ICH Revises Q1 Guideline, Advancing Stability Testing Standards

By Md Saddam Nawaz, head of quality assurance, ACI HealthCare Ltd.

The stability of pharmaceutical products is a cornerstone of quality, ensuring that medicines remain safe and effective throughout their shelf life. In April 2025, the International Council for Harmonisation (ICH) reached Step 2 of a long-awaited revision to its stability guidance, releasing a draft ICH Q1: Stability Testing of Drug Substances and Drug Products for public consultation. This new draft guideline represents the first major overhaul of global stability testing standards in over two decades. It is a consolidated revision that will supersede the ICH Q1A–Q1F guidelines and ICH Q5C (for biotechnological products), unifying them into a single comprehensive guideline.^1–5 The revision was prompted by the need to streamline and modernize stability requirements, address ambiguities in the previous guidances, and incorporate scientific advances and new product types. Notably, the ICH Q1 revision integrates principles from other ICH quality guidelines^6–10 to reinforce a science- and risk-based approach to stability testing. It also introduces guidance for emerging therapies and methodologies, such as advanced therapy medicinal products (ATMPs) and predictive stability modeling.⁵

A Holistic Revision Of ICH Stability Guidelines

The revised ICH Q1 draft guideline combines and modernizes the content of the entire previous stability series (Q1A through Q1F), along with the biotech-specific stability guidance Q5C, into one comprehensive guideline. This holistic approach replaces the patchwork of documents with a unified set of principles for all product types — small molecule new chemical entities, biologics, and others — providing a one-stop reference for stability requirements across the board. The draft guideline explicitly supersedes ICH Q1A–F and Q5C while adding guidance on principles relating to stability to address gaps in the older documents.

Key structural changes make the new guideline more logical and inclusive. The document is organized into 18 sections followed by three annexes, covering the entire stability study process from early development to post-approval. It begins with developmental stress and forced degradation studies (Section 2), then details the design of formal stability studies (Sections 3-7), including selection of batches, containers, test frequency, storage conditions, and photostability. Subsequent sections provide guidance on ancillary stability studies, e.g., processing and holding times for intermediates, short-term storage excursions, in-use stability, and stability of novel excipients or adjuvants (Sections 8-12). The guideline then addresses data evaluation and shelf-life extrapolation (Section 13) and labeling (Section 14), before culminating in a dedicated section on stability commitments and product life cycle management (Section 15). Finally, three annexes cover specialized topics: Annex 1: Reduced Stability Protocol Design, Annex 2: Stability Modelling, and Annex 3: Stability of Advanced Therapy Medicinal Products (ATMPs).⁵ This structure underscores that stability must be considered in an end-to-end manner, from early formulation development through regulatory submission and beyond.

The guideline introduces several content areas not fully addressed in the older Q1 series. For example, it provides new guidance on in-use stability studies (to ensure product stability during the period of patient use after opening), short-term stability studies (such as excursions during transportation or temporary storage), and stability considerations for processing holds during manufacturing. It also explicitly discusses stability of novel excipients and vaccine adjuvants and includes considerations for managing stability of reference standards — topics reflecting challenges in modern product development. By incorporating these areas, the guideline fills known gaps and aligns stability expectations with current scientific and regulatory needs.

Quality By Design And Risk-Based Science In Stability Studies

Building upon ICH Q8,⁶ Q9,⁷ Q10,⁸ Q11,⁹ and Q14,¹² the updated ICH Q1 advocates for a modernized quality by design (QbD) paradigm. Stability testing is reframed not as a regulatory formality but as a science-driven quality assurance mechanism.

Stability-indicating critical quality attributes (CQAs) must be selected based on risk assessment and mechanistic understanding. These should include physical, chemical, microbiological, and functional properties subject to change over time. Emphasis is placed on analytical method validation under stress and forced degradation, ensuring the sensitivity and specificity of detection methods.

The revised guideline fully embraces a risk-based approach to stability study design. Rather than a one-size-fits-all mandate for testing, it provides flexibility for manufacturers to design leaner stability protocols if they can justify them scientifically. Annex 1 provides new guidance on knowledge- and risk-based protocol reductions beyond the traditional bracketing/matrixing examples.⁵ This means that if a company has sufficient knowledge (from development or prior experience) indicating that certain test conditions or time points are low-risk, they may omit or minimize those in the formal study — provided a sound scientific rationale is given.

The commitment to science-driven stability extends to how the data is ultimately evaluated. ICH Q1’s revision retains the familiar statistical approaches (e.g., regression analysis for shelf-life determination),⁵ but with an openness to enhanced data analysis tools. It encourages the use of appropriate statistical models and even mentions Bayesian methods for incorporating prior knowledge into shelf-life predictions. This forward-looking stance ties back to QbD: the more knowledge and data one has, the more confidently one can predict stability outcomes and set expiry dating.

