Shelf-life estimation

The first step in shelf life estimation is to determine the parameters controlling the loss of product quality. Shelf life may end for a product due to moisture uptake, oxidation, spoilage from microbial action, or a combination of these and other factors. Therefore, one must determine what is causing the end-point to occur. Having done that, calculations to estimate when that will occur in a package can be made. 

To determine the behavior of a product, it must be stored at known conditions for a period of time and its properties measured. In the case of oxidation, for example, some method must be available to determine the amount of reaction with oxygen that the product has undergone. This is often done by measuring peroxide values for oil-containing products, or hexanal values for products that have hexanal as the end degradation product for oxidation. For moisture sorption, the product can be stored over a saturated salt solution until moisture uptake is at equilibrium. Then taste or texture is often the measured parameter to determine the end-point of shelf life. For pharmaceuticals, the true end-point is determined by the bioavailability of the drug. 

For any type of product that gains or loses water, one can measure the moisture content as a function of relative humidity, or water activity, and determine a moisture isotherm. As shown in Fig. 14.14, moisture isotherms are usually sigmoid shaped curves. However, one can sometimes use only the linear portion of the curve for shelf life predictions. 

Let us look at an example of shelf life prediction where the Ap is constant throughout the storage. 

Calculate the minimum thickness of PET for protection of a product that has an end of shelf life when it has reacted with 0.005% (wt/vol) of oxygen. The package design is a 500-ml container with 400 cm area. The product is a water-based liquid. Storage conditions are 25°C and 60% RH. The desired shelf life Is six months. Also, calculate the water loss at the end of six months in this package. 

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Shelf Life Estimation for Drug Substances or Drug Products Intended for Room Temperature Storage... 

The shelf life for a single batch is usually computed based on regression techniques. An appropriate approach to shelf life estimation when using regression analysis is by calculating the earliest time at which the 95% confidence limit for the mean intersects the proposed acceptance criterion [8]. A detailed description of shelf life calculations is provided in Sections 7.2.3 and 7.2.4. 

This Appendix contains four computer programs in MatLab that can be used by the reader to perform typical calculations related to shelf-life estimations. 

This program computes the degradation line for single batch-and-save results to be input into the program called shelf life estimation ... 

Chen, J. I, Ahn, H., and Tsong, Y. (1997), Shelf-life estimation for multifactor stability studies, Drug Inform. /., 31, 573-587. 

Shelf-life estimation involves developing a thermodynamic model of the dry reagent chemistry. This model is used to make projections of the shelf-life and the estimates are continuously compared with real time data to substantiate the validity of the model or to revise it. A typical study to create a database for shelf-life estimation may consist of subjecting a dry reagent chemistry, in its final packaging format, to continuous thermal stress for 2-3 years in the temperature range of 0-70 °C. An example of a schedule for such a study is shown in Fig. la. At each check point, dry reagent chemistries are removed from each of the stress conditions, allowed to come to thermal equilibrium, and analyzed, and the per-... 

Fig. 7. (a) Sample schedule for shelf-life estimation, b) Sample plot of reactivity remaining vs. time after thermal stress, (c) Arrhenius analysis of decay rate vs. temperature. 

Before a bracketing design is applied, its effect on the shelf life estimation should be assessed. If the stability of the extremes is shown to be different, the intermediates should be considered no more stable than the least stable extreme (i.e the shelf life for the intermediates should not exceed that for the least stable extreme). 

FIGURE 6 Shelf life estimation with upper and lower acceptance criteria based on assay at 25 C7 60% RH. 

Regression analysis is considered an appropriate approach to evaluating the stability data for a quantitative attribute and establishing a shelf life. The nature of the relationship between an attribute and time will determine whether data should be transformed for linear regression analysis. The relationship can be represented by a linear or nonlinear function on an arithmetic or logarithmic scale. In some cases, a nonlinear regression can better reflect the true relationship. An appropriate approach to shelf life estimation is to analyze a quantitative attribute (e.g., assay, degradation products) by... 

FIGURE 7 Shelf life estimation with upper acceptance criteria based on degradation product at 25 C/60% RH. 

Shelf-Life Estimation from Temperature-Accelerated Studies... 

Presently, shelf life is usually estimated by regression analysis according to Eq. (4.8) and its variants using computers. A simplified method for shelf-life estimation, regardless of reaction order, has been proposed,769 2 and various computer programs have been developed. However, it should be noted that the application of Eq. (4.8) is limited to a temperature range in which Ea can be regarded as constant (as discussed in Chapter 2). 

The shelf life estimated from more than three values of degradation percentage observed at an elevated temperature exhibits a smaller distribution range than that estimated from a single value shown in Fig. 195.775 This is because the use of more than three observed data values provides information on the data variation and enables a Monte Carlo simulation of degradation data.776 This simulation method yields a longer shelf-life estimate because of the smaller distribution range. 

Figure 197. Relationship between degradation percentage observed at 40°C and shelf life estimated at 95%...

APPENDIX A DECISION TREE FOR DATA EVALUATION FOR RETEST PERIOD OR SHELF LIFE ESTIMATION FOR DRUG SUBSTANCES OR PRODUCTS (EXCLUDING FROZEN PRODUCTS)... 

Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm Res 24(4) 780-790. 

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