Dispelling Cleaning Validation Myths: Part I B

By: Destin A. LeBlanc

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 2This 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).

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