Biopharmaceutical products in storage change as they age, but they are considered to be stable as long as their characteristics remain within the manufacturer's specifications. The number of days that the product remains stable at the recommended storage conditions is referred to as the shelf life. The experimental protocols commonly used for data collection that serve as the basis for estimation of shelf life are called stability tests.
Shelf life is commonly estimated using two types of stability testing: real-time stability tests and accelerated stability tests. In real-time stability testing, a product is stored at recommended storage conditions and monitored until it fails the specification. In accelerated stability tests, a product is stored at elevated stress conditions (such as temperature, humidity, and pH). Degradation at the recommended storage conditions can be predicted using known relationships between the acceleration factor and the degradation rate.
Stability and Degradation Since degradation is usually defined in terms of loss of activity or performance, a product is considered to be degrading when any characteristic of interest (for example potency or performance) decreases. Degradation usually follows a specific pattern depending on the kinetics of the chemical reaction. The degradation pattern can follow zero-, first-, and second-order reaction mechanisms.6 In zero-order reactions, degradation is independent of the concentration of remaining intact molecules; in first-order reactions, degradation is proportional to that concentration.6,7 Zero- and first-order reactions involve only one kind of molecule, and can be described with linear or exponential relationships. Second- and higher-order reactions involve multiple interactions of two or more kinds of molecules and are characteristic of most biological materials that consist of large and complex molecular structures. Although it is common to approximate these reactions with an exponential relationship, sometimes their degradation pattern needs to be modeled more precisely, and no shortcuts will suffice.
The degradation rate depends on the activation energy for the chemical reaction and is product specific. We don't always have to deal with higher-order equations; in many cases, the observed responses of different orders of reactions are indistinguishable for products that degrade slowly.
The degradation rate depends on the conditions where the chemical reaction takes place. Products degrade faster when subjected to acceleration factors such as temperature, humidity, pH, and radiation. Modeling of the degradation pattern and estimation of the degradation rate are important for assessing shelf life. Experimental protocols used for data collection are called stability tests. In practice, evaluators use both real-time stability tests and accelerated stability tests. The real-time stability test is preferable to regulators. However, since it can take up to two years to complete, the accelerated tests are often used as temporary measures to expedite drug introduction.
Real-Time Stability Tests In real-time stability tests, a product is stored at recommended storage conditions and monitored for a period of time (ttest). Product will degrade below its specification, at some time, denoted ts, and we must also assure that ts is less than or equal to ttest. The estimated value of ts can be obtained by modeling the degradation pattern. Good experimental design and practices are needed to minimize the risk of biases and reduce the amount of random error during data collection. Testing should be performed at time intervals that encompass the target shelf life and must be continued for a period after the product degrades below specification. It is also required that at least three lots of material be used in stability testing to capture lot-to-lot variation, an important source of product variability.1,2