The importance of cleaning validation

by Sheila Galatowitsch

Warning: The FDA is serious about equipment and utensil cleaning. Failure to provide adequate cleaning validation could lead to plant closure.

If you think equipment and utensil cleaning are tasks best left for rainy days, consider the case of Ganes Chemicals Inc. (Carlstadt, NJ), a 75-year-old manufacturer of active pharmaceutical ingredients (APIs).

On Christmas Eve 1998, the company received a warning letter from the FDA after investigators documented significant deviations from current good manufacturing practices (cGMPs). First among the five items cited: Cleaning procedures for non-dedicated reaction vessels, holding vessels, recrystallizers, centrifuges and dryers used to produce APIs and intermediates had never been validated.

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Although the company had developed a cleaning validation program for multi-use equipment, it had never got around to completing validation studies. And until the FDA confirmed that the validation program was completed, Ganes had lost the ability to get new products approved.

After the warning letter arrived, Ganes' board of directors fired several top managers who had failed to follow through on the cleaning commitments. Then the company played catch-up for most of 1999, conducting validation studies on non-dedicated equipment to document that its cleaning procedures worked as intended. An FDA re-inspection in November 1999 uncovered no cleaning deviations, says Chris Smith, Ganes' director of quality and compliance, and cleaning validation continues to be an ongoing process for the multi-purpose facility as it introduces new products.

For Ganes, cleaning validation was a new and difficult requirement to meet because its plant was designed to flexibly manufacture multiple products. It wasn't designed for cleaning equipment, which adds no obvious value to the product and consumes costly technical expertise and processing time. But the Christmas Eve episode made Ganes rethink its priorities. Now cleaning is at the top of the list.

Inadequate cleaning or lack of cleaning validation is often cited in the hundreds of warning letters sent out each year by the FDA. In a warning letter from January, a crushable glass ampoule supplier was notified that its cleaning validation studies and procedures were inadequate to prevent cross-contamination of products manufactured and filled with non-dedicated equipment. A biotech company was informed in December that it had failed to establish and follow written procedures for cleaning and maintenance of equipment and utensils. Another API manufacturer was told in November that its cGMP deviations, including failure to validate cleaning and maintenance of critical equipment, had rendered its products adulterated.

Even industry giants need reminders about the importance of cleaning. Last December, Pharmacia & Upjohn Co. received a warning letter from the FDA that identified “numerous significant” deviations from cGMPs at its

Friedman: Residue removal can’t be ignored.
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Kalamazoo, MI, operations. Among those listed, the FDA claimed the manufacturer had failed to provide a written record of major equipment cleaning, as required by Title 21 of the Code of Federal Regulations, section 211.182. Specifically, the agency cited a failure to document the daily cleaning and sanitizing of aseptic fill lines.

These companies have learned that no segment of the pharmaceutical industry is exempt from the FDA's cleaning validation requirement. That includes manufacturers of dosage form medications, biotech firms working with living organisms, medical device manufacturers, chemical companies supplying active ingredients, contract and government facilities, and the new nutraceutical manufacturers. Every company involved in the pharmaceutical industry should take cleaning as seriously as the FDA does, says Dr. Bill Hall, a cleaning validation expert based in Winterville, NC, and a member of the Parenteral Drug Association's (PDA) Cleaning Validation Task Force.

The FDA's position on cleaning is “get your act together or we are going to shut you down,” Hall says. Insufficient cleaning combined with the extreme potency of today's pharmaceuticals can lead to product contamination and injury to human health. “If management doesn't think cleaning is a major issue and doesn't get around to it, there's an accident waiting to happen,” Hall says.

LeBlanc: Users need to validate cleaning.
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“Cleaning has always been part of the GMPs. What's new in the past 10 years is that the FDA is now saying users need to validate the cleaning,” says Destin LeBlanc, vice president of technical support for Steris Corp.'s (St. Louis) scientific division. LeBlanc is also the author of the book Validated Cleaning Technologies for Pharmaceutical Manufacturing, published in March by Interpharm Press (Denver), and a faculty member on the topic at PDA's Training and Research Institute.

Cleaning validation is one of the most complex types of validations that the industry performs, says LeBlanc. Typical validations focus on only one product, but cleaning validation has to consider two products—the product to be cleaned and how its residue will affect the next product to be manufactured.

