When To Conduct GMP Versus Non-GMP Stability Studies — And Why Both Matter

These studies generate data that supports shelf-life claims, shipping and storage requirements, formulation decisions, and broader development and regulatory strategies. Regulators expect to see several types of stability evaluations, including:

• Forced degradation, in which the drug product is put through extreme stress (oxidation, UV light, freeze-thawing) to identify its degradation pathway and robustness against external stress factors.
• In-use studies that evaluate the physical, chemical, and microbiological integrity of the original product following clinical in-use scenarios (e.g., diluting the product in saline and pumping through infusion line and filters).
• Long-term studies which monitor the product under recommended storage conditions over the expected shelf life to ensure stability.
• Accelerated studies that expose the product to elevated stress conditions, e.g., temperature excursions, to speed up decision making during long-term stability studies, predict long-term stability, and identify potential vulnerabilities.
• Shipment studies under simulated or real transportation conditions. This is mandatory to assess stability during distribution of the commercial product, but may also be helpful for early phase transportation risk assessment

While each serves a distinct purpose, the value of the resulting data depends heavily on when the studies are performed and whether they are conducted under GMP or non-GMP conditions. Although GMP stability studies are critical for product scaleup, commercial manufacturing readiness, and clinical trial activation, non-GMP studies play an essential role in the early stages of product development, as they provide powerful insights to guide candidate selection, formulation strategy, risk mitigation, and bolster future regulatory activities. Understanding when to leverage GMP and non-GMP studies, how to bridge the resulting data, and where each approach delivers the greatest value can help sponsors make better development decisions and support a more efficient path to the clinic.

What Value Do Non-GMP Studies Provide In Early Development?

When sponsors start non-GMP stability studies as early in development as possible, they gain meaningful insight into the stability of lead and backup candidates, helping reduce development and business risk. If stability issues emerge that cannot be readily addressed, teams can make informed decisions about whether to pivot to a backup candidate that demonstrates a more manageable stability profile or to carry out advanced formulation development activities to address those challenges. Another use for these studies is determining the ideal product formulation, including whether a drug product should be liquid, lyophilized, or frozen. Early-stage studies that evaluate whether a product is stable at room temperature or if a continuous cold chain is necessary inform lead candidate selection and long-term storage strategies. Once the lead candidate is selected and sponsors move into preclinical studies, they must design a lifecycle stability study approach. In the preclinical and discovery setting, sponsors will likely manufacture small, controlled batches via different techniques, but as they begin to scale into development of a GMP process, their processes and analytical methods should become more refined and standardized. After a sponsor solidifies their primary manufacturing process, they will start to take drug product samples from this process to begin generating stability data. As production scales up, their teams can compare data from earlier runs with data from initial GMP batches.

Advanced kinetic modeling (AKM) in non‑GMP stability studies of biologics is primarily used to predict long‑term stability and shelf life from short‑term accelerated data while gaining mechanistic insight into complex degradation pathways. This enables faster formulation screening, candidate selection, and risk assessment early in development without waiting for real‑time studies. In industry, AKM is increasingly adopted as part of predictive stability approaches, especially in early development, but its routine use for regulatory (GMP) shelf‑life claims is still evolving and not yet universally established.

Ideally, the analytical assays sponsors use for non-GMP stability studies should be stability indicating and aligned with the methods they plan to use under GMP conditions. Sponsors should consider transitioning the same methods from non-GMP to GMP use to enable consistent stability data from early to late-stage processes. However, in non-GMP studies, sponsors can also secure supplemental data from methods that are difficult to validate under GMP conditions, but which provide valuable supplemental data.

When Should A Sponsor Pivot To GMP Studies?

It is a challenge for a sponsor to initiate formal GMP stability studies in a timely manner, as sufficient material from a representative manufacturing process must be available. For this reason, it is crucial to start with non-GMP stability studies well in advance. This will allow the sponsor to reconcile GMP and non-GMP data. The appropriate transition depends on the product, formulation, manufacturing process, and risk tolerance. For example, well-understood molecules like mAbs can rely on non-GMP stability studies for longer. In general, 1 to 3 months (or less) of real-time GMP stability data are typically sufficient to enter a phase 1 clinical trial when supported by 6 to 12 months non-GMP stability data. For complex, novel entities, a longer stability period may be covered by GMP studies.

In summary, stability studies conducted under GMP conditions become mandatory once a sponsor defines their final process for Phase 1 clinical studies. These efforts require validated stability-indicating methods and representative “GMP-grade” materials as used in formal toxicology studies and derived from a manufacturing process that largely corresponds to the final Phase 1 GMP manufacturing process.  If designed appropriately, corresponding non-GMP studies evaluating the same formulation can be structured to bridge effectively into GMP-studies, even if the material comes from a less mature production process. Furthermore, if a sponsor lacks sufficient long-term data generated under GMP conditions at the time of IND/IMPD submission, properly bridged non-GMP data may help support shelf-life.

Sponsors should establish long-term, accelerated, and stress stability studies appropriate for the product and development stage. Once these are running, a sponsor must develop and finalize their GMP process, validate their methods, and start conducting GMP stability studies in parallel. In practice, bridging requires either testing samples from the non-GMP stability study with the GMP methods or incorporating a reference standard that is tested on both sides to enable direct comparison and bridging of the two data sets. The goal is to use non-GMP and GMP stability data to tell one consistent story from initial development into market preparation.

How Does Stability Data Support Regulatory Approval?

Regulators are seeking supportive stability data to affirm a sponsor’s shelf-life claim prior to approving their clinical trial. Demonstrating that non-GMP data is relevant for the GMP product helps support regulatory decisions regarding entry into early-phase trials. By leveraging scientifically sound data from non-GMP studies, sponsors will streamline their pathway into first-in-human (FIH) studies and mitigate any delays associated with waiting to gather additional GMP data to support stability. Despite the widespread misconception that scientifically sound data can only be generated under GMP conditions, non-GMP stability studies can demonstrate a high degree of rigor and reliability when supported by experienced, well-trained teams and a robust quality management system. When properly designed and bridged to later-stage studies, these data can provide meaningful support for IND/IMPD submissions and broader development activities.

In terms of small molecule versus biologic stability compliance, small molecules and biologics require evaluation of different degradation mechanisms. These degradation pathways are significantly more diverse in biologics compared to small chemical active ingredients. For this reason, biologics must be assessed for conformational unfolding, covalent changes, and other chemical modifications as well as the presence of aggregates and fragmentation. Biologic potency must be demonstrated early via appropriate assays that account for the high complexity of these molecules.

How Do Sponsors Position Their Stability Strategy Toward Success?

The goal is to design non-GMP and GMP stability studies to produce data that is as congruous as possible. Sponsors should consider the advantages of working with one partner that can execute both GMP and non-GMP studies, using the same instrumentation and methods to generate comparable data sets. Though stability studies are an essential component of regulatory filings, they are also an important tool to derisk the early stages of product development, helping teams evaluate product stability, reduce development risk, and support IND/IMPD submissions and FIH studies.