Michael P. Thien, Sc. D.

SVP, Global Science Technology & Commercialization, Merck & Co., Inc.

22 Mar 2017

Perspectives on Continuous Manufacturing: Where Are We Now, Where Are We Going 3rd FDA/PQRI Conference on Advancing Product Quality

To reliably and compliantly supply an (innovative) safe, effective and quality product

that is accessible at a competitive price

2

Challenges

Poor process / method understanding

Crude, open loop control

Manual control (batch)

Long lead times

High fixed costs, high working capital

Properties

What is the Role of Manufacturing?

Attributes of a Manufacturing Facility

• Enhanced quality through online process monitoring

• Minimal offline testing

• Energy efficient with low environmental impact

• Highly automated with advanced technologies

• Small facility footprint

• Short cycle times with low inventory

• Flexible facility with fast changeover

• Rapid response to customer demand

Compliant

Reliable

Quality

21st

Cen

tury

Accessible

Competitive

Innovative

Manufacturing as Strategic

Asset

20th

Cen

tury

Manufacturing as Task

21st Century

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Rejoice! All Problems are Fixed…

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The case for change is compelling …but does not include all products

What Type of Products?

• The more complex the product and less understood the process…

• Risk a new product? Invest in an old one?

• High volume? Low volume?

ICH Q6A (1999): The suitability of either a drug substance or drug product for its intended use.

• Identity • Strength • Purity

Patient

Product

5

What is Quality?

20th

Cen

tury

ICH Q9 (2005): The degree to which a set of inherent properties of a product, system or process fulfills requirements

Process

Product

6

Availability

What is Quality? 21

st C

entu

ry

• Conformance to specifications • Robustness • Reproducibility

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Increased Detectability Clearly see what once

was blurred

Enabled Real Time Control Detect and correct

problems

Improved Consistency Reduce variability

through steady operation

+

+

predictability:

Availability for patients

Quality Wins with Continuous Manufacturing

Why Does Quality Win?

Predicting the Future

• Enhanced quality through online process monitoring

• Minimal offline testing

• Energy efficient with low environmental impact

• Highly automated with advanced technologies

• Small facility footprint

• Short cycle times with low inventory

• Flexible facility with fast changeover

• Rapid response to customer demand

Compliant

Reliable

Quality

21st

Cen

tury

Accessible

Competitive

Innovative

Manufacturing as Strategic

Asset

20th

Cen

tury

Manufacturing as Task

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Attributes of a Manufacturing Facility

21st Century Photos courtesy of Nucor

1960 1970 1980 1990 2000 2010 2020

No.

Art

icle

s / y

r

1980 1990 2000 2010 2020 2030 2040

No.

Art

icle

s / y

r

Pharmaceutical AND “Continuous Processing”

Nucor combines Electric Arc furnace with Mini-mill

1950’s: Continuous

Casting Debuts Nucor focuses on steel

Nucor ushers in Thin Slab technology

Nucor Micromill online

Nucor becomes most diverse steel producer

Steel AND “Continuous Processing”

Un-informed optimism

Vision, Informed Pessimism

Acceptance, Informed Optimism,

Learning Wins

Institutionalization

Un-informed optimism

Vision, Informed Pessimism

Acceptance, Informed Optimism,

Learning Wins

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Nucor Timeline Does This Sound Familiar?

www.nucor.com/story

Quality Win: Enabled Real Time Control

QbD Design Space Media Feed Surge

Bag Surge Bag

Surge Bag

Surge Bag

Surge Bag

Process & Product Quality

Data

Multivariant Model

Data Historian

Feed Forward & Feedback Control

Real Time Release

Raman Bioreactor Feedback

MuScan Bioburden

Rapid Detection

On-Line UPLC Quality Monitoring

Multi-Attribute Methods for

Real Time Release PAT Tools

Controller IT Infrastructure

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Where Are We Now? Continuous Adaptive Bioprocessing: PAT, Automated Control & Real Time Release

Quality Win: Increased Detectability

0

10

20

0 20 40 60Tota

l aci

dic

[%]

BXR Time [Days]

0.0

1.0

2.0

Man

5 [%

]

Supply Chain Responsive Bioprocessing Production: Lab scale feasibility for flexible ‘on demand’ continuous drug supply

Media Feed Surge

Bag Surge Bag

Surge Bag

Surge Bag

Surge Bag

Change Perfusion feed rate doubled

Feed rate change

Impact Minimal impact to purity & quality

Outcome: Agile biologics production enables reliable supply

30 MM cells/mL 1VVD

60 MM cells/mL 2VVD

0

20

40

HC

P [p

pm]

Output (kg)

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Quality Win: Improved Consistency

Where Are We Now?

• What will processes, plants and filings look like in the future?

• How can I learn without asking questions? How can I review complex filings without more time?

• How long will old batch processes stick around?

• Why isn’t industry moving faster, when the incentives are clear?

• Is it worth all the extra work and risk?

• Will all regulators approve of our new processes? Plants? Filings?

• Will we get too many questions with this new process? Will approvals be delayed?

• Can we justify converting old products?

• Can we financially justify a new plant when we have idle capacity?

• Is it worth all the extra work and risk?

Industry Perspective Regulatory Perspective Cautiously Optimistic

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The transition to the continuous manufacturing platform takes time • Everyone must learn: vendors, developers,

operations/quality, regulators • Change: Always in danger?

• Supply chains are strongly interconnected, globally

• Disruptions in one site or supplier ripple throughout the chain

• Similarly, differences in approved applications can strain or break the whole supply chain

Success in continuous manufacturing is dependent upon mutual understanding and aligned expectations

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The transition to the continuous manufacturing platform takes time • Our timeline can be burdened with non-aligned regulations

What Are the Risks? Connectivity in Pharmaceutical Manufacturing

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The case for change is compelling …but does not include all products

Quality wins with Continuous Processing

The transition to the continuous processing platform takes time

• Everyone must learn: vendors, developers, operations/quality, regulators

• Change: Always in danger? • Our timeline can be burdened with non-aligned

regulations

Some Takeaways

1) Provide Opportunities o Pharma companies o Equipment & Raw Material Suppliers o Academia o Regulators

2) Engage and Learn

3) Collaborate and Coalesce o All align on best practices to meet

each other’s needs

Examples

• 1:1 early engagement discussions

• Factory tours

• Professional societies and conferences

• White papers and publications

• Regulator Pilot Programs for harmonization

• E.g., FDA/EMA QbD Pilot

• Direct sharing of knowledge • E.g.,PMDA’s Asian Training

Center for Pharmaceuticals and Medical Devices

• Potential ICH guidance

16 Experiment: Change the Conversation

How Do We Accelerate Moving on OUR timeline?

• Robert Meyer • Cat MacConnell • Christine Moore • Mark Brower • David Pollard • Ganapathy Mohan

• Anthony Tantuccio • Juliana Drinane • PK Yegneswaran • Yanxi Cain • Brendon Ricart • Samantha Hurley

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Team Acknowledgements

Questions?

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