The irony is that no manufacturer can guarantee 100 percent cleanliness of any one piece of equipment. Thanks to the super sensitivity of forensic-type analytical methods, chemists can now quickly identify compounds that were present in the equipment immediately before an examination. Even with equipment or utensils that have been cleaned, nanogram- or picogram-size particles of previous compounds can be detected. “The cost of doing 100 percent clean is horrendous, and if we define everything as being zero carryover, companies wouldn't be able to manufacture product,” Hall says. “So the question becomes 'how much contamination is acceptable and how much is unacceptable?' “

Good science—the backbone of a cleaning validation master plan—will determine the cleaning limits, cleaning methods and sampling techniques appropriate for individual products based on their toxicity and pharmacological characteristics. A validation master plan should include the products involved, cleaning objectives and protocols, the manufacturing process and equipment, and the validation plan itself.

Hall: How much contamination is acceptable?
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But developing a suitable master plan that specifies cleaning priorities and tasks could take years to fully complete and demands a significant investment of money, time and personnel resources, particularly on the part of a company's analytical lab. To make it manageable, users should tackle serious contamination issues first, then work through the remainder of the plant.

Users should also remember that equipment cleaning isn't performed out of a sense of benevolence. “It's required by the FDA and the law of the land,” Hall says. “The GMP regulations are official laws passed by Congress, and they require us to consider cleaning.”

Manufacturers like Ganes Chemical have learned the hard way that cleaning is a regulatory requirement. The best advice Smith of Ganes offers to other users is to simply get started on a cleaning program. “You won't be 100 percent successful in every way, but just move through it and learn,” he says. “Part of Ganes' problem in the old days was if a failure occurred, we could not move beyond the failure and that stymied progress. Now we have learned that not everything will be perfect, but we deal with it correctly and move on.”

Follow the rules

Getting started involves looking at the entire scope of what goes on in a facility and developing a matrix that lists equipment and products. Equipment that touches the most products, and products that are particularly toxic or potent, are major sources of contamination. While no single cleaning validation template exists for the entire industry, there are some general rules to follow.

Rule No. 1: Any equipment or utensil that comes into contact with a product poses a potential source of contamination and must be part of a cleaning program. Such items include tanks, mixing vessels, hoses, pipes, drying ovens, lyophilizers, centrifugers, tablet machines, filling equipment and pumps.

Rule No. 2: Distinguish between dedicated vs. multi-use equipment and utensils. Unlike equipment dedicated to a single product formulation, equipment used to manufacture multiple products creates a high risk of cross-contamination and must be part of a cleaning program. However, even dedicated equipment must be cleaned routinely because most product formulations, particularly proteins, are unstable. Particles from previous batches that remain in equipment may degrade when exposed to agitation, high temperatures, pressures and other manufacturing conditions. The degraded material can contaminate a fresh product batch.

Rule No. 3: For each piece of equipment or utensil, determine which method is appropriate for cleaning—either manual or automated clean-out-of-place (COP) or clean-in-place (CIP) methods.

For automated COP, users disassemble equipment and place the parts in an automatic parts washer. For automated CIP, the washer is taken to the equipment. Manual CIP or COP methods require personnel to physically scrub an item or use high-pressure sprays to clean. The equipment itself usually dictates how it should be cleaned. For example, some parts, such as filters, don't lend themselves to CIP methods.

Automated methods are preferred over manual cleaning because they provide more consistent results, are easier to validate and reduce personnel exposure to cleaning agents. However, for automated systems to be effective, the equipment has to be designed with automation in mind. “Trying to retrofit old equipment for automation can be done, but it will require lots of compromises,” says LeBlanc. And in certain cases, manual cleaning is still required for pre-cleaning parts or hard-to-clean areas. Whatever method is selected, users must ensure they can control it, validate it and achieve consistent results.

Moreover, because many pieces of equipment are complicated and difficult to clean, experts recommend using disposable parts, such as plastic or silicon-based tubing, filters and membranes, where possible.

Rule No. 4: Cleaning should always be performed when changing from one product to another on the same manufacturing equipment. For “campaign-style” manufacturing, where multiple product batches are produced successively with the same equipment configuration, cleaning should be performed frequently enough to preserve individual lot integrity. Dry materials can cake and lower the process quality; liquid materials may produce microbial contamination. Users may opt to perform a partial cleaning between batches and a comprehensive cleaning after the campaign's conclusion.

