How to do stability research? ICH Q1 has the answer

[Guide] ICH Q1: Stability Research

Let us further understand an important result of ICH, namely the Guideline. Starting today, let’s understand the quality part (ICH-Q) of one of the four major categories.

1. Overview of the composition and content of ICH Q

First, let’s take a look at the ICH quality guidelines as a whole, that is, the composition and content of the Q guidelines.

According to the different topics, the Q guide is mainly divided into 12 sub-categories, providing basic concepts and guiding directions in chemistry, production and control (ie CMC), and quality management. Please refer to the table below for specific guidelines and content topics for the 12 sub-categories.

2. Overview of the composition and content of ICH Q1

Next, let’s get to know the first sub-category of the Q guidelines: ICH Q1 stability study.

The ICH Q1 guide includes a total of 6 independent guide documents, namely Q1A-Q1F. They play a guiding role in stability research from different thematic perspectives. Please refer to the table below for the names and abbreviations of specific guidelines. The abbreviations of the guidance documents will be directly quoted in the following introduction.

    As the main content of the ICH Q1 series of guidance documents, Q1A explains the principle and purpose of stability research, and separately describes the general content, conditions and precautions of stability research for APIs and drugs.

    The content of Q1B-Q1F supplements Q1A from different focuses.

The purpose of stability research: to reflect how the quality of the API or drug changes under the influence of time and a series of environmental factors, so as to establish the retest period of the API, the validity period of the drug, and the storage conditions.

Q1A provides guidance on how to carry out stability studies of APIs and drugs in terms of batch selection, packaging, quality standards, testing frequency, storage conditions, stability commitment, evaluation and labeling.

It should be noted that the scope of Q1A’s guidance is the registration application of new molecular entities and related drugs. Other registration applications are not within the scope of Q1A, and relevant specific guidelines and requirements should be referred to.

3. The main content of Q1A:

3.1 Batch selection and packaging

Q1A suggests to conduct stability studies on three batches of APIs or drugs, and the production process and packaging of the three batches of APIs or finished products should be consistent or similar to the final process and packaging. Multi-dose or multi-packaged drugs can use the bracket method or matrix method to reduce stability studies under the conditions that meet the requirements.

3.2 Quality standards

The definition and content of the quality standard will be explained in detail in the guidelines Q6A and Q6B in the future. We already know that stability studies are to test attributes that may change and affect the quality, safety, and/or effectiveness of APIs or drugs. These tests may include physical and chemical testing, biological or microbiological properties testing, preservative content, and functional testing (route of administration), etc. Related analysis methods should be verified and have stability indicating ability (stability indicating). The quality standard of stability study can be different from the quality standard of batch release, and appropriate demonstration should be provided.

3.3 Detection frequency

In terms of detection time points, Q1A provides different basic requirements for long-term, accelerated, and intermediate stability studies. See the table below:

Combining actual product demand and continuously obtained stability data, formulating a suitable stability research program on the basis of these basic requirements is more conducive to supporting the formulation of the product’s expiration date. For example, for a drug with a validity period of 2 years, long-term stability studies need to be done for 24 months.

3.4 Storage conditions

The storage conditions of stable samples usually include two main factors: temperature and humidity. According to the different climates of the regions where it is marketed, ICH is divided into 4 climate zones, and detailed regulations on the temperature and humidity conditions for long-term, accelerated, and intermediate stability studies should be carried out in different climate zones. Friends in need and interest can view the corresponding part of the content in Q1A and Q1F. We will not list them here.

3.5 Stability Commitment

When the applicant submits the application, the existing stability data does not include the entire retest period or validity period, the applicant shall promise to continue to complete the stability study to obtain reliable data after approval to finally establish the retest period or validity period.

3.6 Label

The label content should include the storage conditions of the bulk drug or drug. The description of storage conditions should be formulated in accordance with relevant local regulations and existing stability data. If there are special storage requirements, such as drugs that are not resistant to cold, specific instructions should be written as far as possible. Words such as room temperature should be avoided as much as possible. In addition, the label should state the retest date or the latest retest date of the drug substance, or the expiry date of the drug.

Above, we briefly introduced the ICH quality guidelines and Q1 guidelines among them.

As a coordination function, ICH provides more basic suggestions and guidance. Therefore, when reading and understanding the ICH guidelines, we should pay attention to flexibility and avoid taking a certain suggestion or viewpoint in the guidelines more seriously. In practice, the ICH guidelines should be used as a reference book, and review and read from time to time. When carrying out R&D projects, more attention should be paid to specific product characteristics and the needs of the target market.