Purpose
To describe the procedure for Handling and Analysis of
stability samples and Compilation of Stability Data.
Procedure:
Stability study shall be carried out to understand any
chemical, physical and microbiological changes in products during their shelf
life when exposed under different storage conditions and to confirm that drug
products are assured for their efficacy and safety in marketed packs. Storage
conditions and shelf life for finish products are established through stability
studies.
Selection of the batches
At development stage of product, at least three primary
batches of the product shall be selected for stability testing. For commercial
production batches, three primary batches of validation study shall be selected
for stability testing.
The batches selected for charging in stability shall be
of same formulation and packaged in the same container closure system
(including, as appropriate, any secondary packaging and container label) that
shall be proposed for production batches and shall provide product of the same
quality and meeting the same specification as that intended for marketing.
Stability study shall be performed on each individual
strength and container size of the product unless bracketing or matrixing is
applied.
Bracketing and matrixing are reduced study designs in
which samples for every factor combination are not all tested at all-time
points.
Assumptions in bracketing and matrixing should be
assessed and justified.
Potential risk should be identified because reduced
amount of data is collected in bracketing and matrixing. A matrixing design has
less precision in shelf-life estimation and yields a shorter shelf-life than
the corresponding full design. If there is an excessive reduction in the number
of factor combinations tested and data from the tested factor combinations
cannot be pooled to establish a single shelf life, it may be impossible to
estimate the shelf lives for missing factor combinations.
Bracketing: Bracketing can be applied to
studies of same container closure system where either container size or fill
varies while the other remains constant. The design assumes that the stability
of any intermediate levels is represented by the stability of the extremes
tested. Bracketing can be applied to the following conditions:
Multiple strengths of identical or closely related
formulations.
e.g. Aerosol of different strengths made from same
formulation.
Aerosol of different strengths with formulations that
differ only in minor excipients (e.g. fragrance)
Different container sizes or different fills in the
same container closure system.
In case where different excipients are used among
strengths, bracketing should not be applied.
Example of Bracketing Design:
Strength
|
S1
|
S2
|
S3
|
||||||||
Batch
|
1
|
2
|
3
|
1
|
2
|
3
|
1
|
2
|
3
|
||
Container Size
|
W1
|
T
|
T
|
T
|
---
|
---
|
---
|
T
|
T
|
T
|
|
W2
|
---
|
---
|
----
|
---
|
---
|
---
|
----
|
---
|
---
|
||
W3
|
T
|
T
|
T
|
---
|
---
|
---
|
T
|
T
|
T
|
||
*T = Sample tested, S= Strength, W= Container Size
Matrixing: Matrixing is the design in which
selected subset of the total number of possible samples for all factor
combinations would be tested at a specified time point. At a subsequent point,
another subset of samples for all factor combinations would be tested. The
design assumes that the stability of each subset of samples tested represents
the stability of all samples at a given time point.
In matrixing, all selected factor combinations should
be tested at the initial and final time points, while only certain fractions of
the designated combinations should be tested at each intermediate time point.
For matrixing at accelerated or intermediate storage
condition, testing occurs at minimum three time points, including initial and
finial, for each selected combination of factors.
If one strength or container size and/or fill from any
matrix design is no longer intended for marketing, stability testing of that
strength or container size and/or fill can be continued to support the other
strengths or container sizes and/or fills in the design.
Example of Matrixing Design:
One half reduction initially eliminates one in every
two time points from the full study design.
Time points (months)
|
0
|
3
|
6
|
9
|
12
|
18
|
24
|
36
|
|||
Strengths
|
5 mg
|
Batch 1
|
T
|
T
|
----
|
T
|
T
|
----
|
T
|
T
|
|
Batch 2
|
T
|
T
|
----
|
T
|
T
|
T
|
----
|
T
|
|||
Batch 3
|
T
|
----
|
T
|
----
|
T
|
T
|
----
|
T
|
|||
10 mg
|
Batch 1
|
T
|
----
|
T
|
----
|
T
|
----
|
T
|
T
|
||
Batch 2
|
T
|
T
|
----
|
T
|
T
|
T
|
----
|
T
|
|||
Batch 3
|
T
|
----
|
T
|
----
|
T
|
----
|
T
|
T
|
|||
One Third reduction initially removes one in every
three time points from the full study design.
Time points (months)
|
0
|
3
|
6
|
9
|
12
|
18
|
24
|
36
|
||||||
Strengths
|
5 mg
|
Batch 1
|
T
|
T
|
----
|
T
|
T
|
----
|
T
|
T
|
||||
Batch 2
|
T
|
T
|
T
|
----
|
T
|
T
|
----
|
T
|
||||||
Batch 3
|
T
|
----
|
T
|
T
|
T
|
T
|
T
|
T
|
||||||
10 mg
|
Batch 1
|
T
|
----
|
T
|
T
|
T
|
T
|
T
|
T
|
|||||
Batch 2
|
T
|
T
|
----
|
T
|
T
|
----
|
T
|
T
|
||||||
Batch 3
|
T
|
T
|
T
|
----
|
T
|
T
|
----
|
T
|
||||||
*T = Sample tested
In case if the products are packed in different
container closure system, then all type of packing configuration shall be
considered for stability testing.
