QRM Process

Achieving Clean Pharmaceutical Water

Controlling microbiological contamination is an ongoing process laden with risks. The best weapon against biofilm is prevention.

By Bill Swichtenberg, Senior Editor

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.”

Photo 1. A totally integrated and automated biopharmaceutical water purification system installed at a pharmaceutical manufacturing plant in Canada.

The measuring of TOC is mandated by USP and European Pharmacopeia (EP) compendial standards for release of water to manufacturing. TOC is an indirect measure of the organic molecules present in pharmaceutical waters, measured as carbon. USP states that these molecules may be introduced into the water from the source water, from purification and distribution system materials, and from biofilm growing in the system.

While using properly collected grab samples and analyzing them in the lab can be more accurate than some online measurement methods, it is not an instantaneous method. Online TOC methods still have merit in continuous monitoring, as long as chemical interferences or instrument readings do not compromise the test results. “The TOC test, as described in USP, is not intended to be a quantitative test. It is simply a pass/fail test,” says Soli. “However, most people use their TOC instruments quantitatively for process control purposes.”

The problem is the possibility that not all online TOC analyzers work reliably on all waters (www.pharmamanufacturing.com/articles/2006/236.html). According to Soli, this might be particularly true when used for analyzing ultra-pure water or water produced by distillation. ASTM’s E-55 committee is now working on a standardized procedure that can be used for validating various online TOC methods.

Minimizing Waste

Even though some companies are putting back their spent water into the process, they may not do it for economic reasons. A project Manfredi recently worked on put roughly 35 gal./min. (of 50 gal./min.) of wastewater, which normally would have been sent to the sewer, back into the front end of the system. However, it costs the company more money to accomplish this compared with just using more municipal water. In this case, the reason this is done is that there is a limited amount of feed water available to the company.

Some companies are using the spent water (after running it through another RO system) to sprinkle their lawns, run cooling towers, run their boilers or flush toilets. These systems can save 15-30% of the water. Again, most of these systems are built out of concern for the environment and good citizenship rather than monetary gain. The return on investment for many of these systems is well over 10 years.

“If you are really concerned about saving money, your plant should do an audit of your water usage,” says Comb. “Typically, you’ll find simple areas where you’re wasting water.” For example, you might discover that a seal flush on a sanitary pump is leaking, wasting thousands of gallons of water.

Photo 2. A continuous electrodeionization system installed at a pharmaceutical plant in Puerto Rico.

Blueprint For Success

Designing a new pharmaceutical water system is not a job for an inexperienced engineer. There are many nuances in these systems. Both the plant’s current needs and its anticipated needs must be taken into consideration. Even plant designs that include more capacity than needed can result in problems.

“Plants that are over-designed tend to have long periods between regenerations, backwashes or other regular maintenance events, allowing more biofilm to develop,” Soli explains.

In addition, Siemens’ Costello points out that those involved in plant design or renovation must truly know what the plant is supposed to do. A critical step in the design process is finding the answers to these questions:

  • How much water will be used?
  • What tolerances are needed for equipment?
  • What data will need to be collected?

Another important step is determining the quality of the water coming into the plant. According to Manfredi, most municipalities will tell you that the water is great. You won’t really know what you have until you test the water and ask the right questions.

Future PAT Applications

The tools currently used to measure water are not especially friendly to process analytical technologies (PAT), experts suggest. “TOC and conductivity instruments aren’t typically linked to any specific process control measure, as is required by PAT,” says Soli. “Instead, they are for monitoring process and water suitability and are more closely aligned with real-time release (RTR). Even if such online instruments could be used for RTR, a similar technology doesn’t exist for microbiological content, the third element of pharmaceutical water quality.”

An online device that could measure microorganisms would likely change the industry. “We already have devices that measure turbidity and water hardness,” says Costello. “But microorganisms are a different story. We need a device that quickly measures the rate of growth.” Manfredi points out that this day may come soon. This device could also be used as a basis for a PAT/RTR application. Currently, it takes three to five days to determine if microorganisms are present in the water and to what extent.

“An online, rapid micro-monitor that could determine what is in the water would be ideal,” says Manfredi. “[Device manufacturers] are exploring the use of laser technology, but it is not yet ready for prime time.”

USP for Purified Water and Water for Injection

The ISPE Baseline Guide (Water and Steam Systems)
focuses on engineering issues and is intended primarily
for the design, construction and operation of new water
and steam systems.

According to the Guide, the USP official monograph for
Purified Water states that the water must:

  • be obtained from water complying with the “U.S.
    Environmental Protection Agency National Primary Drinking
    Water Regulations” or comparable regulations of the
    European Union or Japan.
  • contain no added substances.
  • be obtained by a suitable process.
  • meet the requirements for water conductivity.
  • meet the requirements for total organic carbon
    (TOC).

The USP monograph for Water for Injection requires the
water to:

  • meet all of the requirements for “Purified Water.”
  • be obtained by a suitable process and purified by
    distillation or reverse osmosis or equivalent method.
  • meet the requirements of the bacterial endotoxin
    test and contains not more than 0.25 USP endotoxin
    unit per ml.
  • be prepared using suitable means to minimize microbial
    growth.

 

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