Updating International Standards For Pharmaceutical Waters

By Dr. Anthony Bevilacqua, Director of R&D
and Nick Dowd, Market Segment Manager
Mettler-Toledo Thornton

Historically, quality tests for bulk purified water (PW) and water for injection (WFI) were confined to the laboratory. Water samples were checked for single chemical impurities, such as carbon dioxide, ammonia, chloride, sulfate, and calcium, using traditional wet chemistry methods. Other wet chemistry tests for screening classes of impurities included oxidizable substances, heavy metals, and pH. These tests complemented other existing tests for particulates, micro-organisms, and endotoxins. In some pharmacopoeia, tests for nitrate, nitrites, and other impurities were also required.

As far back as 1989, the United States Pharmacopoeia (USP) and the Pharmaceutical Research and Manufacturers of America (PhRMA) began investigating alternatives to the wet chemistry tests. At that time, the principal focus was not on the water, but on the reliability of the water testing. The testing was archaic (several tests go back to the midnineteenth century), labor intensive, susceptible to analyst bias, and very sensitive to container cleanliness and analyst handling. PhRMA and USP investigated the measurement technologies of conductivity and total organic carbon (TOC) as direct replacement tests for the wet chemistry methods. Both technologies have the distinct advantage of being widely used for industrial online process control for years. (These measurements were also becoming a critical part of the microelectronics industry, where water purity had a significant impact on the efficiency, speed, and cost of advanced semiconductors.) At that time, conductivity measurements already existed on laboratory and skidbased pharmaceutical water systems, and TOC measurements were becoming increasingly employed. These measurements were primarily used to verify that the water purification equipment specification was met. The technical group leaders at PhRMA and USP realized the potential to take advantage of these process analytical measurements and use them for greater and more productive means.