The journey from product development to market launch requires a trip down a critical side road: cleaning validation.
Outside experts can help you navigate the course, but they can't complete it alone. Here's a look at how to choose and work successfully with a cleaning validation consultant
by Sheila Galatowitsch
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Cleaning validation is one of the most complex types of validation performed on a manufacturing process and one in which regulators brook no shortcuts. Yet many small- and mid-sized pharmaceutical, biotech, medical device and cosmetics manufacturers simply don't have the in-house microbial, chemical and analytical experts to do the job. Or a company's full-time staff has the expertise, but not the depth of experience necessary for creating and executing a cleaning validation plan that will satisfy the most rigorous regulatory requirements.
That's when it's time to call in outside help-those cleaning validation experts with long years of experience in industry, academia and government service. They help cleanroom users conceive master plans and write protocols, collect and analyze samples, train employees and prepare standard operating procedures.
“It's too expensive for many companies to keep a cleaning validation specialist on staff, someone who keeps abreast of where the technology is and where the regulatory bodies are moving. Most companies just aren't big enough,” says Allan Pfitzenmaier, president of Vectech Pharmaceutical Consultants, Inc. (VPC; Farmington Hills, MI), which designs critical systems and provides a range of consultation services, including cleaning validation.
Even those companies with in-house experts may want to benchmark how other companies are approaching cleaning validation. “A consultant has seen the good, bad and the ugly of cleaning validation plans,” says VPC consultant Dr. Jeanne Moldenhauer. “Plus, we are able to deal with the FDA and other regulatory bodies without identifying specific companies. We can pose questions about a particular approach a company might want to evaluate and find out what would be acceptable, then bring that back to the user.”
Perhaps the greatest advantage of using a cleaning validation partner is that as an outsider, he or she can focus on the ultimate goal without any distraction, says Dr. Bill Hall, a consultant based in Kure Beach, NC. “Manufacturers are focused on other aspects, such as how to develop the process and manufacture the product, the toxicity and potency of product and bringing it to market. As overburdened as typical workloads are these days, it would take much longer for in-house personnel to complete a cleaning validation project if they did it on their own.”
“There are always twists and turns that projects take. However, with proper planning and foresight, serious problems should be prevented, leaving only those minor to moderate in severity. You can work your way through those with good scientific input and managerial judgment.”
– Dr. Jim Akers
Finding the right partner
Ultimately, you want a cleaning validation consultant to provide guidance that is defensible with regulators, so choose your partner wisely. First, users should carefully evaluate the credentials and expertise of a consultant before employing his or her services. Look for specific expertise in your industry niche. Some consultants work exclusively with solid oral dosage facilities, while others specialize in aseptic processing. Talk to industry colleagues for references and recommendations. “Make sure that the consultant is not a 'self-declared' expert but one that the industry has declared is an expert,” says Hall.
Check out a prospect's knowledge of microbiology, chemistry and biochemistry, and their experience in setting limits and working with regulators. Talk to other clients the consultant has worked with, then confirm that the company received the validation and determine if any warning letters or 483s (GMP violation citations) were issued.
“No matter who you select, look for someone with a lot of experience,” advises Jim Wilson, who earlier this year retired from his post as vice president of quality assurance and regulatory affairs at The Validation Group (Conshohocken, PA), a cleaning validation and consulting services company. He now works part-time with the company on selected projects. “The range of acceptance criteria at the FDA varies widely; you should select someone who understands this, has been through it with other companies and knows the FDA's preferences.”
Know what you want and be prepared to discuss it with the consultant on the first call. Create a checklist that includes the product(s) under discussion, which regulatory requirements you need to meet and what work must be done to complete the cleaning validation. Do you already have a master plan or do you need help in creating one? Prepare specific questions for the consultant on any topics of concern, such as rotating disinfectants and the type of reports required for cleaning validation.
Define the services you need from a consultant. Do you need guidance on certain problem areas or are you looking for a firm to help plan, then implement the project? Large consultancies can provide extra “hands” to do the cleaning validation work itself-the swabbing, testing and writing of reports. Find out about the experience and background of the people who will be doing this work. “Talk to the technical types and not the marketing guys. Otherwise, you only get the commercial perspective. That's the gravest mistake companies can make and could lead to bad decisions,” says Wilson.
Users should also consider a consultant's personal characteristics, advises Dr. Jim Akers, a microbiological contamination-control consultant with Akers Kennedy and Associates (Kansas City, MO). “Find someone who is compatible with the operational style of the organization. You don't want to bring in someone who will butt heads with the project team and unnecessarily ruffle feathers. A consultant's personality, operating style and how they deal with pressure and difficult situations has a lot to do with their effectiveness.”
Companies that make an informed decision at this stage of the partnering process have the most successful validation projects and, in the end, save both time and money. Another ingredient for success: senior management buy-in. “If you don't have a high-level of commitment, your project won't work,” says Pfitzenmaier.
“Manufacturers that give consultants free reign and have no buy-in don't succeed as well as companies that take more responsibility. Plus, they spend more money than necessary,” says Moldenhauer. “Companies need to take control and be involved at some level-even if all they have is a trained person to maintain the system and who understands when it needs to be re-qualified.”
Bringing the partner in
Some companies have the foresight to see that cleaning will be a big issue and bring in their cleaning consultant early in the process, as early as initial start-up and equipment qualification. Others, however, don't appreciate the full value of a cleaning program until late in the development process when they become aware that cleaning validation is a drop-dead issue, “meaning, if we don't have it, the FDA will not approve our product,” says Hall. “And sometimes they know an FDA inspection is imminent. Ideally, it's better for a company to determine what their needs are early on. It's always a frantic effort to put out a fire when a product is going to market.”
