What
is Stability?
Stability is a study to
provide evidence on how the quality of product varies with time under the
influence of a variety of environmental factors such as temperature, humidity
and light.
i.e. evaluation of product
under recommended storage conditions (with appropriate tolerances) that test
its thermal stability and, if applicable, its sensitivity to moisture.
To establish a re-test
period for the drug substance or a shelf life for the drug product at
recommended storage conditions.
In
simple words Stability can be also defined as
The capacity of a drug to remain within
specifications established to assure its identity, strength, quality and
purity”
Stability study Lifecycle:
Stability studies are incorporated at all
stages of drug product life cycle from early stages of product development to
last stage follow-up studies. In particular the life cycle can be divided in to
6 different stages as follows.
Stage-1: Early stage stress and accelerated
testing with drug substance.
Stage-2: Accelerated & Long term testing
of drug substance
Stage-3: Stress testing on scale up batches of
drug products
Stage-4: Accelerated & Long term testing
for registration purpose
Stage-5: On-going stability testing.
Stage-6: Follow-up stabilities.
Stress Testing:
Ø Stress testing is to be
carried out on a single batch
Ø The testing should include
the effect of temperature (50/60 oC, i.e. 10 oC
increment) above that of an accelerated testing, humidity (e.g.: 75% RH or
greater) where appropriate oxidation & photolysis on the product has to be
performed.
Ø Stress testing can help
identify the likely degradation products which can help to establish:
i. The degradation pathways.
ii. The intrinsic stability of the molecule.
iii. Developing & validating the suitable analytical procedures.
Ø Photo stability Testing (ICH
Q1B) should be an integral part of stress testing.
Selection
of batches:
Ø Data from at least 3 primary
batches required.
Ø Primary batches could be
from pilot / plant scale.
Ø Plant / pilot batches should
be Apple to Apple (process, equipment, route should be similar).
Ø The overall quality of the
batches of drug substance placed on formal stability studies should be
representative of the quality of the material to be made on a production scale.
Container
Closure system:
The stability studies should be conducted on
the drug substance packaged in a container closure system that is the same as
or simulates the packaging proposed for storage and distribution.
Specification:
Ø Specification, which is a list of tests, reference to
analytical procedures, and proposed acceptance criteria, is addressed in ICH
Q6A and Q6B.
Ø specification for degradation products in a drug
substance is discussed in Q3A
Ø Stability studies should
include testing of those attributes of the drug 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.
Ø 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.
Ø The testing should cover as
appropriate : chemical, physical, biological & microbiological parameters
Testing
Frequency:
Long Term
: First year
: Every 3 months.
Second year : Every
6 months.
Thereafter : Annually.
Intermediate
: 0, 6, 9, 12 months. (Min 4
time point)
Accelerated
: 0, 3, 6 months. (Min 3 time point)
Ø If 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.
Ø When testing at the intermediate storage condition is
called for as a result of significant change at the accelerated storage
condition, a minimum of four
time points (0, 6, 9, and 12) study is recommended.
Storage Condition:
A very important point in conducting
stability studies are storage conditions.
