Dispelling Cleaning Validation Myths: Part I

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

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.

Key points

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.

Rinse sampling has also been misused by not performing recovery studies. A concern of FDA (expressed in its guidance document) is the dirty pot analogy.¹ Do you determine the pot is clean by evaluating the pot or the rinse water? One obvious answer is to test the pot. However, another is to test the rinse water providing it can be established that any residue on the pot would be present in the rinse water. Just as recovery studies for swab sampling are done by spiking model surfaces with the target residue and then sampling by the swab procedure, rinse sampling recoveries should also be performed by spiking model surfaces with the target residue and performing rinse sampling on those surfaces to demonstrate quantitative recovery.

Lab rinse sampling recoveries cannot replicate production equipment rinsing. However, it is possible to simulate the rinsing conditions to demonstrate whether the rinsing process quantitatively removes surface residue. If it does demonstrate acceptable recovery, then the dirty pot analogy has been overcome. Where rinse sampling is used to demonstrate cleanliness of inaccessible surfaces (for example), rinse sampling recoveries should be performed to 'validate' that method. In this scenario, quantitative recovery is not 100% recovery. The acceptable recovery level is generally the same as that for swab sampling, which can vary from about 50–75%.

I believe the misuse of rinse sampling has lead to the myth that its use is unacceptable. Correct use of rinse sampling includes

• Carefully defining and controlling the rinse conditions.

• Performing a rinse recovery study.

• Making sure what you analyse is a direct measure of the target residue.

• Setting limits for that target residue (in the rinse solution) based on scientific principles.

Myth 2

This is the idea that to use rinse sampling, you have to correlate it with swab sampling results. If what you mean is: "I need to make sure I get passing results by both swab and rinse samples," there may be an element of truth in this. However, if what is intended is that there should be a direct 1:1 (or similar) mathematical relationship between swab and rinse sampling values, then it is unreasonable to expect this to occur. Why? Swab sampling and rinse sampling measure two different things.

Swab sampling involves measuring the residue on a small area, which generally includes the worst-case locations (those most difficult to clean or likely to have unacceptable residue if cleaning is inadequate). However, rinse sampling covers a much larger surface area (perhaps the entire surface area of a manufacturing vessel), and, therefore, essentially averages the residue over all sampled surfaces. If failure occurs in swab sampling, it is reasonable to expect it to come from the worst-case locations and that, perhaps, other swabbed locations provide acceptable results.

If such is the case, it may be possible (if not probable) that a rinse sample will give acceptable results. But, if rinse sample results are unacceptable, you can expect that at least one swab sampling site should have failing results. The assumption in this is that you have calculated your limits appropriately (and did not do something such as set rinse limits based on compendia specifications for water).

I find it difficult to speculate on this myth's origins, except perhaps from an overzealous analytical group. Cleaning validation is hard enough in terms of ensuring necessary resources are available. Performing studies to mathematically 'correlate' swab and rinse sampling values does not add any value. What's more, do not expect them to mathematically correlate.

Myth 3

It is amazing how this one myth, that nonspecific methods are either unacceptable or less acceptable than specific methods, persists. Specific methods measure the target analyte (usually a given compound) in the presence of expected interferences.³ Specific methods include HPLC developed for a given compound.

Nonspecific methods measure a general property, but do not determine what compound that property is a result of. Methods include TOC and conductivity. TOC measures the organic carbon in a sample. In finished drug manufacture, the measured organic carbon in a cleaning validation swab sample may exist because of any combination of the active, excipient(s) and cleaning agent (as well as contributions for the blank, which could include the water, the swab and the vial).

Somehow, nonspecific methods are viewed as less robust than specific methods. In fact, for cleaning validation, using a method such as TOC actually makes it more difficult for a manufacturer to meet its cleaning validation acceptance limits (again provided the limits are set correctly and the TOC data are converted appropriately into the target residue).⁴ If such methods were unacceptable, almost all biotechnology facilities would be shut down because TOC is used widely in the industry for measuring residues of the actives (in biotech, TOC is usually measuring degraded actives, but the measured TOC is expressed as if it were the undegraded active).

