2. Stability Definition
These studies provide information about the packaging in that it
is not reactive, additive, or absorptive so that the identity,
strength, quality and purity of the drug product is not affected,
also to provide clearance on stability process flow.
To assessment of the stability characteristics of all
drug products manufactured / packaged and/or
repacked by Pharmaceuticals companies.
To establish and extend the shelf life for products
3. General Principles
The purpose of stability testing is to provide evidence on how the quality
of an active substance or pharmaceutical product varies with time
under the influence of a variety of environmental factors such as
temperature, humidity, and light. In addition, product-related factors
influence the stability, e.g. the chemical and physical properties of the
active substance and the pharmaceutical excipients, the dosage form
and its composition, the manufacturing process, the nature of the
container-closure system, and the properties of the packaging
materials. Also, the stability of excipients that may contain or form
reactive degradation products, have to be considered.
4. Active Substance
Information on the stability of the active substance is an integral part of
the systematic approach to stability evaluation. For active substances
not described in an official pharmacopoeial monograph, stability
studies are required. For active substances described in
an official pharmacopoeial monograph, which covers the degradation
products and for which suitable limits have been set but a re-test
period is not defined, two options are acceptable:
5. Active Substance
The manufacturer of the pharmaceutical product confirms that the active
substance complies with the pharmacopoeial monograph immediately
prior to the manufacture of the pharmaceutical product. In this case no
stability studies on the active substance are required. The suitability of
the pharmacopoeial monograph for the active substance used from a
named source of supply has to be demonstrated.
6. Stress Testing
Stress testing of the active substance can help
identify the likely degradation products, which
can in turn help establish the degradation pathways
and the intrinsic stability of the molecule
and validate the stability indicating power of the
analytical procedures used. The nature of the
stress testing will depend on the individual active
substance and the type of pharmaceutical
product involved.
7. Stress Testing
For an active substance the following approaches
may be used:
a) When an active substance is described in an
official pharmacopoeial monograph, and
fully meets its requirements, no data are required on
the degradation products if they
are named under the headings “purity tests” and/or
“section on impurities
8. Stress Testing
b) For active substances not described in an official
pharmacopoeial monograph, there are
two options:
− When available, it is acceptable to provide the
relevant data published in the
literature to support the proposed degradation
pathways;
− When no data are available in the scientific
literature, including official
pharmacopoeias, stress testing should be performed.
9. Specification
Stability studies should include testing of those
attributes of the active substance that are
susceptible to change during storage and are likely to
influence quality, safety, and/or efficacy.
The testing should cover, as appropriate, the physical,
chemical, biological, and
microbiological attributes. Validated stability-indicating
analytical procedures should be
applied. Whether and to what extent replication should
be performed will depend on the results
from validation studies
10. Storage Conditions
In general, an active substance should be evaluated
under storage conditions (with appropriate
tolerances) that test its thermal stability and, if
applicable, its sensitivity to moisture. The
storage conditions and the lengths of studies chosen
should be sufficient to cover storage,
shipment, and subsequent use with due regard to
the climatic zone(s) in which the active
substance is intended to be stored .
11. Storage Conditions
Station 1: (40
°C 2 & 75 %
RH 5).
Station 2: (30 °C
Station 3: (25 °C
2 & 65 % RH
2 & 60 % RH 5).
5).
Station 5: (30 °C
Station 4: (2 - 8) °C. 2 & 35 % RH
5).
12. Product storage Storage condition Testing stations
Stability condition Zone Station
conditions Temperature/Humidity (Month)
all Room temperature 1 40°C 2°C / 75% 5%RH
Accelerated 0, 1, 2,3 and 6
all Refrigerator storage 3 25°C 2°C / 60% 5 %RH
30°C 2°C / 65% 5%RH
III, IV Room temperature 2
30°C 2°C / 35% 5%RH
0, 3, 6, 9, 12,
Long-Term 18, 24, 36, 48
and 60
I, II Room temperature 3 25°C 2°C / 60% 5 %RH
all Refrigerator 4 (2 – 8)°C
Intermediate I, II Room temperature 2 30°C 2°C / 65% 5%RH 0, 3, 6, 9 and 12
13. Testing Frequency
For long term studies, frequency of testing should be
sufficient to establish the stability profile
of the active substance. For active substances with a
proposed re-test period of at least 12
months, the frequency of testing at the long term
storage condition should normally be every
three months over the first year, every six months
over the second year, and annually thereafter
through the proposed re-test period.
