Limitations of Accelerated Stability Model Based on the Arrhenius Equation for Shelf Life Estimation of In Vitro Diagnostic Products

Stability studies are usually performed by manufacturers of diagnostic products to estimate expiry dates for their products. This helps to ensure that during the shelf life for their intended uses, the performance characteristics and requirements of these products, under defined storage and handling conditions are maintained. in order to meet quality system, compliance and regulatory requirements. Appropriate testing techniques are employed to ensure that shelf-life claims and expiration dates are accurately calculated for these products. Various types of stability studies can be conducted to estimate and establish shelf life for these products. For many diagnostic products, their shelf life is long, usually greater than 1 year, which makes it necessary to also conduct accelerated aging and forced degradation studies. With these studies, the performance of the product and stability issues can be observed faster than those observed during real-time stability studies. There are several domestic and international standard documents that provide guidance and describe how accelerated stability studies can be conducted.

In a new study by Dr. Alireza Ebrahim, Mr.. Karl DeVore, and Mr.. Tim Fischer from the Research and Development Department at Bio-Rad Laboratories, Inc. in California examined and compared the results of accelerated stability studies performed at raised temperatures with corresponding real-time stability studies performed at the indicated storage and handling conditions for the intended-use of the products. They showed that in two studied reagents, the stability predictions obtained from the accelerated stability studies were significantly longer and in another studied reagent significantly shorter than those found in real-time stability studies. The original research paper is published in the Journal of Clinical Chemistry.

The Bio-Rad Laboratories research team prepared quality control materials containing hemoglobin A1c, B-Type natriuretic peptide and fructosamine in human whole blood based and serum based matrices. Afterwards they conducted accelerated stability studies at increased temperatures and real-time stability studies at the recommended storage temperature for several analytes in quality control materials.

For example, in the case of Hemoglobin A1c which is a form of hemoglobin used as a diagnostic indicator in prediabetic and diabetic patients to assess long term control of blood sugar. The team prepared a whole blood-based quality control product containing hemoglobin A1c and then carried out accelerated testing on it. They found that the predicted shelf life from their testing was much greater than the one observed by the real-time stability test results. In another study, they studied Fructosamines which are compounds formed from the combination of glucose and proteins Frutosamines are also used as a marker for monitoring the long-term compliance of diabetic patients with their diets. A quality control product containing fructosamine was prepared by the authors, then it underwent accelerated testing. They found that the predicted shelf life from the testing was also greater than the one demonstrated by the real-time stability test results. The third tested molecule was B-Type natriuretic peptide which is produced by cardiac muscles and it helps to dilate blood vessels. It has been identified as an essential regulatory factor for cardiovascular health. When the B-Type natriuretic peptide quality control material underwent accelerated stability and real-time stability tests, the authors found that the estimated shelf life from accelerated stability studies was significantly shorter than the real-time stability studies.

In summary, the authors identified discrepancies between stability results from accelerated stability studies and those from the real-time stability studies using 3 different examples. This provides evidence that the accelerated stability model based on the Arrhenius Equation which was used in this study does not accurately predict the stability of diagnostic reagents. They therefore advise that this model be used with caution by reagent manufacturers and also advise that the currently available stability documents be revised to highlight the limitations of the accelerated stability model and provide more guidance and direction on when and how to use the accelerated stability model.