1Biogen | Confidential and Proprietary

Established Conditions and Enhanced

Process Controls

Patrick Swann, Global Regulatory Affairs

Japan CMC Strategy Forum

December 2016

2Biogen | Confidential and Proprietary

• Post-approval CMC changes are difficult

to manage globally

o ~100 countries; several have very long

review times (> 3 years in some cases)

o One change could take up to 5 years to

implement globally

o Supply chain complexities

o Patient supply concerns

• Innovation impacts

Current Issues

3Biogen | Confidential and Proprietary

Unleash the Potential of Productivity –

Constant Drive for Improvement

Process Intensification• High-producing cell line

• Media development

• Process Design

• Advanced Process Control (APC) technologies

Operation Intensification• Process optimization

• Facility utilization optimization

Cell line & Process Development Technology Transfer & Process Lifecycle Management

Pro

du

cti

vit

y

CO

GS

Desired State:“A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high

quality drug products without extensive regulatory oversight”

Dr. Janet Woodcock (Director, CDER, FDA)

4Biogen | Confidential and Proprietary

Linking Technical and Regulatory Risk (2012)

ICH Q11 – Development and Manufacture of Drug Substance

5Biogen | Confidential and Proprietary

CMC Strategy Forum Japan 2013 (see CASSS.org)

Mikio Suzuki, ChugaiPatrick Swann, Biogen

Linking Technical and Regulatory Risk (2013)

6Biogen | Confidential and Proprietary

Linking Technical and Regulatory Risk (2015)

Cook and Robert, EMA

See EMA website…WC500196657.pdf4

7Biogen | Confidential and Proprietary

ICH Q12, Enhanced Approaches & Regulatory Flexibility

• ICH Q12 successful implementation should promote

innovation and continual improvement.

• ICH Q12 builds from ICH Q8 – Q11. ICH Q8 describes

relationship between enhanced approaches and regulatory

flexibility

• A greater understanding of the product and its

manufacturing process can create a basis for more

flexible regulatory approaches. The degree of

regulatory flexibility is predicated on the level of

relevant scientific knowledge provided in the

registration application.

8Biogen | Confidential and Proprietary

Future manufacturing processes will utilize :

Enhanced process controls -much greater level of process understanding and control

Scientific models and process signatures will support product quality prediction

Adaptive control will be a critical element of process consistency

What does this mean for ICH Q12 and Established Conditions?

Scientific Models Adaptive Process

Controls/optionality

Adaptive

Control

9Biogen | Confidential and Proprietary

Enhanced Process Controls

15kL3750L950L

Seed

train

Production

ReactorHarvest

Raw

MaterialsPurification Filling

DS

Rele

ase

Bioreactor: in-line

Raman, capacitance UF/DF: in-line Protein

concentration

feedback feedback

Feed

forward

Screening and Genealogy

Multivariate analysis for process monitoring and disposition decisions,

Predictive model for RTRT or FF control

Prospective RM

control

Consistent cell growth =

consistent PQ & TiterRapid PQ assessment

(MA assay or model)

“Right Time” Release Testing (Expedite PQ assessment &

batch release)

Increase process robustness by better control of raw material / process

variability

DS Safety

Foundations:• Extensive raw material, process, product characterization and understanding

• Right technologies at right places – value added, reasonable cost

• A fully-integrated, implementable, reliable and sustainable control system

10Biogen | Confidential and Proprietary

Established Conditions - Decision Tree

ICH Q8

ICH Q9

11Biogen | Confidential and Proprietary

Established Conditions for Monoclonal Antibodies with

Effector Function

Production Bioreactor UF/DF Drug Substance

Testing

Traditional

Temperature, pH, dissolved oxygen,

culture duration, viability,

bioburden, mycoplasma, in vitro

virus

Feed and retentate

bioburden/endotoxin,

Diavolumes,

System prime/rinse pH

and osmolality

Attribute 1Attribute 2Attribute x…Glycoform, Aglycosylationand charge variants

pH, osmolality

Enhanced

Culture duration, viability,

bioburden, mycoplasma, in vitro

virus, parameters used for the basis

of the predictive model or in-process

test for glycoform, Aglycosylation &

charge variants

Feed and retentate

bioburden/endotoxin,

inline pH/conductivity of

retentate

Attribute 1

Attribute 2

Attribute x…

These controls are EC in addition to a high level description of the process, facility,

product-contact equipment (e.g. scale) and input materials (e.g. MCB).

