Searching for nothing would seem to be an absolute waste of time — unless you are responsible for cleaning validation. In that case, success is deliciously ironic since you can say, “I found nothing and that’s good news.”

But perhaps we should start at the beginning.

Those involved in the manufacture and quality control of pharmaceuticals and biotechnology products are aware of the need to prove that the production equipment and the manufacturing environment are sufficiently clean such that the next lot of product will not be contaminated by materials from the previous lot (i.e., cross contamination will not be an issue). The procedures and documentation for that proof constitute what is known as cleaning validation. Essentially, one wants to prove with a high degree of certainty that any residues of drug product from a manufacturing lot and any residues of cleaning agents used to remove those drug residues, are below acceptable limits. To put a fine point on it, we’re not exactly searching for nothing (as in a zero value), but for extremely low values of residues — both drug product residues and cleaning agent residues.

CLEANING VALIDATION
Cleaning validation can be considered a three step process, involving 1) thecleaning and rinsing of the requisite surfaces, 2) sampling any drug or cleaningagent residues that might still remain on those surfaces and, 3) analyzing thesampled materials with the appropriate instrumentation. Steps 1 and 2 are manual,sometimes tedious procedures, but only if they are done properly do they permitaccurate results to be reported in Step 3. The cleaning of surfaces (what cleaningagents to use, how to do the cleaning, etc.) and the analysis of the sampledmaterials (calibration curves, limits of detection) are themselves fascinatingtopics (at least to some people), but they are not our focus here. For this discussion,we will look only at Step 2 — the procedures that enable one to samplea cleaned surface with a high degree of reproducibility, to ensure that whatis reported in Step 3 truly represents the condition of the sampled surface.

It may seem intuitively obvious, but one does not begin the cleaning validationprocess until there is an absence of visible residue on the surface. Residuesare visible at surface concentrations of between 1 and 4 ug/cm2. The simple ruleis that if you can still see residues on the surface, forget about any samplingactivities, you haven’t finished Step 1 — the cleaning activities.

Figure 1: A polyester knit swab used for surface sampling

SAMPLING SURFACES WITH SWABS
Assuming the surface is free of visible residue (i.e., that the cleaning stage is done), the challenge is now to sample that surface in a reproducible manner so that any (invisible) residues, present in extremely small amounts, are collected and delivered to the instrument for measurement. The best type of swab for sampling is one with a head made of laundered polyester knit fabric (Figure 1), since that material provides the lowest levels of releasable particles, the highest recovery, and the lowest background when total organic carbon (TOC) measurements are employed as the analytical technique. To sample the surface, the swab is moistened then drawn across the surface in a thorough and reproducible manner to collect any residue into the interstices of the polyester knit fabric. The swab is then deposited into a suitable collectionvial, then the residues extracted from the swab head for subsequent anaysis.

It is worth devoting a moment to the technique for moistening a swab, since errors in technique here will lead to inconsistent results. There might be a temptation to simply saturate the swab head with high-quality (e.g., TOC-grade) water to do the residue collection. This will cause problems, since the excess liquid on the swab head will simply spread the residue over the surface to be sampled and will not allow the residue to be picked up reproducibly into the swab fabric. For best results, the swab should be damp, but not saturated. This is best accomplished by immersing the head into a container of high-quality water, and pressing both sides of the swab head against the side of the container a few times to expel any air trapped in the fabric and allow the water to fully penetrate the fabric. Then the swab head is raised out of the water and the flat sides of the swab are drawn across the rim of the container to expel excess water and leave the swab head moist. The degree of moistness of the swab head (otherwise known as the percent wetting level) need not be identical from run to run, since residues will be picked up over a fairly wide range of swab headmoistness.