Battling biofilm


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The best sanitation programs are designed along with the product and aggressively implemented early in the manufacturing process.

By Sarah Fister Gale

The cleaning, disinfecting, and sanitization of a clean manufacturing environment determine the safety and effectiveness of the end product. These steps make the difference between a pristine product and a sullied reputation, yet product designers across industries tend to spend little up-front time designing and prioritizing sanitation programs in the product development process–and that can lead to costly delays in getting products to market and surprising sanitation issues down the production line.

Every industry has different procedures to ensure the cleanliness of its products and the processing environment based on the risks to the end user. And while a manufacturer of raw food products that will be cooked by the consumer may have more contamination leeway than those making injectable pharmaceutical products or implantable medical devices, they all have the same agenda: to produce consumable products free from bacteria and other contaminants that could ultimately harm the user and the brand.

The most successful manufacturers see the sanitization program as an integral part of the product design process, says Lisa Foster, vice president of Steripro, the consulting and laboratory services division of Sterigenics International, a contract sterilization organization in Corona, CA. “People think cleaning, disinfecting, and sterilization are the last act so they can be left till the end, but that’s a huge mistake, whether you are in pharmaceuticals, medical devices, or food,” she says. “You need to look at these steps up front in the product design process long before you get to manufacturing.”

She advises clients to consider attributes of cleaning, disinfecting, and terminal sterilization during product design and assess those goals against all materials, ingredients, and process steps in the product. She points out that it’s easy to select materials that won’t be compatible with your sanitization or sterilization choices–Teflon, for example, can’t be gamma sterilized. “If you want a Teflon stopper or a pre-filled syringe, the product can’t be closed prior to sterilization.”

If a material you want or need conflicts with your sanitization goals, you can make decisions during the design phase to address the problem before the manufacturing environment is established. In the case of the Teflon stopper, you could opt to pre-sterilize the components separately using an aseptic filling step followed by terminal sterilization of the outside barrier, or choose another material for your stopper.

“You need to determine what methods will work and design the product around that,” Foster says. “When you develop a product with effective sterilization processes from the beginning, you will save a lot of time and money during production phases.”

A clean education

Once a product is designed and the sanitization program is established, the only way to ensure it remains effective is through training. “Good sanitization is all about education, and reminding people of the little things that they may know to do but can forget when they are under pressure to get the job done,” says Chris Celusta, manager of food processing sanitization for Spartan Chemical, a Maumee, OH-based manufacturer of chemical specialty maintenance products and industrial degreasers. “But don’t inflict paralysis by analysis. Sanitation crew training has got to be simple, to the point, and ongoing.”

Figure 1. Gamma sterilization is one method for sanitization of materials. Shown: A radiation source glows blue underwater, where it is kept when not in use. Photo courtesy of Steripro/Sterigenics.
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Celusta points out that while senior management may be committed to a clean environment, sanitation crews are often less tied into the corporate goals and strategies. They often work in low-level positions with high turnover, despite the fact that they serve a critical role in the production process. To ensure they are as committed to sanitization goals as the rest of the team, sanitation training must also incorporate the reasons behind the cleaning program. “You can’t just tell your cleaning crew what to do; you have to explain why they are doing each step and what the result will be if they skimp on or skip something,” Celusta says. “Otherwise, crews may make assumptions that can result in problems.”

Those problems are not just issues of yield or delays. When sanitation crews skip steps dangerous bacteria, including E. coli and Listeria, can gain a foothold in processing facilities and lead to outbreaks of foodborne illnesses. Each year an estimated 76 million people contract a foodborne illness and 5,000 die because of food safety issues from bacteria that can be prevented with proper sanitation.

Figure 2. The Cobalt 60 radioisotope is used for gamma sterilization in the underwater chamber. Photo courtesy of Steripro/Sterigenics.
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Those outbreaks don’t just hurt one company or brand. Every time the public learns of a food recall it loses faith in the entire food production industry, says Celusta, who notes that consumer confidence in food safety is at an all-time low. “When you have a national recall, it draws a lot of attention to sanitation strategies throughout the food industry,” he says. “Company owners and consumers want to know you are doing what you are supposed to be doing, and that every ingredient in a product comes from a reputable source.”

Ready-to-eat products, such as lunch meat or fresh-cut produce, pose the greatest risks because they don’t involve a cooking, cleaning, or other “kill step” by the consumer. Whatever goes out the door on the product will be ingested.

