2. Many factors affect the stability of the pharmaceutical product
including the stability of the active ingredient's. The potential
interaction between active ingredients, the manufacturing
process, the dosage form, the container and closer, storage. The
environmental conditions encounter during transport, storage,
handling and length of times, between manufacture and use.
The purpose of the stability study testing is to prove on how the
quality of a drug substance or the drug product varies with time,
under the influence of variety of environmental factors such as
temperature, humidity and light.
Many factors affect the stability of the pharmaceutical product
including the stability of the active ingredient's. The potential
interaction between active ingredients, the manufacturing
process, the dosage form, the container and closer, storage. The
environmental conditions encounter during transport, storage,
handling and length of times, between manufacture and use.
The purpose of the stability study testing is to prove on how the
quality of a drug substance or the drug product varies with time,
under the influence of variety of environmental factors such as
temperature, humidity and light.
3. The mean kinetic temperature in any part of the
world can be derived from climatic data and world
can be divided into four climatic zones (I-IV).
The stability information generated in any one of the
three regions i.e. Japan, U.S and E.C would be
mutually, acceptable to the other two regions.
Information on the stability of the drug product is an
integral part of the systematic approach to stability
evaluation.
Interpretation of data is critical in stability studies. It
comes with experience and is important in
establishing “OOT” (out of trend) results. OOT
means abnormal fluctuations in the test results,
which are not acceptable.
The mean kinetic temperature in any part of the
world can be derived from climatic data and world
can be divided into four climatic zones (I-IV).
The stability information generated in any one of the
three regions i.e. Japan, U.S and E.C would be
mutually, acceptable to the other two regions.
Information on the stability of the drug product is an
integral part of the systematic approach to stability
evaluation.
Interpretation of data is critical in stability studies. It
comes with experience and is important in
establishing “OOT” (out of trend) results. OOT
means abnormal fluctuations in the test results,
which are not acceptable.
4. The stability studies are separated into
1.Chemical
2.Biochemical
3.Physical stability
Physical factors such as heat,light, and moisture
may initiate or accelerate the chemical reactions.
So chemical compound, physical dimensions are
included in stability studies. Physical and chemical
stability will be discussed to predict shelf life.
The stability studies are separated into
1.Chemical
2.Biochemical
3.Physical stability
Physical factors such as heat,light, and moisture
may initiate or accelerate the chemical reactions.
So chemical compound, physical dimensions are
included in stability studies. Physical and chemical
stability will be discussed to predict shelf life.
5. 1.Incompatibility
2.Oxidation-reduction
3.Hydrolysis
4.Decorboxilation
5.Racemization
6.Photochemical
7.Ionisation radiation
Stability studies include statistical
evaluation of stability data, determination of shelf-
life or expiration date and informing the storage
conditions of a drug product and raw materials.
1.Incompatibility
2.Oxidation-reduction
3.Hydrolysis
4.Decorboxilation
5.Racemization
6.Photochemical
7.Ionisation radiation
Stability studies include statistical
evaluation of stability data, determination of shelf-
life or expiration date and informing the storage
conditions of a drug product and raw materials.
6. Stability studies should be conducted to evaluate
1.New procedures or new manufacturing process.
2.REprocess / rework batches.
3.Batches where change control effected.
4.Existing commercial batches evaluation.
5.Validated batches for filing.
Stability Category should be of there types:
1.Accelerated-A
2.Intermediate-M
3.Long term-L
Stability studies should be conducted to evaluate
1.New procedures or new manufacturing process.
2.REprocess / rework batches.
3.Batches where change control effected.
4.Existing commercial batches evaluation.
5.Validated batches for filing.
Stability Category should be of there types:
1.Accelerated-A
2.Intermediate-M
3.Long term-L
7. Procedure for stability study:
After collecting the samples for stability study
prepare the stability study schedule as for the
following stability study schedule Tracker.
