III.

Critical Stability Operations

d St bilit P t l and Stability Protocols
Critical Stability Systems
Regulations Procedures Regulations
(I)
Procedures
(II)
Stability Systems
Operations
(III)
Investigations
(IV)
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Discussion Topics
3. Best Practices on Stability Operations
Establish compliant stability protocols Establish compliant stability protocols
Define Stability Day-to-Day Operations
Discuss best practices on these operations
Discuss key factors of environmental chambers
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Documentation Practices: Stability Protocol
1. Contents of a Stability Protocol
2. Storage conditions
3. Selection of batches
4. Testing frequency
5. Specifications / tests
6. Reduced design (Bracketing and Matrixing)
7. General considerations
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Typical Global Stability Protocol
TEMP
TZ
1 2 3 6 9 12 18 24 36
HUMIDITY
TZ
Mo Mo
3
Mo
6
mo Mo Mo
8
Mo mo
36
Mo
25 C 25 C
60%RH
X X X X X X X X
30 C
65%RH
X X X X (X) (X) (X)
(30 C
75%RH)
X X X X X X X X
40 C
75%RH
X (X) X X (X) (X)
75%RH
( ) ( ) ( )
50 C X
5 C H O L D
Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best
Practices, K. Huynh-Ba (ed.), Springer, November 2008, Chapter 2.
Special Storage Conditions
Photostability: two types of studies:
Forced degradation study to generate potential g y g p
degradation products
Confirmatory study to confirm product and package
f performance
For liquids in semi-permeable package
Long term: 25C/40%RH
Intermediate: 30C/65%RH
Accelerated: 40C/<25%RH and 40C/75%RH
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Special Storage Conditions
To support adverse shipping and unusual storage of
samples (liquid)
Freeze Thaw Cycling (-10C to -20C four days, 25C or
25C/60%RH for three days)
Th l C li (40C f d ilib t t 25C Thermal Cycling (40C four days, equilibrate to 25C
and then 5C for three days)
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Contents of a Stability Protocol
Stability studies are initiated based on approved stability
protocols:
Identity of product: name, strength
Description of dosage form or formulation
Purpose of study
Manufacturing site, packaging and testing sites.
Details of packages (container/closure)
Instructions for receipt and allocation of material
Shipping of material (if needed)
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Contents of a Stability Protocol
Storage conditions, time-points, configuration,
orientation (if applicable)
Testing information: tests and specifications
Each study has unique, identifying number for LIMS or Each study has unique, identifying number for LIMS or
specific tracking system.
Global conditions for products which are expected to be Global conditions for products which are expected to be
sold and used worldwide.
Change of protocols: Deviations vs Admendments g p
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Specification / Tests
The testing covers physical, chemical and
microbiological attributes, preservative content (e.g.
ti id t ti i bi l ti ) d antioxidant, antimicrobial preservative), and
functionality tests (e.g. for a dose delivery system).
What tests at each time points? Which labs? What tests at each time points? Which labs?
Shelf life acceptance criteria derived from available
stability information? Alert limits? y
Differences between the shelf life and release specs
are justified based on the stability evaluation and the
changes observed on storage.
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Stability Practices
Management of deviations and protocol amendments
Chamber Monitoring System Chamber Monitoring System
Study Activation Procedure
Sample Pulling and Testing Procedure
Sample Custodian Procedure
Sample Destruction Procedure
Sample Shipping Procedure Sample Shipping Procedure
Study Cancellation
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Chamber Inventory Program
Critical Stability Dates
Expiration Date Study Start Date
Packaging
Date
p
(Study End Date)
Release
Date
Stability Pull
Dates
Manufacturing
Date
y
Date
Batch
Manufactured
R l T ti
Stability Scheduled Testing
Drug Product
Expiry
TZ* Testing
Release Testing
S
12
Stability Testing in Pharmaceutical Development Handbook: Regulations, Methodologies and Best Practices,
K.Huynh-Ba, ed., Springer 2008.
Environmental Chambers
Two basic types: Reach-In and Walk-In
Reach-in chambers can be a self-contained units with
good profile control, but have limited space.
Walk-in chambers have more storage space but are more
difficult to control and validate
All chamber units must have temperature and humidity
control over a defined range with suitable tolerances to control over a defined range with suitable tolerances to
meet ICH specifications. Must have continuous
monitoring of parameters to allow documentation of
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chamber integrity at all times.
Environmental Chambers
Walk-in
Chambers
Courtesy of Luwa Americas
www.luwaamericas.com
14
Key Factors of Stability Chambers
Chamber should be calibrated to appropriate technical
specs.
Chamber should be validated with profiling matrix.
Temperature and humidity should be recorded
ti l continuously.
SOPs for operation of chamber should be prepared and
controlled controlled.
Units should have logbooks for maintenance and
repairs. p
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Key Factors of Stability Chambers
Units should have secured access to prevent tampering.
If electronic information is collected, the system should
be compliant with 21CFR11 requirements.