World has been divided in to 4
stability zones based on real climate conditions in the respective regions
ICH Stability zones
Zone
|
Type of climate
|
Kinetic Average temperature
|
Average relative Humidity
|
Zone I
|
Temperate Zone
|
21°C
|
45 %RH
|
Zone II
|
Mediterranean/ Sub
tropical zone
|
25°C
|
60 %RH
|
Zone III
|
Hot dry zone
|
30°C
|
35 %RH
|
Zone IV
|
Hot / Humid
(Tropical zone)
|
30 °C
|
65 %RH
|
Zone IVb
|
Hot / Very Humid
|
30 °C
|
75 %RH
|
Long term testing Conditions:
Climate Zone
|
Temperature
|
Humidity
|
Minimum Duration
|
Zone I
|
21°C±2°C
|
45% RH ± 5% RH
|
12 Months
|
Zone II
|
25°C±2°C
|
60% RH ± 5% RH
|
12 Months
|
Zone III
|
30°C±2°C
|
35% RH ± 5% RH
|
12 Months
|
Zone IV
|
30°C±2°C
|
65% RH ± 5% RH
|
12 Months
|
Zone IVb
|
30°C±2°C
|
75% RH ± 5% RH
|
12 Months
|
Refrigerated
|
5°C±3°C
|
No Humidity
|
12 Months
|
Freezer
|
-20°C±5°C
|
No Humidity
|
12 Months
|
Accelerated testing conditions:
Climate Zone
|
Temperature
|
Humidity
|
Minimum Duration
|
Zone I to 1Vb
|
40°C±2°C
|
75% RH ± 5% RH
|
6 Months
|
Refrigerated
|
25°C±2°C
|
60% RH ± 5% RH
|
6 Months
|
Freezer
|
5°C±3°C
|
No Humidity
|
6 Months
|
Intermediate testing conditions:
Climate Zone
|
Temperature
|
Humidity
|
Minimum Duration
|
All zones
|
30°C±2°C
|
65% RH ± 5% RH
|
6 Months
|
Storage condition
|
Long term
|
Intermediate
|
Accelerated
|
Ambient
|
25°C ± 2°C/
60% RH ± 5% RH
(or)
30°C ± 2°C/
65% RH ± 5% RH
|
30°C ± 2°C/ 65% RH ± 5% RH
|
40°C ± 2°C/
75% RH ± 5% RH
|
Below 30°C
|
30°C ± 2°C/
65% RH ± 5% RH
|
NA
|
40°C ± 2°C/
75% RH ± 5% RH
|
Cool (15°C-25°C)
|
25°C ± 2°C/
60% RH ± 5% RH
|
30°C ± 2°C/
65% RH ± 5% RH
|
40°C ± 2°C/ 75% RH ± 5% RH
|
Refrigerated
|
5°C ± 3°C
|
NA
|
25°C ± 2°C/ 60% RH ± 5% RH
|
Freezer
|
- 20°C ± 5°C
|
NA
|
NA
|
Ø If 30°C ± 2°C/65% RH ± 5% RH is the long-term
condition, there is no intermediate condition.
Ø If long-term studies are
conducted at 25°C ± 2°C/60% RH ± 5% RH and
“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
Ø If “significant change”
occurs between 3 & 6 months of accelerated study, data on long term study
should be submitted.
Ø If “significant change”
occurs within 3 months of accelerated study, it is unnecessary to continue
further testing.
Ø In the absence of an
accelerated storage condition for drug substances intended to be stored in a
freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C
or 25°C ± 2°C) for an appropriate time period should be conducted to address
the effect of short term excursions outside the proposed label storage
condition, e.g., during shipping or handling.
Ø Drug substances intended for
storage below -20°C should be treated on a case-by-case basis.
Stability Commitment:
Ø When available long term
stability data on primary batches do not cover the proposed re-test period
granted at the time of approval, a commitment should be made to continue the
stability studies post approval in order to firmly establish the re-test
period.
Ø If the submission includes
data from stability studies on at least three production batches, a commitment
should be made to continue these studies through the proposed re-test period.
Ø If the submission includes
data from stability studies on fewer than three production batches, a
commitment should be made to continue these studies through the proposed
re-test period and to place additional production batches, to a total of at
least three, on long term stability studies through the proposed re-test
period.
Ø If the submission does not
include stability data on production batches, a commitment should be made to
place the first three production batches on long term stability studies through
the proposed re-test period.
The stability protocol used
for long term studies for the stability commitment should be the same as that
for the primary batches, unless otherwise scientifically justified.
Statement
& Labelling:
Ø A storage statement should
be based on the stability evaluation.
Wherever applicable, specific instructions should be provided. For eg:
drug substances that cannot tolerate freezing.
Ø Avoid use of “ambient condition” or “Room
temperature”.
Ø Need direct link between the label storage
statement & the demonstrated stability.
Ø A retest period for drug substance should be
derived from stability information, and should be displayed on the container
label as appropriate.
