Understanding
the standards
Conductivity, TOC and other methods for testing pharmaceutical waters

Different regulatory authorities continue to set different rules for the quality of different grades of pharmaceutical water, and the ways in which this quality is measured, but Europe, the USA and Japan are making progress towards harmonization.

Historically, quality tests for pharmaceutical waters were confined to the laboratory. Water samples were checked for single ionic impurities, such as carbon dioxide, ammonia, chloride, sulfate and calcium, using wet chemistry.
In the early 1990s the U.S. Pharmacopoeia (USP) and the Pharmaceutical Researchers and Manufacturers of America (PhRMA), started looking at alternatives to wet chemistry, which was no longer considered the state of the art. They looked at online measurement of conductivity and total organic carbon (TOC). In 1996, the publication of USP 23 Supplement 5 allowed on-line measurements of conductivity and TOC (general chapters 645 and 643 respectively) for the first time in the pharmaceutical industry. The document set minimum standards for the measuring equipment used for bulk Purified Water (PW) and bulk Water for Injection (WFI).
In 2000, the European Pharmacopoeia (EP) changed the analytical test methods for bulk Aqua Purificata and bulk Aqua ad Injectabilia. The EP’s TOC testing was virtually identical to that set out by the USP, but for conductivity, both the test limit and the measurement technique were different from those of the USP. This was a problem for pharmaceutical manufacturers serving both the U.S. and European markets. Industry requests for a more standardized test philosophy began the process of harmonization between the U.S., European and Japanese pharmacopoeias. The first effects of this harmonization were seen in January 2002, when the EP published a proposal to revise the requirements for conductivity. Currently there are just two limits: 4.3 µS/cm at 20 °C for PW and 1.1 µS/cm at 20 °C for WFI. From July 2004 the requirements will be given by two tables, one each for PW and WFI, showing conductivity as a function of temperature. The EP’s conductivity standard for WFI will be the same as that given by the USP for both PW and WFI. EP limits for nitrate, aluminum (when used for dialysis solutions) and heavy metals will remain unchanged, and so too will quality tests for all packaged waters (sterilized WFI and PW in containers).


Also to be revised by the EP in July 2004 are the requirements for calibrating instrumentation. At present there are no calibration requirements for the instrument itself, while the reference solution prescribed for sensor calibration is flawed. The new requirement for the meter tolerance will be 3% + 0.1 µS/cm and the sensor tolerance will be 2%, which is the same as the current USP requirement. The differences in conductivity calibration requirements between EP and USP are small.
For TOC, the EP and USP methods are considered to be fully harmonized, though there is a subtle difference in the test limit.
The Japanese Pharmacopoeia (JP) still relies heavily on wet chemistry for control of pharmaceutical waters, but a major revision is planned. JP 15, developed in co-operation with the USP’s Pharmaceutical Water Expert Committee, will come into force in 2005, replacing most of the wet chemical methods with tests equivalent to those of the USP for conductivity and TOC. This has not yet been finalized.
Within USP 27, effective from January 2004, there are no immediate major changes planned in general chapters 645 (conductivity) and 643 (TOC). There is, however, a major revision of the “Method of Manufacture Requirements” for WFI. Previously, WFI could be made by distillation or reverse osmosis (RO); now the USP requires merely “distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms”. This change will open the door to all validatable manufacturing methods for WFI, while retaining distillation as the “gold standard”. Europe will continue to allow distillation only; in Japan, distillation or RO plus ultrafiltration is required.
This year will also see new tests for packaged waters to replace the antiquated methods currently specified by USP 27. Methods under review include conductivity (already used for packaged waters in the EP) and a quantitative spectrophotometric oxidizable substances test. A new monograph for Water for Hemodialysis is proposed for USP 27 Supplement 1, with a concurrent General Chapter 1230, Water for Health Applications.