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Might European officials reverse their position on acceptable production methods?
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.
Image is courtesy of William Collentro
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."
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.
The prospects for harmonization
Harmonization of requirements would give pharmaceutical manufacturers a choice of technologies for producing WFI. Two-pass reverse osmosis could help firms reduce the capital costs, operating costs, and maintenance costs of their WFI system, which "would be of considerable benefit for world market needs," says Michael Foster, water group lead at OBK, a provider of water-purification systems. Harmonization also would lower costs for drugmakers in emerging countries because one type of water would suffice for purified-water and WFI applications, he adds.
Events indicate that harmonization of EP, USP, and JP requirements for WFI is possible. During recent meetings of the Parenteral Drug Association, European regulators showed openness to discussing the topic of producing WFI through reverse osmosis, says Maik Jornitz, senior vice-president of marketing bioprocess at Sartorius-Stedim North America.
On Mar. 24, 2011, the European Directorate for the Quality of Medicines and HealthCare (EDQM) held a water workshop with experts from JP, USP, the pharmaceutical industry, and equipment manufacturers. By the end of the meeting, the experts saw sufficient reason to recommend that the European Pharmacopoeia Commission initiate discussions regarding the potential use of membrane systems for producing WFI, says Georg Roessling, senior vice-president of Parenteral Drug Association Europe. Regulators stipulated that the discussions should consider a potential revision of current specifications for WFI and the introduction of methods to deal with the contaminants likely to be present in reverse-osmosis systems to ensure the safety of the resulting WFI.
European regulators are looking for robust, long-term data that show that the quality of WFI produced by reverse osmosis is comparable to that produced by distillation, says Jornitz. They want to be sure that reverse osmosis can produce WFI reliably, and sharing experience of reverse-osmosis WFI systems with them would be advantageous, he adds.
In June 2011, EP decided that advances in membrane systems since the late 1990s warranted a review of its previous policy. "However, the data collected in the past months still need to be reviewed to answer questions about new multimodule reverse-osmosis systems and associated improvements (e.g., hot water and chemical sanitization) designed to overcome concerns linked to the microbiological quality of the water," says Susanne Keitel, director of EDQM. It is likely that EP ultimately will receive a request for revision of the monograph on WFI, she added.
*Theodore Meltzer, who served as a respected member of Pharmaceutical Technology's Editorial Advisory Board for more than 20 years, passed away in August 2011. He is dearly missed by his colleagues in industry and on this magazine.
1. USP 34–NF 29 (US Pharmacopeial Convention, Rockville, MD, 2011), p. 4596.
2. EurPh, General Text 01/2009:0169 (EDQM, Strasbourg, France, 2010), p. 3219.
3. EMA, "Reflection Paper on Water for Injection Prepared by Reverse Osmosis," Doc. Ref. EMEA/CHMP/CVMP/QWP/28271/2008, Mar. 5, 2008 (London).
4. T. Meltzer et al., PDA J. Pharm. Sci. Technol. 63 (1), 1–7 (2009).
5. FDA, Guide to Inspections of High Purity Water Systems (Rockville, MD, July 1993).