“Cleaning, how hard can that be,” is the sentiment of those not in the bio/pharmaceutical industry. Even for those within the industry, the general consensus regarding Cleaning and Cleaning Validation is that it is something best avoided and that once it is done, it is best forgotten. No one wants to relive that nightmare. But the reality of the New Process Validation Guidance from the FDA means that the industry needs to verify, control and improve previously completed cleaning process validations.
Certainly cleaning is a science that has been practiced in numerous industries for many years, but no other industry is more greatly impacted by critical process cleaning than that of the bio/pharmaceuticals. Clearly the repercussions of residuals and cross-contamination may have very real consequences on lives and corporate profitability. The importance and impact of cleaning and its documented cleaning validation have been clearly stated in numerous government regulations, industry articles and community conferences. Those vehicles have established minimal expectations and explored facets of cleaning validation programs’ improvement.
The understanding and adaptation of rudimentary critical process cleaning and cleaning validation have now been adopted by most bio/pharmaceutical companies. Certainly there is a broad spectrum of cleaning program development in the United States and abroad ranging from protocols verifying visually that the critical process manufacturing is “free” of residuals to well documented development, implementation and qualification of cleaning skids and process equipment. Some companies have even invested in hiring cleaning validation experts to ensure an effective and compliant program is in place.
But is that where the thinking ends? Is there no room for innovation and process improvement especially where the age of risk assessment in process validation has dawned? Some large companies with numerous systems and assets to clean have developed grouping strategies to reduce the number of validation runs or soils on which to analytically demonstrate cleanliness. But grouping strategies are not a novel concept to the field of equipment qualification. Are there challenges that plague manufacturing operations groups that could be addressed in a scientific manner, yielding data to effectively demonstrate to Quality groups and Regulatory Inspectors alike that efficiency does not simply mean short cuts but instead represents process improvements backed by science that deliver the a high quality of product at a reduced cost of goods?
Three issues that should be considered immediately are how a manufacturer deals with dirty hold transgressions, handles clean hold transgressions and manages hold times on small equipment pieces and utensils.
As part of the cleaning validation process, the time from when process equipment is no longer manufacturing to when the cleaning process starts is considered the Dirty Hold Time (DHT). Does a water soak of the equipment stop the validated DHT clock? In cases where unforeseen delays occur prior to beginning the validated cleaning cycle, does a quick water rinse facilitate and/or change the character of the validated cleaning cycle? Should all various hold permutations be conducted as part of the cleaning cycle development and the worst case scenario validated and both documented?
Likewise, the time from when a validated cleaning cycle ends to when process equipment is used in the next manufacturing process is called the Clean Hold Time (CHT). When process equipment is used beyond that validated time window, what are the concerns? If the equipment is stored such that assurances can be had that no other soils have been introduced and that microbial concerns are controlled for, what other activities and/or data does a manufacturer need to produce to safely use the equipment in the subsequent process? Can the risk of use be easily mitigated with demonstration data? Has it the cleaning cycle has lost its effectiveness? Or is it more of an environmental control issue?
Similarly but with more intricacy, when small parts, such as spool pieces, probes and reagent utensils, are lost or chain of custody cannot be demonstrated, what is a manufacturer to do? Should the manufacturer consider disposables? Is that expense even feasible? How many manufacturers, especially those making multiple products at one site, have a color or bar coding system in place?
These thoughts and questions should spur much discussion in corporations with well-developed cleaning and cleaning validation programs. For companies just establishing their cleaning validation program, forethought into designing risk mitigating studies and subsequent qualification protocols to address these concerns may make future operations more efficient, compliant and lower cost of goods. The era of continued process verification and improvement has only begun and new issues concerning critical process cleaning will only increase.
February 22, 2013
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