Watch the webinar here: https://bit.ly/2YLDzTE This webinar will take you through the story of a CMO preparing for the manufacture of a Commercial Antibody Drug Conjugate (ADC). Join us to learn about how we grew as a CMO to develop a Commercial ADC program. We will walk through the full timeline from development, process risk assessment and control strategy development and validation, finishing off with preparation for a Commercial ADC Pre-Approval Inspection Audit. In this webinar you will learn how to: • Properly structure your development work • Perform a thorough process risk assessment • Prepare for pre-approval inspection

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Commercializing
antibody-drug
conjugates:
a CMO’s journey
Jake Spies, Elizabeth McKee, Kerry Keith
June 18, 2020

2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

3. Agenda
1
2
3
Development Approach
Journey to Process Performance
Qualification (PPQ)
Pre-approval Inspection Readiness
4 Summary

4. Development
Approach

5. Where it Begins
Webinar, June 18, 20205
Our Journey to Commercialization
Vast Experience working with Antibody Drug
Conjugates (ADCs)
 Making ADCs for > 15 years
 Significant experience introducing clinical supplies
 > 65 different development projects
 > 600 unique development batches
 Various ADC Technologies
Commercial Experience
 Many small molecules and bio-organics
 Internal knowledge base

6. Webinar, June 18, 20206
Microbial Control Strategy
Development Approach
Biologics vs. Small Molecule Drugs
 Biologics
 Greater control of endotoxin and bioburden
 Regulating agency focus
 Setting in-process solution specification and process step limits
 Basis:
 Worst-case inputs
 Historical process data
 Reassess – process capability

7. Quality by Design
Webinar, June 18, 20207
Development Approach
Step Attribute Matrix (SAM)
 Material inputs and unit operations impact on Critical
Quality Attributes (CQAs)
 For example: TFF step may impact level of impurities
 Basis:
 Development work
 Manufacturing
 Scientific understanding
 Purpose:
 “Jumping-off point” for formal process understanding
SAM
Unit Operation
Attribute Step 1 Step 2 Step 3 Step 4
A1 Low N/A Low N/A
A2 N/A N/A High N/A
A3 N/A Medium N/A N/A

8. Quality by Design
Webinar, June 18, 20208
Development Approach
Parameter Attribute Map (PAM)
 SAM indicated which unit Ops can affect product quality
 PAM assesses potential impact of parameter variation on
CQAs
 For example: to what degree could TFF parameters affect
impurity levels
 Basis:
 Development work
 Manufacturing
 Scientific understanding
 Purpose:
 Next step in process understanding – feed process
characterization design
Process
Step
Step
Parameter
Potential
Effect
Severity
Attribute
Affected
Step 1
Parameter 1 High A2
Parameter 2 N/A N/A
Parameter 3 N/A N/A
Parameter 4 Low A1
Step 2
Parameter 1 Medium A3
Parameter 2 N/A N/A
PAM

9. Process Characterization
Webinar, June 18, 20209
Development Approach
SAM
PAM
Process
Characterization
Design
Design Space
DoE
OFAT
Max
Qualified Scale
Down Model
Development Experiments

10. Journey to Process
Performance
Qualification (PPQ)

11. Commercialization
Webinar, June 18, 202011
Journey to PPQ
What is needed for an ADC process to get ready for PPQ and commercialization?
 Needed to focus on expectations for commercial ADCs
 Biologics have few specific regulations
 ADCs still very new to the industry (<5 approved at start of commercial ADC journey!)
 Combines complexity of biologic manufacture with environmental controls for high potent
Our Journey
 Collaboration with customer and experts in the field to gain insight into general expectations
 Incorporated a holistic review of ADC manufacturing and controls, to build our roadmap for
commercialization
 Need to build of assessments and knowledge for clinical manufacture
This journey allowed us to grow and further develop ourselves as
Subject Matter Experts in ADC commercialization

12. Commercialization
Journey to PPQ
1 Validation Master Plan Scoping
What are the important aspects of a validation master
plan?
2 Risk Assessment & Control
What is expected for assessment of risk and
demonstration of process control?
3 Process Performance Qualification
What are the key considerations for PPQ?
Let us Share
what we have
learned!
Webinar, June 18, 202012

13. Validation Master Plan Scoping
Journey to PPQ
Webinar, June 18, 202013
Equipment &
Facility
Qualification
Analytical
Method
Validation &
Microbial
Method
Verification
Risk
Assessments
Cleaning
Validation
Validation
Supporting
Studies
Process
Specific
Control
Strategies
Characterization
and Risk
Assessment
Reports
Shipping
Validation
Microbial
Risk
Assessment
and Control
Holistic look at all aspects of the process
Final review of all potential risks, controls, and requirements for commercial
manufacture