Alarm and backup systems should be in place to detect
f il d t t ti f hi power failures and prevent station from crashing.
Procedures should be in place for man-made or natural
disasters disasters.
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B k ti d M t i i Bracketing and Matrixing
What is Bracketing?
The design of a stability schedule such that at any time
point only the samples on the extremes of certain
d i f t ( t th k i ) t t d design factors (e.g., strength, package size) are tested
at all time points as in a full design. The design
assumes that the stability of the intermediate levels is
represented by the extremes tested
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What is Bracketing?
...Where a range of strengths is to be tested,
bracketing designs may be particularly applicable if the
t th id ti l l l l t d i strengths are identical or very closely related in
composition (e.g., for a tablet range made with different
compression weights of a similar basic granulation, or a
capsule range made by filling different plug fill weights
of the same basic composition into different size of
capsule shells) capsule shells).
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Bracketing
Bracketing can be applied to different container
sizes of or different fills in the same container closure
t system...
The use of a bracketing design would NOT be
appropriate if it can not be demonstrated that the appropriate if it can not be demonstrated that the
strengths or container sizes and fills selected for testing
are indeed the extremes.
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Bracketing and Matrixing
o Example of simple bracketing design
Strengths
10mg 20mg 30mg
Batch 1 2 3 1 2 3 1 2 3
100s T T T - - - T T T 100 s T T T T T T
Fill size 500s - - - - - - - - -
1000
s
T T T - - - T T T
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Rationale for Matrixing
Long term trends are approximately linear
Can design so that the effect of each factor may be Can design so that the effect of each factor may be
determined
Can evaluate comparative stability of each
presentation
Each storage condition has its own matrix
Each testing can have its own matrix Each testing can have its own matrix
Can revert to full testing
Resource saving Resource saving
22
What is Matrixing?
The statistical design of a stability schedule such
that a selected subset of the total number of that a selected subset of the total number of
possible samples are tested for all factor
combinations is tested at a specified time point. At
a subsequent time point, another subset of sample
for all factor combinations is tested. The design
assumes that the stability of each subset of
samples tested represent the stability of all samples
at a given time point
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at a given time point.
What is Matrixing?
The differences in the samples for the same drug
product should be identified as for example covering product should be identified as, for example, covering
different batches, different strengths, different sizes of
the same container and closure, and in some cases,
different container/closure systems.
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Matrixing
o Example of one half factorial design
Time point
Months on stability
Time point
Months on stability
Batch 0 3 6 9 12 18 24 36
10 mg 1 T T - T T - T T
10 mg 2 T T T T T T 10 mg 2 T T - T T T - T
10 mg 3 T - T - T T - T
20 mg 1 T - T - T - T T 20 mg 1 T - T - T - T T
20 mg 2 T T - T T T - T
20mg 3 T - T - T - T T
25
20mg 3 T T T T T
Matrixing
o Example of two third factorial design (1/3 reduction)
Time point
Months on stability
Batch 0 3 6 9 12 18 24 36
10 mg 1 T T - T T - T T
10 mg 2 T T T - T T - T 10 mg 2 T T T T T T
10 mg 3 T - T T T T T T
20 mg 1 T - T T T T T T g
20 mg 2 T T - T T - T T
20mg 3 T T T - T T - T
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g
Bracketing and Matrixing
Example of a complete complex design
Strengths
10mg 20mg 30mg
Container
size
X Y Z X Y Z X Y Z
Batch A T1 T2 T3 T2 T3 T1 T3 T1 T2
Batch B T2 T3 T1 T3 T1 T2 T1 T2 T3
Batch C T3 T1 T2 T1 T2 T3 T2 T3 T1
Time
point
Months on stability
0 3 6 9 12 18 24 36
T1 T - T T T T T T
T2 T T - T T - T T
27
T3 T T T - T T - T
Bracketing and Matrixing
o Example of an incomplete complex design
Strengths
10mg 20mg 30mg
Container
size
X Y Z X Y Z X Y Z
Batch A T1 T2 - T2 - T1 - T1 T2 Batch A T1 T2 T2 T1 T1 T2
Batch B - T3 T1 T3 T1 - T1 - T3
Batch C T3 - T2 - T2 T3 T2 T3 -
Time
point
Months on stability
p
0 3 6 9 12 18 24 36
T1 T - T T T T T T
2
28
T2 T T - T T - T T
T3 T T T - T T - T
Limitations of Matrixing
All presentations must be set-up on storage
Realistically only the Long-Term storage is matrixed y y g g
May not pick up as much on differences
Data evaluation can be more complex Data evaluation can be more complex
Confidence intervals may be wider
Regulatory experience is limited Regulatory experience is limited
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Bracketing and Matrixing
of complete removal of some presentations from testing
and then reduced testing of those that remain. This is a
j d ti d d j tifi ti major reduction and needs justification.
Not very common. Definitely need to work with the
Agency to do this, unless there is lots of supportive
data.
Reduction of batches of all presentations
Matrix different tests to different extents
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