Regulators Debate Methods for Producing Water for Injection

Might European officials reverse their position on acceptable production methods?
Sep 01, 2011

Image is courtesy of William Collentro
The market for vaccines is expanding, thanks partly to the discovery of new biologics and to public-health officials' emphasis on preventive medicine. This expanding market highlights the importance of water for injection (WFI), which is required to prepare parenteral solutions. Many vaccine ma-kers seek to sell their products to markets around the world, but regulatory officials still disagree about which methods for producing WFI are acceptable.

Pharmacopoeial specifications

The US Pharmacopeia (USP) describes specifications for conductivity, total organic carbon (TOC), and bacterial endotoxin that WFI must meet. For years, USP only allowed companies to produce WFI through distillation. That process had a long history, and experts viewed it as a safe and robust method for producing water with a low bioburden. In the late 1970s, new language was adopted that enabled manufacturers to use reverse osmosis, provided the water met the same specifications. USP now states that, "WFI is water purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms" (1).

Based on studies conducted by the US Centers for Disease Control and Prevention, FDA concluded that reverse osmosis could produce WFI to USP specifications, provided that the process was operated adequately. FDA also recommends that the reverse-osmosis system be designed appropriately and include precautions such as regular sanitization and maintenance, and periodic validation.

In general, FDA seems to be concerned more about whether WFI meets USP specifications, and less about the type of process a firm uses to create the water, as long as it is based on sound science. "FDA requires that you have a validated system that demonstrates that you consistently make water meeting the specifications in USP," says Terry Munson, technical vice-president at consulting firm Parexel. "How you get there is not a major concern."

The Japanese Pharmacopoeia (JP) has taken a similar approach. For more than a decade, it has allowed a combination of reverse osmosis followed by ultrafiltration as an alternative to distillation, says Gary Zoccolante, pharmaceutical technical director of Siemens Industry.

The European Pharmacopoeia (EP) contains the same specifications for conductivity, TOC, and endotoxin as USP does, but it requires firms to produce WFI through distillation. According to the document, WFI "is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority or from purified water by distillation" in a suitable device (2).

The EP seeks to ensure that WFI is produced through a robust process. "Europeans don't consider reverse osmosis or equivalent processes to be a robust, proven process for long-term continuous removal of bacteria and bacterial endotoxins," says William V. Collentro, senior consultant for ConcordiaValSource. Distillation changes water from its liquid phase to its steam phase. "The Europeans consider the phase change to be extremely important," says Collentro, because it ensures that bacterial endotoxins, bacteria, and other nonvolatile impurities "are left behind with the water, ulitimately removed from the evaporator section by blowdown."