Bringing Contaminant Control In-Line

The United States Pharmacopoeia (USP) is a compendium of quality control tests for drugs and excipients to be introduced into a medicinal formulation. It forms the basis of enforcement actions by the US Food and Drug Administration (FDA) and the US Drug Enforcement Administration (DEA), and is the official pharmacopoeia of many other nations besides the US.

Monograph 645 of the USP is an American legislation that has been in force for a few years and must be considered by any pharmaceutical company that wishes to sell products to the US. It has a direct impact worldwide on water analysis and quality in the pharmaceutical manufacturing industries.

Water is the world’s most abundant solvent and one of the primary vehicles for drug administration in pharmaceutical applications. Water for injection (WFI) and purified water (PW) needs to be rigorously tested for trace impurities. Before the updated monographs, WFI and PW tests for chloride, sulphate, calcium, ammonia and carbon dioxide were done off-line in laboratories. For example, the test for the chloride ion was to carefully take a grab sample, neutralise it with nitric acid and then add silver nitrate. Depending on the chloride content, the sample became turbid. To determine whether the sample of WFI or PW exceeded the stipulated chloride limits, this turbidity was compared against a standard solution.

This is a very labour-intensive method and, when added to the requisite tests for sulphate, calcium, ammonia and carbon dioxide, proved highly inefficient. Being a pass/fail only methodology, it also gave no indication of how far the sample was from the acceptable limit. An alternative method was needed to maintain or improve the existing water quality and the reliability of testing, whilst reducing the number of manual tests, permitting qualitative in-line control, and ensuring quality standards continue to apply in WFI and PW production methods destined for the US.