B.N
o
Loade
d date
ACC/LT/IN
T
Initia
l
Test stations in months
1 2 3 6 9 1
2
1
8
24 36 48
B.N
o
Loade
d date
ACC/LT/IN
T
Initia
l 1 2 3 6 9 1
2
1
8
24 36 48
8. Storage Conditions
I. For products storage conditions labeled as store at 25%
Temp.˚c Humidity % period
Long term (L) 25 2 or30 2 60 5 or 65 5 12months
Accelerated (A) 40 2 75 5 6months
Intermediate (M) 30 2 65 5 6months
II. For products storage conditions labeled as store at 8 c to
15 c.
Temp. c Humidity%
Long term (L) 15 2 ---------
Accelerated (A) 30 2 65 5
Storage Conditions
I. For products storage conditions labeled as store at 25%
Temp.˚c Humidity % period
Long term (L) 25±2 or30±2 60±5 or 65±5 12months
Accelerated (A) 40±2 75±5 6months
Intermediate (M) 30±2 65±5 6months
II. For products storage conditions labeled as store at 8°c to
15°c.
Temp.°c Humidity%
Long term (L) 15±2 ---------
Accelerated (A) 30±2 65±5
9. III. For products storage conditions labeled as store in
refrigerator 2 c to 8 c.
Temp. c Humidity%
Long term (L) 5 3 -------
Accelerated (A) 25 2 60 5
Other accelerated temperature and humidity. As per
the requirement of the regulatory bodies.
The number of samples to be taken depends upon the
number of stations 3months, 6months, 9months and
1 year.
III. For products storage conditions labeled as store in
refrigerator 2°c to 8°c.
Temp.°c Humidity%
Long term (L) 5±3 -------
Accelerated (A) 25±2 60±5
Other accelerated temperature and humidity. As per
the requirement of the regulatory bodies.
The number of samples to be taken depends upon the
number of stations 3months, 6months, 9months and
1 year.
10. Stability samples should be stored in containers that simulate
the market containers.
Example: If the product is packed in bags within fiber drums for
marketing, Stability samples can be packed in the same containers.
Separate sample pack should be prepared for each station of testing
for microbial test. Collect additional quantity of sample to conduct
two complete tests. Sample pack should be labeled as for SOP.
Normally first 3 production batches should be place on the stability
monitoring program to conform the expire date, how ever if data
from previous studies shows that the product is expected to remain
stable for at least for two years, fewer than 3 can be used.
Stability samples should be stored in containers that simulate
the market containers.
Example: If the product is packed in bags within fiber drums for
marketing, Stability samples can be packed in the same containers.
Separate sample pack should be prepared for each station of testing
for microbial test. Collect additional quantity of sample to conduct
two complete tests. Sample pack should be labeled as for SOP.
Normally first 3 production batches should be place on the stability
monitoring program to conform the expire date, how ever if data
from previous studies shows that the product is expected to remain
stable for at least for two years, fewer than 3 can be used.
11. After that at least one batch per year manufactured
should be added to the stability-monitoring program
and tested annually to conform the stability.
If the products are with short shelf-life testing
should be done more frequently.
Example: bio-technological, biological and other
products with shelf-life of one year or less should be
tested monthly for the first three months and at three
months interval afterwards. If data available at nine
months interval can be consider. Should not test the
retention/reserved samples for stability studies they
are meant for the evaluation of a quantity of the
product.
After that at least one batch per year manufactured
should be added to the stability-monitoring program
and tested annually to conform the stability.
If the products are with short shelf-life testing
should be done more frequently.
Example: bio-technological, biological and other
products with shelf-life of one year or less should be
tested monthly for the first three months and at three
months interval afterwards. If data available at nine
months interval can be consider. Should not test the
retention/reserved samples for stability studies they
are meant for the evaluation of a quantity of the
product.
12. Analysis of stability samples
A documented on going program should be designed
to monitor the stability characters of the product
and the results should be used to confirm the
storage conditions and expiry date or retest date.
1.Stability samples should be kept in the chambers
with in 15 days after the batch release.
2.If delayed for more than 15 days sample should be
re-analysed for initial results.
3.The release / re-test results should be used as initial
Data for test parameters.
