For businesses that lack the space to house stability chambers, require additional storage capacity, or need assistance with study design for a complex drug product or substance, it is commonplace to outsource stability studies to a trusted partner. Here, Malcolm Saxton, Senior Consultant for Chemistry at Broughton, explores the considerations for commissioning stability storage and analysis projects.
Stability studies are used to determine the shelf life, active ingredient efficacy, and long-term safety and stability of a pharmaceutical product. They involve placing samples (within their container closure system and any other primary packaging) into environmentally controlled chambers to determine how the product or substance will change over time when subjected to specific environmental conditions. According to the study protocol, samples are periodically assessed for changes in physical, chemical, biological or microbial makeup. For example, changes to pH, degradation, dissolution, assay, microbial activity, and moisture content can be identified.
In the pharmaceutical sector, stability studies are essential for regulatory submissions as evidence of a product's efficacy and safety over time. Stability studies typically start at the pre-clinical stage and continue during clinical trial phases. However, to streamline route-to-market, many pharmaceutical businesses are adopting stability studies into their development process, rather than conducting them later.
Standards for Stability Testing
While drug manufacturers must submit their applications to the regulatory body (e.g. FDA or MHRA), stability studies are guided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). A typical stability study comprises of two key stages, stability storage and analysis. The ICH has guidance on the proposed length of the study and frequency of sampling based on the product and its intended shelf life, although some products may require custom conditions (anything from -80°C up to 70°C or 10-80% RH).
The ICH guidance explains three types of studies, long-term, intermediate and accelerated, and lays out specific storage conditions. These are intended to measure the product's condition in different circumstances, such as near the end of its shelf life or during transport. In addition, depending on the product's intended markets, the ICH guidance has created corresponding test conditions for the five climactic zones of the world.
Accelerated storage studies are an efficient way to highlight and troubleshoot any problem areas early on, supporting the early identification of potential degradation processes. In addition, accelerated storage conditions are used to support the extrapolation of real-time stability storage data. Forced degradation studies can help identify areas for future testing, and analytical chemists can use the results to devise a future testing program. This can help avoid costly reformulations and redesigns and accelerate time to market (TTM).
Before beginning a formal study, it is important to understand the product and its likely degradation pathways so that the study can be designed to follow those. Study design will depend on the drug product or substance, the drug delivery method, the stage of the drug development process, and more. For example, due to their sensitivity, biologics may need to be tested at a narrower temperature range. Or, it may be required to go beyond standard ICH environmental test conditions to check the product's stability during simulated shifts from hot to cold that may occur during transportation. Ultimately the study should be designed to answer product-specific questions.
Study design involves creating a plan that specifies sample sizes, testing times, specific storage conditions, validated test methods, and more. While guided by ICH, different regulatory bodies have different requirements, so the plan must be devised with a specific location in mind; some data is mandatory in some areas but not others and certain microbiological limits differ by region.
Industry Changes Ahead
Last updated in 2003, ICH Q1A-Q1F is in the process of refinement to become a combined Q1 guideline. The amended version will streamline the series, align it with other current ICH guidelines, promote harmonized interpretation, and cover new topics such as advanced therapies. The ICH's business plan highlights that the first draft of the revised guidelines should be available for comment in late 2024.
It's not just guidelines that are changing; the types of drug products and substances being tested are also changing. As other large molecule drug products, like biologics, come to market, stability storage and analysis must adapt — these molecules are more prone to degradation, and typically, this means more complex analysis, with additional parameters to measure or the need for custom test conditions. Biopharmaceuticals, for example, tend to exhibit more unpredictable degradation pathways than small-molecule APIs and may precipitate during the test due to their concentration and/or low solubility. Study design may be more challenging as a result.
Outsourcing Stability Studies
Pharmaceutical businesses outsource stability studies for several reasons: lack of space, facilities, or resources being common ones. In addition, stability testing and analysis is a specialist field. Outsourcing may offer a good solution if a company does not have in-house experts for method development and validation, particularly when working with a complex drug product.
Stability experts typically work with a manufacturer's in-house scientists to consult on study design and create forward-looking testing strategies. With experience in similar studies, the partner should have a broad understanding of product types and their possible stress points and can suggest the best ways to monitor them proactively.
Some businesses will have broader scientific subject matter experts available, such as analytical chemists and toxicologists, who can help provide a complete analysis of test data, understand deviations, and troubleshoot problems. If the partner is also an expert in extractables and leachables (E&L), studies can be run in parallel, streamlining the route-to-market. Finally, a partner with an in-house regulatory team can help prepare everything needed for submission to the regulatory body.
For stability studies, it is of the utmost importance to document that test conditions were maintained appropriately for the duration of the study, so that the study can be validated. Therefore, the stability study provider must offer end-to-end quality-controlled processes for the receipt, management, and disposal of samples. This is typically managed by a Quality Management System (QMS) in line with GMP, GLP, or ISO/IEC 17025 requirements for sample management. Important factors include managing traceability, temperature controls and data logging, procedures for limiting cross-contamination, data integrity, and more.
Some study providers will go further by offering real-time access to stability data and trend reports through a secure Laboratory Information Management System (LIMS), validated to meet the requirements of FDA 21 CFR part 11 and MHRA Annex 11 for electronic record keeping and signatures. This can give manufacturers peace of mind that there are no changes to the chamber's conditions.
Ahead of upcoming changes to ICH Q1A-Q1F and as more large molecules are put forward as drug candidates, pharmaceutical companies are looking for help with stability studies. A good stability study partner can consult throughout the process, give you confidence in the study design, and keep you up to date with the results.
Broughton has been offering stability services since 2006. Its chambers are controlled via a fully validated data management system in accordance with GMP requirements and ICH harmonised guidelines for stability testing new drug products and substances. The company currently has more than 250 live stability studies.