ADC manufacturing presents a unique set of challenges as compared to the well established practices employed for more traditional biologic products. The development and commercialization of key intermediates, complex small-molecule APIs and biologic drug substances shouldn’t be such a headache. The uniqueness, versatility, and complexity involved in each project only means you need to make sure you’re well informed when it comes to the dos and don'ts of manufacturing commercial Antibody Drug Conjugates (ADCs). Tune in to hear a CMO perspective for an in-depth understanding on the subject of manufacturing commercial ADCs. Our team will discuss all of the considerations that must be addressed to successfully manufacture ADCs. In this webinar you will learn: - Facility Design and Cleaning Validation - Advantages of Single Use Systems - Process Control and Regulatory Strategies

1. Merck KGaA
Darmstadt, Germany
Jyothi Swamy, Josh Morris & Mark Cooley
- A CMO Perspective
Considerations for
Manufacturing
Commercial
Antibody Drug
Conjugates (ADCs)

2. 2 Considerations for Manufacturing Commercial ADCs | 08.24.2017
The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.

3. 3
• History and Future of ADCs
• CMO Considerations for ADC Manufacturing
• Facility Design Requirements
• EM Strategy
• Process Development Activities
• Cleaning Strategy
• Regulatory and Process Validation Strategy
• Summary
Outline
Considerations for Manufacturing Commercial ADCs | 08.24.2017

4. Elements of an ADC
4
Antibody
Specific for a tumor-associated
antigen that has restricted
expression on normal cells
Cytotoxic Agent
Designed to kill target cells when
internalized and released
Linker
Attaches the cytotoxic agent to
the antibody. New linker
systems are designed to be
stable in circulation and release
the cytotoxic agent inside
targeted cells
Conjugation is the step
of linking the cytotoxic
agent to the antibody
Considerations for Manufacturing Commercial ADCs | 08.24.2017

5. 5
History of ADCs - Globally
ADCETRIS®
(Seattle Genetics)
approved in 2011
KADCYLA®
(Genentech)
approved in 2013
MYLOTARG®
(Pfizer) approved
in 2000 and
Withdrawn from
US & EU markets
in 2010*
BESPONSA®
(Pfizer) approved in
2017
Classical
Hodgkin
lymphoma
CD33
positive acute
myeloid leukemia
HER2-positive,
metastatic
breast cancer
CD22-positive
B-cell precursor
acute
lymphoblastic
leukemia
*Based on the new clinical data, FDA advisory committee voted in favor of MYLOTARG on
July 11, 2017
Considerations for Manufacturing Commercial ADCs | 08.24.2017

6. 6
ADCs – Where are we today Globally?
Clinical Phase
Active ADC
Programs 2015*
Active ADC
Programs 2016*
Active ADC
Programs 2017**
Phase 1 37 39 38
Phase1/2 Not reported Not Reported 10
Phase 2 13 18 11
Phase 3 2 6 3
Commercial 2 2 4
Total 54 65 66
* Beacon Report, World ADC Conference, Berlin February 2017
** Beacon ADC’s, August 2017 Edition
Considerations for Manufacturing Commercial ADCs | 08.24.2017

7. 7
• >200 trials registered in clinicaltrials.gov with only <100 ADCs - Multiple Indications and
Combination Therapy
• ADCs with Bi-specific mAbs - Drives Efficacy by Improving Internalization
• ADCs Beyond Oncology Treatment1
‒ Immunological Modulation
‒Anti-infection (Antibody antibiotic conjugate)
‒Cardiovascular Diseases
‒Liver Metabolic Disorders
1Renhe Liu, Rongsheng E. Wang & Feng Wang (2016) Antibody-drug conjugates for non-oncological indications, Expert
Opinion on Biological Therapy, 16:5, 591-593
ADCs – Looking Forward
Considerations for Manufacturing Commercial ADCs | 08.24.2017

8. 8
Small molecules
• Commercial Products Since 1999
ADCs
• Clinical Facility ADCs Opened in 2008 - Material for Phases 1 & 2
• Commercial Facility for ADCs Opened in 2015 - Material for Phases 1 - Commercial
• Produced > 80 cGMP batches of >25 different ADC constructs
Considerations for ADC Manufacturing
Considerations for Manufacturing Commercial ADCs | 08.24.2017

10. 10
Combining Small Molecule and mAb
Requirements
• Conflicting Containment and GMP
Requirements
• High-Potent Containment
• Satisfy GMP Environmental Control
Requirements
• Considerations
• HVAC Configuration
• Floor Design and Drain Strategy
• Personnel Safety
• Unidirectional Flow (Materials and
Personnel)
Facility Design: Unique ADC Requirements
Considerations for Manufacturing Commercial ADCs | 08.24.2017

