Regulators Debate Methods for Producing Water for Injection - Pharmaceutical Technology

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Regulators Debate Methods for Producing Water for Injection
Might European officials reverse their position on acceptable production methods?

Pharmaceutical Technology
Volume 35, Issue 9, pp. 48-52

EMA's concerns about reverse osmosis

Biofilm. Unlike distillation, reverse osmosis is not conducted at temperatures that kill bacteria. Instead, this process is operated at ambient temperature, which gives rise to some of European regulators' concerns. One major worry is that organisms can grow and form biofilm on both sides of the membranes. Biofilm consists of gram-positive, gram-negative, and pathogenic bacteria, according to an EMA paper on WFI prepared by reverse osmosis. "The biofilm will build up and become increasingly resistant to sanitization by hot water or chemicals because of the glycocalyx material," it says. "Biofilms cannot be destroyed" (3).

But companies contain and manage biofilm formation routinely, according to a response to EMA cowritten by Theodore Meltzer, a consultant at Capitola Consultancy and member of Pharmaceutical Technology's Editorial Advisory Board.* "The statement that biofilms will become increasingly resistant to sanitization by hot water or chemicals is untrue," he wrote. Microbial biofilms only resist chemical and physical treatment agents at much lower temperatures and chemical concentrations than industry uses (4).

"Similarly, the statement that biofilms cannot be destroyed is also incorrect," Meltzer added. Common agents such as peracetic acid, hydrogen peroxide, and combinations of the two hydrolyze biofilms (4).

Endotoxins. Another main concern among European authorities is that a biofilm may exist in product water tubing from any membrane process. The way that a reverse-osmosis system is operated and maintained can increase the risk that WFI will contain microorgansms. About 25% of the feed water from a reverse-osmosis unit is directed to a waste line, and this waste is rich in bacterial endotoxins and bacteria. Usually, a portion of the waste is diverted back to the system's feed water in a process called waste recycle. This technique is required to maintain velocities throughout the final membranes in an array to avoid precipitation of material within the membranes.

"If you're going utilize waste recycle, consider the fact that the piping will contain a well established biofilm. Attempt to remove microorganisms with a process such as ultrafiltration," says Collentro. Firms could also operate the reverse-osmosis unit at a lower level of water recovery and send the recovered stream to a break tank of chlorinated water at the beginning of the system. "I try to eliminate waste recycle as much as I can," says Collentro.

Microbial fouling. European regulators also have expressed concern that membranes are subject to microbial fouling. Impurities can build up on membranes in layers of biofilm, organic material, and scalants such as calcium or magnesium compounds. A preventative maintenance program is required to control microbial fouling, which significantly increases the probability of microorganisms in product water.

"When fouling occurs, firms must conduct a three-step cleaning process to remove scalants, the organic material, and the bacteria. Chemical sanitization is the only effective method of remove biofilm from the membrane surface and assocaited microorganisms," says Collentro.

But fouling can be avoided. "Appropriate chemical treatment regimes developed as part of the validation process prevent fouling and associated flux declines," wrote Meltzer. In addition, bacteria cannot grow through reverse-osmosis membranes, "which are permeable only to some ions and water molecules" (4).

European regulators often cite the heat associated with the distillation process as an advantage over reverse osmosis because it kills microbes and prevents contamination. But operators can heat-sanitize membrane systems frequently or operate them continuously hot. These techniques "will minimize or eliminate microbial problems to the same extent as distillation," says Zoccolante.

Metabolic byproducts. Biofilm concentrates various metabolic byproducts, notes the EMA paper. If it forms on the upstream side of a membrane, "the concentration is sufficient for these to pass through the membrane" (3).

But the scientific evidence does not support this assertion, according to Meltzer. "The minimum ... molecular weight ... for the lipid-A portion of endotoxins (required to elicit a fever response) is on the order of 10,000; the approximate organic molecular weight cutoff for [reverse-osmosis] membranes is on the order of 300" (4).

Global concerns about distillation

Several observers point out that distillation raises some of the same concerns that European regulators have about reverse osmosis. For example, an FDA Inspection Guide describes various ways that stills have produced water contaminated with endotoxins. The log reduction of endotoxin that stills can provide is limited. In many failures, an insufficient pretreatment system produced an endotoxin feed to the stills that was greater than they could remove (5).

Also, biofilm formation can occur during distillation just as it can during reverse osmosis, wrote Meltzer. "Biofilm is an inevitable occurrence in all water systems except those continuously maintained hot, at above at least 65 C" (4).

Other observers have noted an apparent inconsistency within EP. The document lists the exact same water-quality specifications for highly purified water (HPW) as it does for WFI, but allows the former to be made through reverse osmosis and other processes, says Zoccolante. "WFI may be used for more critical applications, but HPW is also used for applications where water quality is extremely important. A process is either reliable or it is not. The application does not change that fact."

Both distillation and reverse osmosis require water to be pretreated to protect the equipment and to provide acceptable results. Operating the processes at the proper temperature—or, in the case of reverse osmosis, performing frequent sanitizations—and validating them properly should help ensure that they yield WFI that meets compendial specifications.


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