Biopharmaceutical products in storage change as they age, but are considered to be stable as long as their properties remain within the manufacturer's specifications. The number of days the product remains stable under recommended storage conditions is called shelf life. Experimental protocols commonly used to collect data that form the basis for estimating shelf life are referred to as stability tests.
Shelf life is generally estimated using two types of stability tests: real-time stability tests and accelerated stability tests. In the real-time stability test, a product is stored under the recommended storage conditions and monitored until the specification fails. In accelerated stability tests, a product is stored under high stress conditions (such as temperature, humidity and pH). Deterioration in the proposed storage conditions can be estimated using known relationships between acceleration factor and deterioration rate.
Temperature is the most common acceleration factor used for chemicals, pharmaceuticals, and biological products because its relationship to degradation rate is characterized by the Arrhenius equation. The article describes several methods of estimating shelf life based on accelerated stability testing. Moisture and pH also have acceleration effects, but will not be discussed in detail here as they are complex. In addition, the details of statistical modeling and estimation are beyond the scope of the article, but we provide references to computer routines.
Regulations and History The assessment of shelf-life has evolved from consciously educated estimation through the study of data and the application of complex physical-chemical laws and statistical techniques. Regulators now insist that sufficient stability testing be performed to provide evidence of the performance of a drug or biopharmaceutical product in different environmental conditions and to establish recommended storage conditions and shelf life. 1-3 Recently, Tsong reviewed the latest approaches to statistical modeling of stability tests, 4 and ICH published some guidelines for advanced test design and data analysis.
Modeling has become easier due to the availability of standard statistical software that can perform calculations. However, the general stability testing principles need to be understood to ensure that these programs are implemented correctly and to obtain appropriate results. Therefore, the purpose of this article is to outline the main approaches to stability testing and to provide a basis for improved statistical modeling and shelf life prediction.
Stability and Degradation Since degradation is generally defined in terms of loss of efficiency or performance, a product is considered to be degrading when any property (eg effect or performance) is reduced. Decay usually follows a specific pattern depending on the kinetics of the chemical reaction. The degradation model can follow zero, first and second order reaction mechanisms. In the zero-degree reactions of 6, degradation is independent of the remaining concentration of intact molecules; In first order reactions, the degradation is proportional to that concentration. 6,7Zero and first order reactions involve only one type of molecule and can be identified by linear or exponential relationships. Second and higher-order reactions involve multiple interactions of two or more types of molecules and are characteristic of most biological materials consisting of large and complex molecular structures. Although approximation of these reactions with an exponential relationship is common, sometimes patterns of degradation should be more precisely modeled and no shortcut is sufficient.
The rate of degradation depends on the activation energy for the chemical reaction and is product specific. We don't always have to deal with high-order equations; In many cases, the observed responses of the different reaction sequences for the slowly degrading products are indistinguishable.
The rate of degradation depends on the conditions under which the chemical reaction takes place. The products deteriorate more quickly when exposed to acceleration factors such as temperature, humidity, pH and radiation. It is important to model the degradation model and evaluate the estimated shelf life of the degradation rate. Experimental protocols used to collect data are called stability tests. In practice, the evaluators use both real-time stability tests and accelerated stability tests.