11. 11
• Solvent Requirements
• Required in Conjugation Process
• Solvents Required for Decontamination and
Cleaning
• Planning for Future Technology
• Advanced Purification Techniques
(Chromatography)
• Scale Variability
• Demand Requirements
• Single-Use Systems Versus Fixed Equipment
Facility Design: Unique ADC Requirements
Considerations for Manufacturing Commercial ADCs | 08.24.2017

12. 12
• Fixed Facility Equipment and Systems
• Drug Isolator
• Fill Isolator- Grade A Space
• Facility WFI System
• Autoclave
• Clean Steam System
• Parts Washer
• Facility Air Supply
• Fixed Versus Single Use Equipment
• CMO Flexibility
• Future Technology
Facility Design: Fixed Equipment Requirements
Considerations for Manufacturing Commercial ADCs | 08.24.2017

13. 13
Facility Design: CMO Flexibility
Considerations for Manufacturing Commercial ADCs | 08.24.2017

14. 14
• Single-Use: Manufacturing Materials
• Tubing and Filtration Assemblies
• Buffer and Solution Bags
• Processing Fittings and Aseptic Connectors
• Single-Use: ADC Manufacturing Unit
Operations
• TFF/Ultrafiltration Systems Membranes and
Flow Path
• Chromatography Systems: Flow Path and
Columns
• Conjugation Reactors: Reactor System with
Mixing Assembly
Opportunities in ADC Manufacturing Single-Use Systems
Considerations for Manufacturing Commercial ADCs | 08.24.2017

15. 15
• Advantages of Single-Use
• Minimize Carry-Over Quality Risks
• Enhanced Microbial Control
• Transfer Portability
• Remove or Minimize Cleaning Validation Requirements
• Perceived Challenges
• Film Integrity and Potential Leaks
• Processing Limitations- Mixing and Temperature Compatibility
• Scale Limitations
• Demonstration Units
• Commercial Scale
• Extractable and Leachable(s)
Single Use Systems: Advantages and Perceived Challenges
Considerations for Manufacturing Commercial ADCs | 08.24.2017

16. 16 Considerations for Manufacturing Commercial ADCs | 08.24.2017

17. 17
• EM Program Design
• Sampling: Risk-Based Approach Utilizing Analytical Data
• Dynamic Monitoring: Open Process Steps
• Gowning and Operating Procedure
• Standard Requirements for Biologics
• Training and Qualification
• Aseptic Technique Training
• Gowning Qualification- Media Touch-Plating
Environmental Monitoring
Considerations for Manufacturing Commercial ADCs | 08.24.2017

18. 18
• Establishing Specifications: Consider Individual
Components
• mAb: Binding Assay
• Drug Linker: Conjugatable Impurities
• ADC: Drug-Antibody Ratio, Residual Solvent,
Residual Drug-Linker, ID, BioAssays
• Microbial Controls
• Raw material, Equipment, Personnel Contributions
• Processing Conditions and Times
Process/Analytical Development Strategies
Considerations for Manufacturing Commercial ADCs | 08.24.2017

19. 19
• Microbial Monitoring and Process
Understanding
• Quantitative Endotoxin Contribution
Assessment
• In-Process Bioburden and Endotoxin
Testing
• Understand Processing Endotoxin
Clearance
• Utilize Facility and Batch Data to
Establish Alert and Action Levels
Process Development- Microbial Strategy
• Microbial Control Strategy:
Utilize Early-Stage Data
• Additional In-Process Filtrations
• Hold-Time Studies- Chemistry
and Microbial Aspects
• Solution Stability Studies
• Incorporate Closed Final-Fill
Process
Considerations for Manufacturing Commercial ADCs | 08.24.2017

20. 20
• ADC Cleaning Requirements
• mAb and mAb Degradants
• Drug-Linker and Drug-Linker Degradants
• ADC and ADC Degradants
• Where? Multi-use Product locations.
• Quantitative Analytical Requirements
• Analytical- Mass Spectroscopy and UV
• Coupon Studies
• Allowable Carryover Limits
Cleaning Strategy:
Considerations for Manufacturing Commercial ADCs | 08.24.2017

21. 21
• Process Development/Characterization
• Identify Critical Process Steps and Associated Critical Process Parameters
• Required Range-Finding Experiments
• Process Performance Qualification (PPQ)
• Complete Equipment and Method Validation
• Prepare PPQ Protocol
• Execute 3 Batches and Release
• Finalize PPQ Report
• Continued Process Verification
• Annual analytical performance assessment
Regulatory Requirements
Considerations for Manufacturing Commercial ADCs | 08.24.2017

22. 22
• ADC’s: A New Class of Molecule
• No ADC-Specific Regulatory Requirements
• Robust ADC Pipeline Driving Demand
• CMO’s Act as Quality Partners
• Founded in Facility Design
• Supported with Robust Environmental Monitoring, Process
Development, and Regulatory Strategies.
• Prepare for Evolving Technology
• Single-Use Opportunities
• Purification Strategies
Summary
Considerations for Manufacturing Commercial ADCs | 08.24.2017

23. Thank You!
Q&A