The document discusses the importance of proactive stability testing programs for biologics manufacturing. It highlights the need to select assays that address important quality attributes and can indicate stability over time under different environmental conditions. The document also emphasizes advanced planning and alignment between stability testing timelines and manufacturing schedules to avoid issues.

1. The life science business of Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma in the U.S. and Canada.
Get Proactive with
your Stability
Program
Pamela Hamill, Ph.D.
Greg Pirozzi, Ph.D.

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

3. “Provide evidence of how the quality of a Drug
Substance (DS) or Drug Product (DP) varies
with the influence of environmental factors –
Temperature, Humidity and Light to establish a
shelf life or retest period” - Guidance: ICH
Q1(A) R2 – 2003
3
• Physico-chemical
and structural
attributes
• Purity/impurities
• Biological activity
Assessment of Critical
Quality Attributes
over time
Stability study types
Real Time
Accelerated
Stress

4. 4
Stability testing in biologics manufacturing
Banks
 Master Cell banks
 Working Cell banks
Batches of Product
 Purified Bulk Drug Substance (DS)
 Final Drug Product (DP)
Bioreactor Purified Bulk
Substance
Final Drug
Product
Unprocessed
Bulk Product
Process
Chromatography
Formulation
development,
fill & finish
Research
Cell Line
Master
Cell Bank
Production
Working
Cell Bank
Production
Upstream
Bioprocessing
Downstream
Bioprocessing
Other
• Shipping
• Process hold steps
Material types requiring stability testing

5. Considerations in timeline planning for GMP stability: Overview
5
Batch
Release/T0
time point for
GMP stability
study
Establish/validate assays:
Feasibility and planning
Generate samples to
assess stability- indicating
properties
Source of Reference
Standard/representative
material to establish and
validate methods
GMP study protocol
(min 2 months, to allow for
review & signature)
Planning/alignment with
manufacturing schedule
and sampling plan
For outsourced studies, scope
out stability conditions needed
and identify providers
Start
Phase I
Clinical Trial
Minimum 12 months
3-6 months
Data

6. 6
6
6
Stability studies enable understanding how these attributes change over time under different
environmental conditions
• Select assays that address these important attributes
• Challenge with samples with known altered physicochemical and purity profiles
Structural variability and consequences-mAb example
Sources of
structural
variability
RISKS
Differences or changes in physico-chemical
properties, post-translational modification and
higher order structure can significantly affect
product quality attributes and present risk to:
N-Glycosylation
Oxidation
Deamidation
Aggregation
-
-

7. “Analytical procedures should be fully validated and
stability indicating” ICH Q1A (R2)
Plan Ahead
• Build in contingency for
custom methods aimed
at product specific
attributes
• What if approach needs
to change?
Challenge stability-
indicating properties
Allow time to assess
performance
1 3
2
4
Establishing
Methods
7
Reflect knowledge of
CQA in assay choices

8. 1 Plan ahead to ensure there will be sufficient
representative material to;
• Establish assays and assess their
performance
• Support testing for all timepoints in the
program (for methods that need RS)
• Avoid bridging studies
2 If bridging a references or changes in
critical materials is unavoidable, have
the strategy planned before the study
starts
• Establish protocols and acceptance
criteria in advance
Reference standards &
critical reagents
8

9.  Critical manufacturing
document
 Details samples, volumes,
intended use, and destination
 Lot size will determine # of
samples required
 Complex & lengthy process
 Multiple batches/fills
 Close coordination with CMO
Manufacturing
Alignment
Sampling Plan
9
Align the GMP manufacturing and sampling plan

10. Conducting your
study
In-house vs
outsourced
Do you have capacity and expertise in-house
to manage the project for the duration?
Can one provider meet all your requirements?
If multiple providers are needed, what are the
logistical and project management
considerations?
10

11. Challenging assays to assess stability-indicating properties
2
3
1
11
?
Source of samples with
altered properties?
• Stress testing?
Where/when?
• Outsourcing?
• Requirements (conditions,
timing)
Planning to align
with method development

12. Assays
Required Repeat
testing
Testing
specifications
Time
Points
Final sample
disposition
instructions
Test samples
& retains
Other
required
materials
Study
conditions
Objective/
Scope
GMP
Stability
Protocol
12

13. 13
Advanced
Planning &
Contingency in
timelines
Alignment with
manufacturing
Assay Selection
• Focus on CQAs
• Suitability for
stability testing
key
takeaways

14. Greg.Pirozzi@milliporesigma.com
Pamela.Hamill@milliporesigma.com
Greg Pirozzi, Ph.D.
Pamela Hamill, Ph.D.
© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
The vibrant M and BioReliance 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.