On April 11, 2025, the ICH endorsed a draft guidance titled “Stability Testing of Drug Substances and Drug Products Q1” (here). This is a large, comprehensive guidance that applies to stability testing of chemically synthesized drug substances, biologics, vaccines, gene therapies, and combination products. The guidance addresses primary stability studies, commitment, ongoing and stability studies as part of post approval changs, and supersedes ICHQ1A-F.
What is notable is that the guidance is promoting that risk management should underpin all aspects of the stability program and that stability studies are risk-based (in fact, the term “risk” is referenced over 100 times throughout the guidance!). This naturally begs the question of what does a risk-based stability program look like?
At a high level, the goal of the stability program is to determine the respective material’s shelf life/retest period based upon protocol-driven testing of the material’s stability-indicating Critical Quality Attributes (CQAs). Such a protocol will consider the results from development stability studies which may include stress testing and/or forced degradations runs (the latter is more often used to confirm the stability-indicating capabilities of your methods) where stability CQAs are hopefully established/defined. Therefore, the application of risk management is to identify and control those risks that would impact the goal of generating an accurate shelf life/retest period. The same concept could apply to determining in use stability time periods, stability data for reference material, intermediate hold times etc. (all addressed within the same draft guidance document).
The above concept is illustrated within the guidance, Section 3.2, Table 1, which discusses the amount of stability data to be included in the submission to support initial re-test period/shelf life. For each product type (new/existing synthetic chemical entity and biologic), the number of batches to base the initial, proposed re-test period/shelf life is three (for a full design), but then references Annex 1 (within the same guidance document) for considerations when attempting to proceed with a reduced stability protocol design. Within the Annex, the matrixing and bracketing approaches are discussed along with knowledge and risk-based protocol reductions. The key to a reduced protocol design is the justification (which is to be incorporated into the stability protocol) which in turn, should be based upon stability data/knowledge. As stated in the Annex:
“Where justified, a reduction may be applied to attributes, timepoints, samples and/or storage conditions. To apply these strategies, the applicant should present an understanding of what attributes are subject to change over the re-test period/shelf life and what conditions might impact their rate of change. This should be supported by data and/or product knowledge and used to conduct a risk assessment that justifies the proposed reductions.”
For stability studies associated with the post approval changes, the greater the knowledge and understanding of the stability characteristics/behavior for the subject of the stability protocol, facilitates the risk analysis, which is critical when addressing the potential impact to the accuracy/validity to the assigned re-test period or shelf life (associated with any post approval changes). Section 15.3 of the guidance proposes two scenarios when addressing stability impact for post approval changes, where Scenario 1 covers:
A stability risk assessment indicates the proposed changes will not have an impact on the stability profile (e.g., change to a comparable analytical procedure, change in outside cap color). Stability data in this case is unnecessary and the re-test period or shelf life will not be re-established.
Scenario 2 addresses:
“[P]roposed changes that may potentially impact the stability profile (e.g., manufacturing process change, change in formulation). A stability study, a stability risk assessment, or a combination thereof may be appropriate to support this change. The risk assessment process may include a well-designed study to determine whether additional formal stability studies or other supportive stability studies are necessary. The assessment should establish whether the re-test period/shelf life and storage condition may be maintained or if they should be re-established.”
Ultimately, quality risk management is fundamental to a company’s stability program. Above are only examples of where risk analysis/management needs to be considered, but risk management must be addressed in every aspect of the stability program. What must be recognized is that inherent to a robust risk management program, is knowledge management and that where there are gaps in any knowledge then data/an understanding must be acquired prior to the risk analysis so that the level of risk can be accurately measured and that informed follow-up actions can be defined. You cannot risk manage the need to address any gaps in data/knowledge as the data/knowledge is at the core of making any risk-based decision. For example, when discussing Confirmatory Photostability within the primary container closure system, the guidance states that:
“Alternative science- and risk-based approaches may be considered when appropriately justified and may include scenarios where confirmatory photostability testing is not required. For example, if no photodegradation is observed in the fully exposed drug substance sample or the fully exposed drug product sample, no further testing as part of the confirmatory study is needed.”
If you have any questions related to ensuring that Quality Risk Management is inherent to your firm’s stability program, please reach out to LCS@LachmanConsultants.com for a consultation.
