Regulatory compliance for the manufacture of pharmaceutical products is largely concerned with minimizing, managing and controlling risk, with a robust data-trail to provide full traceability. The critical nature of the sector makes it – quite rightly so – one of the most heavily regulated, with a variety of national and international regulatory bodies and standards with which pharmaceutical manufacturers have to comply.
The situation is, to a degree, simplified thanks to the work of the International Council for Harmonization for Pharmaceuticals for Human Use (ICH). This body brings together regulatory authorities from around the world to share best practice and harmonize the safe and efficient development and manufacture of high-quality medicines to internationally agreed standards.
Although the scope of these regulatory bodies is extensive, one of the key areas in the development of non-sterile pharmaceutical products is measuring their susceptibility to microbial contamination. These products often contain high levels of moisture that can quickly lead to the growth of microbial organisms. Microbial risk assessment is therefore crucial during both new product formulation and the subsequent design of associated manufacturing processes. In general terms, a risk assessment would include the microbiological potential of both the drug product and its excipients, its formulation and product attributes, as well as consideration of the manufacturing, distribution, storage and usage conditions.
In this context, the test procedures and acceptance criteria for new drugs specified in ICH Q6A, and the stability testing parameters detailed in ICH Q1A, provide important guidelines for microbial measurement and control during the drug development and production cycle.
Mitigating the risk of microbial growth in non-sterile pharmaceutical products depends primarily on the ability to reduce moisture levels to the point below which they can support microbial growth. In products where this is difficult, then anti-microbial additives can be introduced. In each case, however, the critical factor is to be able to measure the level at which microbial growth begins to occur and to be able to demonstrate that the risk has been managed as part of product traceability procedures.
ICH Q6A references two decision trees (#6 and #8) that are used to determine if the product is sufficiently ‘dry’, to prevent the risk of microbial growth. This concept of dryness can, however, be mistakenly associated with the water content of the product.
Water content is a quantitative measurement of the total water within a substance, including both bound water (ionically bonded to the atomic product matrix) and free or active water (absorbed water with a higher energy state, which is available for microbial activation). Although water molecules can move between the two states, it is essentially active water – normally called water activity (aw) – that determines the ability of the substance to support microbial growth. This fact is reflected in various industry standards; for example the US Pharmacopeia (1112 Application of water activity determination to non-sterile pharmaceutical products) lists the minimum aw levels at which a range of different molds and yeasts begin to propagate. It also describes the appropriate methods for qualitative measurement of aw.
To learn more about water activity read our blog post.
As mentioned above, water activity is now a defined measurement technique within international pharmaceutical quality standards. It is a key tool for monitoring product quality and stability, and for determining the state at which microbial growth will begin to propagate. It can also be a useful tool during drug formulation and the development of manufacturing processes; for example, if it is possible to prove conclusively that the inherent aw values of a particular product are consistently beneath the growth threshold for microorganisms then it may be possible to reduce the need – and thus the cost – of microbial testing once the product enters full-scale production.
Measuring water activity is a straightforward, reliable and efficient process when using instruments from Rotronic. These include devices for both laboratory and spot analysis, all of which are supported by advanced analytical software. Our latest instruments are developed according to GAMP5 criteria for pharmaceutical product development, while our HygroLab benchtop analysis system is compliant with FDA CFR 21 Part 11 and European Annex 11, making it ideal for quality and traceability procedures.
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We are the world’s leading experts in water activity, moisture monitoring and Dew Point measurement. We have eight different technologies covering all moisture applications, backed by unrivalled technical and customer support. To learn more, talk to one of our application specialists today.
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