Analysis of stability samples
A documented on going program should be designed
to monitor the stability characters of the product
and the results should be used to confirm the
storage conditions and expiry date or retest date.
1.Stability samples should be kept in the chambers
with in 15 days after the batch release.
2.If delayed for more than 15 days sample should be
re-analysed for initial results.
3.The release / re-test results should be used as initial
Data for test parameters.
13. 4.Keep samples in the respective environment
chamber and record the IN-OUT of stability samples
in environmental chamber (Stability chamber) Log
book.
5.After with drawl of sample form stability chambers,
the sample should be taken for analysis with in
5days of the schedule. If it is delayed the sample
should be kept in the refrigerator.
6.The refrigerator samples should be analysed with in
15days.
7.Incase of any deviation take approval of QA and
plan the activity accordingly. Investigate as for
OOT-SOP.
4.Keep samples in the respective environment
chamber and record the IN-OUT of stability samples
in environmental chamber (Stability chamber) Log
book.
5.After with drawl of sample form stability chambers,
the sample should be taken for analysis with in
5days of the schedule. If it is delayed the sample
should be kept in the refrigerator.
6.The refrigerator samples should be analysed with in
15days.
7.Incase of any deviation take approval of QA and
plan the activity accordingly. Investigate as for
OOT-SOP.
14. 8.Record the analytical findings in approved analytical
protocol and maintained all raw data along with data
sheet.
9.Summarize the stability protocol and prepare the
final stability report.
10.If any failure observed during stability studies
investigation should be carried out on analytical
parameters only.
Before reporting the results compare the test results
for the present test station with that of the previous
test station or with that of the other stations. Trend
should be checked with the report, which determine
the percent of fluctuations of the range.
8.Record the analytical findings in approved analytical
protocol and maintained all raw data along with data
sheet.
9.Summarize the stability protocol and prepare the
final stability report.
10.If any failure observed during stability studies
investigation should be carried out on analytical
parameters only.
Before reporting the results compare the test results
for the present test station with that of the previous
test station or with that of the other stations. Trend
should be checked with the report, which determine
the percent of fluctuations of the range.
15. Abnormal Ranges
When significant change occurs during storage under
accelerated condition, Discontinue the accelerated study and
continue for intermediate or long term storage conditions.
Significant change for a drug product is defined as follows.
1. A 5% change in Assay from initial value or failure to meet
the acceptance criteria for potency.
2. Failure to meet the acceptance criteria for appearance
(color), physical attributes and functionality test.
3. Failure to meet acceptance criteria for PH.
The following values are considered for the molecules,
which does not show a degradative trend, based on the
previous data available.
Abnormal Ranges
When significant change occurs during storage under
accelerated condition, Discontinue the accelerated study and
continue for intermediate or long term storage conditions.
Significant change for a drug product is defined as follows.
1. A 5% change in Assay from initial value or failure to meet
the acceptance criteria for potency.
2. Failure to meet the acceptance criteria for appearance
(color), physical attributes and functionality test.
3. Failure to meet acceptance criteria for PH.
The following values are considered for the molecules,
which does not show a degradative trend, based on the
previous data available.
16. 1. Water content or LOD:
Ex:<1% --- 20%
Ex: 1% --- 20%
Ex: >2% --- 10%
2. Specific optical rotations(SOR):
Form 0 to 25 --- 1
Form 25 to60 --- 2
Form 60 and above---3
3. Color absorbance:
Increase in colour more than 0.15AU.
1. Water content or LOD:
Ex:<1% --- 20%
Ex: 1% --- 20%
Ex: >2% --- 10%
2. Specific optical rotations(SOR):
Form 0° to 25° --- 1°
Form 25°to60° --- 2°
Form 60° and above---3°
3. Color absorbance:
Increase in colour more than 0.15AU.
17. 4. Related substances:
Some degradable impurities may come more than
the expected % then look for the accelerated data
and the extent of degradation of that impurity up to
6 M station.
5. Assay: Variation may be more than 1% for raw
materials and intermediates, variation is more than
3% for formulations and for dissolution tests the
variation is more than 5%.
