Cleaning Validation

By Brian Hammond and Philip Payne

Why cleaning should be a priority in pharma production

No one doubts that cleaning is an essential part of pharmaceutical production. Yet despite the fact that cross contamination can harm or kill patients, cleaning as a discipline is often not given the attention that it justifies. Rather than being viewed as a process in its own right, cleaning is often seen as something that has to be done after the real work has been completed.

The failure to get it right, however, can prove extremely costly, especially with regulators paying closer attention to cleaning validation.

Regulating Cleanliness

Regulators began focusing on cleanliness in 1993 when the Food and Drug Administration (FDA) issued its Guide to Inspections Validation of Cleaning Processes. Several companies received warning letters in 1993 and 1994 for failing to validate cleaning procedures in an acceptable manner (see "FDA Warning Letters," p. 44). As FDA REG 07/01/93 clearly states, "Equipment shall be maintained in a clean and orderly manner. … The FDA expects firms to have written general procedures on how cleaning processes will be validated." What is sometimes overlooked is that the written procedures aspect of validation is as crucial as the actual process, and it is here that some companies often fall short of expectations.

The EU Guide to Good Manufacturing Practice (GMP) makes a similar demand for documentation. A15 section 36 states that "Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure," with cleaning validation defined as documented evidence that an approved cleaning procedure will provide equipment suitable for processing medicinal products.

As with every aspect of pharmaceutical production, people are key to cleaning, and staff must be motivated to recognize its importance. Just as standard operating procedures (SOPs) for production are written clearly to avoid errors, SOPs for cleaning require the same level of detail. It is not sufficient to write an SOP that states only that equipment needs to be cleaned. The SOP must state how it should be cleaned, when it should be cleaned, and with which cleaning agents. Of course, staff also need to be trained to carry out those procedures properly. RSSL Pharma’s own cleaning validation training program offers lessons in how to establish proper cleaning procedures.

Walking the Plant

Walking the plant is an essential skill that can be learned, but it is one that also benefits from years of experience. Its purpose is to make a detailed study of the plant to determine the areas that are at the greatest risk for cross contamination. No feature should be left unquestioned in this process. Walking the plant requires the inspection team to look at everything with a fresh and critical eye, paying special attention to risk areas such as:

• awkward crevices and corners;
• service lines, particularly nitrogen and vacuum;
• dead ends;
• condenser reflux lines;
• screw mechanisms;
• lines that slope uphill to a vessel;
• filter meshes;
• valves;
• sampling equipment; and
• seals and gaskets.

A careful and thorough walk-through conducted by a qualified team will certainly help prevent contamination issues, but the team must have the wider support of the company in order for its findings to be acted on. A thorough inspection will almost certainly identify aspects of plant design that need modification. When possible, it is preferable to "engineer out" the problem areas; the short-term expense in plant design will have long-term benefits in removing problem areas.

The inspection should also determine areas of the plant that may need to be dismantled and inspected following cleaning, while at the same time identifying items that should be manually cleaned rather than cleaned in place.

Documentation

Most important of all is the need to document the team’s findings. The importance of documentation is neatly summarized by this quote from R.F. Tetzlaff, formerly of the FDA, who observed, "If it’s not written down, it’s a rumor."

The inspection should also determine areas of the plant that may need to be dismantled and inspected following cleaning, while at the same time identifying items that should be manually cleaned rather than cleaned in place.

With this idea in mind, certain documents must be in place before cleaning begins. They include the cleaning validation master plan, which defines, among other things, the scope, rationale, cleaning strategy, acceptance limits, and references to methods. A cleaning protocol is also required to define swab points, break- in points, run numbers, and items to be manually cleaned. Cleaning instructions should give detailed information on how to carry out the cleaning sequence, offering the same level of detail expected in a manufacturing instruction.

It is also necessary to record the outcome of each cleaning run with analytical data and recommendations for change. These are the key requirements, but various appendices and sections within the EU Guide to GMP list other documentary records that pertain to cleaning and are needed to provide complete evidence that cleaning is performed in an acceptable manner.

It is worth re-emphasizing the definition of cleaning validation given in the EU Guide to GMP: "Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products."

What Is Clean?

