API Stability Study | Finished product | ICH Q1F Overview

 Stability study of API and Finished product

ICH Q1F Overview

As we all know pharmaceutical industry runs on regulations and guidelines. For, stability studies also some guidelines are followed by pharmaceutical industries. ICH gives details on stability requirements. One of the guidelines is for Stability Study testing of API and finished Pharmaceutical products (ICH Q1F).

Q1A: Stability testing of new drug substances and products 

Q1B: Stability testing: Photostability testing of new drug substances and products Q1C: Stability testing for new dosage forms 
Q1D: Bracketing and matrixing designs for stability testing of new drug substances and products
Q1E: Evaluation for stability data 
Q1F: Stability testing of API and finished Pharmaceutical products (it withdraw from the ICH website)

For a general idea about stability study in pharmaceutical, you can refer to my blog. As we know stability is a vast topic I make fragments of it to describe it more efficiently. 

In this blog, we will study about ICH Q1 F guideline for stability testing of active pharmaceutical ingredients and finished pharmaceutical products. 

General-purpose of the stability study is to provide evidence of how the quality of an API (Active Pharmaceutical Ingredient) or FP (Finished Product) varies with time under the influence of different environmental factors. Such as temperature, humidity, and light. Some product-related factors also affect the quality such as the interaction of API with an excipient, Container closure system, and packaging materials. In fixed-dose combination interaction between API are also considered.

This stability study outcome can help in determining the shelf life of FP and identification storage conditions can be recommended. Failure in stability study is defined by any significant change observed.

Stress testing of API and FP:

It is part of the development strategy in which testing is carried out under more severe conditions than those used for accelerated testing. For API it is carried out to elucidate the intrinsic stability of an API. In short stress testing is carried out by changing environmental conditions to severe states or stringent limits to study the effect of that condition on the product. 

For a finished product, this Stress testing is carried out to assess the effect of severe conditions on the product.

This study includes photostability testing and specific testing on certain products. Stress testing should be done when no published data is available to support the identified degradation product and Pathways. 

A study should carry out by increasing temperature by 10°C and relative humidity 75% or greater. In this primary degradation product is identified. If total absence of degradation products after 10 days then API is stable.

In the case of API, stress testing may be carried out on a single batch of API. Whereas in the case of Finished Product photostability testing should be conducted on at least one primary batch. Additional stress testing of specific types of dosage forms may be appropriate e.g. cyclic studies for semisolid products for freeze-thaw studies for liquid products.

Selection of batches of finished product and API:

In the case of API data from the stability studies on at least three primary batches should be normally be provided. The batches should be manufactured at a minimum of pilot-scale by the same synthesis method as production batches and using a method of manufacturing and a procedure that simulates the final process to be used for production batches. 

In the case of the finished product, there are some criteria's

1. When FP contains new API data on at least three primary batches of each proposed strength of FP. Two of these three primary batches should be at least pilot scale, and the third can smaller batch.

2. FP containing existing API (example generic) then data should be provided on not less than two batches of at least pilot-scale or in case of uncomplicated FP (example immediate release solid FP or non-sterile solutions) at least one batch of at least pilot scale and the second batch may be smaller of each proposed strength of the FP.

3. Stability studies should be performed on each individual strength, dosage form and container type, and size of FP (except when bracketing and matrixing are not applied).

A container closure system for stability study:

In the case of API stability studies should be conducted on the API packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.

In the case of FP primary container closure system is considered to conduct a stability study. If the secondary container closure system has protective properties and is labeled as stored in Primary and secondary packaging.

Product packing semi-permeable container where components from secondary packaging can migrate into a product, then secondary packaging will be part of Stability Study.

Testing specification for stability study:

The testing specification should cover physical, chemical, biological, microbiological attributes, preservative contains, and functionality tests. Shelf life acceptance criteria of FP should be derived from consideration of all available stability information.

Testing Frequency of stability study:

The proposed retest period or shelf life of API and FP should be at least 12 months. The frequency of testing at the long-term storage condition should normally be every 3 months over the first year, every 6 months for the second year, and after that annually till the proposed retest period or shelf life. 

Condition for frequency of stability testing at accelerated condition is a minimum of 3-time points including initial and final time points. Generally, time points for the accelerated conditions are like the initial, 1 month, 2 months, 3 months, 6 months but any 3-time points including initial and final time points are recommended. 

Condition for frequency of stability study at the intermediate study when there is significant change identified in accelerated condition study then additional sample testing is recommended with any 4-time points till 12 months in the intermediate study including initial and final time point that is 12 months is recommended. Any fore time point from initial, 3 months, 6 months, 9 months, and 12 months including initial and final time point can be considered. 

Storage conditions for stability study :

Storage conditions of API and FP should be studied in stability testing considering all factors covering like thermal study, sensitivity to moisture, solvent loss, storage, shipment, different climatic conditions, the orientation of product within packaging during storage and shipment like upright, on the side, or inverted side, container closure system. 

Storage conditions must be controlled, monitored, and recorded. Any variation in the storage condition for more than 24 hours should be reported and assessed. Storage conditions for Accelerated condition, intermediate and long term for FP and API are given below 

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

Long-term stability study condition depends upon the climatic zone of the country in which the product will be used. intermediate study is not considered when long term study condition is 30 ⁰C ± 2 ⁰C/ 65 % RH ± 5 % RH  or 30⁰C ± 2 ⁰C/ 75 % RH ± 5 % RH

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 commitments:

Some stability commitments can be done during the submission of the product.

Primary batch stability commitment- 

When the available long-term stability data on primary batches do not cover the proposed shelf life granted at the time of approval then commitment should be made to continue the stability studies post-approval throughout the proposed shelf life. 

Production batch stability commitment- 

If the submission includes data from stability studies on fewer than three production batches then commitment should be done to place the next 3 production batches on long-term stability studies throughout the proposed shelf life and on accelerated studies for six months.

Ongoing stability commitments- 

For each product, an ongoing stability program is required to monitor the product over its shelf life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. 

Stability study related more posts:

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

Stability Study Overview | Stability Zones In Pharma

What is significant change in stability study:

In case of Significant change means that the product fails to meet specifications.

whereas in case of finished product significant change can be defined considering some cases like

1. 5 % variation in Assay test from initial results which determine the contains of API in that product or failure to meet acceptance criteria for potency when using biological or immunological procedures. 

2. Any degradation product exceeding its acceptance criteria

3. Failure to meet acceptance criteria for appearance, physical attributes, and functionality test

4. Failure to meet acceptance criteria for pH 

5. Failure to meet acceptance criteria for dissolution for 12 dosage units. 

Any failure observed during the stability study should be reported and evaluated. Any Out of Specification (OOS) and Out of Trend (OOT) should be explained in detail.

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Evaluation and conclusion of stability study:

Stability study evaluation starts from the need of study means the categorization of study e.g. study of new API, new primary packaging material new product, etc. The first step is to prepare a detailed stability study protocol and specifications for the study. once protocol finalizes the study starting from the initial stage. All-time point study is evaluated and a systematic summary report for it is presented as a final report.

This summary report should include the details of the product (Product name, Strength, Batch number, Batch size, Stability protocol number, Stability condition with time point) results of physical, chemical, biological, and microbiological tests, the Shelf life of the product, container closure system and storage condition. This summary report is the final conclusion of the stability study.