Dispelling Cleaning Validation Myths: Part I A

By: Destin A. LeBlanc
Every regulated technology seems to come up with a list of what regulatory authorities supposedly say you should and should not do. Cleaning validation for pharmaceutical process manufacturing equipment is no different. Unfortunately, while many of these 'thou shalts' and 'thou shalt nots' have a partial basis in fact, they are actually distortions of the truth that come to have a life of their own. Hence I call them myths even though cleaning validation is only about 15 years old.
This article will explore eight of these myths and attempt to explain the origin of each (although in many cases the explanation of the origin is just speculation on my part). In addition, I will try to explain why the myth is wrong, how something seemingly prohibited can be properly used, and how those things apparently required may be unnecessary.
My list of myths is not intended to be exhaustive. The first three are examined in Part I of this article. Myths 4–8 will be covered in Part II to be published in a forthcoming issue.
1. Regulatory authorities do not like rinse sampling.
2. You must correlate rinse sampling results with swab sampling results.
3. You cannot use nonspecific analytical methods.
4. If you use total organic carbon (TOC), you must correlate it with a specific method, such as HPLC.
5. Any measured residue is unacceptable.
6. Dose-based calculations are unacceptable.
7. Recovery percentages of different spiked levels should be linear.
8. You cannot validate manual cleaning. Myth 1

Key points

The notion that regulatory authorities do not like or allow rinse sampling is false. FDA's cleaning validation guidance says: "There are two general types of sampling that have been found to be acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions."¹ Some may want to emphasize that because direct sampling (i.e., swab sampling) is more desirable, it must follow that rinse sampling is less desirable. Although there may be certain logic to this, it overlooks the clear statement that both methods are acceptable. The Pharmaceutical Inspection Cooperation Scheme (PIC/S) guidance document says: "There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions)."² Again, this is a clear statement that rinse sampling is acceptable. I should point out that the PIC/S document goes on to say that a "combination of the two methods is generally the most desirable."
Why, therefore, has the myth arisen that rinse sampling is unacceptable? In the early days of cleaning validation, rinse sampling was used inappropriately. For example, some companies using rinse sampling set limits such that the rinse sample was acceptable if it met compendia specifications. In other words, they worked by the maxim: "water-for-injection [WFI] in, WFI out, therefore, my equipment is clean." This use of rinse sampling is inappropriate, but still survives despite the fact that FDA's guidance document clearly states that "...it is not acceptable to simply test the rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates [sic]."¹ I should make it clear here that you can use TOC to measure a contaminant in the rinse water. However, the acceptance limit of TOC is not automatically 500 ppb: it must be justified based on traditional limit calculations, and may be higher or lower than 500 ppb.