Conducting stability studies in accordance with regulatory requirements requires technical expertise, established infrastructure and compliant facilities. There are multiple contractors available to offer these services and often the selection of a lead contractor is based on top level quotes and business development feedback. However, based on such selection strategies, once the studies are established at a contract site, additional factors may arise that further impact the overall costs and timelines for your project. These include hidden costs due to factors such as data mining, trending and investigations required during an established study. Factors that affect timelines include flexibility required to ensure relevant data is available as required for key submission dates. If this is not the case, this will result in reduced shelf life assignment and may have a direct impact on product development timeline. This talk will look at key points to consider in the selection process and provide tools to aid in selection of a lead contractor.

1. KEY CONSIDERATIONS IN
STABILITY STUDIES FOR
BIOLOGICS
Stella Chotou, MSc
SGS Life Sciences UK, Team Leader, Stability Services
BioProduction – 15 October 2015

2. DRUG DEVELOPMENT
Long-term commitment by small start-ups / biotech / big
pharma companies
Common goal:
Deliver efficient & safe drugs to patients
Cure diseases / prolong and improve quality of life
2
Cure diseases / prolong and improve quality of life
Long process, years of planning, tremendous costs
Multiple guidelines / regulations
Many problems to deal with – what is the best way?

3. STABILITY (DURING DRUG DEVELOPMENT)
Requirement by ICH Q1A/Q5C to demonstrate that the
therapeutic does not show significant change of
characteristics during its shelf life → safe to deliver →
effective against the disease
Heavily regulated (ICH, GMP & regional guidelines)
3
Storage conditions, final container / presentation and
expiry date – integral for regulatory submissions
Duration: few months to a few years
Drug developers frequently forget to include contingency
planning into their study design and project planning

4. WHAT IS THIS ABOUT?
NOT about ICH guidelines…but:
Stability is not a stand-alone project
Highly dependant on early / pre-clinical phase strategies
Forward planning is key to a successful stability program
without unnecessary costs and delays
4
without unnecessary costs and delays

5. WHAT IS THIS ABOUT?
NOT about ICH guidelines…but:
Stability is not a stand-alone project
Highly dependant on early / pre-clinical phase strategies
Forward planning is key to a successful stability program
without unnecessary costs and delays
5

6. DRUG DEV PROCESS AND STABILITY
Pre-Clinical
IND /
IMPD
Clinical Phases
I II III Commercial
Drug Product
Pilot Stability Studies
Product
Selection,
Cell line
Selection GMP batches
BLA /
MAA
Marketed
Drug
Pilot Scale
Stability Studies
Placebo Stability Studies
Shipment Support
Studies
Formulation Studies
6
Process
Development,
Process
Scale-up Stability
Studies
In-use studies/
shipment support
Commercial Reference
Standard Stability
End of Shelf Life
Specification for
Commercial Product
Stability Studies
Licence application support
studies: compatibility
(biochem and E&L)
Drug
Product
GMP Batch
Placebo Stability Studies
Forced Degradation
Studies
PPQ series (PV) Stability Studies
Commercial
Reference
Standard Stability
Comparability
Stability Studies
as required
(characterisation
/stability)
Early Phase Supporting
Stability Studies
Reference Stability
Study
Formulation Studies
Characterisation

7. STABILITY – PLANNING AHEAD
Stability study design depends on a variety of factors:
availability of material (during early drug development →
low quantities of material available → requiring smart
designs / low volume methods)
presentation of the final product (final formulation,
7
presentation of the final product (final formulation,
concentration / dosage, primary and secondary container)
long-term storage conditions
transportation / shipment of the product

8. BEFORE STARTING STABILITY PROGRAM –
SUPPORT ACTIVITIES (1)
Activity Details
Formulation
Development
• Product stabilised in optimum formulation → commercially viable shelf life /
stability during clinical trials / on the bench
• Method development & qualification are accurate
• Product characterisation reflects final formulation
• Reference Standard representative of Drug Product
• No additional development later on
8
Product
characterisation
FT-IR / CD: structural analysis
SEC-MALS / DLS / AUC: Aggregation profile
AAA / N-terminal sequencing: sequence
Peptide mapping / N-Glycans - MS: PTMs
icIEF / IEX: charge variants profile
Shipment support
studies
• Shipping route risk assessed for excursions, high risk points evaluated and
data available before the event

9. BEFORE STARTING STABILITY PROGRAM –
SUPPORT ACTIVITIES (2)
Activity Details
Primary container /
Container Closure
• Determine possible Extractables & Leachables (E&L) from final container &
process contact materials → Do they affect product stability & patient
safety?
• Eg. antioxidants, additives in final container
• Recommended vials: pharmaceutical grade USP Type I glass with
bromo/chloro-butyl rubber stoppers
9
Analytical Methods • Fit for purpose & product-specific
• Technically sound & stability-indicating
• Appropriate acceptance criteria
Recommendations:
• Assess formulation buffer components interference
• Include degraded material in method development
Forced degradation • Early on at lab-scale / pilot material
• Understand key degradation routes
• Avoid surprises in stability studies

