February 27, 2025
by Sarah Srokosz, Marketing Communications Specialist, ACD/Labs
Stability Assessments Ensure Safe, Effective Medicines
Drug molecules slowly degrade over time depending on the storage environment’s temperature, humidity, and light. For patients, these stability issues can lead to a loss of medicinal potency or increased side effects. To ensure there are no stability concerns, pharmaceutical development scientists thoroughly assess drug substances and drug products. However, it is impractical to only use experimental methods to test drug stability, particularly in early stages of drug development. This has led researchers to develop computational approaches to assess drug stability. Chemical processes such as degradation follow mathematical rules, allowing scientists to predict the degradation rates under a range of conditions. This method is known as accelerated predictive stability (APS).
A Brief Introduction to Accelerated Predictive Stability and the Accelerated Stability Assessment Program
The Accelerated Stability Assessment Program (ASAP) is a well-established APS method. It uses a linear regression analysis to predict the degradation of drug products in their packaging, based on temperature and relative humidity. Degradation follows a modified Arrhenius equation:
Where:
k is the reaction rate
A is the collision factor
Ea is the activation energy
R is the gas constant
T is the temperature
B is the humidity sensitivity factor
RH is the relative humidity
To determine the rate of degradation, scientists run experiments at a range of temperatures and levels of humidity. Concentrations of degradants are typically assessed through chromatography data, where the area of product and degradant peaks are compared over multiple time points. This information can be used to compute the k, A, Ea, and B rate constants, which can then be generalized over a range of conditions.
In many cases, more than one degradant is being produced simultaneously, or certain degradants are consumed in secondary degradation reactions. Each chemical reaction follows its own kinetics. This means rate constants for each degradative process must be calculated separately. Unlike traditional stability studies that compare degradant levels at various time points, the ASAP method relies on the principle of isoconversion time. This is the time it takes to reach the specification limit for a given degradant. This eliminates the need to consider complex and non-linear degradation kinetics.
Together, these equations can be combined to act as a “digital twin” of the drug, allowing chemists to model the level of each degradant over time. This can then be cross-referenced with toxicity data to assess the likelihood of adverse effects for patients.
Challenges of APS Workflows
While APS workflows have advantages over purely experimental stability assessments, they come with some unique challenges.
Accelerated Stability Experiments are Complex to Design
Before an APS study can begin, certain data about the API is required. This includes relevant physicochemical characteristics (melting point, deliquescence, chances of crystallization, hydration/dehydration, etc.), the specification limit for degradation, and ideal storage conditions.
A suitable analytical test must also be designed and properly validated for each degradant before starting APS experiments. This ensures high sensitivity and obtains more accurate and reliable stability prediction models.
Finally, the degradation experiments themselves must also be carefully designed. Suitable conditions of temperature and relative humidity and time points must be strategically chosen, which may require preliminary screening experiments.
Sample Aging Still Takes Time
A well-designed APS study requires a minimum of five sets of randomized conditions. For each condition, there will be several time points, each of which must also have repetitions. So, while still shorter and less costly than traditional stability studies, there are a substantial number of samples involved that must be aged anywhere from 7 to 21 days. And over this time, temperature & relative humidity conditions must be carefully maintained.
Data Analysis, Visualization, and Predictive Modeling is Scattered
Unsurprisingly, with the significant number of samples also come a significant amount of analytical data that must be processed and analyzed. Unfortunately, many of the tools used to perform accelerated stability analysis do not integrate with analytical and chemical software. Researchers must process their analytical data in one application and then manually transcribe it or transfer it into another, which is inefficient, tedious, and prone to errors.
Luminata eliminates these challenges by offering tools for automated analytical data processing and analysis alongside those to calculate the parameters of the Arrhenius equation based on the ASAP method. From there, Luminata has helpful tools for Modeling, visualization, and reporting to make the most of the insights from your analysis.
Learn more about Accelerated Stability Assessment with Luminata.
Get the Most Out of Your APS Studies
APS methods continue to gain popularity as efficient, reliable alternatives to traditional experimental stability studies. They are particularly useful in determining shelf life of a drug in the early phases of drug development, and can be accepted in regulatory submissions. Using the right software can help realize the full benefits of these workflows. By combining chemical and analytical data with tools for ASAP calculations and modeling, Luminata is an invaluable aid to scientists in making informed drug stability decisions.
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