3. Definitions
Pull Date – The date a sample is
taken out of a stability chamber
for testing.
Testing Date – The date in
which the last test was completed.
4. Definitions
Pilot Batch – 100,000 units or
10% of full commercial batch
size, whichever is greater.
Small Scale Batch - Smaller than the
10 percent of the proposed production
batch, but should not be less than 25
percent of the pilot scale batch.
5. Definitions
Significant Change – A change equal or
greater than 5% in Assay; or, an out of
specification result in any test for any
single batch.
6. Definitions
Proportionally Similar –
• When the active and inactive ingredients
are not in exactly the same proportion but
the ratios of inactive ingredients to the
total mass of the dosage form are within
the limits defined by SUPAC guidelines.
• The difference in active ingredient content
between strengths may be compensated
for by mass changes in one or more of the
IPIs provided that the total mass of the
pharmaceutical product remains within 10
% of the mass of the pharmaceutical
product on which the bioequivalence
study was performed.
7. • Preserved drug products:
Products containing
antimicrobial preservatives,
antioxidants or chelating
agents.
• Commercial container: Any
bottle, jar, tube, or other
receptacle in which a drug
product is held for distribution
or dispensing to an ultimate
user, and in addition, any box
or package in which the
receptacle is held for
distribution or dispensing to
an ultimate user.
8. Definitions
• Bracketing: a stability testing
schedule where only samples
on the extremes of certain
design factors (e.g., strength,
container size and/or fill) are
tested at all time points.
• Matrixing: a stability testing
schedule where a selected
subset of the total number of
possible samples for all factor
combinations are tested at a
specified time point. At a
subsequent time point,
another subset of samples for
all factor combinations are
tested.
12. Long Term Stability
Conditions
Zone II
Zone IVa
Zone IVb
• FDA will accept Zone IVa or IVb with no significant
change, in lieu of Zone II data.
• If significant change is seen in Zone IVa or IVb, then, Zone
II samples can be subsequently tested from that time point
on. Stability reports to be submitted to FDA would include
Zone IVa or IVb data (up to the time point where
significant change was observed), followed by Zone II data
up to expiry date.
Accelerated, intermediate and
long-term stability studies should
start at the same time for any
given batch.
13. Stability Batch Criteria
• Scale
o Three pilot scale batches or, two
pilot scale batches and one small
scale batch.
• Not less than two (2) drug substance
lots must be used to manufacture
each strength (i.e., 3 FP lots
manufactured with NLT 2 API
batches).
15. Stability Batch Criteria
• NLT 100,000 units must be packaged [high and low
count and unit dose(if applicable)].
o Bulk is not considered a
commercial packaging configuration.
o The batches should be packaged
in the same number of containers
per presentation.
16. Bottle Orientation
• Irrelevant for Solid Dosage Forms
= =
• Inverted or side ways for liquids or suspensions
o Upright only serves as control
= ≠
17. Alternate API Supplier
• A single pilot scale batch per product strength
subject to BE studies
• If no BE studies were required, then a single pilot
scale batch of the highest product dosage
strength.
18. Alternate API Supplier
• Same active moiety
• Same degradants
• Same degradation
profile
• May have different
impurities
o Different impurity profile
does not interfere with FP
analytical methods
19. Alternate API Supplier
No annual batches need to be placed on stability
studies for both, the primary and secondary source of
API. Only one batch per strength, irrespective of API
source, needs be placed on annual stability.
20. Time Points
• Accelerated time
points: 0, 3, and 6
months
• Intermediate time
points (0, 6, 9, and 12
months)
• Long-term time points
(0, 3, 6, 9, 12, 18, 24, 36
months)
21. When to Pull Samples
The stability protocol should establish a three (3) day
range, centered about the pull due date, for pulling
samples out of the stability chamber. The actual
sample pull date should be recorded in the stability
report.
23. {[(Bracketing)]}
Test only the samples on the extremes of certain
design factors (container size/fill/strength) at all-time
points as in a full design.