The use of TOC is further supported by a Human Drug Current Good Manufacturing Practice (cGMP) Note from FDA in which it states: "We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation."⁵ The cGMP note was replicated as a "Q&A for cGMP for Drugs" in 2002.⁶ FDA goes on to state the conditions that should be adhered to if TOC is used as the analytical method. However, the implication is that such methods are acceptable if used correctly.

Where did the myth come from? My speculation is that it came from using TOC as an analytical method, but only setting limits based on compendia water specifications (that is, 500 ppb TOC). It should be clear from the Myth 1 discussion that in this case TOC is an unacceptable method (correctly stated, it is the limit setting that is unacceptable, but it is easy to see how this became "TOC is unacceptable"). This is further complicated by a statement in the PIC/S guidance document that analytical methods for measuring residues "should be specific for the substance assayed".² Could this be interpreted that only a "specific analytical method" be used? Again, such an interpretation would wreak havoc with the biotech industry. If a specific analytical method was required, the statement would be more explicit. This statement is probably akin to that in FDA's guidance that for rinse samples, "a direct measurement of the residue or contaminant" should be made.¹ Is TOC a direct measure of an organic active? I would argue that it is. This conundrum of what is meant in the PIC/S guidance should be recognized, but it should not deter us from using TOC appropriately for cleaning validation purposes.

Some believe that FDA's guidance document requires specific methods. What it actually says is that you should "determine the specificity and sensitivity of the analytical method...."¹ This is a far cry from requiring specific methods. A more reasonable interpretation is that you should understand the specificity of your analytical method, and take that into consideration as you utilize that method so that it is used correctly.

This brings us to the issue of using nonspecific methods such as TOC correctly. For simplicity, I will discuss the correct use of TOC. One FDA requirement is that the TOC appropriately oxidize and measure the organic species in the target residue.⁶ Therefore, you will perform analytical method validation using the residue and TOC to confirm the method's applicability. Applicability indicates that the target residue is appropriately oxidized, and that it is appropriately water soluble such that it can be measured.

Another requirement is that any detected carbon be attributed to the target residue. The carbon in a sample may be partially from the active, excipients and cleaning agent. However, we are not allowed to apportion the measured carbon among these different sources. If we use TOC, we must consider (as a worst-case assumption) that all the carbon is because of the target residue (the active, if that is the target residue). FDA also states that you "should limit background... as much as possible." Why? Because it is just good practice to decrease the background (the TOC blank) to as low and as consistent a value as possible. This is why low TOC water, ultra-clean swabs and precleaned vials are typically used for swabbing with TOC. A final requirement is determining sample stability to confirm method applicability under expected holding conditions (post sampling, before analysis). Of course, this last requirement is relevant to any analytical method. There are other TOC requirements that are common to all analytical methods, including performing sampling recovery studies.¹ The bottom line is you can use TOC, but use it correctly.

Summary

Recognition of these myths, and their lack both of scientific and written regulatory justification, can help companies avoid unnecessary work that adds little or no value to a cleaning validation programme.

References

1. www.fda.gov/ora/inspect_ref/igs/valid.html

2. PIC/S Document PI 006-2 www.picscheme.org

3. www.ich.org

4. D. A. LeBlanc, "Why TOC is Acceptable", Cleaning Memos3, Cleaning Validation Technologies, 24–27 (2003).

5. FDA, Human Drug cGMP Notes, 1st Quarter 2002, PDA Letter 38(9), 9–13 (2002).

6. www.fda.gov/cder/guidance/cGMPs/equipment.htm

Destin A. LeBlanc is a consultant at Cleaning Validation Technologies, San Antonio, TX, USA.