14. Testing Frequency
At the accelerated storage condition, a minimum of
three time points, including the initial and
final time points (e.g. 0, 3, and 6 months), from a 6-
month study is recommended. Where an
expectation (based on development experience)
exists that results from accelerated studies are
likely to approach significant change criteria,
increased testing should be conducted either by
adding samples at the final time point or by
including a fourth time point in the study design
15. For products stored at room temperature.
For products stored at refrigerator.
for products stored at room temperature (for long term conditions at 25 °C
60 % RH).
For products stored at room temperature in climatic zone III and IV.
For products stored at room temperature in climatic zone I and II.
For products stored at refrigerator.
16. Type of Placement Batches:
A- New product registration.
B- Process Validation Batch.
C- Formulation Change.
D- Annual Commitment Batch.
E- Raw material manufacturer change
F- Primary packaging material manufacturer change
G- Reprocessing batch
17. H- Batch size change
I- Manufacturing process change
J- Stability condition change
K- Machine change
L- Site transfer
18. Product Name/Strength Study Number Purpose of Study
Batch Number Batch Size Date Study Started
Date Manufactured Manufacturer/Site Container/Size/Supplier
Date Packaged Packager/Site Closure Supplier
Storage Condition Storage Orientation Seal Supplier
Drug Substance Manufacturer/Site/Batch Number
Approved/Proposed Expiration Dating Period
Tests Method Specification Time (Months)
SOP# (Low/High)
appearance 0 3 6 9 etc.
Color
Degradation
Assay
Dissolution
Clarity
19. In-use stability
The purpose of in-use stability testing is to establish –
where applicable – the period of time
during which a multi-dose product can be used whilst
retaining acceptable quality once the
container is opened and the first dose is removed.
A minimum of two batches, at least pilot scale batches,
should be subjected to the test. At least
one of the batches should be chosen towards the end of
its shelf life. If such results are not
available, one batch should be tested at the final point of
the submitted stability studies.
20. Variations
Once the pharmaceutical product has been
registered, additional stability studies are required
whenever major variations are made like the
following:
1. Change in the manufacturing process;
2. Change in the composition of the pharmaceutical
product;
3. Change of the immediate packaging.
21. Stability tests for dosage forms:
1. Tablets
Dissolution (or disintegration, if justified), water content and hardness/friability.
For coated and colour tablets additional tests may require for texture and
colour stability.
2. Capsules
Hard gelatin capsules: brittleness, dissolution (or disintegration, if justified),
water content, and level of microbial contamination.
3. Emulsions
Phase separation, pH, viscosity, level of microbial contamination, and mean size
and distribution of dispersed globules.
4. Oral solutions and suspensions
Formation of precipitate, clarity for solutions, pH, viscosity, extractables, level of
microbial contamination.
22. Stability tests for dosage forms:
Additionally for suspensions, redispersibility, rheological
properties, mean size and
distribution of particles should be considered. Also,
polymorphic conversion may be examined, if applicable.
5. Powders and granules for oral solution or suspension
Water content, and reconstitution time.
Reconstituted products (solutions and suspensions) should
be evaluated as described in
“Oral solutions and suspensions” above, after preparation
according to the recommended
labeling, through the maximum intended use period.
23. Stability tests for dosage forms:
6. Nasal sprays: solutions and suspensions
Clarity (for solution), level of microbial contamination, pH, particulate matter,
unit spray
medication content uniformity, number of actuations meeting unit spray content
uniformity
per container, droplet and/or particle size distribution, weight loss, pump
delivery,
microscopic evaluation (for suspensions), foreign particulate matter and
extractable/leachable from plastic and elastomeric components of the container,
closure and
pump.