10. STABILITY – PLANNING AHEAD - QUESTIONS
Do we have a good understanding of our molecule?
Have we determined the right environment for it?
Which degrading factors is our molecule susceptible to?
Can we transport the product in liquid or frozen form?
Are our analytical methods technically robust and fit for
10
Are our analytical methods technically robust and fit for
purpose?
Is the reference standard material fully characterized and
available?
Is collaboration / sub-contracting required for stability
testing? Is the contractor accredited to perform GMP
testing?
Which CQAs must be monitored during stability studies?
(ICH Q9)

11. REAL-LIFE EXAMPLE
Product: Monoclonal Ab X (at clinical phase I)
Issue: Long-term storage condition failed stability
specification at T=3 months as degree of opalescence was
> reference suspension IV by visual appearance
OOS investigation conducted
11
OOS investigation conducted
Investigation outcome: result was valid
Client had to re-formulate the product (Tween was added
to the formulation to prevent aggregation)
> 1 year delay in development program

12. ENTERING THE STABILITY PROGRAM
Protocol
Clear (avoid ambiguities)
Defined storage conditions, timepoints and analytical
methods
(ICH Q1A/Q5C as a minimum, are any additional required?)
Timepoint initiation & testing windows
Material requirements (how much material is required for all
12
Material requirements (how much material is required for all
methods at all timepoints?) – early on calculations important
when deciding on pilot or early clinical batches
Recommended to include up to 50% additional material into
stability (used for OOS/OOT, investigations, shelf life
extension, repeat testing / assay failures)
Responsibilities (of the hosting site and any sub-contractors)
Establish assay trending & real-time data trending

13. STABILITY PROGRAM
Example stability methods for biologics:
Test Method Characteristic Additional information
SDS PAGE Identity / Purity
Quick, robust, performed at all timepointsSEC Purity
Protein Concentration Strength
13
pH Physical Characteristics
Visual appearance (visible particles,
opalescence, colouration)
Physical Characteristics First test to be performed to avoid cross-contamination, compendia
method available
Sub-Vis particles by Light Obscuration Physical Characteristics Compendia method available, high volume consumption per
sample
IEF/CEX/cIEF Identity / Charge profile Quick, robust, performed at all timepoints
Peptide mapping UV Identity / oxidation &
deamidation quantification
Performed at selected timepoints (if required)
Sterility / bioburden / CCI Safety Performed annually or at beginning & end of study
ELISA / Bioassay Activity / Potency Performed at all timepoints
Moisture Content (lyo) Physical Characteristics Performed at all timepoints

14. REAL-LIFE EXAMPLE (2)
Project: stability study on clinical batch of product Y, MAb
presented in a clear glass vial
Study setup according to ICH guidelines
≤-65oC assessed as alternative long-term storage
condition to +5oC
14
condition to +5oC
Multiple ≤-65oC glass vials cracked upon thawing after
timepoint initiations and no additional vials were available
according to the protocol
Not possible to assess stability at ≤-65oC → no alternative
storage condition for the product
→

15. WHAT TO DO WHEN THINGS GO WRONG
Typical examples:
OOS
Delayed timepoint testing
No result produced for the product at certain timepoint
Pivotal for the testing site to communicate with drug
developer / program manager and internally
15
developer / program manager and internally
Problem acknowledged by the study director and clearly
documented - crucial to assess impact on the stability study
Ensure additional costs have been cleared upfront between
the testing site and drug developer for any unexpected
investigations – no hidden costs
Availability of wide range of characterisation techniques to
support product-related investigations (eg. mass
spectrometry)

16. WHAT TO DO WHEN THINGS
GO WRONG - EXAMPLE
Case:
1 year into stability program
SEC showed increased resolution compared to method validation
(single peak in validation split into two at T=12M)
Acceptance criteria for resolution set on the single peak which were now
unreliable
16
Investigation confirmed result was valid
Data mining required from the validation onwards to propose and assess
better defined criteria to support validation
Duration: 20 man days but no resource availability before 2 months
AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Minutes
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00
AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
Minutes
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00

17. HOT TOPICS IN STABILITY TESTING
Identification / characterisation of new impurities
Eg. When a new species has risen in the product profile for
long-term storage condition → important to demonstrate it
has no impact product efficacy and patient safety
Safety of biologics:
Data on particles that can be present in liquid formulations
17
Data on particles that can be present in liquid formulations
and their impact on patient safety (visible, sub-visible,
aggregates)
EP / USP methods available (USP <788> and Ph.Eur.
2.9.20) - recommended despite requiring large volume
of product
SEC-MALS
Tox / animal study data

18. CONCLUSION
Stability is not a stand-alone project
Discuss requirements upfront internally or with your
supplier
Establish a plan → prevent problems!
18

19. QUESTIONS?
Thank you for your attention!
19

20. WWW.SGS.COM
SGSisaregisteredtrademarkofSGSGroupManagementSA
WWW.SGS.COM
©SGSGroupManagementSA–2015–Allrightsreserved-SGSisaregisteredtrademarkofSGSGroupManagementSA