Final Concept Paper

Targeted Revisions of the ICH Stability Guideline Series

(Guidelines ICH Q1A-F, ICH Q5C)
Endorsed by the Management Committee on 15 November 2022

Type of Harmonisation Action Proposed

Revision of the ICH Stability Guideline Series Q1A-F and Q5C is recommended to a) streamline the
series by combining the various guidelines into a single guideline focused on core stability principles;
b) promote harmonised interpretation by addressing potential gaps and areas of ambiguity; c) address
additional technical issues, including relevant stability strategies and innovative tools that strengthen the
application of risk management; and d) consider inclusion of new topics, such as stability considerations
for advanced therapies. The informal working group proposes to establish these updates through the
Revision procedure. The envisioned result is a combined guideline, ICH Q1, with integrated annexes
and/or appendices that address specific topics beyond the core principles on stability recommendations
and to address product type1 specific recommendations, as required. It is also recommended to update
and supplement current training material.

Statement of the Perceived Problem:

Further to a comprehensive assessment of existing Quality guidelines and in consideration of potential

future topics, ICH’s Quality Discussion Group (QDG) issued the report to the ICH Management
Committee entitled “Future Opportunities & Modernization of ICH Quality Guidelines: Implementation
of the ICH Quality Vision from the ICH Quality Reflection Paper”, which was subsequently published
on the ICH website in October 2021. Maintenance of the Q1/Q5C Stability guideline series was
determined as one of the highest priorities based on the evaluation and recommendations from the QDG.

As written, ICH Q1A-E (plus content of the withdrawn ICH Q1F currently covered by WHO) and ICH
Q5C do not align with the format of more recently developed ICH guidelines that embrace a harmonised
core document approach supported by topic-specific annexes/appendices. The individual guideline
approach leads to interpretation of the guidelines on an individual basis, with uncertainty around how
they should work together. ICH Q5C, for example, is specific to stability of biotechnological/biological
products and it is often unclear which chapters of the ICH Q1 series apply to biologics as well.

Furthermore, the stability guidelines do not reflect modern analytical technologies and tools.
Incorporation of guidance that addresses the use of stability modelling and risk management could
enable earlier patient access to high quality medicines. Additionally, the current guidelines do not
address stability considerations for advanced and emerging product types1.

1
Product type refers to all aspects of the drug product, including drug substance, intermediates, and devices.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

ICH Secretariat, Route de Pré-Bois 20, 1215 Geneva, Switzerland

Telephone: +41 (22) 710 74 80 - admin@ich.org, http://www.ich.org
 FINAL Q1/Q5C Concept Paper Endorsed: 15 November 2022

Issues to be Resolved:

The Expert Working Group will aim to address the following identified issues:

• Consistency of interpretation:
o Through reorganisation into a core guideline with topic-specific annexes/appendices,
the update will clarify which parts of the guideline apply to which product types.
o Improve harmonisation by clarifying perceived ambiguities within the current
guideline.

• Clarification of technical components of current guideline and stability-related concepts; may

include but not limited to:
o Combine common/overlapping principles and expand on items specific for Drug
Substances (DS)/Intermediates/Drug Products (DP).
o Additional products not comprehensively covered by the existing ICH stability
guidelines to be considered can include Cell and Gene Therapy Products / Advanced
Therapy Medicinal Products (ATMPs), Oligonucleotides, Peptides, Generics,
Biosimilars, New products developed from approved active substances, Vaccines,
Plasma-derived products, and regulated over the counter (OTC) products. As part of
this consideration, certain stability concepts (e.g., retest date) may not be applicable to
all product types.
o Data and evaluation strategies for defining the retest period/shelf-life (DS) (align with
ICH Q7) and shelf-life (DP).
o Baseline considerations in designing a stability protocol (e.g., storage
temperatures/%RH/study timepoints, stability-indicating methods, Climatic Zones III
and IV (former ICH Q1F guideline).
o Container Closure System: packaging configurations on stability; related conditions for
drug and drug-device combination products.
o Photostability: testing expectations, relevant testing conditions and applicability
o The practical use of bracketing and/or matrixing.
o For compatibility studies, consideration for microbial testing and compatibility with
drug delivery systems (e.g., infusion bags, pumps, syringes, in-line filters and tubing).
o Clarification of how in-use stability and container closure integrity studies are
conducted (i.e., in-use stability vs. open dish/worst case stability and container closure
integrity (CCI) testing in lieu of sterility, including multidose containers).
o Clarity on in-use/end user storage conditions (storage of drug product as supplied),
including multidose containers.
o Expectations for products requiring preparation prior to use (e.g., [re]constitution or
dilution, mixing with other media).
o Excipient (when applicable) and adjuvant stability considerations.
o Clarity on application of antimicrobial effectiveness testing (AET) on stability.
o Update of the current glossary to define the new topics and terms.
o Clarify the difference and intent of studies under accelerated and stressed stability
conditions, as well as forced degradation studies.
o Stability profiling of reference materials/standards when applicable.
o Acceptance criteria for stability testing versus release testing.