14. Evolution from Clinical
• Additional risk
assessments needed for
commercial readiness
• Scope outlined in
Master Plan
Risk Assessment
• Process Risks
• Operational/Equipment
Risks
• Raw Material Risks
• Microbial Risks
Assessments Drive
• Additional Studies
Needed
• Final Process Changes
• Determination of Critical
Process Parameters
(CPP)
Inputs
• Risk Assessment conclusions and
mitigations
• CPPs
• Critical Quality Attributes (CQAs)
• Acceptance criteria
• Process Characterization
• Quality Management Systems
Outputs
• Control space
• Control of MFG process to meet CPPs
• Documentation of CPP ranges and
relationship to CQAs
• Raw Material Control
• Equipment Control
• Testing & acceptance criteria rationale
Webinar, June 18, 202014
Journey to PPQ
Risk Assessment & Controls
Risk
Assessment for
Commercial
Readiness
Commercial
Control Strategy

15. Webinar, June 18, 202015
Journey to PPQ
Risk Assessment & Controls
OutputsProcessInputs
• Scope of risk assessments
defined in master plan
• MFG process
• Process controls
• Raw materials
• Equipment
• Quality Management System
controls
• Determination of failure modes
• Severity:
• Impact to the process?
• Impact to Critical Quality Attributes
(CQAs)?
• Occurrence
• Detection:
• What controls are in place?
• Mitigation:
• What additional controls are needed?
• Summary of
process risks
• Detailed outline of
inputs impact on
product quality
• Additional
mitigations needed
• Summary of
current controls
and risk mitigations

16. Justification of Validation Approach
 Validation approach, including components such as:
 Number of consecutive batches
 Level of variability:
 Batch size
 Raw materials
 Processing & hold times
Acceptance Criteria & Test Plans
 Will PPQ include additional testing
 Excipient testing
 Impurity clearance
 Decide on what parameters to monitor
 Critical Process Parameters
 In Process Controls (IPC) or additional Process Parameters
Webinar, June 18, 202016
PPQ: Development of PPQ Protocol
Journey to PPQ

17. Journey to PPQ
PPQ & Beyond
Execution of
PPQ
and supporting
validation
studies
Time for journey
to continue to
Pre-Approval
Inspection
readiness!
Webinar, June 18, 2020
Outline
requirements
for Commercial
ADC MFG
Comprehensive
risk assessment
and control
strategy
development

18. Preparing for
a PAI

19. Webinar, June 18, 202019
Preparing for a PAI
 Small molecules
 Commercial Products Since 1999
 ADCs
 Clinical Facility for ADCs Opened in 2008
 Commercial Facility for ADCs Opened in 2015
 Produced >150 cGMP batches and enabled >30 INDs
Evolution of the Site

20. Webinar, June 18, 202020
Preparing for a PAI
Why was preparation for this PAI unique?
 Changed audit philosophy
 SME driven and not QA driven
 Many SMEs did not have regulatory inspection experience
 New facility in scope of the audit
 Host >25 customer audits a year, but not inspected by regulatory body
 Biologics audit versus non-biologics
 Focused on control strategy of facility and process
 Regulations not as well defined
Audit Preparedness

21. Webinar, June 18, 202021
Preparing for a PAI
Audit Readiness
Scripts
storyboards
Facility & People
readiness
Audit Logistics
• Determine timeline
• Determine process flow
• Organize documents
• Prepare the entire site
• Anticipate questions from the agency
• Clarify roles and responsibilities of each
participant
• Conduct walkthroughs and mock audits
• Identify Scripts/Storyboards
• Determine Subject Matter Experts (SME)
• Learn from previous audits

22. Webinar, June 18, 202022
Preparing for a PAI
Timeline for Preparation
9 months prior 6 months prior 3 months prior
Identify scripts/storyboards
Audit management
philosophy
Facility walkthrough
PAI prep awareness/training

23. Webinar, June 18, 202023
Preparing for a PAI
Audit Process Flow
FDA
HostSME

24. Webinar, June 18, 202024
Summary
What Did we Learn?
 Control strategy starts early in process development characterization
 Microbial control, risk assessments, scale-down model qualification
 A holistic view is required for process validation readiness
 Master plan scoping, risk assessment & PPQ
 Preparing for PAI
 Unique approach compared to traditional drugs

25. kerry.keith@milliporesigma.comelizabeth.mckee@milliporesigma.com
jake.spies@milliporesigma.com
Kerry KeithElizabeth McKee
Jake Spies

26. The vibrant M, MilliporeSigma and SAFC are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their
respective owners. Detailed information on trademarks is available via publicly accessible resources.
© 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.