This document summarizes a presentation given by Merck KGaA on post-approval changes to biologics manufacturing from a supplier's perspective. It discusses the challenges of post-approval changes, including unclear regulations and high regulatory burden. It provides examples of how suppliers can help customers justify lower risk categorizations for changes through comparative studies, improved analytics, and collaboration on change management protocols. The presentation aims to illustrate how suppliers and customers can work together to make post-approval changes more efficient.

1. Merck KGaA
Darmstadt, Germany
Janmeet Anant, Ph.D.
Regulatory Advocate
Guido Kremer-van der Kamp,
Associate Director, Technology Management
A Practical Assessment from a Supplier’s Perspective
Post Approval
Changes in Biologics
Manufacturing

2. 2 Title of Presentation | DD.MM.YYYY
The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.

3. Why are post-approval changes (PAC) so challenging?
Two main reasons:
Risk Safety
1 2

4. What are the motivations to implement changes?
Biopharmaceutical manufacturing

5. Why are we changing? Why do we hate it so much?
Industry Perspective
• CMC Change Avoidance – Limits potential for highest
business impact
• Unclear Regulations – Hinder innovation
• Regulatory Concerns – Hard to change approach
• High Burden – Time and money, just for regulatory
approval
• Speed to Market Pressure – Inevitable post-approval
manufacturing changes

6. What do the Regulations Say?
WHAT DO YOU MEAN WHAT DOES IT MEAN?
Risk Level US EU AKA
Impact on quality,
safety, efficacy
Major Prior Approval
Supplement (PAS)
Type II “Tell and Wait” Significant impact
Moderate Change being
effected (CBE-30 or
CBE-0)
Type IB “Tell and Do” Moderate impact
Minor Annual Report Type IA “Do and Tell” Minimal or no
impact
Note: Europe more conservative for biologics, typically defaulting to Type II. Japan has only Major and
Minor categories (Minor in Japan = Moderate in US/EU, in terms of regulatory notification).

7. Regulatory Agencies – Highest Risk Considerations
Potential Contaminants in Biologic Drug Manufacturing

8. FDA Indicates that Risk Assessments are Too
Conservative
“The number of CMC manufacturing supplements for
NDAs and ANDAs has continued to increase over the
last several years. In connection with FDA’s
Pharmaceutical Product Quality Initiative and our risk-
based approach to CMC review, we have evaluated
the types of changes that have been submitted in
CMC post approval manufacturing supplements and
determined that many of the changes being
reported present low risk to the quality of the
product and do not need to be submitted in
supplements.”
SOURCE: FDA Guidance for Industry, CMC Postapproval PManufacturing Changes To Be Documented in Annual Reports. March
2014.

9. A Consultant Shows where Major Risk Categorization is Unjustified
• Calcott Consulting, LLC worked with one company that
designated 90% of their PACs as prior approval.
• The consultant suggested picking a few lower risk
projects to push through as CBE-30s, and it worked!!
• Then they picked a few more, and they also got
approved as CBE-30s.
• Everyone in the company was shocked, and Calcott’s
reputation for effectiveness grew.
• The regulators shared complimented the approach.
Remember that the agency will never downgrade a submission from
prior approval to CBE if you recommend the more conservative
approach!
Risk?
Yes
No
SOURCE: Angelo DePalma, Post Approval CMC Changes. Increasingly a fact of biopharmaceutical life. BioProcess
International 16(1)e January 2018 E-Book

10. How do we determine PAC risk categorization?
1. Higher specificity identity test
2. Higher sensitivity or selectivity impurity test
3. Further distance from production
4. Further upstream from final product
5. More automation; less manual operations
6. Move towards closed systems
L
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Design
Space
Control
Space
QbD:
ICH Q8,
Q9 & Q10
Increased Process Understanding

11. More detailed regulatory guidance….!
Change Type
Conditions to be
fulfilled
Supporting Data
Reporting
Category
New equipment
with different
operating principles
& different product
contact material
None
• In-process control testing info
• Process validation study reports
• One commercial batch
comparison*
• E&L information
• Compare/contrast operating
principles
Moderate
No impact to
manufacturing
process or product
quality
All of the above except:
• One commercial batch
comparison*
• E&L information
Minor
Change in equipment used in the drug substance manufacturing process:
SOURCE: WHO Annex 3. Guidelines on procedures and data requirements for changes to approved biotherapeutic products (2018).
Also: WHO Annex 4: Guidelines on procedures and data requirements for changes to approved vaccines (2015); PQRI. Post Approval
Changes for Sterile Products Working Group. Final Report. April 19, 2007.
*Number of commercial batches for comparison studies may be more than one, based on requirements of NRA

12. Merck KGaA
Darmstadt, Germany
Supplier and Biologic Drug Manufacturer Collaborations
Case Studies

13. Two Disclaimers
• Company names and identifying details have been changed or
omitted to protect the privacy of individuals.
• Please note that this is just guidance. We are utilizing a variety of
case studies as supportive information. Please utilize your own
judgement in making final regulatory decisions