Strength 50 mg 75 mg 100 mg
Batch 1 2 3 1 2 3 1 2 3
Container Size
15 ml T T T T T T
100 ml
500 ml T T T T T T
Key: t = Sample Tested
24. Matrixing
• Matrixing is applicable
to long-term protocols.
o Degree of Matrixing depends
on:
• Data variability
• Known product stability
• Amount of R&D data
• Stability significant
difference between
product strengths
• Number of combinations in
the study
o Matrixing should attempt to
reduce NMT 25% of full testing
o Factors that can be matrixed:
• Common blends
• Identical formulations
• Container sizes
• Fill sizes
• Similar formulations (colors
and flavors)
o Factors that should not be
matrixed:
• Initial and final time points
• Test parameters
• Dosage forms
• Storage conditions
• Proportionally similar
formulations
25. Matrixing Designs for a Product With Three
Strengths and Three Container Sizes
Matrixing on Time Points
Strength S1 S2 S3
Container
Size
A B C A B C A B C
Batch 1 T1 T2 T3 T2 T3 T1 T3 T1 T2
Batch 2 T2 T3 T1 T3 T1 T2 T1 T2 T3
Batch 3 T3 T1 T2 T1 T2 T3 T2 T3 T1
Matrixing on Time Points and Factors
Strength S1 S2 S3
Container
Size
A B C A B C A B C
Batch 1 T1 T2 T2 T1 T1 T2
Batch 2 T3 T1 T3 T1 T1 T3
Batch 3 T3 T2 T2 T3 T2 T3
Key:
Time-point
(months)
0 3 6 9 12 18 24 36
T1 T T T T T T T
T2 T T T T T T
T3 T T T T T T
S1, S2 and S3 are different strengths
A, B and C are different container
sizes
T = Sample tested
26. Matrixing Designs Common
Granulation/Blend
• Manufacture three (3)
common
granulations/blend lots.
• Use one common
granulation/blend lot to
manufacture all product
strengths.
• The second and third
common
granulation/blend lots will
be used to manufacture
the highest, lowest and
any other strength used in
BE studies
Strength S1 S2 S3 S4 S5
Batch #1 X X X X X
Batch #2 X X
Batch #3 X X
Key:
X – Manufactured
X – Stability tested
28. Scored Tablets
Tablets must be split
The split tablets must be bottled in
proposed CCS – not sealed, no
filler/dessicant.
Need 90 days in long term
conditions
One batch per strength
29. Preserved Products
In addition to
chemical assay of
preservatives, one
exhibit batch
needs to be
subjected to
preservative
efficacy testing at
expiry date.
30. Testing
• Batches should be placed
in stability within 30 days
of manufactured.
• Time zero data should not
be older than 30 days
from the day the batch is
placed on stability.
• Sample testing should be
completed within 15 days
of pull date.
• Reports should be
updated within 30 days of
pull date.
31. In Use Stability
• For products for
reconstitution or dilution.
• Performed once on two
batches:
o One batch tested after 6 month
accelerated (if no significant
change) or 6 month long term
storage..
o Second batch tested at expiry
date.
• To cover product at initial
reconstitution, at end of
use time and intermediate
points.
32. Data Reporting
• Always report the actual numerical value of those
tests which yield numerical values as results. Do not
use conforms.
• For degradants:
o Results below limit of quantitation should be reported as ≤ LOQ.
o Results below limit of detection should be reported as ND.
o Results below specifications but above LOQ should have the actual result
reported.
• Dissolution results should not have decimal values
reported.
33. Data Reporting
Significant changes should be accompanied by a
failure analysis to provide understanding and clarity to
the cause of the failure/significant change.
34. Trend Analysis
• Procedures to identify Out
of Trend (OOT) results
should be in place:
o OOT analysis procedures should
first establish what is expected
• Within a batch
• Across historical stability
batches
o OOT identification methods
should discriminate between
substantive events and spurious
values expected from the
inherent randomness.
o If an OOT result is found, then
steps need to be delineated to
determine the presence of an
underlying cause and if present,
the consequence that it has for
the batch under consideration.
35. Data
• Minimum stability data in support of an original
submission:
o Accelerated Stability
• With no significant change: 6 months Accelerated Conditions
• With significant change: 6 months Intermediate Conditions
o Ambient Temperature (Zone II, IVa or IVb): Six months
o Scored tablet stability report.
o In use stability report including data from 6 month samples.
• Stability conclusions need to be written up by R&D,
verified by QC/QA and approved by RA before the
study reports are submitted to FDA.
36. Retention
Submission stability batches should be retained for 1
year after application approval, or one year after the
conclusion of the stability study, whichever comes
later.