12Biogen | Confidential and Proprietary

Established Conditions for Monoclonal Antibodies with

Effector Function

Production Bioreactor UF/DF Drug Substance

Testing

Traditional

Temperature, pH, dissolved oxygen,

culture duration, viability,

bioburden, mycoplasma, in vitro

virus

Feed and retentate

bioburden/endotoxin,

Diavolumes,

System prime/rinse pH

and osmolality

Attribute 1Attribute 2Attribute x…Glycoform, Aglycosylationand charge variants

pH, osmolality

Enhanced

Culture duration, viability,

bioburden, mycoplasma, in vitro

virus, parameters used for the basis

of the predictive model or in-process

test for glycoform, Aglycosylation &

charge variants

Feed and retentate

bioburden/endotoxin,

inline pH/conductivity of

retentate

Attribute 1

Attribute 2

Attribute x…

These controls are EC in addition to a high level description of the process, facility,

product-contact equipment (e.g. scale) and input materials (e.g. MCB).

Extreme ranges allowed by

controls results in

acceptable

quality

13Biogen | Confidential and Proprietary

Viral Inactivation

Capture Column

Polish Column #1

Polish Column #2

Viral Filter

UF/DF

Harvest

Rapidly

Measure %

Aggregate in

Column Load

At-Line

Load to X g/L

Below threshold

Load to 0.5X g/L

Above threshold

Feed Forward (FF) Control Opportunity

Aggregate controlled to acceptable level

EC: Feed forward control strategy = at-line aggregate

measurement pre-column determines column loading

Maximize yield Increased aggregate removal

14Biogen | Confidential and Proprietary

How Could ICH Q12 Help Facilitate Innovation?

Effort

• Clarify binding and non-binding information via Established Condition to support project prioritization

• Use PACMP to facilitate post-approval changes by reducing reporting category as appropriate

• Use LCM plan to prospectively and strategically plan future changes

15Biogen | Confidential and Proprietary

How ICH Q12 could help? Examples:

High PriorityInternal change control

Median/High PriorityLifecycle Management Plan

Post Approval Change Management

Protocols

Median Priority Internal change control

Low PriorityNo investment

Effort

Bu

sin

ess Im

pact

Low

High

HighNon-EC EC

Col. lifetime

extension

Titer increase or

consistency ↑

Yield% increase or

consistency ↑

Buffer

optimization

Desired State:

ICH Q12 Tools unleash the potential of productivity by clear

identification of Established Conditions and a proactive LCM strategy

Effort

16Biogen | Confidential and Proprietary

How to Manage Lifecycle of Established

Conditions?

• Lifecycle Management Plan

o Provides proof that the Company is operating in a state of control with respect to PQS

Reference approaches from to ICH Q8, Q9, Q10, and Q11

o Provides transparency for Health Authorities and plan to get agreement on how to report post-approval changes:

Contains Established Conditions decision tree and a comprehensive list of Established Conditions with a link to the Module 3 section(s) (Module 1.2 for Japan)

Contains a link to the Module 3 section(s) where the justification for the Established Conditions is located. For PMDA, provide a link to Module 1.2

Contains any planned/estimated changes to Established Conditions throughout the product’s lifecycle and the proposed reporting category for the changes

References any PACMPs that may be associated with planned changes and used to justify a lower reporting category

ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

slide 17

How ICH Q8, Q9, Q10 guidelines are working together throughout

the product life cycle

© ICH, November 2010

Q8(R2) - Example QbD Approach

• Quality Target Product Profile (QTPP)

• Determine “potential” critical quality attributes (CQAs)

• Link raw material attributes and process parameters to CQAs

and perform risk assessment

• Develop a design space (optional and not required)

• Design and implement a control strategy

• Manage product lifecycle, including continual improvement

CQA’s

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement

18Biogen | Confidential and Proprietary

Are QbD Approaches Facilitated by Q12?

CQA’s

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement

Established Conditions (EC) and Lifecycle Management (LCM)

Clarify LCM for lower risk process

parameters and raw materials

Criticality of attributes based on ranges possible under EC

19Biogen | Confidential and Proprietary

Summary and Conclusions

• ICH Q12 is intended to work with ICH Q8 to Q11 Guidelines to facilitate the management of post-approval CMC changes

• The concept of “Established Conditions” provides clarity for post approval regulatory activities

• Examples were provided to illustrate how the identification of EC can reflect the development strategy (traditional vs enhanced)

• Successful implementation of Q12 concepts will (hopefully) promote innovation and continual improvement to the benefit of industry, regulators and patients

20Biogen | Confidential and Proprietary

Veronique Bailly, Technical Development

Shannon Holmes, Regulatory Affairs

Canping Jiang, Manufacturing Sciences

Helena Madden, Regulatory Affairs

Tadashi Mikami, Japan Global Operations

Amy Morrison, Technical Development

Brad Stanley, Technical Development

Valerie Tsang, Technical Development

Kimberly Wolfram, Regulatory Affairs

Rohin Mhatre, Regulatory Affairs

Acknowledgements