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 FINAL Q1/Q5C Concept Paper Endorsed: 15 November 2022

o Analytical procedure validation aspects including stress testing conditions to

demonstrate the stability-indicating ability of the test method, algorithms used (to align
with ICH Q2 and Q14).
o Clarity on the determination of water loss calculations when used in place of storage of
the drug product at low humidity conditions for semi-permeable containers.

• Address new technologies and modern tools/strategies used as part of enhanced product
understanding:
o Modelling techniques, criteria for selection of batches, applicability, and
caveats/limitations.
o Expectations for statistical approaches and potential for Artificial Intelligence
modelling methodologies.
o Expectations for the justification of appropriate studies to determine shelf life for drug
products and retest date/shelf life for drug substances.
o Advances in understanding accelerated stability conditions and prior knowledge which
may support extrapolation.
o Use of risk management to define appropriate stability strategies.
o Importance of justifying the product-specific stability test conditions and methods in
the stability protocol.
o Ensure consistency with (or refer to) the ICH Q13 discussion of stability considerations
for continuous manufacturing.

• Pharmaceutical Quality System (PQS) related stability topics:

o Stability related considerations through the product supply chain (e.g., excursions
during storage and transportation, freeze-thaw cycle stability).
o Stability related considerations related to processing and hold-time studies during
manufacture.
o Stability approaches for manufacturing of DS and/or DP at multiple manufacturing
sites.
o Considerations of Out of Specification (OOS), Out of Trend (OOT) and significant
change for stability data, and expectations for trending within the PQS.

• Clarify applicability of requirements across development and lifecycle:

o Application of an integrated, science and risk-based approach to stability.
o Labelled storage statements/recommendations (e.g., in-use periods, temperature
conditions).
o Common filing considerations, e.g., stability protocol/report; minimum data sets.
o Consider and clarify applicability of phase specific stability throughout the different
stages of product development.
o Address how concepts should be applied to address product lifecycle/post-approval.
changes (risk-based approaches based on change) and ensure consistency with ICH Q12
principles.

• Training strategies and alignment with other guidelines

o Development of training materials related to the guideline updates with a focus on new
content.
o Development of case studies.

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 FINAL Q1/Q5C Concept Paper Endorsed: 15 November 2022

Background to the Proposal:

The original Q1A guideline (reaching Step 4 in 1993) was one of the first guidelines to be finalised at
ICH. In the early 2000s, the parent Stability guideline had undergone a revision process and several
further guidelines were developed and finalised. Multiple ICH guidelines in the Q1 series had been
endorsed as ‘supplementing guidance’ and were given the sub-letters, i.e., Q1B, Q1C etc. These
individual guidelines were intended as ‘subchapters’ of the “parent” Q1A(R2) stability guideline. This
was done in the 1990s and in the early 2000s to build on initial achievements of harmonisation and avoid
potentially reopening a section or a guideline where consensus was already achieved. ICH Q5C was
later written to address the biotech/biological aspects of stability. ICH Q1F was later withdrawn in June
2006 and the aspects of stability testing in Climatic Zones III and IV were referenced to the WHO
guideline ‘Annex 10, Technical Report Series, 1010, 2018’ since at that time the ICH Regions resided
in Climatic Zones I and II. With more recently developed ICH guidelines, beginning with ICH Q7 and
through Q14, ICH guidelines typically bear a single number and incorporate a broader array of topics
as structured annexes/addenda.

