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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