Testing conditions where
stability has been shown
|
Required labeling
statement
|
Additional labeling
statement, where relevant
|
25 ± 20C / 60 ± 5% RH (long term)
40 ± 20C / 75 ± 5% RH (accelerated)
or
30 ± 20C / 65 ± 5% RH (long term)
40 ± 20C / 75 ± 5% RH (accelerated)
|
None
|
Do not refrigerate or
freeze.
|
25 ± 20C / 60 ± 5% RH (long term)
30 ± 20C / 65 ± 5% RH (intermediate)
or
30 ± 20C / 65 ± 5% RH (long term)
|
Do not store above 30 0C
or
Store below 30 0C.
|
Do not refrigerate or
freeze
|
25 ± 20C / 60 ± 5% RH (long term)
|
Do not store above 25 0C
or Store below 25 0C.
|
Do not refrigerate or
freeze.
|
5 ± 30C (long
term)
|
Store in a refrigerator or
Store & transport refrigerated
|
Do not freeze
|
Below zero
|
Store in a freezer or
Store & transport frozen
|
None
|
S.No
|
Storage problem
|
Additional labeling statements* depending on the
packaging
|
1.
|
Sensitivity to moisture.
|
Keep the container tightly
closed
|
2.
|
Sensitivity to moisture.
|
Store in the original
package.
|
3.
|
Sensitivity to light
|
Store in the original
package.
|
4.
|
Sensitivity to light
|
Keep the container in the
outer carton.
|
EVOLUTION OF STABILITY DATA TO ESTABLISH RETEST:
·
Retest date shall be established
by extrapolation of real time data
·
Extrapolation is the practice of using a known data set to infer
information about future data. Extrapolation to extend the retest period or
shelf life beyond the period covered by long-term data can be proposed in the
application, particularly if no significant change is observed at the
accelerated condition.
EVOLUTION OF STABILITY DATA TO ESTABLISH RETEST FOR
DRUG SUBSTANCE INTENDED FOR ROOM TEMPERATURE STORAGE
Accelerated condition
|
Long term /ACC Data
|
Data willing to
statistical analysis
|
Retest period / Shelf life
(Y)
(X= available long term
data)
|
No significant change
|
Little or no variability
over time
|
-NA-
|
Y = 2x
(Should NMT X+12)
|
Showing variability over
time
|
Yes
|
Y = 2x
(Should NMT X+12)
|
|
No
|
Y = 1.5x
(Should NMT X+6)
|
||
Accelerated condition
|
Intermediate Data
|
Data willing to
statistical analysis
|
Retest period / Shelf life
|
Significant change
|
Significant change
|
-NA-
|
Y = x
|
No Significant change
|
Yes
|
Y = 1.5x
(Should NMT X+6)
|
|
No
|
Y = x + 3
|
If no significant change at accelerated stability data
for 6 months.
Long-term and accelerated data showing little or no
change over time and little or no variability
X
|
Y
|
|
Accelerated
(6months)
|
Long Term
(9 months OK)
|
y = 2x (Should not more than X+12)
re-test date is 18 Months
|
Accelerated
(6months)
|
Long Term
(12 months OK)
|
y = 2x (Should not more than X+12)
re-test date is 24 Months
|
Accelerated
(6months)
|
Long Term
(18 months OK)
|
y = 2x (Should not more than X+12)
re-test date is 30 Months
|
Accelerated
(6months
|
Long Term
(24 months OK)
|
y = 2x (Should not more than X+12)
re-test date is 36 Months
|
Accelerated
(6months)
|
Long Term
(36 months OK)
|
y = x
re-test date is 36 Months
(No extrapolation beyond 36 months)
|
If significant change at accelerated stability data
for 6 months
X
|
Y
|
|
Accelerated
(6months)
|
Intermediate
9 months OK
|
y = 1.5x (should not more than x+6)
re-test date
is 13.5 months
|
Accelerated
(6months)
|
Intermediate
12 months OK
|
y = 1.5x (should not more than x+6)
re-test date
is 18 months
|
Where significant change occurs at the intermediate
condition, the proposed retest period or shelf life should not exceed the
period covered by long-term data. In
addition, a retest period or shelf life shorter than the period covered by
long-term data could be called for.
|
||
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