People who are not familiar with pharmaceutical development often express surprise and disappointment regarding the time and cost to bring new pharmaceuticals to market. One reason for this is the requirement for testing every drug’s stability and shelf life. In addition to being a regulatory requirement by the FDA, a drug company wants also to know that their product will be safe and effective over long periods of time to the patient population who will be using it. That is the role of stability testing.
The term “stability testing” covers more than the way a compound behaves over time. For every pharmaceutical product, the developer must have studies to test the stability of the active component, and then again separately on the final form of the drug — e.g., the oral formulation or the injectable form — in its final packaging that will be available to pharmacists, doctors, etc. Here are some other interesting facts about stability testing:
1. Standards and Validation
As you could have guessed, there are general regulatory guidelines for stability testing. The International Conference on Harmonization (ICH) has put together these guidelines. There are FDA guidelines as well; however, the actual analytical testing is specific to each drug and will have to be developed for each product.
2. Impurity Testing
Part of stability testing is documenting the components of the formulation and any impurity profiles. Impurities may or may not be harmful. An impurity in one drug may just reduce the activity; however, another impurity, or the same impurity in a different drug, could cause harm to a patient.
Almost every stability test method involves high-performance liquid chromatography (HPLC) for potency and impurities. If it is a liquid formulation, the pH is almost always tested; if pH changes over time, the product may be degrading or turning into something else that may not be active or may even be toxic. If its a solid, analysis by Karl Fischer water titration for moisture content is almost always tested because water may be the culprit in accelerating the growth of impurities. Those tests are relatively routine, but each product may have other specific/unique tests that can be more challenging.
A stability-indicating test artificially stresses the product to create conditions for potential degradation. Some typical stresses include subjecting the compound to an acid or base, and subjecting it to light, humidity, or temperature changes. The goal is to find a method that allows the lab to see and measure the degradation. Understanding and characterizing degradation helps companies to know when drugs are having problems and when medicines may need to have additional development studies before being released to pharmacies or hospitals.
If a stability issue is discovered, it is not necessarily a reason to abandon the compound. If a liquid compound becomes unstable under stress, a different delivery method, like a freeze-dried formulation may be an option for the client. Or testing may show that the product is unstable at room temperature, but is fine refrigerated or frozen. The end goals are efficacy when it is administered and safety for the patient.
To test stability, the contracted lab will sample the product for testing after one month, three months, six months and so on for two years. There are several ways to shorten the timeline to collect meaningful data before two years are up. Accelerated testing might include stability at 40°C (104°F) and 75% relative humidity, which effectively simulates a year’s stability at room temperature over a period of three months; however, those tests only apply to development through clinical trials. Before the final submission to bring a drug to market, it must have undergone real-time stability testing over at least two years. Every pharmaceutical product has an expiration date and it is created based on these types of stability studies.
Understanding how stability testing works should help companies and even patients to better comprehend why there are long lead times for new drug products and why there are sometimes startling costs to the developer before the drug starts generating its first dollar of commercial revenue. Stability testing is important in the drug development process whether the client is a drug development company with an idea or they have an active ingredient whose therapeutic value isn’t fully understood. It may also be used for a client who has taken compounds through early stability studies and even toxicology screenings, but needs additional stability data to support clinical trials. Most importantly, stability testing helps to ensure safety and gives patients peace of mind that their medicine will perform as it is intended.
See Singota’s range of Stability Chambers.