernise

Pharmaceutical Manufacture

3

Opportunities for Innovation

• Novel Product Types for QbD

– More Complex Traditional Medicines

• Prolonged release Oral, Inhaled DPI, Nanoparticulates

– Novel products

• Advanced Therapeutics, Oligonucleotides, Microneedles

• Novel Methods of Manufacture & Control

– Continuous

– Synthetic Biochemistry - Biotransformations

– Discrete Manufacture & Novel Analytics

• Others?

4

Continuous Manufacturing:- Enabling Things Batch Can’t Do

Process

Factory

Business

• Shorter End to End Process Times

• Faster, Lower Cost Development

• More Process Understanding

• Lower Work In Progress Costs

• Safer

• More Scale Independent

• Reliable Consistency

• Volume Flexibility

• Sustainable & Greener

Benefitting

- Quality for Patients,

- Environment

- Business

Enzyme

Chemoenzymatic Approach

Enzyme

Cascade Synthesis

Synthetic Biochemistry

Moving to Microbial

Cell Factories

• Greener, Cleaner, Cheaper

- No solvents, fewer reagents

- Fewer isolations & by-products

- Aqueous based benign waste

Biotransformations can be very

specific in terms of chirality,

position and functional group.

Liquid Dispensing Technology Platform

Industrial scale machine installed to provide Phase 3 and Launch Capability

Capacity: 1 million tablets/day, upgradable to 2 million/day

7

Manufacturing - A Paradigm Shift

“Population of Many”

Quality assessed by

sampling post manufacture

Mfg….. Batch Mfg….. Discrete Units

Quality assessed on-line

for every tablet

“Population of One”

8

Drug Solution or

Suspension

+ Placebo Tablets

Low Volume

(c. 2-20ul)

Dispensing

On-Line

Analysis

Chemical

Imaging

Surface

Coating

& Printing

Liquid Dispensing Technology with PAT

Drying

IR orMicrowave

1. Image analysis2. NIR Chemical

Imaging

1. Vision system,droplet size

2. Droplet weight

UV / NIR[suspensionconcentration]

No Linkage between First and Last Tablet

9

Video Image of Droplet:“What was Delivered”

Process Analytical Technologies

NIR Chemical Imaging:“Where on the Tablet”

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80 82 84 86 88 90 92 94 96 98 100102104 106 108110112114116 118

LSL -3.*S Nominal +3.*S USL

0

25

50

75

100

125

150

Comparison of Droplet Content Uniformity vs

Typical 2mg Tablet Content Uniformity

6.9

4E

6

6.9

6E

6

6.9

8E

6

7E

6

7.0

2E

6

7.0

4E

6

7.0

6E

6

7.0

8E

6

7.1

E6

7.1

2E

6

7.1

4E

6

7.1

6E

6

7.1

8E

6

7.2

E6

7.2

2E

6

7.2

4E

6

7.2

6E

6

7.2

8E

6

7.3

E6

7.3

2E

6

7.3

4E

6

7.3

6E

6

LSL -3.s +3.s USL

0

50

100

150

200

250

300

350

Fre

qu

en

cy

DropletN= 606PpK =16

Tablet N= 520PpK =1.4

115%85%

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Control and Testing

Incoming

core tabletDosing Drying

Coating &

Printing

100% Vision

QC Inspection

System monitoring – tablet shift register and rejection confirmation

UV

Solution

Analysis

Reticule

Calibration

Drop

Volume/Dose

Content

Wet Dose Position

Inspection

Droplet

Weight CheckPad Inspection/

Coating Confirmation

Tunnel Temp.

Conditions

NIR Dose

Position

Inspection

100% Vision

QC Inspection

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Desired State

• A Vision to Modernise Pharmaceutical

Manufacture

• Enabling Regulatory Strategy and Process that

keeps pace with Innovation

• Increased Opportunities for Scientific Dialogue

around innovative platforms

• Education and Training to Provide New Skillsets

• Enhanced scientific and risk based approaches

to QbD to match new technologies

• A Simplified and Streamlined Variations Process13

Challenges to Innovation

• Current Levels of Technical Capability

• Availability of New Skillsets

• Unwillingness to Deploy New Technology

• Large Investment in the Current State

• Perceptions of High Regulatory Hurdles

• Lack of Process to Manage Complex LCM

Changes

• Lack of an Overall Vision on How to Modernise

Pharmaceutical Manufacture

14

Desired State

• A Vision to Modernise Pharmaceutical

Manufacture

- Industry driven

• Enabling Regulatory Strategy and Process that

keeps pace with Innovation

– Facilitate within existing Regulation

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Desired State

• Increased Opportunities for Scientific Dialogue

around innovative platforms

- Scientific Advice (EMA/NCA)

- Working Parties e.g. QWP, BWP

- PAT team

- early interactions recommended

• Education and Training to Provide New Skillsets

- Should also include Regulators

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Desired State

• Enhanced scientific and risk based approaches

to QbD to match new technologies

- Apply and build on existing learning

• A Simplified and Streamlined Variations Process

- EU legislation (Common system since August 2013)

- Changes already classified on a risk based basis

- Detailed classification guideline

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Type IA Type II

Evaluation Procedure adapted to the level of risk

Changes not requiringany prior approval

Changes requiringprior approval

Type IB

(Default)

ExtensionDesignSpace

Variations

Summary - Types of Variations

‘Do & tell’‘Tell, wait & do’

No submission required if within an approved design space

Desired State

• A Simplified and Streamlined Variations Process

- EU - Changes already classified on a risk based basis

- Additional flexibility – Post Approval Change

Management Protocol (PACMP)

- justify downgrading in type of required variation

- no restrictions to the nature of changes

- limit (Type IB) regarding level of downgrading for biopharmaceutical products.

- Global challenges

- What do you want?

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Conclusion

• By No Means a Comprehensive View of the Challenges Facing All of Us or the Possible Solutions

• But a Stimulus for Further Discussion

• So How do you See the future Challenges and Opportunities for Innovation?

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