The ICH Q1 series (Q1A-Q1E) as a Tier 1 guideline, ICH Q5C, and the WHO stability guidance
covering Climatic Zones III and IV (i.e., content of the withdrawn ICH Q1F) are implemented
successfully in the regulatory framework by most regulatory authorities. However, experience gained
with the implementation since the finalisation of these guidelines shows uncertainties related to the
interpretation of the individual guidelines and how they fit together. Furthermore, it is recognized that
innovation in analytical testing including approaches as described in ICH Q2 and ICH Q14 along with
the development of control strategies (ICH Q8 and Q11), Quality Risk Management principles (ICH
Q9) and lifecycle approaches (as addressed in ICH Q10 and ICH Q12) create additional uncertainty for
industry and regulatory agencies regarding how these pieces contribute to the assessment of product
stability. This results in technical issues regarding stability that should be addressed to harmonise
approaches and expectations during product development and regulatory review and inspections.

Type of Expert Working Group Recommended:

The EWG should include regulators and industry representatives with background and expertise in either
(or both) the technical and regulatory aspects of pharmaceutical stability. Representatives should
comprise expertise in Chemistry, Manufacturing and Controls (CMC), Good Manufacturing Practices
(GMP), API/drug substance, drug product, small and large molecules, statistics, and predictive
modelling. The EWG should also include experts in Cell and Gene Therapy/ATMP product types to
help add this topic in the revised guidance.

Timing:

It is proposed that this work is initiated in Q4 calendar year 2022, following finalisation of the Concept
Paper and Business Plan and establishment of an Expert Working Group. It is anticipated that the
development of an ICH Q1 guideline using the concepts outlined in ICH Q1A-Q1E, WHO-Stability
(Q1F) and ICH Q5C guideline could reach Step 1 two years after initiation of an EWG and Step 4 in the
year after that. Training materials will be initiated during Step 3 and available after Step 4.

• Q4 calendar year 2022 - Final Concept Paper, Business Plan

• Q4 calendar year 2024 – Complete Step 1
• Q4 calendar year 2025 – Complete Step 4

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 Final Business Plan
Targeted Revisions of the ICH Stability Guideline Series
(Guidelines ICH Q1A-F, ICH Q5C)
25 October 2022
Endorsed by the Management Committee on 15 November 2022

1. The issue and its costs

• What problem/issue is the proposal expected to tackle?

There are four key problems that the proposal is expected to address:
1. The current stability guidelines are written as individual chapters, which leads to interpretation of
the chapters on an individual basis with uncertainty around how they should work together. This
leads to variability in application and interpretation.
2. Certain topics within the guideline are routinely interpreted differently by users and regulators. The
perceived ambiguity leads to diverging expectations.
3. The stability chapters do not reflect modern analytical technologies and tools. Incorporation of
guidance and associated training activities that address the use of stability modelling and risk
management could enable earlier patient access to high quality medicines.
4. The current guideline does not address stability considerations for advanced and emerging product
types1.

• What are the costs (social/health and financial) to our stakeholders associated with the current situation
or associated with “non-action”?

There is general alignment that the science of stability has advanced significantly since the last revision
to ICH Q1 in 2003. Further, it is recognised that the interpretation of the current ICH Q1/Q5C series
is variable. It is also recognised that the guidelines as written do not provide adequate guidance for
advanced product types. Finally, the guideline is not fully aligned with more current ICH regulatory
guidelines and risk management principles (ICH Q8-Q12). Failure to address these issues will result
in continued divergence in regulatory requirements, unnecessary delays of product to patient, and the
potential for unnecessarily short product shelf-life, wasted product and redundant testing.

2. Planning

• What are the main deliverables?

