Chemistry Reference
In-Depth Information
7.7.2.1 sampling methods
Sampling methods can include swabbing, rinsing, boil-outs, and direct extractions,
as appropriate, to detect both soluble and insoluble residues. The sampling method
used should be capable of quantitatively measuring levels of residues remaining on
the equipment surfaces after cleaning. From the FDA perspective, any direct method
of sampling the surface of the equipment is the most desirable. The most common
direct-sampling method is swabbing. A swab sample is obtained by wiping a surface
with solvent-moistened cotton gauze. Using swabs, equipment areas that are hardest
to clean but that are reasonably accessible can be evaluated, and a level of residue
or contamination per surface area can be determined. Also, dried-out or insoluble
residues can be sampled by physical removal. It is important, however, to determine
that the sampling medium and the solvent used for extraction from the medium do
not interfere with sample analyses. For example, the adhesive used in some swabs
has been found to interfere with sample analysis [51].
In some cases, rinsing may be preferred to swabbing. Rinsing can sample a larger
surface area and inaccessible equipment areas. However, if the residue or contam-
inant is not soluble in the rinse solution, ineffective cleaning will result. During
validation, therefore, one must still examine the equipment (the proverbial squeaky-
clean test!), not just the rinse solution used for cleaning. Boil-outs are a variation on
rinsing that involve the refluxing of a solvent to clean internal surfaces. However,
boil-outs are not always feasible for piping or portable equipment. CIP sprayers or
misting nozzles can facilitate the cleaning of hard-to-reach areas.
7.7.3 v
AlIdAtIng
c
leAnIng
m
ethodS
Validated analytical methods must be used to detect residues and contaminants.
Validation of analytical methods used to assay residues and contaminants employs
the same principles as those used for the finished product. In general, equipment-
cleaning methods should provide consistent and reproducible results. The quantita-
tion limit for each analytical method should be sufficiently low enough to detect
the established level of the residue or contaminant. If residue or contaminant levels
are not detected, it does not mean that they are not present in the sample. The ana-
lytical method should be challenged in combination with the sampling methods to
show the level at which the compounds of interest can be determined. A negative
test may just be the result of a poor sampling technique. The recovery and specific-
ity of the method should also be established. Appropriate documentation should be
maintained to prove that critical parameters, such as time, temperature, turbulence,
cleaning agent concentration, number of rinse cycles, etc., are achieved with each
cleaning cycle.
Several different types of analytical methods are used to evaluate equipment
cleanliness. In general, methods are classified as either residue nonspecific or residue
specific. Residue nonspecific methods include TOC, colorimetric assays (for protein
residuals), UV/VIS absorbance, and conductivity testing. As mentioned previously,
TOC analyses are commonly used because most contaminants contain organic car-
bon. TOC is relatively easy to perform and is compatible with most sampling tech-
niques; however, it is not very specific. One potential drawback to TOC testing is that
