Stability testing and prediction of shelf-life

It is clearly most important to be able to ensure that a particular formulation when packaged in a specific container will remain within its physical, chemical, microbiological, therapeutic and toxicological specifications 

Reproduced from J. T. Carstensen et Pharm. Sci., 57, 23 (1968) with permission. 

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Factors influencing drug stability 1 13 Stability testing and prediction of shelf-life 127 Summary 136... 

Figure 2.1 Accelerated stability testing. The percentage of drug remaining at elevated temperatures with time is measured (left) and the rate constants for the degradation reaction calculated. Using the Arrhenius relationship, a plot of the log of the rate constant against the reciprocal of absolute temperature of measurement yields a straight line (right). Extrapolation of the line permits calculation of the rate constant at lower temperatures and the prediction of shelf life.

Elevated temperature is often used to estimate the in-can stability of adhesives and sealant formulations. This is usually applied by a simple rule of thumb that says the reaction rate of the degradation mechanisms involved doubles for every 10°C increase in temperature, and therefore 1 week storage at 50°C approximates to 8 weeks at room temperature (20°C). Application of this rule will likely be conservative in the prediction of shelf life and must be verified by real-time validation testing conducted at room temperature for the targeted shelf life. 

Over a 7-month period, SPME-MS-MVA has been shown to be an accurate technique for predicting the shelf life of reduced-fat milk. Despite the fact that during the testing period significant changes occurred with the mass spectrometer (replacement of the turbomolecular pump and replacement of the electron multiplier) and the fact that several different Carboxen/PDMS fibers were used, internal standard normalization with chlorobenzene allowed accurate prediction over the 7-month period. Long-term stability, a problem with many e-nose instruments based on solid-state sensors, does not appear to be a significant problem with MS-based e-nose instruments. 

To illustrate the application of the Q-Rule, let us assume that the stability of a product at 50°C is 32 days. The recommended storage temperature is 25°C and M = (50 - 25)/10 = 2.5. Let us set an intermediate value of Q = 3. Thus, Qn = (3)2.5 = 15.6. The predicted shelf life is 32 days x 15.6 = 500 days. This approach is more conservative when lower values of Q are used. Both Q-Rule and the bracket methods are rough approximations of stability. They can be effectively used to plan elevated temperature levels and the duration of testing in the accelerated stability testing protocol. 

Accelerated stability tests provide a means of comparing alternative formulations, packaging materials, and/or manufacturing processes in short-term experiments. As soon as the final formulation and manufacturing process have been established, the manufacturer carries out a series of accelerated stability tests which will enable the stability of the drug product to be predicted and its shelf-life and storage conditions determined. Real-time studies must be started at the same time for confirmation purposes. Suitable measures should be taken to establish the utilization period for preparations in muitidose containers, especially for topical use. 

To estimate the oxidative stability or susceptibility of a fat to oxidation, the sample is subjected to an accelerated oxidation test under standardized conditions and a suitable end-point is chosen to determine appropriate levels of oxidative deterioration (Figure 7.1). Several parameters such as temperature (60-140°C), metal catalysts (5-100 ppm), oxygen pressure (3-165 psi), or variable shaking to increase reactant contact, are manipulated to accelerate oxidation and development of rancidity in oils and emulsions. The oxidation level used for an end-point varies widely according to the time desired to obtain stability data. For practical purposes, predictions of oxidahve stability in foods and oils based on measurements of induction period should be related to actual product shelf life, and the conditions used should be as close as possible to those under which the food is stored. To translate the induchon period obtained under accelerated conditions to the actual shelf hfe of a product, it is necessary to use an arbitrary factor based on prior experience with the desired product. Much effort has been devoted to more accurately eshmate the shelf hfe of foods... 

To evaluate oxidative stability, different methods are used to measure lipid oxidation after the sample is oxidized under standardized conditions to a suitable end-point. In Table 7.1, different lipid oxidation tests are ranked in decreasing order of usefulness in predicting Ae stability or shelf life of a food product. Methods for sensory evaluations, conjugated diene, gas chromatography of volatiles, peroxide values and thiobarbituric acid-reacting substances were discussed in Chapter 5. 

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