Stability testing, requirement of regulatory body (Part-1)

In this article I’ve tried to simplify the terminology and tried to explain the stability requirement mentioned in ICH Q1A (R2) for the new drug substance.

Guideline Name: Stability testing of new drug substance and product

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

Revision date: 6th Feb 2003

• Principle:

Stability study helps to understand the behavior 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.

• Climatic 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.

• Climatic Zones:

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

Zone I (Temperate Zone): Temperature: 21°C ± 2°C, Humidity: 45% RH ± 5%

Zone II (Mediterranean/Subtropical Zone): Temperature: 25°C ± 2°C, Humidity: 60% RH ± 5%

Zone III (Hot Dry Zone): Temperature: 30°C ± 2°C, Humidity: 35% RH ± 5%

Zone IV is divided into two sub zones:

IVa (Hot Humid/Tropical Zone): Temperature: 30°C ± 2°C, Humidity: 65% RH ± 5%

IVb (Hot/Higher Humidity Zone): Temperature: 30°C ± 2°C, Humidity: 75% RH ± 5%

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 commercial production, a pilot-scale batch is around 10% of the final production-scale batch size".

• Sample quantity required at each interval:

To perform the stability testing at each interval sample quantity required is 2X of the actual quantity required for one time analysis/ per batch/per station/per storage condition.

• 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 of Drug substance:

Those tests which is having impact on 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 and requirements.

Stability testing shall be performed using validated *stability-indicating analytical procedures.

"*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 widely being used. These conditions are as below,

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

II. Intermediate condition: 30°C (+/-2°C), 65% RH (+/- 5%)

III.?Accelerated condition: 40°C (+/-2°C), 75 % RH (+/- 5%)

IV.?Refrigerated condition

V. Freezer Condition

• 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.

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 behavior.

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 stability condition as a supportive data.

Intermediate condition:

This testing is performed when the product shows the *significant changes in the accelerated condition.

This 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.

*Significant change is defined as product fails to meet its specification.

Why to perform intermediate conditions:

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

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

Refrigerated Condition: It contains two sub testing conditions

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 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 of than 3 months but with higher testing frequency than usual i.e. testing at 15 days, 30days, 60 days, 75 days and 90 days or intervals shall be defined based on the assessment and requirement.

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 re-testing 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. ?

• 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.

• Stability commitment during the regulatory submission approval:

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 does 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.

When the submission data covers the long-term stability data for 3 production batches and it covers the proposed re-test period in such case commitment is not required.

In this article I've covered the approach given in ICH guideline for the stability study of new drug substance. I have also tried my best to simplify the approach so that this will be helpful to those who are new to pharmaceutical industry and also for those who have less experience or no experience on stability study. Soon will cover the stability study of new drug product in my next article.

I know this is long article but hope you have liked it.

Thanks for reading.