Procedure for initiation of stability studies for Active pharmaceutical ingredients in bulk manufacturing industries

1. The purpose of stability testing / monitoring is to provide
evidence on how the quality of a drug substance varies
with time under the influence of a variety of
environmental factors such as temperature, humidity, and
light to determine/estimate the re-test period of the drug
substance and recommended pack and storage conditions
 It is a regulatory requirement and suggested by varies
authorities like WHO,ICH,USFDA,CPMP(Committee for
Proprietary Medicinal Products ),EMEA( 'Europe, the
Middle East, and Africa), CDSCO...etc

2. Definition:
Stability of a pharmaceutical product means how long it
can maintain its original form without any visible and
chemical changes under the influence various
environmental factors like temperature, humidity, light. ...
Types of Stability studies for drug substances:
There are mainly 3 types of studies are as fallow
1. Physical stability:
The original physical properties such as appearance,
colour, dissolution are retained and it is important for
the efficacy and safety of the product.

3. 2. Chemical stability:
It is the tendency to resist its change or
decomposition due to the reactions that occur due to
air, atmosphere, temperature, etc.
3. Microbiological stability:
The microbiological stability of the drugs is the
tendency to resistance to the microbial growth. This
microbiological instability could be hazardous to the
sterile drug product

4. As per ICH climatic Zones

5. Climatic Zones & Environmental conditions
Zone Temperature & Humidity Countries
Zone I 21ºC ± 2ºC & 45% RH ± 5%
RH (temperate zone)
United Kingdom,
Russia, USA
Zone II 25ºC ± 2ºC & 60% RH ± 5%
RH (subtropical zone)
Japan, Southern
Europe
Zone III 30ºC ± 2ºC & 35% RH ± 5%
RH (Hot dry zone)
Iraq, India
Zone IVa 30ºC ± 2ºC & 65% RH ± 5%
RH (Hot and humid zone)
Iran, Egypt
Zone IVb 30ºC ± 2ºC & 75% RH ±
5% RH (Hot and higher
humidity zone)
Brazil, Singapore

6. Types of stability studies with respect environment condition:
Types of stability studies( at Room
temperature)
Storage Conditions
Long Term or Alternative long term
storage condition (for zone III & IV)
25±2°C and 60±5% RH or 30±2°C
and 65±5% RH
Intermediate 30±2°C and 65±5% RH
Accelerated 40±2°C and 75±5% RH
Zone-IVB 30±2°C and 75±5% RH
For refrigerator condition Storage Conditions
Long-term 5 ±3°C
Accelerated condition 25 ± 2°C and 60 ± 5%
For Freezer condition Storage Conditions
Long term -20 ± 5°C
Accelerated condition 5 ± 30C

7. Relation between Retest date & Expiry date:
 The Expiration Date defines the total shelf life
of the product.
 The term "shelf life" of a drug slightly differs
from a drug's "expiration date." The shelf life
generally relates to a drug's quality over a
specified period of time, whereas the expiration
date relates to both quality and safety of a
medication at a specific point in time.
 Retest dates are assigned to new products
and to products which are continuing on
stability testing. The retest date is assigned
during product design, at the time of initial
production, or at a stability testing interval.

8. Our practices here in
Sop no: XXXXXX
Title of the SOP: MANAGEMENT OF STABILITY
SAMPLES
Responsibility:
Quality assurance:
 To notify production and Quality control about the
initiation of the stability study and to ensure
whether the study is initiated.
 To review the stability testing results and the retest
period/expiry proposed.

9.  To coordinate with QC in the investigation of
the stability failure/incident
Production:
 Acknowledge stability initiation notification
and facilitate collection of the stability samples
by the QC.
Quality control:
 Sampling of stability samples based on the QA
notification and Packing of samples as per the
storage condition. Determine testing frequency
and placing of the samples in appropriate
stability chambers.