“The ???ready-to-eat’ companies are the most nervous, but they are also the most committed to good sanitation practices,” Celusta says. “Their attention to detail has to be stepped up, and that commitment comes from the top. The better buy-in you have from the top, the better the program runs.”

Effective cleaning and sanitation programs at food processing facilities include regular cleaning and disinfecting shifts, along with environmental monitoring that may include plate counts and/or adenosine triphosphate (ATP) or bioluminescence tests, which rapidly detect the amount of food residue and other organic matter–such as bacteria, yeast, and mold–that remains on a surface after cleaning.

Good programs also implement strategies within the environment to prevent bacteria and other contaminants from migrating to high-risk areas. These include everything from controlling the traffic in food processing plants–requiring workers and equipment to always move away from finished product areas so as not to track bacteria into that environment–to adding sanitizer foams in doorways that disinfect any shoes or rollers moving from room to room.

Cleaning and disinfecting are not the same

A common misconception sanitation crews can make in the food, pharmaceutical, or medical device industries is thinking sanitization cleaners will eliminate any dirt or bacteria left behind from a poorly done cleaning process. “The sanitizer won’t bail you out,” Celusta points out.

He often uses ATP tests as a teaching tool for sanitation crews, to show them just how much dirt and bacteria they left behind after a cleaning shift. “It’s a very effective way to prove there are no short-cuts,” he says.

This is an important lesson because if the dirt isn’t completely eliminated in the cleaning step, remaining bacteria can deactivate the sanitizers, creating a biofilm, which is a breeding ground for deadly contaminants. “Biofilm creates a lot of pain for manufacturing facilities,” Celusta says, noting that the only way to get rid of it is through mechanical agitation with scrubbers, green pads, or other agitators. “You can’t just apply a solvent and assume it will break a biofilm down. You have to scrub it away.”

Biofilms aren’t just a problem for food manufacturers, notes Art Vellutato, senior consultant for API at Veltek Associates, a contamination control company in Malvern, PA. He works primarily with pharmaceutical manufacturers and encounters the same kinds of problems. When biofilms build up, it has a costly and time-consuming impact on production. “Every time high bioburden levels set off an environmental alarm, it costs $20,000 to $40,000 to figure out where the contamination came from,” he says. “You can’t just make guesses; you have to find the source.”

Like Celusta, Vellutato encounters many sanitation crews that think disinfectants can be used in place of cleaning. “Cleaning and disinfecting are not the same,” he insists.

The cleaning step is the physical act of removing particulates, microbes, and other debris from surfaces in the manufacturing environment. These include floors, walls, ceilings, drains, equipment, and any other contact surface. During this step crews must also eliminate residues and build-up that can complicate disinfection.

Cleaning is the most important part of a successful disinfection step because it eliminates the bioburden prior to disinfecting, Vellutato points out. “If you just disinfect a surface without cleaning it, it will cause the bioburden levels to go up, leading you to use more disinfectants, which creates a higher level of residue.”

If you aren’t careful, this can lead to a film of dead organisms left on a surface that is difficult to remove. “These biofilms are just as harmful in a product as live bacteria, particularly if they get into a drug vial or injectable,” he says. Because the contaminants are dead, they are difficult to detect, and can pass under the radar of conventional environmental monitoring tools. “It happens every day,” Vellutato admits.

Once surfaces are clean, the disinfecting step is performed–the application of a chemical agent that will kill any remaining bacteria or fungi. Disinfectants are most effective when a surface has been thoroughly cleaned of all particulates, residues, and any other contaminant that may have hitchhiked into the clean environment.

Everything should be cleansed before being disinfected to enable the full penetration of the disinfecting agent, Vellutato says. “Everyone wants a magic chemical that will quickly and safely kill all the bacteria in one step,” he laments. “But the products and the processes haven’t changed. It takes hard work and elbow grease to get rid of contaminants.”

Sanitation myths

Among cleaning professionals there is an ongoing debate about the value of periodically rotating disinfectants from a high-pH phenol to a low-pH phenol in order to prevent organisms from becoming resistant. Vellutato disagrees with this practice, noting that most biocidal agents are so strong that there is no way organisms can develop resistance.

“It doesn’t work and it can create a horrific residue on everything,” Vellutato says.

