1112 APPLICATION OF WATER ACTIVITY DETERMINATION TO NONSTERILE PHARMACEUTICAL PRODUCTS
The determination of the water activity of nonsterile pharmaceutical dosage forms aids in the decisions relating to the following:
Reduced water activity (aW) will greatly assist in the prevention of microbial proliferation in pharmaceutical products; and the formulation, manufacturing steps, and testing of nonsterile dosage forms should reflect this parameter.
Low water activity has traditionally been used to control microbial deterioration of foodstuffs. Examples where the available moisture is reduced are dried fruit, syrups, and pickled meats and vegetables. Low water activities make these materials self-preserved. Low water activity will also prevent microbial growth within pharmaceutical drug products. Other product attributes, for example, low or high pH, absence of nutrients, presence of surfactants, and addition of antimicrobial agents, as well as low water activity, help to prevent microbial growth. However, it should be noted that more resistant microorganisms, including spore-forming Clostridium spp., Bacillus spp., Salmonella spp. and filamentous fungi, although they may not proliferate in a drug product with a low water activity, may persist within the product.
When formulating an aqueous oral or topical dosage form, candidate formulations should be evaluated for water activity so that the drug product may be self-preserving, if possible. For example, small changes in the concentration of sodium chloride, sucrose, alcohol, propylene glycol, or glycerin in a formulation may result in the creation of a drug product with a lower water activity that can discourage the proliferation of microorganisms in the product. This is particularly valuable with a multiple-use product that may be contaminated by the user. Packaging studies should be conducted to test product stability and to determine that the containerclosure system protects the product from moisture gains that would increase the water activity during storage.
Reduced microbial limits testing may be justified through risk assessment. This reduction in testing, when justified, may entail forgoing full microbial limits testing, implementing skip-lot testing, or eliminating routine testing.
Nonaqueous liquids or dry solid dosage forms will not support spore germination or microbial growth due to their low water activity. The frequency of their microbial monitoring can be determined by a review of the historic testing database of the product and the demonstrated effectiveness of microbial contamination control of the raw materials, ingredient water, manufacturing process, formulation, and packaging system. The testing history would include microbial monitoring during product development, scale-up, process validation, and routine testing of sufficient marketed product lots (e.g., up to 20 lots) to ensure that the product has little or no potential for microbial contamination. Because the water activity requirements for different Gram-reactive bacteria, bacterial spores, yeasts, and molds are well described in the literature,1 the appropriate microbial limit testing program for products of differing water activities can be established. For example, Gram-negative bacteria including the specific objectionable microorganisms, Pseudomonas aeruginosa, Escherichia coli, and Salmonella species will not proliferate or survive in preserved products with water activities below 0.91, while Gram-positive bacteria such as Staphylococcus aureus will not proliferate below 0.86, and Aspergillus niger will not proliferate below 0.77. Furthermore, even the most osmophilic yeast and xerophilic fungi will not proliferate below 0.60, and they cannot be isolated on compendial microbiological media.1 The water activity requirements measured at 25 for the growth of a range of representative microorganisms are presented in Table 1.
Table 1. Water Activities (aW) Required to Support the Growth of Representative Microorganisms
Pharmaceutical drug products with water activities well below 0.75 (e.g., direct compression tablets, powder and liquid-filled capsules, nonaqueous liquid products, ointments, and rectal suppositories) would be excellent candidates for reduced microbial limit testing for product release and stability evaluation. This is especially true when pharmaceutical products are made from ingredients of good microbial quality, when manufacturing environments do not foster microbial contamination, when there are processes that inherently reduce the microbial content, when the formulation of the drug product has antimicrobial activity, and when manufacturing sites have an established testing history of low bioburden associated with their products. Table 2 contains suggested microbial limit testing strategies for typical pharmaceutical and over-the-counter (OTC) drug products based on water activity. Other considerations, as listed above, would be applied when setting up the microbial limits testing program for individual drug products because water activity measurements cannot solely be used to justify the elimination of microbial content testing for product release.
Similar arguments could be made for the microbial limits testing of pharmaceutical ingredients. However, this would require pharmaceutical manufacturers to have a comprehensive knowledge of the pharmaceutical ingredient manufacturer's manufacturing processes, quality programs, and testing record. This could be obtained through a supplier audit program.
Table 2. Microbial Limit Testing Strategy for Representative Pharmaceutical and OTC Drug Products Based on Water Activity
Water activity, aW, is the ratio of vapor pressure of H2O in product (P) to vapor pressure of pure H2O (Po) at the same temperature. It is numerically equal to 1/100 of the relative humidity (RH) generated by the product in a closed system. RH can be calculated from direct measurements of partial vapor pressure or dew point or indirect measurement by sensors whose physical or electric characteristics are altered by the RH to which they are exposed.
The relationship between aW and equilibrium relative humidity (ERH) is represented by the following equations:
aW = P/Po and ERH(%) = aW × 100
The aW measurement may be conducted using the dew point/chilled mirror method.2 A polished, chilled mirror is used as the condensing surface. The cooling system is electronically linked to a photoelectric cell into which light is reflected from the condensing mirror. An air stream, in equilibrium with the test sample, is directed at the mirror which cools until condensation occurs on the mirror. The temperature at which this condensation begins is the dew point from which the ERH is determined. Sample preparation should be considered as it may affect the water activity level of the material tested. Commercially available instruments using the dew point/chilled mirror method or other technologies need to be evaluated for suitability, validated, and calibrated when used to make water activity determinations. These instruments are typically calibrated using saturated salt solutions at 25, as listed in Table 3.
Table 3. Standard Saturated Salt Solutions Used to Calibrate Water Activity Determination Instruments
1 J. A. Troller, D. T. Bernard, and V. W. Scott. Measurement of Water Activity. In: Compendium of Methods for the Microbiological Examination of Foods. American Public Health Association, Washington, DC, 1984 pp.124134.
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