7. Topical, ophthalmic and otic preparations
Included in this broad category are ointments, creams, lotions, paste, gel,
solutions, eye
drops, and cutaneous sprays.
24. Stability tests for dosage forms:
Topical preparations should be evaluated for clarity, homogeneity, pH,
resuspendability (for
lotions), consistency, viscosity, particle size distribution (for suspensions, when
feasible), level of microbial contamination/sterility and weight loss (when
appropriate).
Evaluation of ophthalmic or otic products (e.g. creams, ointments, solutions and
suspensions) should include the following additional attributes: sterility,
particulate matter and extractable.
Evaluation of cutaneous sprays should include: pressure, weight loss, net weight
dispensed, delivery rate, level of microbial contamination, spray pattern, water
content, and particle size distribution (for suspensions).
8. Suppositories
Softening range, dissolution (at 37°C).
25. Stability tests for dosage forms:
9. Small volume parenterals (SVPs)
Colour, clarity (for solutions), particulate matter, pH, sterility, endotoxins.
Stability studies for powders for injection solution should include
monitoring for colour, reconstitution time and water content. Specific
parameters to be examined at appropriate intervals throughout the
maximum intended use period of the reconstituted drug product,
stored under condition(s) recommended in labelling, should include
clarity, colour, pH, sterility, pyrogen/endotoxin and particulate matter.
The stability studies for Suspension for injection should include, in
addition, particle size
distribution, redispersibility and rheological properties.
The stability studies for Emulsion for injection should include, in
addition, phase separation,viscosity, mean size and distribution of
dispersed phase globules.
26. Stability tests for dosage forms:
10. Large volume parenterals (LVPs)
Colour, clarity, particulate matter, pH, sterility,
pyrogen/endotoxin, and volume.
27. When re-test is done??
In general, “significant change” for a pharmaceutical product is defined
as:
1. A 5% change in assay from its initial value; or failure to meet the
acceptance criteria
for potency when using biological or immunological procedures;
2. Any degradation product exceeding its acceptance criterion;
3. Failure to meet the acceptance criteria for appearance, physical
attributes, and
functionality test (e.g., colour, phase separation, resuspendibility, caking,
hardness,
dose delivery per actuation); however, some changes in physical attributes
(e.g.,
softening of suppositories, melting of creams, partial loss of adhesion for
transdermal
products
28. When re-test is done?
4. Failure to meet the acceptance criterion for pH; or
5. Failure to meet the acceptance criteria for
dissolution for 12 dosage units.
29. Ongoing stability studies
The stability of the API should be monitored according to a continuous
and appropriate program that will permit the detection of any stability
issue (e.g. changes in levels of degradation products).
The purpose of the ongoing stability program is to monitor the API and to
determine that the API remains, and can be expected to remain, within
specifications under the storage conditions indicated on the label, within
the re-test period in all future batches.
The ongoing stability program should be described in a written protocol
and the results presented in a formal report.
30.
31. To support a shelf life extension, a report must be
generated documenting stability data (for the proposed
interval) for three batches which meet all the following
criteria:
Same product / potency
Same manufacturing Shelf life may be extended as long
process.
term data become available to justify
the extension
Same primary packaging
material
Same formulation
No significant change in
the manufacturing
procedure
32. After registration…
Once the pharmaceutical product has been
registered, additional stability studies are required
whenever variations that may affect the stability of
the active pharmaceutical substance or
pharmaceutical product are made, such as major
variations like the following:
a. Change in the manufacturing process.
b. Change in the composition of the pharmaceutical
product.
c. Change of the immediate packaging.
33. At the market…
If no significant change occurs during six-month's
accelerated and real time stability testing,
the product will be allowed to place in the market with a
provisional shelf-life of up to
twenty-four months. However, real time stability testing
should be continued up to the
proposed shelf-life. The manufacturer should have a
system of recall in place so that the sale
any batch which does not remain within the limit of
approved product specification be
stopped within twenty-four hours.