The envisioned result is a combined guideline, ICH Q1, with integrated annexes and/or appendices that
address specific topics beyond the core stability recommendations and product type1 specific
recommendations, as required. It is also essential to revisit and update existing training material and
create training material for new topics.

1
Product type refers to all aspects of the drug product, including drug substance, intermediates, and devices.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

ICH Secretariat, Route Pré-Bois 20, P.O. Box 1894, 1215 Geneva, Switzerland
Telephone: +41 (22) 710 7480 - admin@ich.org, http://www.ich.org
FINAL Q1/Q5C Business Plan Endorsed: 15 November 2022

• What resources (financial and human) would be required?

One Expert Working Group (EWG) will be designated to establish a core stability guideline for the
stability evaluation of pharmaceuticals, incorporating core content of ICH Q1A-F and Q5C under ICH
Q1. The EWG should include regulators and industry representatives with background and expertise in
either (or both) the technical and regulatory aspects of pharmaceutical stability. Representatives should
comprise expertise in Chemistry, Manufacturing and Controls (CMC), Good Manufacturing Practices
(GMP), API/drug substance, drug product, small and large molecules, statistics, and predictive
modelling. The EWG should also include experts in Cell and Gene Therapy/ATMP product types to
help add this topic in the revised guidance.

What is the time frame of the project?

The revision is anticipated to take 3 years to complete, with a target delivery by end of 2025.

• What will be the key milestones?

The proposed milestones are below:

Q4 calendar year 2022 - Final Concept Paper, Business Plan
Q4 calendar year 2024 – Complete Step 1
Q4 calendar year 2025 – Complete Step 4 and training materials

• What special actions to advance the topic through ICH, e.g., stakeholder engagement or training, can
be anticipated either in the development of the guideline or for its implementation?

The following special actions may help advance development of the guideline:
• Workshops/engagement with technical experts for incorporating guidance on new analytical tools,
modelling, and stability risk assessment.
• Workshops/engagement with technical experts on addressing special consideration for advanced or
emerging product types.

The following special actions may aid implementation of the revised guideline:
• Development of training materials related to the guideline updates with a focus on new content.
• Development of case studies.

3. The impacts of the project

• What are the likely benefits (social, health and financial) to our key stakeholders of the fulfilment of the
objective?

Revision of ICH Stability Guideline Series Q1A-F and Q5C is recommended to a) streamline by
combining into a single guideline focused on core stability principles; b) promote harmonised
interpretation by addressing potential gaps and areas of ambiguity; and c) address additional technical
issues, including relevant stability strategies and innovative tools that strengthen the application of risk
management; and d) consider inclusion of new topics, such as stability considerations for advanced
therapies. The anticipated benefits include:

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FINAL Q1/Q5C Business Plan Endorsed: 15 November 2022

• Increased harmonisation of interpretation and application (reduce diverging interpretations of

guideline) and increased alignment with other ICH guidelines.
• Provision of guidance for use of tools to support application of shelf-life/retest for rapidly
developed programs/breakthrough therapies (improve access of important medicines to
patients and decrease waste).
• Adoption of knowledge-based and platform-based strategies into the guideline could lead to
reduction in redundant stability studies, improving efficiency and decreasing waste and cost.

• What are the regulatory implications of the proposed work – is the topic feasible (implementable) from
a regulatory standpoint?

The topic is implementable from a regulatory standpoint. New content to the guideline will reflect
topics that are well-understood and will aim to align with other current regulatory guidelines.

• Will the guideline have implications for the submission of content in the CTD/eCTD? If so, how will the
working group address submission of content in the dossier? Will a consult be requested with the ICH
M8 working group?

Any CTD content related to the ICH Q1 update should be incorporated into the relevant existing
CTD/eCTD quality modules and therefore this guideline update is not expected to impact CTD/eCTD
submission content.

4. Post-hoc evaluation

• How and when will the results of the work be evaluated?

At the conclusion of each stage, we will determine whether deliverables and their timelines were met
by comparison against our concept paper and business plan. After training is complete, if practical, a
survey may be distributed to regulators to measure its effectiveness.

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