Figure 3. Critical environments must be disinfected and sterilized to control microbial contamination on hard surfaces with a sterilant such as ready-to-use Spor-Klenz®. Photo courtesy of STERIS.
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He also discourages companies from using pre-saturated isopropyl alcohol (IPA) wipes for cleaning, which he says is an industry-wide mistake. “If you wipe a critical surface with an IPA wipe, you aren’t cleaning anything away,” he points out. “The wipe is already saturated, so it can’t absorb materials off the surface. It will just move the contaminants around.”

Multi-wipe dispensers are also not sanitary. “If you open the package to the air and stick your fingers in to pull a wipe out, the rest of them are no longer sterile,” he points out. “It’s better to use an aerosol alcohol spray followed by a single-use dry wipe.

“People need to understand that if they just clean and disinfect the right way, the cost reduction will be huge because they will have fewer contamination issues.”

Clean early, clean often

Along with using effective cleaning and disinfecting strategies, sanitation experts agree that the way to make any cleaning and sanitization program more effective and efficient is to eliminate contaminants early on and to keep them out of the environment.

“If you don’t let the contamination in, you will not have to contend with its presence,” Vellutato points out. But it’s not as easy as it sounds. He estimates that in a typical Class 100 (ISO 5) manufacturing space, up to 100 items can be brought into the processing environment every day. These include equipment, disposable items, cleaning supplies, carts, ingredients, and of course people, who represent the biggest source of contamination in any clean environment.

Figure 4. A high-performance, free-rinsing detergent such as CIP 100 alkaline process and research cleaner can be used in manual, immersion, and recirculating spray equipment including CIP systems to remove a range of soils in pharmaceutical and food/beverage processes. Photo courtesy of STERIS.
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To reduce contamination impact, he suggests cleaning on a more frequent basis with less harsh or intense chemicals, rather than stretching out the time between cleaning shifts and waiting for issues to arise. This reduces the need for sporicides, which can destroy surfaces.

Along with daily or weekly cleaning steps, a more thorough cleaning on a monthly basis is also recommended. That may include scrubbing surfaces with a detergent and mop or a dry wipe, then rinsing the surface before it dries to remove the detergent, followed by a disinfecting step.

Mike Heater, global product manager for process and residue cleaners for STERIS, an infection protection and contamination control products and services company in Mentor, OH, notes that many of the drug companies he works with are moving toward more sanitation steps earlier in the manufacturing process to eliminate the build-up of biofilm further upstream from the end product. “Higher levels of sanitation means higher process controls and fewer risks for product recalls due to contamination,” he says, noting that the further down the line that bioburden is allowed to build up, the harder it is to keep under control during key process steps.

Jon McCabe, global product manager for critical environments at STERIS, adds that the U.S. Food and Drug Administration (FDA) current Good Manufacturing Practices (cGMPs) are pushing for greater contamination management throughout the manufacturing process rather than relying on disinfection steps at the end of the line. “It’s a steady trend to gain control of the biopharmaceutical production environment and not allowing contamination events to occur.”

Figure 5. The environmentally friendly STERIS VHP® 1000ED mobile biodecontamination system offers materials compatibility and easy process validation for pharmaceutical production and packaged medical device sterilization, without residuals. Photo courtesy of STERIS.
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Heater also notes that for biopharmaceutical manufacturers, there are more questions about the ability of current popular detergents to reduce bioburden than there have been in the past. “They were designed to remove soil from surfaces, but you have to be confident they can also achieve bioburden limits set for the manufacturing process,” he says.

For added assurances that their disinfecting agents are working, some pharmaceutical manufacturers will follow a disinfecting step in clean-in-place (CIP) operations with a steam sterilization step to further reduce bioburden levels, or they will use a dry vaporized hydrogen peroxide system in a closed area for whole-room sterilization. “This can help manufacturers quickly disinfect large-volume spaces that you can’t easily do otherwise,”
McCabe says.

Heater and McCabe point out that there are many other time-reduction strategies for sanitation programs that don’t compromise effectiveness. For example, McCabe recently helped a manufacturer in the European Union to reduce cleaning time by transitioning from a bulk product disinfectant to point-of-use dispensers that allowed the sanitation crew to produce just-in-time quantities of disinfectant at the site of cleaning and eliminate the need to store large tanks of mixed product.

“Along with shortening the cleaning process, the change eliminated the need to constantly validate the effectiveness of the stored disinfectant,” McCabe says.