Thereafter, one batch of every year shall be subjected
to long term stability study or charge as per requirement.
Collection and Charging of Stability Sample
IPQA Officer/Designee shall collect sample for
stability study as per approved stability study protocol during batch packing
operation.
QAD shall send the stability sample to stability
department along with “Stability Sample Intimation” within 7 days from the date
of QC release. Stability Sample Intimation shall be filled in duplicate, so
that one copy kept by stability department during receiving of sample and
duplicate copy kept by QAD.
Executive/Designee-Stability shall receive the
stability sample and affix stability sample labels as per following storage
condition given in stability protocol.
For Accelerated Study for temperature and RH condition
40°C±2°C & 75% RH±5%RH refer SOP for “Status Labeling”,
For Long term study for temperature and RH condition
30°C±2°C & 75% RH±5%RH refer SOP for “Status Labeling
For Long term study for temperature and RH condition
30°C±2°C & 65% RH±5%RH refer SOP for “Status Labeling
For Long term study for temperature and RH condition
(25°C±2°C & 60% RH±5%RH) refer SOP for “Status Labeling”,.
For Long Term Study for temperature and RH condition
5°C±3°C refer SOP for “Status
Labeling”.
For Stress condition refer SOP for Status Labeling SOP.
Stability samples shall be stored under controlled room
temperature i.e. not more than 25°C till charging in stability chambers.
Stability sample shall be charged in stability chamber
within 30 days from the date of QC release.
If stability sample is not charged due to any delay in
stability chamber within 30 days, complete analysis shall be performed again
within 15 days and stability samples shall be charged after completion of
analysis. The results of reanalysis shall be considered as initial results.
After keeping the samples in stability chambers,
Executive/Designee-Stability shall make entries in “Stability Chamber Usage
Logbook”.
After charging stability sample
Executive/Designee-Stability shall prepare Monthly Planner on computer with
password protected excel sheet.
Storage of Stability Sample
Stability study of products shall be done according to
climatic conditions of the country. According to the climate, the world is
divided into four different zones given below:
Zone
|
Type of Climate
|
Zone I
|
Temperate Zone
|
Zone II
|
Mediterranean/ Subtropical Zone
|
Zone III
|
Hot Dry Zone
|
Zone IVa
|
Hot Humid/ Tropical Zone
|
Zone IVb
|
Hot/Higher Humidity
|
Since Indian environment condition is covered under
Zone IVa and IVb. So, sample storage condition and minimum testing frequency
for general case shall be as per given below:
Study
|
Storage Condition
|
Testing Frequency
|
Long term*
|
25°C ± 2°C/60% RH ± 5% RH or or 30°C ± 2°C/65% RH ±
5% RH or 30°C ± 2°C/75% RH ± 5% RH
|
First year: Initially and after every 3 months
Second year: Every 6 month
Thereafter: Annually
|
Accelerated
|
40°C ± 2°C/75% RH ± 5% RH
|
Initial, 3 months, 6 months
|
Intermediate **
|
30°C ± 2°C/65% RH ± 5% RH
|
Initial, 3 months, 6 months, 9 months & 12 months
|
* It is up to the applicant to decide whether long term
stability studies are performed at 25°C ± 2°C/60% RH ± 5% RH or or 30°C ±
2°C/65% RH ± 5% RH or 30°C ± 2°C/75% RH ± 5% RH
** Intermediate stability condition will be applicable
only if Long Term is 25°C ± 2°C/60% RH ± 5% RH
Note: Additional study shall be performed as per
customer/ regulatory requirement.
Storage condition and minimum testing frequency for
products stored in refrigerator shall be given below:
Study Storage
Condition Testing Frequency
Long term 5°C
± 3°C Initial, 3 months, 6 months, 9
months & 12 months.
Accelerated 25°C
± 2°C/60% RH ± 5% RH Initial, 3
months, 6 months
Storage condition and minimum testing frequency for
products stored in freezer shall be given below:
Study Storage
Condition Testing Frequency
Long term -
20°C ± 5°C Initial, 3 months, 6 months, 9
months & 12 months.
Storage condition and minimum testing frequency for
products stored in Stress Condition shall be given below:
Study Storage
Condition Testing Frequency
Stress Condition 50°
C or 10°C increments 07, 14 & 21
days
Initial (Zero) month is to be considered as date of QC
release of the batch. Subsequent time intervals are to be counted on the basis
of date of placing the samples into stability chamber (date of charging).
Withdrawal and testing of Stability Sample
According to the “Stability Monthly Planner”
Executive/Designee-Stability shall schedule the plan for sample withdrawal.
Executive/Designee-Stability shall make the entries in
the column of “withdrawn by Sign & Date” of “Stability Monthly Planner”.
