ICH-Q1A (R2) : Stability testing of New drug substance and product

Guideline number and version: ICH-Q1A (R2), Version 4

Revision date: 6th Feb 2003,

In this article I’ve tried to simplify the terminology and tried to explain the stability requirement
mentioned in ICH Q1 A (R2) for the new drug substance

Principle:

Stability study helps to understand the behaviour of drug substance or product at various
environmental conditions such as temperature, humidity and light. Moreover, it also helps in
establishment of the re-testing period for the drug substance and to determine the shelf life of the
drug product.
These studies guarantee that pharmaceutical products remain stable and effective under
recommended storage conditions and are considered basic information for product approval.

Testing conditions:

The test conditions defined in this guideline is based on an analysis of the effects of climatic
conditions in the three regions of the European Country, Japan and the United States.

stability information generated in any one of the three regions—the European Community (EC),
Japan, and the United States—would be mutually acceptable to the other two regions.

Why EC, USP, and Japan is considered:

- These three regions are major players in the global pharmaceutical market.
- When a drug product is approved for market in any of these regions, it may become the subject
of a monograph in the respective pharmacopeia (e.g., USP monographs).
- Therefore, stability data from these regions are crucial for regulatory submissions and global
acceptance.

Stability Zones:

World is divided into 4 zones i.e. Zones I, II, III & IV based on the climatic conditions.

1. Zone I (Temperate Zone):

Temperature: 21°C ± 2°C, Humidity: 45% RH ± 5%

Zone I includes much of Southern Canada, most of Europe, and parts of Russia e.g.

2. Zone II (Mediterranean/Subtropical Zone):

Temperature: 25°C ± 2°C, Humidity: 60% RH ± 5%

Zone II includes Mediterranean region, parts of Australia, and the southern coastal regions of
the USA, where the climate is significantly influenced by warm ocean currents.

3. Zone III (Hot Dry Zone):

Temperature: 30°C ± 2°C, Humidity: 35% RH ± 5%

Zone III includes North Africa, the Middle East, and desert areas in the United States like
Arizona and Nevada, where the climate is mainly dry.
4. Zone IV is divided into two sub zones:

4.1 IVa (Hot Humid/Tropical Zone):

Temperature: 30°C ± 2°C, Humidity: 65% RH ± 5%

Zone IVa includes regions like Southeast Asia, Central Africa, and parts of South America,
where the climate is typically tropical with high rainfall and humidity levels.

4.2 Zone IVb (Hot/Higher Humidity Zone):

Temperature: 30°C ± 2°C, Humidity: 75% RH ± 5%

Zone IVb regions close to the equator or areas with dense rainforests, like the Amazon Basin
and Central Africa, where the climate is exceptionally humid and hot year-round.

India comes under climatic zone III & IVb.

Selection of batch:

Formal stability studies should be provided on at least three primary batches of the drug substance.

These batches shall be manufactured at *pilot scale level by the same route of synthesis through
which the final commercial product will be manufactured.

*A pilot-scale batch is an intermediate step between laboratory-scale experiments and full-scale

Container Closure:

Perform the stability study using the same packaging material which will be proposed or finally used
to pack the product for marketing. If product is proposed to sell in Glass bottle then stability study
shall be conducted on product with glass bottle.

Test to be considered for Stability study:

Those tests which is having impact quality, safety and efficacy of the product shall be considered for
the stability testing below are some examples but are not limited to,

For stability testing of drug substance includes appearance/ description, Assay, Organic impurity, any
other chemical tests based on the evaluation.

Requirement of stability testing parameters vary based on the dosage form e.g.

For drug product the testing should cover the physical i.e. description, container integrity, Dissolution
testing, Assay, Organic impurity, Microbiology testing (in case of sterile product or Oral liquid dosage
form).

For sterile products stability tests should include appearance, colour, clarity, assay, degradation
products, pH, particulate matter, reconstitution time, interaction with the container/closure/device
and sterility etc.

For liquid oral dosage stability tests should include appearance, colour, clarity, assay, degradation
products, pH, specific gravity/ density and microbiology testing etc.

Stability testing shall be performed using validated *stability-indicating analytical procedures should.
*Stability indicating method: It is a validated analytical procedure that accurately and precisely
measures active ingredients (drug substance or drug product) or analyte of interest while remaining
free from peak of other analytes and interference from the drug matrix.