Rule No. 5: After finalizing the appropriate cleaning procedures, validate them to prove to the FDA that they work.

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Validation requires demonstrating a high degree of control, so standard operating procedures (SOPs) must be written with sufficient detail to satisfy the FDA. Items such as detergent concentration, temperatures, water volumes and rinsing conditions should be exactly defined. “The first part is getting a good consistent cleaning process that is adequately defined. The second part is demonstrating in three consecutive process runs that you achieve acceptable residue levels,” says LeBlanc.

For validation sampling, choose the hardest area to clean in a given piece of equipment or groups of equipment. In facilities manufacturing thousands of products, identify the worst-case product, equipment and location, and sample accordingly.

Companies with thousands of products will end up generating tens of thousands of samples, but there's no other option, Hall says. “The FDA expects to see this data when they come in.”

Rule No. 6: Document every cleaning episode in the batch records and equipment log. Get the signatures of the operator who performed the cleaning and a visual witness to it, either a co-worker or supervisor. Maintain a cleaning history of each major piece of equipment so if a contamination issue does arise even years later, the cleaning history can be traced. “Many companies do an excellent job of cleaning, but not documenting that cleaning,” Hall says. “In FDA inspections, companies are guilty until proven innocent, and the only way to prove innocence is to prove that you have done the cleaning.”

Rule No. 7: Schedule regular personnel training on the importance of cleaning. This basic, but often overlooked, aspect of a cleaning validation plan must also be documented.

In addition, after validating a cleaning process, don't make any changes without first evaluating the effect of the change, then completely retraining personnel.

Finally, users are advised to identify critical steps and parameters for cleaning early in the development process. Also, audit outside development and manufacturing contractors to ensure that their procedures are as rigorous as your own. The bottom line: Know your process and clean it well—in every kind of weather.

For additional information on cleaning and cleaning validation, review PDA's Technical Report No. 29, Points to Consider for Cleaning Validation (; 301-986-0293; or the January 2000 issue of CleanRooms, page 18) and the FDA's 1993 cleaning validation guidelines ( html). For information on LeBlanc's book Validated Cleaning Technologies for Pharmaceutical Manufacturing, contact Interpharm Press at (303) 662-9101.

Cleaning studies key to Chesapeake

Cleaning is critical to Chesapeake Biological Laboratories Inc. (Baltimore), a contract manufacturer that has processed more than 150 products for both clinical trials and commercial sale. In fact, the company declines to work with certain toxic and potent products because of potential cross-contamination and cleaning concerns, says Dr. Barry Friedman, director of laboratory services.

Technicians at Chesapeake Biological Labs clean equipment after each product run as part of CBL’s cleaning validation plan.
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“But once we feel comfortable with the material, the first thing we do is run a cleaning study on it,” Friedman says. The material is placed on glass plates or metal pieces called coupons, examined, then cleaned from the glass or metal. Chemists use a total organic carbon analyzer, high-pressure liquid chromatography and other assaying methods to bring the coupons back to background level, thus assuring the contractor “before we ever have the material in contact with our tanks and utensils that it can be cleaned adequately,” Friedman says.

If the cleaning studies indicate sufficient cleaning is possible, the manufacturer performs validation studies to confirm it. But if the company encounters a problem cleaning the material from the coupons, and the problem cannot be solved by going back to the vendor, Chesapeake would either opt not to work with the material or dedicate equipment to it to avoid cross-contamination.

The company's cleaning validation plan was developed simultaneously with the master plan for the Baltimore facility, which includes two ISO Class 5 (Class 100) cleanrooms for filling equipment and one ISO Class 7 (Class 10,000) cleanroom for formulation and tankage. Equipment is cleaned after each product run. Water or steam, either flushed or sprayed at various pressures and temperatures inside of equipment, is the company's preferred cleaning method. Samples are taken with swabs from the hardest-to-clean nooks and crannies of the equipment to document the cleaning.

Chesapeake has learned that not every piece of equipment can be cleaned with water. When water doesn't work, other cleaning materials, such as industry-specific detergents, must be identified and put through the same cleaning studies to ensure they can also be removed from equipment. Cleaning—of product or detergent residue—is one element of a facility's operation that managers can't ignore, Friedman says.—SG


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