Pharmaceutical product shelf-life temperature

Blythe (32) made a survey of the stability practices of 40 pharmaceutical companies. He found that a majority used exaggerated conditions of temperature, humidity, and light to test the stability of pharmaceutical products. Correlations of the data obtained with that of shelf-life data differed considerably. 

Many of these food and pharmaceutical products are heat sensitive that is, the finished product may be damaged or destroyed if it is exposed to too great a temperature over an extended period of time. Even common products like tomato catsup and penicillin spoil or lose their efficacy when exposed to ambient temperatures for long periods of time. The chemical reactions that limit shelf life are strongly temperature dependent. Some biological products may be handled at elevated temperatures in dilute solutions, but may degrade at the same temperature once the concentration exceeds a certain threshold value. 

Finally, as for any pharmaceutical product, ophthalmic products have to be designed to be stable. Ideally, the product should be stable at room temperature over a shelf-life period of 2-3 years. Multidose products must also be stable, after opening the pack, over the period of use. If antimicrobial preservatives are included to maintain sterility over this period, the effectiveness of the chosen preservative has to be demonstrated. There must be a discard statement on the label of multidose products indicating that the contents must not be used after a stated period. Normally, this does not exceed 28 days after opening the pack, unless there is a good justification. 

Thermal stability studies on pharmaceutical formulations have been formalized for many years. Specific protocols have been developed to provide data from which a shelf-life determination can be made (Carstensen, 1995). Thus, procedures followed in one laboratory are readily reproduced in another, and shelf-life is a consistent estimation for the product, independent of the laboratory in which the data were gathered. In thermal stability studies, the principal consideration is how long the drug substance or formulation is exposed to a particular temperature. The nature of the apparatus to be used is not important as long as the temperature of the sample is uniform. Thus, the sample may be contained in a flask, bottle, or tube, or held in a water thermostat or an air incubator — whatever is most convenient for the study. Also, the concentration of the drug studied is not crucial because a thermal degradation usually proceeds by first-order kinetics for which the half-life is independent of the starting concentration. 

In the study of thermal stability, accelerated testing in the form of elevated temperatures has been used by many pharmaceutical companies to minimize time involved in the testing process. This procedure is only valid for simple formulations in which the single major ingredient is broken down by a thermal reaction. In practice, regulatory authorities demand that a shelf-life determined by extrapolation of accelerated test data should be supported by actual stability data obtained by normal temperature storage (Carstensen, 1995). This is because degradation of a product by microbial contamination may well be inhibited at elevated temperatures. 

The MKT approach has some limitations that are to be observed when the impact of temperature on the stability of a substance or product is being evaluated. The most important restriction is the fact that MKT covers only chemical degradation. A drug substance and in particular a pharmaceutical product also has to meet other quality parameters within specified acceptance criteria throughout its shelf-life. Typical examples are a suppository that is not allowed to be transported or stored above 30°C, or a product like cyclophosphamide monohydrate, which melts at 49.5°C... 

From Equation (6.11), it can be seen that reaction rates increase exponentially with the ERH. The values for B typically range from 0 to 0.09. This means that in going from dry conditions (10% RH) to moist conditions (75% RH) at a fixed temperature, the degradation rate will range from equal (B = 0) to 347 times faster (B = 0.09) at the damp conditions compared to the dry conditions. To put another perspective on this, in the latter case, a pharmaceutical product with a shelf-life of only 1 week at 75% RH would increase to 6.7 years with effective desiecant. 

This strategy is adopted because of the sheer complexity of the process and the unavailability in the past of suitable sensors for on-line quality moisture content measurement. The quality of the product such as final moisture content, thickness, porosity, wetting, and rehydration capability (for pregelatinized starch) as well as the right crystal structure (the right therapeutic form for pharmaceuticals) are complex functions of drum speed, temperature, nip width, feed material, feed concentration, and feed-spreading technique. In addition, the final moisture content and thickness of the sheet may not be uniform across the width of the drum dryer that can lead to problems in shelf life and packaging of the product, respectively. 

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