Pharmaceutical manufacturers are also concerned about cross-contamination from other drug ingredients in final products, and managing that is a significant part of the contamination control program. This has become an increasing concern as the potency of active pharmaceutical ingredients (APIs) has steadily increased. “As these companies work through their process validations, they have to prove there is not going to be crossover,” Heater says, noting that as API strength has gone up, acceptable contamination levels have dropped. Cross-contamination management may include separate HVAC systems, unique sets of personnel for different production cycles, and regular environmental monitoring to ensure isolation. “It’s a driver to keep
the process environment under strict control,” he says.

Adding to the challenge for pharmaceutical manufacturers to meet validation requirements for their products is the lack of public industry standards for contamination control, says Veltek’s Vellutato. He points out that FDA’s aseptic processing guide dedicates only half a page to cleaning and disinfecting. Velluto chairs a task force currently writing an independent set of guidelines on cleaning and sanitization for the industry.

“Without guidelines or standards to follow, people have to guess what the FDA wants. They have to do their own research studies, develop their own protocols and training. It’s different for every company, and every product,” he says, adding that the same problems exist in Europe. “It forces pharmaceutical manufacturers to define their own strategies and hope the FDA will validate them.”

Vellutato believes the entire industry would benefit from a guidance document for cleaning, disinfecting, and sanitization as well as training on how to design and implement effective programs. “There is a void of training in this industry, and fewer people have the expertise they need,” he says.

Supply chain management

Keeping their own environments clean is only half the battle for manufacturers, warns Foster of Steripro. They also have to pay closer attention to what their suppliers are doing.

“The primary issue for any clean manufacturing is control of the environment,” she says. “Whether you own the environment or you are purchasing services from a third-party vendor–or a combination–you have to know how your materials are being handled.”

Foster notes that although manufacturers may have confidence in their in-house cleaning and sanitization strategies, they often overlook what’s going on in their supply chains, which is a major mistake in any industry. Any time you purchase materials or ingredients from vendors, particularly those in emerging markets, it is critical to ascertain the parameters of their production environment and what impact it will have on the finished product. “Buying materials from outside the country is becoming more and more common every day, but you have to remember that third-world countries have bugs that we don’t tend to see in the U.S.,” she points out.

Foster has had many experiences with clients who purchase seemingly innocuous materials from third-world vendors that end up having an enormously disruptive impact on the end product. For example, cotton-based products from China are typically fixed with a chlorine rinse before being sold. That’s fine, she says, unless you are using ethylene oxide as part of your end product sanitation process–one of the most common sanitization steps for medical products–because the combination of chlorine and ethylene oxide drives up the epichlorohydrin (ECH) residue levels on the product to a point that it won’t be able to pass ISO certification requirements.

“You go through all this sterilization validation for your product and then you’ve got to change your processes because you didn’t look at how this one part was manufactured,” Foster says. “That delays your ability to bring your product to market.”

Foster finds that many clients don’t do basic front-end fact checking with third-party vendors, which can bring about costly consequences. She suggests at the minimum manufacturers should visit the vendor production site at least once and ask basic questions relating to cleaning and sanitization processes to ensure their cleaning and sanitization steps won’t interfere with the final product manufacturing–before signing a contract.

She also urges manufacturers to provide the vendor with a list of specifications that includes expectations for bioburden levels, cleaning and sanitation requirements, and notification expectations for changes in processing steps.

“Otherwise, you could end up buying two years’ worth of materials that you can’t use,” she says.

In industries such as medical device manufacturing where there are fewer experts on staff and more steps are being outsourced, this is particularly important, she says. “There is no one in-house who is thinking about this.”

Fortunately, both food and pharmaceutical industries do benefit from one commonality: a willingness among their members to share best practices when it comes to sanitation. In both markets, companies understand how important it is for the entire industry to adhere to the highest standards of cleanliness and safety. Since 2005, the food industry has agreed to view food safety as a common goal rather than a competitive advantage, and the pharmaceutical industry has always embraced a similar attitude. This kind of cooperative approach to sanitization is the strongest tool these industries have to rely on because it creates a knowledge pool that everyone can tap into.

“Industry people learn from each other,” says Veltek’s Vellutato. “They are very sharing and cooperative, and that benefits everyone.”

Resources and contacts

Spartan Chemical
Maumee, OH

Steripro Consulting
(div. of Sterigenics International)
Corona, CA

Mentor, OH

Veltek Associates
Malvern, PA