Stability Studies Guideline in Pharmaceutical Industry
Stability Studies Guideline in Pharmaceutical Industry
¨ The
purpose of stability studies is to provide the documented proof that how the
environmental conditions like temperature, humidity and light can affect the
quality of pharmaceutical ingredients and finished products.
¨ Stability
studies guideline tells about the retesting schedule of the pharmaceutical
ingredients and products in the climatic conditions of the area where they are
to be used.
Climatic zones
¨ For
the testing the world is divided into four climatic zones on the basis of the
environmental conditions.
|
Climatic Zone |
Climate definition |
Long term Stability Conditions |
|
Zone 1 |
Temperate |
21ºC /45% RH |
|
Zone 2 |
Subtropical & Mediterranean |
25ºC /60% RH |
|
Zone 3 |
Hot & Dry |
30ºC /35% RH |
|
Zone 4a |
Hot & Humid |
30ºC /65%RH |
|
Zone 4b |
Hot & Very Humid |
30ºC /75%RH |
Selection Of Batches
¨ Selection
of Batches: For stability testing 3 batches of the API/ Finished products
should be selected.
¨ These
batches should be manufactured on pilot scale batch and the same procedure for
manufacturing should be followed.
¨ The
packing should also be same as that of approved container closure system.
Testing Frequency
¨ Long
Term Study: For long term study the testing schedule should carried out
every 3rd month for 1st year i.e (0, 3, 6, 9 and 12).
¨ On
2nd year every 6th month i.e (18 and 24).
¨ And
thereafter annual testing should be carried out i.e 36, 48 and so on.
¨ Intermediate
Study: For intermediate study testing schedule should be carried out every
3rd month i.e 0, 3, 6th.
¨ Short
Term Study or Accelerated Studies: For accelerated studies a minimum of 3
times studies should be carried out i.e (0, 3 and 6).
¨ However
depending upon the Active conditions the retesting schedule can be increased up
to every month i.e (0,1,2,3,4,5,6)
Storage Conditions
¨ Storage
conditions should be applied as per the nature of the Active Pharmaceutical
Ingredients i.e either they are photo sensitive, heat sensitive or light
sensitive.
¨ The
storage conditions, retesting schedule should be appropriate to fulfill the
requirements of safe storage, shipment and usage of the API/product.
General Case
|
Study |
Conditions |
Minimum Time period of testing |
|
Long Term |
25ºC ± 2ºC/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH |
12 months |
|
Intermediate |
30ºC ± 2ºC/65% RH ± 5%RH |
06 months |
|
Short Term |
40ºC ± 2ºC/75% RH ± 5% RH |
06 months |
¨ It
depends upon the applicant that long term stability studies are carried out
25ºC ± 2ºC/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.
¨ However
if the long term studies are carried out 30°C ± 2°C/65% RH ± 5% RH. Then there
is no need of intermediate study.
¨ Moreover
if long term studies are carried out at 25ºC ± 2ºC/60% RH ± 5% RH and there is
observed and significant change in short term study then in such
conditions intermediate studies should be performed.
Significant Change
¨ Significant
Change: Behavior of the API or Product that doesn’t comply with the given
specifications.
¨ A
5% loss in assay, any degradation product exceeding the limit, change color,
smell, pH, hardness, softness etc are all significant changes.
Refrigerator Storage Conditions
|
Study |
Storage Conditions |
Minimum time Period required |
|
Long Term |
5ºC ± 3ºC |
12 months |
|
Short term |
25ºC ± 2ºC/60% RH ± 5% RH |
06 months |
¨ If
any significant change occur during 3 to 6 month the proposed testing schedule
of long term stability should be applicable.
Freezer Storage Conditions
|
Study |
Storage Conditions |
Minimum time Period Required |
|
Long Term |
-20ºC ± 5ºC |
12 months |
¨ API/Product
stored at Freezer conditions should be evaluated by long terms studies
protocols.
¨ Due
to absence of short term study a single batch should be tested at higher
temperature (e.g., 5ºC ± 3ºC or 25ºC ±
2ºC) to elaborate the effect that may occur in shipment or handling.
Bracketing and Matrixing Design of Stability Studies
¨ Bracketing
and Matrixing designs of stability studies have reduced testing sample as that
of general guidelines.
¨ Proper
scientific justification and clarifications are required to carry out such
designed studies.
Bracketing
¨ Bracketing
design include the testing of samples that are at extremes of strength,
container size or filling volume or weight.
¨ The
samples must have same API and excipients.
¨ Example
is given in the following table
¨ In
the table “T” stands for tested sample
|
Strength |
50mg |
75mg |
100mg |
|||||||
|
Batch |
1 |
2 |
3 |
1 |
2 |
3 |
1 |
2 |
3 |
|
|
Container Size |
15ml |
T |
T |
T |
T |
T |
T |
T |
T |
T |
|
100ml |
||||||||||
|
500ml |
T |
T |
T |
T |
T |
T |
T |
T |
T |
|
Matrixing
¨ Matrixing
design of stability study concern with the selection of selected subset of
possible samples from all the design factors at a specific time.
¨ At
next time point another set of samples of different design factors should be
tested.
¨ The
results of each samples set should be applicable to all the samples of the
different design factors.
One Half Reduction
|
Time Point |
0 |
3 |
6 |
9 |
12 |
18 |
24 |
36 |
||
|
strength |
S1 |
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 |
|||
|
S2 |
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 |
||||
|
“S” Stands For Strength |
“T” stands for sample tested |
|||||||||
One Third Reduction
|
Time Point |
0 |
3 |
6 |
9 |
12 |
18 |
24 |
36 |
||
|
strength |
S1 |
Batch 1 |
T |
T |
T |
T |
T |
T |
||
|
Batch 2 |
T |
T |
T |
T |
T |
T |
||||
|
Batch 3 |
T |
T |
T |
T |
T |
|||||
|
S2 |
Batch 1 |
T |
T |
T |
T |
T |
||||
|
Batch 2 |
T |
T |
T |
T |
T |
T |
||||
|
Batch 3 |
T |
T |
T |
T |
T |
|||||
|
“S” Stands For Strength |
“T” stands for sample tested |
|||||||||
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