10.  Monitoring of stability chambers and
reporting deviation /incidents if any.
 Preparation of master and monthly stability
schedules through SAP as per the approved
protocol. Withdrawal and initiation of samples
as per the schedule timely analysis and
updation of stability data sheets
 Preparation of stability reports, Preparation of
stability specification/MOA and reporting of
any schedule deviations/incidents/OOS and
OOT

11. HOD :
 Assign responsibilities for stability
management and guide analyst in the
evaluation of data and investigation of failure
 Ensure that appropriate retest period/expire
date are assigned to products
 Ensure the lab personnel are appropriate
trained
 Responsible for implementation of the SOP

12. Procedure:
Stability study shall be carried out at three
different cases mentioned below as defined in
ICH guidelines
General case:
Accelerated Conditions:
1. The stability of the product may be estimated
by carrying out stability study of the product
at higher temperature and humidity levels to
accelerate possible degradation of the product.
2. Following environmental conditions shall be
maintained during this study.
Temperature 40 ± 2°C, Relative Humidity75 ±
5%

13. 3. The accelerated study shall be conducted for a
period of six months at minimum five points
(Initial, 1, 2, 3 and 6 months)
4. If significant change (failure to meet the
specification) 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
Long Term conditions:
1. The actual stability of the product shall be
determined based on long term stability study.

14. 2. The environmental conditions for long-term
study are,
Temperature 25 ± 2°C
Relative Humidity 60 ± 5%
Length of study 60 months
3. Quality testing intervals are Initial, 3 , 6 , 9 , 12
,18 , 24 , 36 , 48 and 60 months.
4. The long-term study shall be carried out for a
period of five years or until the product fails to
meet the defined specifications whichever is
earlier

15. Alternative long term storage condition:
1. To address the stability of the product for zone
—III & IV, Alternative long term studies shall
be initiated
2. The temperature and humidity conditions for
'Alternative long term study' are given below
Temperature: 30 ± 2°C
Relative Humidity : 65 ± 5%
Length of study : 60 months
3. Quality testing intervals are Initial, 3 , 6, 9, 12,
18, 24, 36, 48 and 60 months

16. Alternative long term storage condition for
Zone-IVB:
1. To address the stability of the product for
zone—IVB, Alternative long term studies for
zone IVB shall be initiated
2. The temperature and humidity conditions for
'Alternative long term study' are given below
Temperature 30 ± 2°C,
Relative Humidity 75 ± 5%
Length of study 60 months
3. Quality testing intervals are Initial , 3 , 6, 9, 12,
18,24, 36,48 and 60 months

17. Drug substances intended for storage in a
Refrigerator:
Accelerated conditions:-
1. Following conditions shall be maintained
during this study.
Temperature: 25 ± 2°C
Relative humidity : 60 ± 5%
Length of study : 6 months
2. The study shall be conducted for a period of six
months at minimum five time points (0, 1,2,3
and 6 months)

18. Long term conditions:
1. Following conditions shall be maintained
during this study.
Temperature: 5 ± 3°C
2. Quality testing intervals are Initial, 3 , 6 , 9, 12 ,
18 , 24, 36, 48and 60 months.
3. The study shall be carried out through a
period of 5 years or until the product meet the
defined specifications whichever is earlier
Drug substances intended for storage in freezer:
Accelerated conditions:
1. Following conditions shall be maintained
during this study

19. Temperature: 5 ± 3°C
Length of study: 6 months
2. The study shall be conducted for a period of
six months at minimum five time points (0,
1,2,3 and 6 months)
Long term conditions:
1. Following conditions shall be maintained
during this study
Temperature: -20 ± 5°C
2. Quality testing intervals are Initial, 3 months, 6
months, 9 months, 12 months, 18 months, 24
months, 36 months, 48 months and 60 months

20. 3. The study shall be carried out through a period of 5
years or until the product meet the defined
specifications whichever is earlier
Commercial Storage Stability Study:
1. One sample from the commercial batch of every
year production of each product shall be subjected
to stability study for 'Long term' and 'Zone-IVB‘
stability conditions and testing frequency shall be
planned as under
2. If stability data available for the commercial batches
two years or more than two years and no significant
deviation observed in stability data, the samples shall
be tested for quality at below mentioned intervals.
Initial, 12 , 24, 36, 48 and 60 months

21. 3. If stability data available for the commercial batches
less than two years, the samples shall be tested for
quality at below mentioned intervals. Initial, 3, 6, 9, 12,
18, 24 , 36, 48 and 60 months or as per the product
planner.
4. The results shall be summarized and reported in
"Annual Product Review".
General Guidelines for initiation of stability:
1. Products meeting defined specifications only shall be
kept for stability studies.
2. The stability study should be performed on first three
commercial production batches (process validation
batches) of drug substance thereafter; at least one
batch per year of drug substance should be added to
the stability monitoring program. The batches which
are modified by the physical manipulation e.g. Milling
or micronization etc. are also subjected for stability
study at all conditions at one time.

