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In-Situ
In-situ measurement techniques have shown promise oflate due to the fact of their
ease of use. They arequick, requirenosample preparation, are non invasive and are
in line with the FDA’s position on process analytical technology (PAT).
Two in-situ measurement techniques that are being researched for use in
cleaning validation are spectroscopy and TOC measurements.
Mid-infrared (IR) grazing-angle spectroscopy is one of the most sensitive
in-situ techniques for measuring low contaminant concentrations on reflective
surfaces. One study used a mid-IR spectroscopy method and a grazing-angle
sampling fiber optic probe to detect and quantify small amounts (a few m g/cm 2 )
of organic material on metal surfaces. Results suggest that it provides a performance
advantage over traditional HPLC-swab methods (18).
Another in-situ measurement technique that is applicable but is an indirect
measurement of residual containments is the use of in-process TOC tomeasure the
rinse water at the end of the rinse cycle.
Considerations for Cleaning Validation of Single vs. Multi-Products
For multi-product equipment, cleaning and cleaning validation is quite expensive.
For asmall campaign, it doubles the cost of aproduct. Aone week campaign can
result in another week of cleaning, cleaning verification and cleaning validation
(17). Some companies have developed fairly innovative ways to manage cleaning
new products by not only grouping products by their physical recovery properties,
but also grouping equipment trains into logical assembles of use. It is then possible
to perform three consecutive batches of aparticular product group instead of a
specific product.
The degree or level of cleaning and validation required depends largely on
whether or not the equipment is dedicated to a single product, the stage of
manufacture, and the nature of the potential contaminants (toxicity, solubility,
etc.). In general, the higher the potential for finished drug product contamination,
the more important it is to validate cleaning procedures to assure product safety.
For cleaning validation programs in multiple product facilities, it is important
to create amatrix of the solubility coefficients for the actives to determine the worst
case from acleanability standpoint. Since most cleaning procedures are independent
of the material, the worst case active material can be the indicator material for
TABLE 1 Levels of Cleaning Validation
Cleaning
level Situation Validation
Lankford
LEVEL 2 Product changeover of equipment used
in final step
Intermediates of one batch to final step
of another
Validation is essential
LEVEL 1 Intermediates or final step of one Progression between level between 0
product to intermediate of another
Early step to intermediates in aproduct
sequence
and 2depending onprocess and
nature of contaminant based on
scientific rational
LEVEL 0 In-campaign, batch to batch changeover No validation required