4. Related substances:
Some degradable impurities may come more than
the expected % then look for the accelerated data
and the extent of degradation of that impurity up to
6 M station.
5. Assay: Variation may be more than 1% for raw
materials and intermediates, variation is more than
3% for formulations and for dissolution tests the
variation is more than 5%.
18. How to avoid Abnormalities
To avoid the abnormalities in the stability studies, STP’s,
specifications and available literature to be studied before
starting a stability studies project, go through the previous
test station values. Initial values or the available stability
report.
Example: Some sample may be hygroscopic in nature
necessary precaution to be taken while handling these
materials. i.e direct weighing of the sample in the container.
In colour absorbance dilution to be made and colour values
to be taken immediately. Accurate dilutions are necessary to
avoid colour variations.
For specific optical rotation (SOR) experiments temperature
of the sample solution is important
How to avoid Abnormalities
To avoid the abnormalities in the stability studies, STP’s,
specifications and available literature to be studied before
starting a stability studies project, go through the previous
test station values. Initial values or the available stability
report.
Example: Some sample may be hygroscopic in nature
necessary precaution to be taken while handling these
materials. i.e direct weighing of the sample in the container.
In colour absorbance dilution to be made and colour values
to be taken immediately. Accurate dilutions are necessary to
avoid colour variations.
For specific optical rotation (SOR) experiments temperature
of the sample solution is important
19. So maintain the given temperature accurately.
Ifabnormality found in related substances
chromatogram check the integrated parameters with
the blank.
Check the stability of the sample in analyte solution,
repeat the injections. While doing the assay
calculate the values immediately, if the assay values
are not meeting the specification or showing out of
trend the sample can be analyzed immidiately to
verify the results.
So maintain the given temperature accurately.
Ifabnormality found in related substances
chromatogram check the integrated parameters with
the blank.
Check the stability of the sample in analyte solution,
repeat the injections. While doing the assay
calculate the values immediately, if the assay values
are not meeting the specification or showing out of
trend the sample can be analyzed immidiately to
verify the results.
20. How to report the (OOT) Results
If find any OOT results investigate the proper problem
(integration,calculation, dilution, etc). Repeat the
sample analysis with the same solution,still it is an
OOT results, inform to the incharge and go to fresh
or extra sample and analyse.
Still it is an OOT results report the first value. In this
way while conducting the stability studies the
chemist or analyst should take all the precautions
before completion of the analysis and declaring the
results.
How to report the (OOT) Results
If find any OOT results investigate the proper problem
(integration,calculation, dilution, etc). Repeat the
sample analysis with the same solution,still it is an
OOT results, inform to the incharge and go to fresh
or extra sample and analyse.
Still it is an OOT results report the first value. In this
way while conducting the stability studies the
chemist or analyst should take all the precautions
before completion of the analysis and declaring the
results.
21. By producing products with increasing shelf-life will
benefit the organization and give satisfaction to the
analyst who will conduct the stability program.
Evaluation of the results:
1.Based on the 6 months accelerated or 12 months
long term stability study data, a 2 years shelf-life
may be assigned for an API or intermediate product.
2.Final shelf life should be assigned to a product
supported by long term stability data.
By producing products with increasing shelf-life will
benefit the organization and give satisfaction to the
analyst who will conduct the stability program.
Evaluation of the results:
1.Based on the 6 months accelerated or 12 months
long term stability study data, a 2 years shelf-life
may be assigned for an API or intermediate product.
2.Final shelf life should be assigned to a product
supported by long term stability data.
22. Product Name:
Product No.
Batch No.
Mfg.Date.
Month as per schedule.
QA.issue No.
Date of analysis
Exp.Date.
S.No Name of the test Results Analysed By Date
1. Description1. Description
2. Water
3. P.H
4. Absorbance
5. Related substance
6. Assay
7. Additional test
23. Numbering for various categories of stability study is
as follows.
Unit
Code
Stabilit
y study
Stability
category
Product
Code
Year
code
Sequential no
of protocol
E S ACC/LT
/INT
Name of
the
product
Name of
the
product