“Even if you talk only by telephone, you can begin to coordinate among the environmental monitoring program, HVAC and the equipment validation. Integrate those segments early in the process and that will minimize the work that you do,” says Moldenhauer.
Cleaning validation can also be addressed for specific products in the development process. “Typically there is a document that is handed over at the end of development to the production people who must manufacture the product. This document is called a 'development transfer report,' and even though the initial work was done on a small scale in the development lab, the researchers will be concerned with how to clean the product,” says Hall. “They will have developed a cleaning procedure based on the dosage form and preparation of the drug, and how difficult it is to dissolve and wash off. That information should be transferred to the product people by means of this report.”
Once the partner is onboard, the parties meet to assign tasks based on the work that needs to be done, such as completing an initial review of the company's objectives, determining the current status of those objectives and what documents are already available. “Typically, you want to make a program consistent with an existing document. On the other hand, the existing document may have to be modified and brought up to date,” says Destin LeBlanc, a consultant with Cleaning Validation Technologies (San Antonio, TX).
Depending on a company's resources, it might want to have the consultant involved in writing the protocols, executing the validation and collecting the swab, rinse or environmental monitoring samples, then analyzing the samples. If the company does not have sufficient analytical facilities, the consultant might act as a liaison to secure those services from an outside firm. Whatever the tasks are that both parties agree to perform, they should be outlined upfront in a quality agreement or written and enforceable contract and not left to chance.
The tasks should also be defined in the working master plan, a document that outlines the cleaning validation strategy, assigns responsibilities and a time schedule to each activity, addresses the expectations of regulatory inspectors and controls the overall process leading to validation. It is a collaborative effort between the consultant and representatives from the manufacturer's quality, validation, engineering and manufacturing departments.
The master plan clearly states the objectives of the cleaning validation. It describes the products and facilities covered, and outlines the cleaning validation approach. It should define the level of validation necessary for each process that requires cleaning and identify the acceptance criteria limits in general terms for each specific unit operation or process; how and when the product or equipment will be sampled; how the samples will be handled; who will write results of studies and the final report; who signs off on the documents and the criteria of acceptance of the report as complete. It should also include a training program and preventive maintenance program. According to VPC, the master plan defines “what is to be done and not how it is to be done.” The latter is defined in the cleaning validation protocols.
One way to avoid problems during the validation itself is to ensure that both parties agree on the definition of key terms. Other problems arise when changes are made after the parties have already committed to the final agreement and master plan, or when deadlines are not respected and support staff not made available as outlined in the agreement. Create a system in advance to address problems that will arise, advises Moldenhauer.
That includes a team approach to problem solving and a change control procedure. Any changes contemplated to the validation process should be reviewed by the appropriate expert before changes are made, including a review if the change would require a re-validation of the manufacturing or cleaning processes.
Even with detailed, upfront planning, unanticipated technical and logistical hurdles crop up. “There are always twists and turns that projects take,” says Akers. “However, with proper planning and foresight, serious problems should be prevented, leaving only those minor to moderate in severity. You can work your way through those with good scientific input and managerial judgment.”
Planning for success
Cleaning validation is notoriously the hardest validation to complete successfully, and the failure rate skyrockets if companies neglect preliminary process development work, says John Clapham, project manager for Pharmaceutical Services Corp. (Pasadena, CA), a cleaning validation consulting firm.
Such advance work includes setting meaningful acceptance criteria limits for potential contaminates, cleaning agents and the pharmaceutical or biologic products; and validating the analytical methods on the laboratory instrumentation that the manufacturer will use to monitor the process equipment and cleanroom. “Since all cleaning validation results, including failures, must be recorded and explained to the FDA, you want a minimum amount of deviations and ones that can be easily explained. Process development work identifies flaws in the firm's cleaning validation program and is the key to success,” says Clapham.
For example, some companies get into trouble when they set acceptance criteria limits too tightly. “Acceptance criteria limits have to be developed from the actual cleaning procedures for the room. They must be scientifically sound and based on well-developed rationale. More often than not, firms will choose acceptance criteria that are not suitable and will fail on their cleaning validation,” says Clapham. The master plan should detail how cleaning validation excursions-samples that don't meet acceptance criteria-will be handled.
Another way to plan for success is to emphasize proper sample collection. “Many failures happen during sampling because samples are not collected properly. Contaminates are introduced accidentally during sampling, causing a sample to appear that it failed when in fact it was a sample collection problem,” says Clapham.
Consultants can help users steer around these kinds of common pitfalls, ensuring a successful cleaning validation and, ultimately, a smooth product launch.
Sheila Galatowitsch is a special correspondent to CleanRooms Magazine.
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What it costs
Many factors influence the cost of using a cleaning validation consultant: the amount of work the consultant will perform vs. the work performed by the user; the number of products, cleanrooms and disinfectant agents involved in the validation; whether the validation covers equipment as well as the cleanroom itself; how much data is available before starting the validation and how well the cleanroom was designed for cleaning.
Expect to pay anywhere from $500 to several thousand dollars per day plus travel expenses, which doesn't include associated costs like analytical testing fees if those are outsourced through the consultant. Although it may take as long as several months to complete a cleaning validation project for a single product, consultants will bill only for those hours and days spent working on your job.
Cleaning validation defined
Documented proof that a product or piece of equipment can be consistently and effectively cleaned to predetermined levels of acceptability.