22. 3. The additional stability study batches required
in following conditions
 Change in critical process steps
 Reprocessed / reworked batches
 Change in manufacturing site / block / module
 Use of recovered solvent / recovered material
 Change in source of API starting material/primary
packaging material

23. 4. The product shall be packed in the exact
manner in which the product is packed for
dispatch into market. The packaging
material and manner of packaging shall be
same as for market dispatch.
5. The samples shall be packed as individually
for each stability station, total number of
stability station samples based on frequency
of stability station and study period.
6. Sufficient Quantity of the sample shall be
packed for each stability station and 3 buffer
samples to carry out at least 3 times analysis
of stability indicating test

24. 7. The containers containing samples shall be
kept in validated stability chambers at
specified conditions with appropriate labels.
8. The temperature and humidity of the test
chambers shall be monitored daily and
calibrated periodically.
9. Person withdrawing the samples from the
chamber shall examine immediately the
integrity of sample packing condition and
document the findings in the remark column
of the Stability Chamber usage Log’, if any
abnormal observation with respect to packing
condition of stability samples shall be reported
and investigated through incident report

25. 10. If customer suggests the stability for any
product, preferably follow as per customer
protocol.
11. Termination of stability study shall be done, In
case of cancellation of market plan, project or
changes in the product formula and shall be
documented.
Stability study initiation:
1. Before initiating the stability testing the
“Stability study protocol” shall be prepared.
2. The stability protocol should contain the
following details, but not limited to
 Purpose of stability study

26. Responsibility
Sample quantity detail and stability sample
preparation procedure
Container-closure detail
Stability conditions
Testing frequency, test parameters and test
method reference.
Recording of stability data and conclusion
of the study.

27. Preparation of samples:
1. The quantity and the mode of the packing of
sample shall be packed as per the given in
respective stability study protocol.
2. The stability study shall initiate with in 30 days,
after approval of the respective batches. If the
stability study does not initiate within 30 days,
re-analyze the material for initial results
Specification and Test procedures:
1. The test parameters should cover those features
susceptible to change the quality during storage
and test analysis parameters mentioned in
stability protocol should be analyzed as per
current STP

28. Stability Sample Withdrawal and Analysis:
1. Prepare the ‘Stability samples monthly schedule’ on or
before last working day of every month for next
month’s stability samples to be analyzed.
2. The samples withdrawn dates should not be deviated
by not more than 5 days from monthly scheduled
programme.
3. After withdrawal of sample from chamber the long
term sample, Intermediate sample and Accelerated
sample and cold storage sample shall be stored in a
desiccator which is kept in room temperature
4. If the analysis should not complete within 30 days, the
deviation procedure shall be followed as per SOP

29. Recording and conclusion:
1. All the results of analytical tests, calculations, monitoring of
temperature and humidity and periodic calibrations shall
be recorded.
2. In case if any sample of particular stability station fails to
confirm the specifications and any result observed as out of
trend, then initiated OOS and OOT respectively and the
further procedure fallows as per their respective SOP’s.
3. If OOS is valid… some below possible action to be taken
 Stability shall be stopped as per current storage condition and
alternate storage condition shall be evaluated.
 If packing condition is not suitable, then improve packing
condition by changing primary packing conditions for which are
light sensitive products and can improve by adding oxygen
scavenger and by apply nitrogen blanket.

30. If X=
For Room
Temperature
For Refrigerator
Y=
Re-test
(Months)
Y=
Re-test
(Months)
Long term 9 months OK 2X 18 1.5X 13.5
Long term 12 months OK 2X 24 1.5X 18
Long term 18 months OK X+12 30 X+6 24
Long term 24 months OK X+12 36 X+6 30
Long term 36 months OK X+12 48 X+6 42
Long term 48 months OK X+12 60 X+6 54
Long term 60 months OK X 60 X 60
Evaluation of stability data and assigning the re-test
period of drug substance:
1. If accelerated stability data for 6 months is OK then fallows
below table

31. 2. The maximum 6 months re-test date shall be
allowed in case of initial stability data not
available
Actions to be taken in case of Emergencies:
1. In case of the existence of emergencies like major
power failures, natural calamities, the samples
from the respective test chambers shall be
transferred in the following manner
 Samples at long-term stability studies shall be
transferred and stored at control sample room
 Sample at accelerated storage conditions shall be
transferred to another location and stored at
accelerated conditions only
 Samples at refrigerator shall be transferred to
another refrigerator