Withdrawal of Stability sample shall not be overdue
more than 3 days from its due date of withdrawal.
If stability sample could not withdraw due to any
holiday, sample shall be withdrawn on next working day.
Any deviation occurs in sample withdrawal tolerance
shall be documented and handled as per SOP of Handling of Deviation.
Samples of accelerated stability study shall be
analyzed within15 days from date of withdraw and samples of long term stability
study shall be analyzed within 30 days from the date of withdraw. Failure to
complete analysis within stated time lines shall be handled through SOP
Handling of Deviation.
Executive/Designee-Stability shall record the sample
details in Stability Sample Logbook
Executive/Designee-Stability shall record the analysis
report in test data sheet, which shall be prepared and approved as per SOP of
Preparation of Test Data Sheet. Test Data Sheets shall be prepared for each
individual product.
Executive/Designee-Stability shall assign A.R. Number
and maintain the log
QC analyst Stability shall receive stability samples
and test data sheet by signing and date in monthly planner. QC analyst
Stability shall perform the testing as per approved specification.
Stability tests shall include those attributes of the
products that are susceptible to change during storage and are likely to
influence quality, safety and/or efficacy. e.g. product description, filled
container weight, microbiological limit tests, assay, spray rate, corrosion
test etc.
Stability study shall cover testing of chemical and
microbiological attributes, preservative content, etc. A product specific
protocol shall be prepared for performing the stability testing. Stability
testing parameters shall be performed as per approved stability study protocol.
On the basis of analysis report Executive/Designee-Stability
shall prepare the stability summary sheet and send the summary sheet and
analysis report to QAD for review, evaluation and approval.
Stability person withdraw total charged sample at the
end of last station from all condition.
After completion of analysis the remaining sample shall
be destroyed as per SOP of Destruction of Sample after Analysis.
Evaluation of Stability Data
Head QAD/In-Charge Stability/Designee shall review the
report at each testing period for trend analysis or significant changes. After
completion of the stability testing as per schedule the stability report shall
be prepared and the evaluation of stability data shall be done.
If significant change occurs at any time during 6
months testing at the accelerated storage condition, additional testing at the
intermediate storage condition should be conducted and evaluated against
significant change criteria.
Criteria of Significant Change is given below:
A 5% change in assay from its initial value.
Any degradation product’s exceeding its acceptance
criterion.
Failure to meet the acceptance criteria for product
description, MLT (where applicable) & assay etc.
Failure to meet for the acceptance criterion for pH.
Failure to meet the acceptance criteria for filled
container weight.
Any significant change in stability results shall be
investigated and the investigation report shall be attached to stability
protocol.
If the stability fails to meet the specification
limits, the same shall be investigated through the SOP of Out of Specification
(OOS).
Executive/Designee-Stability shall send request for
additional stability sample to QAD for re-analysis (If required) of the product.
To extend the shelf life beyond the period covered by
long term data can be proposed by extrapolation, particularly if no significant
change is observed at the accelerated condition. Extrapolation is the practice
of using a known data set to gather information about future data. Any
extrapolation shall be performed such that the extended shelf-life will be
valid for a future batch released with test results close to the release
acceptance criteria. A shelf-life granted on the basis of extrapolation should
always be verified by additional long term stability data as soon as these data
become available.
A storage condition statement should be based on the
stability evaluation. Wherever applicable, specific instructions shall be
provided.
Data evaluation for Shelf Life of the product shall be
estimated “Decision Tree for Data Evaluation for Shelf Life Estimation”.
Criteria for additional stability testing
Following are the few cases, but not limited to, in
which the additional stability testing shall be required.
Primary packaging component is changed
Major change in the manufacturing process /
formulation.
Change in key or active raw materials source.
A switch is made to a new manufacturing site.
Significant change in critical manufacturing equipment,
which could have an influence on product
stability.
Change in batch size.
As per party requirement.
Discontinuation of Stability Study
An ongoing stability study shall be terminated subject
to any one of the following conditions:
When a project
is terminated by scientific or management decision.
When the active material source is no longer available
on the commercial market.
When there is a significant change in the product
description, aerosol filled container weight, corrosion testing, spray rate, pH
(where applicable), MLT (where applicable) & assay etc. Investigation shall
be done on the affected batch along with all the batches produced at the same
time.
When container closure system is no longer available on
the commercial market.
The stability study shall be terminated by means of a
written statement given by Head-QAD with appropriate reasons for discontinue of
stability study. The investigation report shall be attached to the study termination
statement.
On Recall of product.
Executive/Designee-Stability or ARD shall raise the
stability termination i.e. “Termination of Stability Study” and maintain the
log “Stability Study Termination Logbook”. Termination number shall be assigned
Executive/Designee-Stability shall perform Stability
Chamber Physical Inventory annually and maintain the record and shall affix the
inventory label as per SOP for “Status
Labeling” on respective stability chamber.
