Convergence: New ICH Q1 guideline is ‘one-stop shop’ for stability testing
PITTSBURGH — The new International Council for Harmonisation (ICH) Q1 draft guideline on stability testing of drug substances and drug products is an attempt to revise the current ICH Q1 guideline, expand its scope, and incorporate more than three decades of related stability guidance documents under one umbrella.Mohamed Ghorab, vice president, Technical PC, Regulatory Strategy at Parexel, told attendees at the RAPS Convergence 2025 conference the upcoming revision to the ICH Q1 guideline is a “huge transformation.”
“We can consider this as a comprehensive one-stop shop for all stability concentrations,” he said.
Released in 1993, the ICH Q1A guidance was one of the first guidance documents issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and focused on basic stability testing and general requirements for stability studies. Over time, the ICH Q1A guidelines were revised in 2000 and 2003, a parent guideline on biotechnology and biological products was released (ICH Q5C), and several ICH Q1 daughter guidelines were released on photostability testing (ICH Q1B), new dosage form stability (ICH Q1C), bracketing and matrixing designs for tests (ICH Q1D), evaluation of data (ICH Q1E), and applications of stability testing for climatic zones III and IV (ICH Q1F).
The new draft ICH Q1 guideline consolidates the previous daughter stability guidelines into one 108-page document that contains new information on in-use studies, short-term stability studies, processing and holding times, adjuvant and reference standard studies, product lifecycle, and modeling. The new guideline also includes information on how to address new technologies such as cell and gene therapies, and has stability considerations for reference materials, novel excipients, and adjuvants. (RELATED: ICH releases overhauled stability guideline for consultation, Regulatory Focus 17 April 2025)
Some industry representatives commenting on the new ICH guidance were in favor of the comprehensiveness of the new document and its attempts to consolidate other guidance documents, while other groups expressed concern about unclear instructions on when to submit shelf-life data for biological drug substances and products as well as the need to expand the guidance to contain botanicals and live bacterial products. (RELATED: Industry wants clarity on scope of ICH stability testing guideline, timing of studies, Regulatory Focus 26 August 2025)
Ghorab acknowledged that the new ICH Q1 guideline does not include everything. Radiopharmaceuticals, whole blood products, and device constituent parts are not within the scope of the guidance, he said.
Stability studies
The new ICH Q1 guidance classifies stability into three groups: development studies under stress and force conditions, formal stability studies, and supportive stability studies.
In development stability studies, stress studies refer to severe conditions that are not designed to degrade the sample, while forced degradation studies do contain conditions that are intended to degrade the sample.
Formal stability studies can include primary, commitment, ongoing, and product lifecycle stability studies. “All these formal stability studies should be conducted under accelerated and long-term stability at the minimum,” Ghorab said.
When considering the protocol design of formal stability studies, sponsors should identify the critical quality attributes (CQAs) that change over time as well as the excipients that affect the CQAs. For vaccines, the mechanism of determination should be identified to evaluate the potency, and this may be impacted by the active pharmaceutical ingredient (API) or another component.
“[I]f the API is in a conjugate with a carrier, then the degree of association over time needs to be monitored. If there is an adjuvant that is required for the potency, the same thing, that adjuvant CQA should be also monitored,” he said.
A protocol design for a drug-device combination product should include the assembled market presentation of the product. “Because the drug constituent part can impact the functions or the functional characteristics of the device part, the stability study should consider determining the impact of the drug constituent part on the functional or performance characteristics of the device, and that should be carried over time and has to be tested in the full assembly,” Ghorab explained.
The shelf life for a combination product is based on the shorter shelf life of the constituent or the assembly. “When it comes to determining what’s the shelf life of your combination product, the concentration here is not only to any of the two constituents or the assembled, but you have to evaluate the shelf life for each one,” he said.
Selection of primary stability batches between chemical synthetic entities and biologicals have “subtle differences,” Ghorab said. The primary batches for the drug substances of both chemical synthetic entities and biologicals can be a similar manufacturing process to the production scale batches. Batches for chemical synthetic entities need to be manufactured at pilot scale at a minimum, while there is no required scale for biological products.
For drug products, synthetic chemical entities need to have a minimum of two batches manufactured at pilot scale as a minimum, while the biological product primary batches need to be “comparable to the production batches at whatever scale you are going to use, but it has to be exactly comparable based on the ICH Q5B recommendations,” Ghorab said.
Other stability considerations
The supportive stability studies are a new addition to the draft guidance, he noted. While photostability studies were included in previous guidances, the in-use, short-term storage, and excursion studies are new, and can include “any clinical studies that have been conducted using the same representative formation and process as the commercial scale batches that will be proposed in the submission,” Ghorab explained.
Another new addition is the stability of intermediates and its relationship to processing and holding time. Sponsors should consider how the intermediate interacts with the equipment being used. They should also consider the maximum holding time for the intermediate as well as the relevant temperature and humidity in storage conditions, light exposure, and transportation of the intermediate.
“At the end of the day, when establishing the maximum hold time, you cannot use the intermediate beyond that hold time,” Ghorab said. “You have to understand before conducting the holding time of that intermediate, what is the amount of time it would take to transport that intermediate from one side to the other?”
The retest period and shelf life for a product is based on the long-term stability data in recommended storage conditions, but can also be based on enhanced stability monitoring or a limited extrapolation of an accelerated date if there is a lack of long-term data. The retest period applies for drug substances of synthetic chemical entities or some biological products, Ghorab said. For the shelf life of a synthetic chemical entity product, the start date is the date for the start of manufacturing or batch release, while the start date for a biological product is the date of filtration or the filling of liquid.
The “easiest way” to perform a statistical evaluation to establish a retest period or shelf life would be to perform a long-term stability study to determine when your data reaches the acceptability limit, but in cases of limited stability data, a sponsor can use another method such as enhanced stability modeling methodologies or limited extrapolation, Ghorab said.
ICH Q1 guideline annexes
The ICH Q1 draft guideline has several annexes containing information on bracketing and matrixing, stability modeling, and advanced therapy medicinal products (ATMPs) which are new to the guidelines.
The section on bracketing and matrixing for stability studies is a continuation of principles outlined in ICH Q1D but “further expands into other science and risk based reduced stability designs strategy” and provides “strategies that allow to reduce the total number of samples and analysis while still generating sufficient data to justify product stability and shelf life,” Elisa Pedone, a pharmaceutical quality senior specialist with the European Medicines Agency, said in her presentation.
A new addition to the annex is information on knowledge and risk-based protocol reductions for stability studies. “These designs are based on the overall product knowledge on development data and/or on the results of the ongoing or completed primary stability studies,” Pedone explained. “When justified, reduction can be applied to certain attributes or storage conditions or time points for new protocols.”
Another addition to the draft guideline is a set of recommendations for advanced therapy medicinal product (ATMP) stability studies, a “diverse category of innovative and complex biological products” with unique characteristics that should be present in the stability study.
The protocol for an ATMP stability study should be based on CQAs and manufacturing knowledge, but Pedone acknowledged that limited data might be available to inform the study design or the establishment of a shelf life.
“In absence of a sufficient real-time data from commercial lots, the development of data and insights from similar products might be used to support the shelf-life estimate,” she said. “For autologous cellular products such as CAR-T cell products, when the patient material is scarce, the use of healthy donor surrogates plus limited patient-derived data might be acceptable.”
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