Stability Study | New Drug Substances, Products | ICH Q1A (R2)

Stability Study of New Drug Substances and Products ICH Q1A (R2)

This post gives us an idea about data that is to be submitted in registration applications for new molecular entities and associated drug products. We are going to see guidelines regarding the stability study of new drug substances and products (ICH Q1A) R2.

Everyone has a basic idea on stability study as I elaborated in an easy way in my previous post (Stability Study Overview) Now let's see guidelines one by one to know the requirements. 

Q1A (R2) where (R2) is a current revised version of this guideline. To register application of new drug substances and products in EC, Japan, and The United States we have to refer to this guideline. This guideline does not currently seek to cover the data to be submitted for abbreviated or abridged applications, variations, clinical trials applications, etc.

Now we all know the purpose of any stability study as we discuss it in my earlier post. Before going further, we will see a few important definitions of some terms.

1. Mean Kinetic temperature- A single derived temperature that if maintained over a defined period of time affords the same thermal challenge to a drug substance or a drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period.
2. Stress Study Testing- Testing of drug substance or a product in severe condition than accelerated testing that is by increasing temperature by 10 ⁰C and humidity is 75% RH or greater is called as stress testing.

The world is divided into 4 zones I, II, III, IVa, and IVb, which depend upon the mean Kinetic temperature. The Q1A (R2) Guideline covers zone I and II. Which has EC, Japan, and The United States region.

Stability study of new drug substance and product should be based on information regarding drug substance behavior and its properties. In the case of drug products, photostability should be studied on at least one primary batch for which a separate guideline is given which is ICH Q1B.

Whereas in the case of drug substances, stress testing should be done which will give us an idea about the degradation product, its degradation Pathways, and intrinsic stability of the molecule. Stress testing should be carried out on a single batch by increasing temperature by 10 ⁰C and humidity by 75% RH or greater.

Stability study related more posts:

API Stability Study | Finished product | ICH Q1F Overview

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Selection of batches for stability study:

Data from three primary consecutive batches manufactured with the same manufacturing method or the same synthesis method is required. In the case of drug substance, these three batches should be pilot-scale while in the case of the drug product at least two batches should be pilot scale and one can be smaller (with proper justification).

In the case of drug product stability study of these three batches should be done with the same container closure system in which the product will be going to the market. For every pack style, every container type, and every strength stability study should be carried out.

Container closure system in stability study:

A product that is packed, stored, and sent to market in packing style, same should be studied in stability study including its Primary, secondary and tertiary packaging including labels. 

Specification in stability study:

Specification of analytical testing procedures proposed acceptance criteria and shelf-life specifications are given in ICH Q6A and Q6B guidelines. Testing should include such attributes which will influence on storage.

The quantitative and qualitative tests should include containing physical, chemical biological, microbiological attributes, and functionality tests. 

Testing frequency for stability study samples:

For long-term study, frequency should be every three months for 1st year, every six months for the second year, and annually thereafter throughout the proposed shelf life. At the accelerated storage condition, a minimum of three-time points including initial and final time points is recommended generally it is initial, 1 month, 2 month, 3 month, and 6 month.

Stability Study Conditions:

As we already discussed in an earlier post, stability conditions are the same as follows. But we will discuss some differences between the previous version and the current version of this guideline. 

The changes are:

1. The intermediate storage condition has been changed from 30 ⁰C ± 2 ⁰C/ 60 % RH ± 5 % RH to 30 ⁰C ± 2 ⁰C/ 65 % RH ± 5 % RH in the case of drug product, drug substance and in the case of drug product packed in the semi-permeable membrane. 
2. 30 ⁰C ± 2 ⁰C/ 65 % RH ± 5 % RH can be suitable alternative long-term storage condition to 25 ⁰C ± 2 ⁰C/ 60 % RH ± 5 % RH in gerenral case of drug substance and drug product. 
3. 30 ⁰C ± 2 ⁰C/ 35 % RH ± 5 % RH has been added as a suitable alternative long-term storage condition to 25 ⁰C ± 2 ⁰C/ 40 % RH ± 5 % RH and the corresponding example for the ratio of water-loss rates have been included in the case of drug products packaged in semi-permeable containers. 

Stability condition for general case: 

Study	Storage condition	Minimum time period
Long-term	25 0C ± 2 0C/ 60 % RH ± 5 % RH or	12 months or 6 months
	30 0C ± 2 0C/ 65 % RH ± 5 % RH or
	300C ± 2 0C/ 75 % RH ± 5 % RH
Intermediate	30 0C ± 2 0C/ 65 % RH ± 5 % RH	6 months
Accelerated	40 0C ± 2 0C/ 75 % RH ± 5 % RH	6 months

Stability study storage condition for refrigerated products:

Study	Storage condition	Minimum time period
Accelerated	25 0C ± 2 0C/ 60 % RH ± 5 % RH or	6 months
	30 0C ± 2 0C/ 65 % RH ± 5 % RH or
	300C ± 2 0C/ 75 % RH ± 5 % RH
Long term	5 0C ± 3 0C	12 months or 6 months

Stability Study Storage condition for Freezer:

Study	Storage condition	Minimum time period
Long-term	-20 0C ± 5 0C	12 months or 6 months

Stability conditions for Drug product packed in semi-permeable container:

Study	Storage condition	Minimum time period
Long-term	25 0C ± 2 0C/ 40 % RH ± 5 % RH or	12 months
	30 0C ± 2 0C/ 35 % RH ± 5 % RH or
Intermediate	30 0C ± 2 0C/ 65 % RH ± 5 % RH	6 months
Accelerated	40 0C ± 2 0C/ not more than 25% RH	6 months

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Stability Commitments:

There are some commitments to be done while submission of Stability Study data to regulatory in the case of drug substance and drug products- 

1. If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue the long-term studies through the proposed shelf life and the accelerated studies for 6 months. while in the case of Drug substances, continue this study through the proposed re-test period. 
2. If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long-term studies through the proposed shelf life and the accelerated studies for 6 months and to place additional production batches, to a total of at least three, on long-term stability studies through the proposed shelf life and on accelerated studies for 6 months.
3. 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 shelf life and on accelerated studies for 6 months while in the case of drug substances to place sample for long-term studies through the proposed re-test period.  

Conclusion and Evaluation of Stability Study of New Drug substance and Drug product:

After testing of three production batches, an evaluation of stability study shall be done. All stability data including results of chemical, biological, physical, and microbiological results obtained are evaluated and the re-test period is assigned on the basis of the variability of results and degradation observed. 

Storage conditions for Drug substances and drug products shall be established which will be mentioned on the label. There should be a direct link between the label storage statement and the stability data collected from the executed results. The label shall be contained the storage conditions and the expiry date of the product.