Testing Conditions:

There are 5 stability conditions out which 3 conditions are generally being widely used. These
conditions are as below,

i. Long term conditions: 25°C (+/-2°C), 60% RH (+/- 5%)

Stability testing frequency at each condition:

Long term condition:

Initially, testing frequency is at every 3 months for the first year i.e. testing at 3 M, 6M, 9M & 12M.

After 1st year, testing shall be at frequency of 6 months i.e. 12M + 6M = 18 M and 18M + 6M = 24 M

After 2nd year, testing frequency shall be at every 12 months till the proposed re-test period.

The long- term testing should cover a minimum of 12 months’ duration on at least three primary
batches at the time of submission and should be continued for a period of time to cover the
proposed re-test period.

While submission of data to the regulatory one should have long term study data of at least 12
month.

Accelerated condition:

Testing shall be conducted at three time points including initial time point i.e. at 0M, 3 M & 6M

When the product are likely to reach to significant changes study shall be further carried out for the
next time point i.e. at 9M to understand the product behaviour.

While submission of data to the regulatory one should have intermediate data of six month. If the
significant change is observed then perform the Intermediate condition as a supportive data.

Intermediate condition:

This testing is performed when the product shows the significant changes in the accelerated
condition, significant change is defined as product fails to meet its specification.

Testing shall be conducted at a minimum of four time points, including the initial and final time
points e.g., 0, 6, 9, 12 months.

While submission of data to the regulatory one should have intermediate data of initial six month.
Why to perform intermediate conditions

This study is very helpful while submitting the data to the regulatory authority i.e. when the
accelerated conditions shows the significant changes in the drug substance we have intermediate
condition data as a backup data to support the behaviour of drug substance after significant change
at accelerated condition.

It is always better to simultaneously keep the stability samples for all the three conditions to avoid
additional time required to generate the data at intermediate condition after significant changes
observed at accelerated condition.

Refrigerated Condition:

Long term condition (5°C ± 3°C):

Testing frequency is at every 3 months for the first year i.e. testing at 3 M, 6M, 9M & 12M.

While submission of data to the regulatory one should have long term study data of at least 12
months.

Accelerated Condition (25°C ± 2°C/60% RH ± 5% RH):

If during the accelerated condition significant change occurs between 3- and 6-months’ testing, then
the proposed re-test period should be based on the real time data available at the long-term storage
condition i.e. at 5°C ± 3°C.

If during the accelerated condition significant change occurs within the first 3 months’ testing, then
further testing shall be continued on a single batch of the drug substance for a period less than 3
months but with higher testing frequency than usual i.e. at 15 days, 30days, 60 days, 75 days and 90
days or interval shall be defined based on the assessment.

6-month testing is not required if a significant change has occurred within the first 3 months.

Based on the above assessment instruction of impact of short-term excursion outside the label
storage condition shall be mentioned.

Freezer Condition:

Long term condition (-20°C ± 5°C):

The retesting period should be based on the real time data of the long-term condition.

As there is no accelerated condition is defined for this storage condition, hence it is recommended to
perform the testing on one batch at elevated temperature i.e. at 5°C ± 3°C and at 25°C ± 2°C/60% RH
± 5% RH to address the impact of short-term temperature excursion on the drug substance on label
during the transportation.

Stability commitment:

While submission of the product to the regulatory body for the approval, if long term stability data
do not cover the proposed re-test period, a commitment should be made to regulatory body to
continue the stability studies after approval to establish the re-test period.

Below commitment shall also be made while submission of the product for approval.
-If the submission includes data from stability studies on at least three production batches, a
commitment should be made to continue these studies till the proposed re-test period.
-If the submission data includes stability data of less than 3 production batches in such case
commitment should be made to continue the stability study till the proposed re-test period and
commitment should also be made to place additional production batches to make a total of at
least three batches as per the requirement, for long term stability study till the proposed retest
period.
-If the submission data doe not include any stability data in such case commitment should be made
that very first 3 production batches shall be kept for long term stability studies till the proposed
re-test period.

Where the submission includes long term stability data on three production batches that covers the
proposed re-test period, in such case commitment for continuation of stability study after approval is
not required.

Statement/Labeling:

AS per the national/regional requirement statement for storage condition should be mentioned on
label this statement should be based on evaluation of the stability data. For the drug substance that
cannot tolerate freezing in such case a specific instruction should be made on label. Terms such as
“ambient conditions” or “room temperature” should be avoided.