Achieving Clean Pharmaceutical Water

Pharmaceutical manufacturing, like life itself, depends on water. The design, operation and maintenance of pharmaceutical-grade water systems are critical, both to keeping drug manufacturing facilities running and to ensuring final product quality.

Unfortunately, improperly maintained and operated systems rank very high on the list of problems cited during FDA and other regulatory inspections. Maintenance and operation are not “set and forget” activities. They require process adjustments and system maintenance. “Water is a critical utility – you have to make sure you have the right design for the system,” says Joe Manfredi, president of the consulting firm GMP Systems.

However, because there is no single blueprint for design, operation or maintenance, matching the production usage requirements to the right water system can be difficult. “It really is a juggling act. You need to weigh water quality against reasonable cost and capital vs. operating costs,” says T.C. Soli, principal consultant, Soli Pharma Solutions. “A poorly designed, cheap system will cost a lot to maintain production of good quality water.”

Manufacturers need to beware of relying too heavily on off-the-shelf designs without conveying their exact requirements. Not heeding this advice will compromise system efficiency and require minor upgrades or changes after commissioning that can strain the system.

“Standard packages from vendors have their pluses and minuses,” Manfredi remarks. “But usually the cost savings doesn’t justify the system compromise.” Customization is essential, he adds.

Types of Water

While many different grades of water are needed for pharmaceutical manufacturing, the two grades that are required most, and require treatment, are Purified Water (PW) and Water for Injection (WFI). Guidance on establishing specifications is provided in the U.S. Pharmacopeia (USP; see box below). Basically, drinking water must be made to pass conductivity and total organic carbon (TOC) requirements for Purified Water, with the additional requirement of passing an endotoxin test for Water for Injection.

Microbial Control

Microbiological contamination is a major concern for pharmaceutical water. The presence of microbes, including bacteria and their endotoxins, is inevitable. Microbes are found in any and all water systems, and they are unpredictable.

“The contamination is so hard to predict because of all the variables involved, such as temperature, pH, velocity, stresses and heat,” says Mike Costello, director of sales and marketing for the biopharm market at Siemens Water Technologies. “You could have two systems with identical designs, and yet one will perform well and the other poorly, [depending on the process environment].”

Heat is most often used to control bacteria, and maintaining water temperature above 80° C (176° F) will kill all microorganisms growing in a water system, says Lee Comb, national sales manager for Tenergy Christ Water.

The use of ozone may also be making a comeback, Comb says. The ozone loop was invented in the early ’90s, but its use dwindled, due to concerns about poor mixing. In addition, users didn’t realize how labile it was and that it could corrode gaskets and seals if it wasn’t properly maintained. Another detractor was the USP’s requirement that “no added substances” be used. Many in the industry may have misinterpreted USP’s monograph, Comb says, and since ozone was not specifically mentioned as a means for producing WFI, they assumed it could not be used.

However, it has gradually become clear that, since ozone does not “produce” WFI, but rather, keeps it clean, ozone would be fine to use as long as it were removed from the resulting water. In addition, Comb says, people became more experienced at using ozone properly and accommodating its effects on water. An inexpensive sanitization method, its use requires that a 254 nm UV light be used to destroy any residual ozone.

Techniques that are most often used to deal with bacteria include reverse osmosis (RO), electrodeionization and distillation. In addition, many companies specify that their tanks be made of 316LSS (a chromium/nickel/molybdenum steel alloy) because of the material’s inertness and resistance to heat and the chemicals used in sanitization.

Most bacteria in pharmaceutical water systems exist as biofilm, populations of microorganisms that adhere to equipment surfaces. They may be found on virtually any environmental surface where sufficient moisture is present.

As a result, contaminants are not likely to be uniformly distributed throughout the system. Therefore, a sample taken at any given time may not be representative of the true level of contamination in the system. “Biofilm is a constant in every system,” says Siemens Water Technologies’ Costello. “Anybody who says they have an easy method to get rid of it completely, once it is there, is overpromising.”

Preventing Biofilm Buildup and Rebound

The key to controlling biofilms is never to allow them to build up in the first place, experts agree. “Biofilm is never easy to treat,” says Soli. “People who cannot sanitize their systems with heat but only use a chemical are typically the ones who call me.”

Incomplete removal of the biofilm will only allow it to return to its equilibrium state and rebound after sanitization. Chemical and physical treatments are used to remove or destroy biofilm. Chemical biocides that may be used include ozone, chlorine, chlorine dioxide, hydrogen peroxide, peracetic acid and sodium hydroxide. However, anything added to the system must be taken out later. Physical treatments include recirculating hot water loops, mechanical scrubbers or scrapers, and high-pressure sprayers.

“Whenever I see the use of a cold-water loop, I arch an eyebrow,” says Comb. Every device in a water system must be sanitized. According to Costello, the closer in the process you are to the final product, the more important sanitization becomes. On the other hand, Manfredi cautions against forgetting about the front end of the system. The system’s beginning often provides the inoculation that is the source for long-term problems.

Contrary to the many rumors and false interpretations, experts note that FDA has never had a policy banning the use of filters in pharmaceutical water systems. Depth- and membrane-type filters are often used. Final filtration as the sole treatment for water purification generally is not acceptable.

“If filters were used as the only barrier and a failure occurred, the water would be recontaminated with the entire volume of organisms that had accumulated,” explains Manfredi. Bugs are notorious for collecting on the surface of the filter. Since these bugs feed on themselves, they are their own source of nutrition as their growth accelerates, while the filters create a place for them to survive.

“It is a poorly designed system if filters are used before the reverse osmosis unit,” says Tenergy’s Comb. “Cartridges are used in houses, not pharmaceutical systems.”

Total Organic Carbon (TOC )

Achieving sterility is the goal of the water system in WFI applications. According to Manfredi, USP allows limited contaminants in the water, yet expects that the water will be sterile. “As I tell my students, you can achieve sterility, but how you measure it, deter-mine that you have done it, or verify it is another story.”