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Sufficient stability studies show a drug product meets regulatory requirements, therefore ensuring the drug reaches the patients who rely on it.
While every drug molecule is unique and brings its own fragile chemical makeup to the production process, one element is consistent across the board: the importance of stability from start to finish. Stability testing is a highly important part of the production and commercialization process because it allows a contract development and manufacturing organization (CDMO) and drug developer to note what production processes, packaging, and shipping options will maintain the drug’s delicate chemical composition without jeopardizing quality.
When a drug developer partners with a CDMO, whether in Phase I, II, III, or beyond, it is not only recommended, but vital for the CDMO to conduct stability studies. This testing must take place in every phase of development, often more than once per phase, and should be integrated into the predetermined timeline. These studies do take time. Therefore, it must be accounted for early on in the process to prevent a delay in achieving commercialization. Injectable drug molecules naturally evolve as they are developed. Stability studies offer a proven method to test the drug ingredients’ quality as it is subject to external conditions such as environment, temperature, humidity, light, and more. Looking beyond the production timeline, stability studies bring added value in determining retest dates, shelf-life, expiration dates, packaging, storage, and shipping conditions.
Without sufficient stability studies, a drug product is failing to meet regulatory requirements and will inevitably never reach the patients who rely on it.
As any drug developer or CDMO will know, creating an entirely new drug poses its own unique challenges, one of which is securing regulatory approval from several authorities in different markets. Submissions for approval to these authorities must contain data from stability testing for the drug substance and drug product. As a result, stability assessments will be performed in nearly every development phase to evaluate a drug product’s overall stability in various instances.
Stability testing begins in early development phases. This is completed by analyzing technical batches and clinical samples to support the identification of proper formulation, primary packaging, and production processes that are best suited to maintain the drug formulation’s quality. Later, testing continues but changes its focus to the generation of expiration dates and obtaining market authorization. Stability studies must be done throughout the full development lifecycle. Should testing show a drop in quality at any point, the problem must be immediately addressed to prevent delays in the production and
commercialization process (1).
A CDMO will bring different study types to the development process (e.g., real-time, accelerated, intermediate, and photostability studies). Real-time testing looks at a product under intended temperature, humidity, and packaging storage conditions. Accelerated testing gathers supportive data through estimations of long-term testing outcomes and evaluations of short, temporary excursions from label storage conditions. Intermediate testing is performed between long-term and accelerated studies when accelerated studies show potential for significant change after six months (2).
Once a product launches, stability testing does not stop. Follow-up studies should be conducted regularly and additionally after post-approval changes. Some might consider stability testing to be one of the most essential elements of a drug product’s entire lifecycle, as it supports the drug and the health of the patients.
Drug products can vary extensively, from small-molecule to large-molecule, complex, highly sensitive, vaccines vs. oral, biotechnologically produced, and more. Therefore, the stability testing conducted for every drug product must differ accordingly. As each drug product evolves, its testing must adapt to address all quality needs.
Consider biologics, for example. These drug products experienced a boom in clinical development in recent years when the global pandemic required a vaccine for treatment. Injectables are delivered through a small, concentrated volume of liquid. Therefore, its potential stability issues are unique to this format and can range from aggregation, viscosity, and thermal degradation. While small-molecule drugs are often more straightforward to test for quality, large-molecule drugs can be much more complicated and require deeper bioanalytical testing methods. Regardless of a drug molecule’s size, testing must be uniquely designed to evaluate all key elements of a one-of-a-kind biologic.
As drug products differ in their formulation, packaging, delivery, and treatment method, so too does the most suitable stability testing approach. A CDMO and drug developer must select stability programs that align with its company philosophy, product type, and regulatory requirements. Customer expectations may also vary and play a role in the testing done by a CDMO.
Above all else, the stability program for a given drug will base itself on the regulatory needs for that product. Selecting stability testing should remain fluid and, on a case-by-case basis with several factors in mind.
When a drug undergoes regulatory evaluation, it will not simply receive a “yes” or “no” during its stability testing. Instead, it sets parameters that guide the development program with quality assurances in mind. While regulators will likely outline drug stability requirements in good manufacturing practice (GMP) guidelines, these programs will include more than the baseline expiration date (3). It will also require written stability studies outlining sample sizes, test frequency, storage needs, validated test methods, and specifications. With these qualifiers in mind, CDMOs and pharma customers will implement the unique stability testing program often enough to maintain quality throughout the process. This testing must be done within the product’s container that it will go to market in.
Luckily, the industry has seen synergy across multiple regulatory authorities and guidelines for stability testing. In fact, the International Council for Harmonisation (ICH) pharmaceutical stability guidelines are now considered a globally accepted standard (4). By following the ICH’s recommendations for amount and type of drug stability data needed per drug substance type, drug developers will be prepared to earn regulatory approval on any new drug product. ICH guidelines, particularly Q1A–Q1F, have measurably improved the overall quality of pharmaceutical drug products on the market, both in small- and large-molecule formats. While this does not mean that every drug product will require the same testing, it does set a precedent that can be adhered to across the board. For example, biologics are notoriously more sensitive so they will require a variety of complex analytical tests including, for example, potency testing.
While stability testing can be done by pharmaceutical and biotech companies, its growing demand is a result of a rising complexity of global regulatory requirements. Many choose to work with an outsourcing partner, or CDMO, to take advantage of their stability testing expertise. It is unlikely that a customer has this level of expertise in-house, but it is often available to leverage when working with an external partner. Besides the knowledge-base, CDMOs often bring added analytical equipment and qualified storage capabilities that would be a cost-add to a customer’s own internal repertoire.
Full-service CDMOs allow a customer to bring production, release, and stability testing together within the oversight of one quality management system. By entrusting the comprehensive stability testing process to one partner, a drug developer mitigates the need for additional organization, coordination, and logistic activities. This saves both cost and capacity for other drug development projects. In addition, changes can be addressed more seamlessly when both production and stability testing are with one company.
This outsourcing method opens pharmaceutical and biotech company capacities for product development, leaving an experienced CDMO to manage stability studies.
Across the industry, some trends are consistent, ranging from increased complexity of drug molecules, shortened timeframes for development and delivery, and decreased batch sizes. There is also a shift to greater collaboration between pharma and biotech companies, CDMOs, and regulatory bodies. By working together to create guidance for stability testing based on risk assessment, drug developers can get ahead of regulatory expectations and establish new testing criteria to address quality expectations.
As stability testing and regulatory approval become increasingly intertwined, the value customers place on it is growing and becoming a high-value service provided by CDMOs. As more customers engage CDMOs for stability testing support, there is also an increase in the related requirements placed on outside partners.
The current landscape and future forecasts of the stability testing market indicate a need for global standardization and improved approaches. As this becomes reality, CDMOs will have greater adaptability to provide streamlined testing with better quality results generated.
Karin Kottig, PhD, is head of Contract Service Analytics, Vetter Development Service.
Vol. 36, No. 12
When referring to this article, please cite it as Kottig, K. Stability Studies: An Essential Step for Quality Management in Drug Development. BioPharm International 2023 36 (12).