The Importance of Water Activity for Risk Assessing Pharmaceutical Products
Water activity is an established concept for food science, especially with the assessment of food preservation and understanding which microorganisms might present a risk to the manufacturing process in relation to ingredients. Where there has been less research and discussion are with effect of water activity and appreciating the risks in relation to pharmaceutical products.
All pharmaceutical preparations will contain water. Some water will be free water and other water will be bound within the substance. The water that is bound is generally not biologically available to microorganisms, and simply measuring water content in a product through an established process like Karl Fisher titration would not be meaningful for a microbiological assessment. Water activity assesses the level of ‘free water’ (how, more accurately, tightly bound water is chemically) and it follows that water activity, in a sense, provides a measure the amount of available water for any microorganisms present (it goes without saying that water is an essential requirement for microbial growth). For instance, one product may contain 15% water and 8% water, and yet the product with 8% could be more at risk to microbial growth because there is more ‘free’ water.
Thus, there is an important difference between water content and water activity. Higher water activity generally means more available water; however, the relationship is non-linear. Because of this uncertainty, microbiologists regard an index of water activity as more meaningful than a measure of water content.
Water activity (represented by the symbol aw) is a product of principles of thermodynamics and physical chemistry. It is defined as the partial vapor pressure of water in a substance (when in a completely undisturbed balance with the surrounding air media) over the standard state partial vapor pressure of water. The standard state is temperature dependent. Here, in general, an increase in temperature leads to an increase in water activity (although this can be altered by the crystalline nature of the material). A secondary factor is the type of water used for the standard; the vapour pressure of distilled water, for example, will differ to a water containing ‘impurities’ like salts (such as potable water). A third factor relates to humidity. If a non-sterile pharmaceutical product, for example, was exposed to an environment of high humidity then the water activity could alter relative to the activity leveled observed when the product was manufactured. In pharmaceutical products there are other factors that affect water activity, including osmotic, matrix, and capillary forces.
The assessment of water activity is of microbiological importance. The higher the water activity of a substance, then the more likelihood is it that the substance will support the growth of microorganisms. Different microorganisms will be able to survive or proliferate at different levels of water activity. There are, however, cut-off values for different microorganisms. It is generally accepted that a water activity of 0.91 is required to support bacterial growth and a level of 0.7 or higher is needed to support fungal growth.
There are different means by which to assess water activity. Traditional readings can be obtained using a resistive electrolytic (based on a liquid electrolyte sensor); a capacitance (using dual charged plates divided between a polymer membrane dielectric); a dew point hygrometer (based on the physicochemical understanding that the temperature at which dew forms is directly proportional to the vapour pressure of the air). More advanced instruments include chilled mirror dew point technology; or relative humidity sensors that change electrical resistance or capacitance.
As well as food, some forms of pharmaceutical products are at risk from microbial contamination over their period of intended use. This is so for non-sterile products designed for multi-use.
It is recommended by authors like Cundell and Hussong that pharmaceutical manufactures, of non-sterile aqueous products, assess and understand the water activity levels of their products. This understanding allows, as United States Pharmacopeia guidance chapter sets outmicrobiologists to:
• Undertake the optimization of product formulations in order to improve the antimicrobial effectiveness of preservative systems.
• Reduce the degradation of those active pharmaceutical ingredients within product formulations susceptible to chemical hydrolysis.
• Incorporate critical quality attributes into the manufacturing process to assess factors that could lead to an increase in water activity in the finished product.
• Lower the susceptibility of formulations (especially liquids, ointments, lotions, and creams) to microbial contamination.
In addition, the characterization of water activity may provide the means to reduce the frequency of microbial limit testing and screening for objectionable microorganisms for product release.
The USP provides some representative examples of different the water activities required to support the growth of microorganisms. Here, if certain classes of objectionable organisms are of concern, then knowing the water activity allows for an assessment of the relative risk. For instance, the water activity of the pathogen Pseudomonas aeruginosa is relatively high, at aw 0.97; whereas for an endospore former like Bacillus cereus it is 0.95 (notably not all members of the Bacillus genus are the same, for Bacillus subitlis is 0.90). In contrast, a filamentous fungus, like Aspergillus niger has a much lower water activity at 0.77, meaning that the fungus can grow in conditions with considerably less available water. While water activity is important, there are other factors that can affect microbial growth, such as available nutrients, temperature, pH and so forth.
An overlooked area is with microbiological control relates to culture media. Media used for the purposes of monitoring environments will be subject to desiccation, in the form of water loss, over time. While the effect of water loss on microbial growth promotion can be assessed by post-incubation microbial challenge studies, the effect on water activity is less clear. The risk is that a loss of water may still be enough to support a range of more robust environmental contaminants; it may be insufficient to support the growth of more fastidious bacteria (such as a slow growing organism, like a species of Streptococcus).
An understanding and characterization of water activity for non-sterile pharmaceutical products can form a key part of contamination control risk assessment. Manufacturers of this class of product should assess the water activity and draw up a list of objectionable pathogenic microorganisms. From this, the manufacturer should know which organisms are capable of survival and this will allow appropriate steps to be taken to minimize the risk of contamination or consideration made to adjusting product formulation, packaging or storage , so that if a microbial contamination event occurs the possibility of microbial growth is minimized.
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