Dispelling Cleaning Validation Myths: Part I C

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. 
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.
1. http://www.fda.gov/ora/inspect_ref/igs/valid.html2. PIC/S Document PI 006-2 http://www.picscheme.org/
3. http://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. http://www.fda.gov/cder/guidance/cGMPs/equipment.htm
Destin A. LeBlanc is a consultant at Cleaning Validation Technologies, San Antonio, TX, USA.

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