Introduction
Why stability testing is important: The FDA and other regulatory bodies control for every significant aspect of manufacturing, storage, and distribution, leaving little room for error. In order to achieve market success, new drugs must not only be effective and safe, but also predictable in their stability and storage.
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This essential information is only revealed through thorough in-house investigation, involving rigorous testing early-on in the drug manufacturing process known as “stability testing”. Stability testing determines the drug’s safety, integrity, shelf life, and responsiveness to various storage conditions. Before a drug can move further along on its path toward market approval, researchers must first place tangible and accurate windows for the substance’s shelf life and degradation.
Foundationally, stability testing assesses how a drug’s quality and may vary with time under different environmental conditions, such as temperature, humidity, and light. The above process ensures that pharmaceutical products are safe and effective, regardless of the location or environment they are distributed to.
Stability testing, however, is far more than a mere recommendation for prudent pharmaceutical companies. Rather, it is a codified mandate handed down by the regulatory entities which act as the industry’s gatekeepers. Furthermore, due to increasing collaboration between various relevant institutions, geographically specific agencies such as the FDA and EMA have begun to accept reciprocal standards.
This trend is largely due to the emergence of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH outlines types of conditions that should be applied to any drug seeking to gain market approval. This creates an interplay between pharmaceutical companies and the watchdogs overseeing them, as firms initially set stability testing standards which are later accepted or rejected by regulatory entities, all in the name of increased consumer safety and reduced commercial liability. This is not to say, however, that regulatory entities obligate every pharmaceutical firm to follow the same uniform process in their stability testing.
As long as the parameters set out by the ICH are met, companies can do so in whichever way they consider most convenient.
How stability testing is performed: The open-ended nature of regulatory demands, in regard to stability testing, means that there is a plethora of ways that firms can potentially investigate their product. FDA statute 211.166 (a) (3), for example, merely requires that the test methods employed are “reliable, meaningful, and specific”. By ensuring that regulatory standards are still flexible in their implementation, the FDA intentionally allows for creativity within pharmaceutical firms. In short, firms are handed down a set of mandated standards but unencumbered by a mandated process.
However, while the lack of a mandated uniform process encourages intellectual freedom, regulatory guidelines are still strict enough to discourage foul play. For example, FDA section 211.165 (e) mandates clean and concise records, calling for the documentation of the firm’s test methods, as well as their accuracy, sensitivity, specificity, and reproducibility. Section 211.194 (a) (2) further requires that all testing methods used by the company “shall be verified under actual conditions of use”.
As previously stated, while firms are not forced to employ any particular techniques, specific methods are critical to determining product stability.
For example, while the stability indicating test does not have to be the same assay method used in determining the product strength, a reliable investigation of a drug’s stability should distinguish the active ingredient from any degradation products. Furthermore, if one is found, it is essential to reliably estimate the quantity of any present degradate.
One common technique of conducting a forced degradation study is through the use of “degradation chambers”, also referred to as “stability chambers”. These cabinets are specifically designed to subject the tested substances to prolonged exposure of various combinations of light, temperature, and humidity. The length of the drug’s exposure is also varied to analyze the compound’s longevity under assorted conditions, lasting several months at minimum.
It is also crucial, in addition to conducting stability tests, for pharma companies to constantly assess the reliability of instrumentation as well. Without regular maintenance and proper calibration, the results are at risk of critical inaccuracies.
Furthermore, before ignoring the arduous logistics of highly specialized technology, companies must consider the regulatory hurdles involved. For instance, 21 CFR part 11 stipulates that all associated data collection and storage systems must be designed to prevent falsification, corruption, untraceable alteration, or loss of data.
Taking control of your stability testing: While diligence, meticulous documentation, and a strict set of rules offer a reliable safety net, the adoption of technological innovation and new testing methodologies should not be avoided.
Even under the assumption that new regulations won’t change the status quo, the mere reality of evolving technologies perpetually pushes companies to update their approach. In fact, this natural tendency to change with the times is one surefire method of staying up-to-date with the most modern stability testing methods. As biotech is one of the world’s most technologically innovative fields, it is important that pharmaceutical firms do not adhere to their traditional procedures. Instead, companies should seek out opportunities to integrate new software and instrumentation into their stability testing framework.
Furthermore, maintaining tight controls over the drug’s storage environment and tools involved is another simple way to improve stability testing. As previously mentioned, incubators and storage cabinets used in accelerated stability studies must be calibrated and closely monitored to ensure continued accuracy.
Mapping storage space temperature is also another key component of validation. Solutions such as PerkinElmer OneSource® Services, provide GLP/GMP compliant thermal mapping studies and open-door re-stabilization testing, both of which ensure the reliability of stability testing results.
As simple as it sounds, another effective way to improve stability testing is to do it thoroughly. Although it is true that only the drug product will reach pharmacy shelves, it is still necessary to sufficiently test both the drug substance and the drug product for stability.
In the best-case scenario, both the drug substance and the drug product are tested in at least two different storage conditions to best simulate degradation. The drug substance and the drug product are kept in both long-term ambient temperatures and accelerated storage conditions in order to forecast long-term stability. The accelerated storage conditions are meant to give an indication of the drug’s shelf-life before acquiring the results of long-term studies. Thus, it is recommended to submit both the real-time data and accelerated data throughout the duration of the real-time study.
Finally, while regulations may be seen as an inconvenient impediment, they are also meant to lead companies in the right direction. In short, if a company goes through the effort of checking every regulatory box, there is rarely room left for an error.
Before embarking upon the meticulous task of implementing a stability testing framework, it will behoove pharmaceutical companies to check up on the ICH’s recommendations, such as the minimum of three drug product batches and using the same packaging and materials as in the intended finished product.
SOURCES
- Price, E. (2017, September 8). The role of stability testing in pharmaceutical manufacturing. Retrieved from https://www.pcisynthesis.com/how-to-know-when-to-toss-your-prescription-drug-or-refrigerate-it/.
- Office of Regulatory Affairs. (2014, November 7). Expiration Dating and Stability Testing for Human Drug Products. Retrieved from https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-technical-guides/expiration-dating-and-stability-testing-human-drug-products.
- Stability Chamber Testing. (n.d.). Retrieved from https://www.dactecltd.com/products/stability-climate-chambers/stability-chambers/.