Life Cycle Stability Management And Regulatory Flexibility

The revised ICH Q1 guideline integrates life cycle management principles as articulated in ICH Q10⁸ and Q12.¹⁰ Stability testing is no longer treated as a one-time activity but as a continuous responsibility throughout the product's life cycle. Section 15 of the draft provides detailed guidance on stability commitments and post-approval stability testing.

Under the revised Q1, when a manufacturer files for approval with less than the full long-term data, they must undertake commitment stability studies to continue gathering data. The guideline also details handling of products with inherently short shelf lives, indicating the minimum data for submission will be case-by-case and managed post-approval.

Another important life cycle element is handling post-approval changes. Changes in formulation, manufacturing process, packaging, or site can all potentially affect product stability. The updated guideline includes new guidance for post-approval changes within the stability section. This aligns with ICH Q12, which provides a framework for managing CMC changes through established conditions and risk management.

The guideline’s flexibility extends to novel manufacturing technologies and analytical methodologies. Innovations like continuous manufacturing¹¹ are considered under the umbrella of “new technologies.” The importance of having robust, stability-indicating analytical methods is implicit in the guideline and aligns with ICH Q14.¹²

Stability Modeling And Predictive Approaches

Annex 2 provides a framework for using mathematical and statistical models to predict stability outcomes, supplementing the traditional real-time studies. This is a significant step, acknowledging enhanced stability modeling techniques such as accelerated stability assessment programs (ASAP), kinetic modeling, and simulation.

The guideline stresses that any modeling approach must be grounded in sound science and subject to validation and verification. It notes that enhanced stability models are an evolving area and thus provides principles rather than strict rules. Modeling can support real-time stability testing, but it must be done rigorously. Applicants should pre-specify models, justify their assumptions, and continuously verify model predictions with real data as it emerges.

By formally including modeling, ICH Q1 is keeping pace with technological advancements. Health authorities have seen an increase in applicants using predictive tools and, now, with ICH alignment, there is a clearer global expectation on how to document and justify such approaches.

Stability Of Advanced Therapies

Annex 3 addresses ATMPs,⁵ a category that includes cell therapies, gene therapies, and tissue-engineered products. These pose unique stability challenges due to their biological complexity and sensitivity to environmental conditions.

Annex 3 is supplemental to the core guideline and not a stand-alone document. It likely covers scenarios such as extremely short shelf-lives, cryopreserved products, and unique potency assays for living products. Ensuring product integrity and biological function over time is the essence of stability for ATMPs, but the methods to achieve and test that can be very different.

Including ATMPs pushes the boundaries of stability science. By acknowledging ATMPs, ICH Q1 encourages regulators globally to harmonize how they expect stability to be demonstrated for such products.

Conclusion

The revised ICH Q1 guideline ushers in a new era of pharmaceutical stability testing. By consolidating prior guidances and embracing modern science, it provides a comprehensive framework that is flexible, scientifically sound, and future-ready. It calls upon industry to integrate stability considerations throughout the product life cycle, apply risk-based decision-making, and explore predictive modeling. The incorporation of guidance for ATMPs and other advanced products ensures its relevance for years to come.

References

1. ICH. ICH Q1A(R2): Stability Testing of New Drug Substances and Products. International Council for Harmonisation, Geneva, 2003.
2. ICH. Q5C: Stability Testing of Biotechnological/Biological Products. International Council for Harmonisation, Geneva, 1995.
3. ICH. Concept Paper: Targeted Revision of ICH Q1A-F and Q5C. International Council for Harmonisation, Geneva, 2022.
4. ICH. Business Plan: Revision of ICH Q1A-F and Q5C. International Council for Harmonisation, Geneva, 2022.
5. ICH. Draft Guideline: ICH Q1 Stability Testing of Drug Substances and Drug Products (Step 2, April 2025). International Council for Harmonisation, Geneva, 2025.
6. ICH. Q8(R2): Pharmaceutical Development. International Council for Harmonisation, Geneva, 2009.
7. ICH. Q9: Quality Risk Management. International Council for Harmonisation, Geneva, 2005.
8. ICH. Q10: Pharmaceutical Quality System. International Council for Harmonisation, Geneva, 2008.
9. ICH. Q11: Development and Manufacture of Drug Substances. International Council for Harmonisation, Geneva, 2012.
10. ICH. Q12: Lifecycle Management. International Council for Harmonisation, Geneva, 2019.
11. ICH. Q13: Continuous Manufacturing. International Council for Harmonisation, Geneva, 2022.
12. ICH. Q14: Analytical Procedure Development. International Council for Harmonisation, Geneva, 2022.

About The Author:

Md. Saddam Nawaz serves as the site quality management head at ACI HealthCare Limited. He is an experienced GMP, regulatory, and quality management systems (QMS) expert with experience in developing, implementing, and improving QMSs. He has extensive knowledge of GMP regulations and technical processes, has led greenfield pharmaceutical projects, and has secured several generic drug approvals. He has implemented initiatives to streamline operations, reduce costs, and enhance compliance. At conferences, he frequently speaks on the topics of data integrity, pharma 4.0, and quality culture. You can reach him on LinkedIn.