14. Goal(s) of change: Decrease batch-to-batch variability;
increase purity of antigen
What to change? UF/DF from hollow fiber to new
membrane cassette system
Additional benefit: Platform change at facility
Justification of Risk as Minor to Moderate:
• Analytical method change to better control the process and
product quality attributes
• Contact material change minimum impact (both regenerated
Cellulose) and same nominal cut-off (30 kDa). Change in Housing
material (Polycarbonate to Polypropylene & Polyurethane)
• All process parameters (e.g., flow rate, recirculation, pressures,
etc.) were non- critical as CMC based on 20 years of final product
experience.
• Immune response testing in animal model – perceived as ‘simple’
check/confirmation
Vaccine
“old”
process
(Part 1)

15. Vaccine
“old”
process
(Part 2)
Project Timeframe: 9 months, first discussion to
system IQ/OQ.
Regulatory Hurdles: Analytics and material changes all
went through fine. Surprise came
in immune response testing… no
response at all in animal model!
Results: Loss of money, time and
reputation.
Lessons Learned: CQA is critical. It is essential to
know the effects of purity on
clinical outcomes, especially for
vaccines which require an
immunological response.
In this case, CQA understanding of vaccine purity versus
immunological response was lacking!

16. Change driver: Poloxamer 188, from a selected
alternative supplier, showed a substantial
improvement in cell culture performance.
What to change? Poloxamer 188 (Supplier 1 to Supplier 2)
Justification of Risk as Minor:
• Similar material from different supplier
• No change in risk of TSE/BSE or viral safety
• No change in drug substance purification process
• No change to drug substance quality
• More sensitive identification method for Poloxamer 188 (not
compendial)
– While Supplier 1 meets the compendial method for identification, Supplier 2 uses
a validated method that is better (more selective) and accepted by industry
– The compendial method lacks specificity and size distribution information versus
Supplier 2‘s SEC method
Results: Proposal to categorize as 2 minor changes:
(1) SEC analytical method and (2) Raw material
change
Cell
Culture
Additive
In this case,
compendial method is
"outdated”, behind
industry expertise

17. Change Drivers:
• A supplier to a manufacturer of a sterilizing grade filter
discontinued production of a PES resin, therefore an alternative
resin had to be sourced
• The membrane manufacturing shifted sites (US to EU)
Justification of Risk as Major:
• Change in supplier and change in manufacturing site
• Change in filter membrane, potentially used for final sterilization
Project Timeframe: 1-2 years
• Early communication with end users
• End user meetings and evaluations at the two sites
• Pre-change and post change material overlapped
• Validation and comparison studies
Supplier
Induced
Change -
Sterilizing
Grade Filter
(Part 1)

18. Studies Required:
• Comparison with pre-change lots
− Bacterial Retention validation: No change
− Bubble point tests: No statistical change
− Extractables: Lower TOC overall
 One extra compound (diphenylsulfone-DPS) identified
 DPS is only extracted with 100% ethanol and toxicity studies
showed no toxicity risk.
Results:
• Change was implemented. Main questions were around
extractables results.
• Multiple drug manufacturers tested the change for their DS/DP.
• The regulatory affairs manager from a multi-national company
commented that they reported this change in their annual report
Supplier
Induced
Change -
Sterilizing
Grade Filter
(Part 2)
Changes can be downgraded from major to minor risk with
the right support and documentation from the supplier

19. Justification of Risk as Major:
• Change in filter (equipment) for critical downstream viral clearance
unit operation
Project Timeframe: 1-2 years
• Early communication, project charter and meeting scheduling
• Small scale studies for proof of concept
• DOE for optimal process update design
Regulatory Hurdles
• Confirm acceptable LRV with formal viral clearance study
• Lower risk categorization with Post Approval Change Management
Protocol (PACMP) from major to moderate.
• Leverage industry associations (BPOG, PDA, ISPE, etc.) and NRAs
to implement change across multiple countries as efficiently as
possible
Update
Virus
Clearance
Filter
Goal of Change:
• Improve efficiency and productivity of the virus filtration unit
operation by updating to next generation virus clearance filter

20. Merck KGaA
Darmstadt, Germany
Let us work together to make PACs more efficient
Conclusion

21. Work with suppliers to help with PAC, in the following ways:
• Leverage their knowledge on how best to shift to innovative products and
services.
• Access expertise in manufacturing unit operations to help define the critical
process parameters correlated with risk.
• Utilize small-scale models developed and validated by suppliers to support
comparability studies.
• Take advantage of validation information, data and documentation packages (e.g.
Emprove® dossiers), which have supported a wide breadth of PACs, comprising of
process optimization, continual improvement and scale/throughput flexibility.
• Strengthen regulatory strategy by codeveloping post approval change
management protocols (PAMCP) to lower regulatory hurdles for high risk PACs.
• Collaborate as thought leaders to influence regulatory agencies around the world.

22. The potential future of PACs:
Risk Safety
1 2

23. Acknowledgements
Kerry Roche-Lentine, Director, Technology Management Growth Programs
Ulrich Reichert, Head of Pharma Food and Materials, Regulatory Management
Najib Sehat, Head of Regulatory Management
Andrew Clutterbuck, Associate Director, Manufacturing Sciences & Technology
Aine Hennessey, Strategy Execution Manager, Process Solutions
Dawn MacNeill, Business Innovation, Supply Robustness
Dr Isabelle Colmagne-Poulard, Senior Director, Regulatory CMC
In addition, …
Numerous partners in drug manufacturer companies and regulatory agencies

24. Questions?

25. The vibrant M and EMPROVE 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.
© 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
Contact:
Janmeet Anant
janmeet.anant@milliporesigma.com