But documentation is only part of the story. After all, there is no point in documenting—and carrying out—a cleaning procedure unless it can be shown to be effective.

Visual inspection can go some way toward exposing a cleaning problem, though contamination will very seldom be visible at levels even approaching the calculated acceptance level. Visual inspection cannot be relied upon as a measure of cleanliness, but it is nonetheless necessary as a first check.

As with all things, there is a good way to carry out a visual inspection and a bad way. Before any visual inspection, it is necessary to understand and have available all procedures and documentation. It is also important to know what condition the plant was in before the cleaning began. Thereafter, all areas of the plant must be examined thoroughly. This investigation may require use of a powerful flashlight and suitable inspection mirrors, making sure the plant has been dismantled sufficiently to allow inspection of all product contact surfaces. Particular attention should be paid to hard-to-see areas such as the underside of the vessel roof, inlet ports, baffles, or stirrer blades. Carefully recording all observations and comparing results with historical data should allow the observation of any changes that require a further cleaning exercise.

Because visual inspection can only go so far, it is common practice to swab test. Swabbing is an art in itself, however, and all attempts to validate cleaning procedures are meaningless if the swabbing is not carried out properly. The same is true if the analytical method applied to the swab is inappropriate. Validating the analytical method is as important as validating the cleaning process.

Sampling and Testing Issues

Regulators require verification data for cleaning, which largely means providing test results that show that the plant is clean to an acceptable level.

Various sampling techniques can be used to provide material for testing. One such technique is rinse sampling, which can cover a much larger sample area than any other method but cannot guarantee that the rinse will remove all contamination, especially from hard-to-see pipework. In short, not all pieces of equipment can easily be rinsed, and in any event, rinse sampling is roughly equivalent to determining the state of domestic dishwashing by measuring the amount of dirt that is left in the sink water. (In other words, it’s not very conclusive.)

Placebo testing is sometimes used, but this method relies on the risky assumption that any contamination will be evenly spread through the placebo batch. Because it also dilutes the sample, making accurate analysis difficult, some regulators find it unacceptable.

Swab testing is probably a better technique than either rinse sampling or placebo testing, because it can be used to test the cleanliness of difficult areas and hard-to-remove contamination. This method relies heavily on the skill of the operator and on the quality of the analytical validation, however.

Because their role is so vital to successful swab testing, operators must be properly trained. Indeed, lack of training is one of the biggest sources of error in cleaning validation. It is also important to carefully choose the swab points and to list these in a cleaning protocol. Finally, it is vital that sampling equipment does not introduce contaminants.

Method Validation

Because their role is so vital to successful swab testing, operators must be properly trained. Indeed, lack of training is one of the biggest sources of error in cleaning validation.

Analytical method validation can be a complex and time-consuming process, and for many pharmaceutical companies, outsourcing to a specialist laboratory is preferable to committing in-house R&D expertise to this function. Indeed, a good laboratory practice-compliant third-party laboratory with method validation expertise and testing resources will often save both time and money in method development and routine analysis.

Clearly, there are some issues to address if testing is conducted off-site, most particularly to ensure that the swab is not further contaminated during transit and that any residual chemicals that need to be assessed are stable enough to be analyzed once the sample reaches the laboratory.

Clean Now, Benefit Later

Society often views cleaning as a low-paying job for workers with low level skills, but in the world of pharmaceutical production that is a dangerous attitude. Cleaning should be seen as a process in the same way that actual manufacturing is seen as a process. It is integral to the production of safe pharmaceuticals, not merely the job that has to be done when the most important task is completed.

FDA guidelines are very clear in their expectations with respect to cleaning, and they underline the fact that any company that fails to validate its cleaning is at risk of regulatory action. While validation is often seen as a time-consuming and expensive exercise, it has the potential for dramatic payback when done properly. When compared with the cost of unnecessary testing and the major expense of having to withhold and destroy contaminated product, the one-off expense of validation is negligible. By paying more attention to walking the plant, maintaining good documentation, and training staff in swabbing techniques, pharmaceutical companies can go a long way toward ensuring the production of safe pharmaceuticals.

Hammond is a cleaning validation consultant and Payne is a business development manager at RSSL Pharma. For more information, contact Payne at philip.payne@rssl.com or +44-0-1189-868541.