Cleaning Procedures

Pharmaceutical equipment cleaning procedures are detailed in written documents to ensure that the equipment is cleaned in a consistent manner, according to a validated process. The level of detail in these cleaning protocols will vary depending on the complexity of the equipment and the nature of the product residue being removed from the equipment. Normally, the protocol will specify equipment disassembly requirements, the type and concentration of any cleaning agent(s) used, the volume of cleaning solution, the types of rinse solvents used, the number of rinses, and procedures for proper handling and disposal of rinse solutions. In addition, documentation should include procedures for the sampling and testing that are conducted to evaluate the levels of residual contaminants.

11.3 Sampling Plan

The integrity and safety of a pharmaceutical product can be easily jeopardized by the presence of even trace level contamination. Used alone, visual inspection for cleanliness, as evidenced by the lack of visible residues, often will not provide the necessary assurance that the probability of cross-contamination has been minimized. This is especially critical with those drug residues that have high toxicity and/or therapeutic potency. Accordingly, the validation of a given cleaning procedure should normally include sampling and testing of the cleaned surfaces to verify the adequacy of the process. The most common sampling procedures include: (1) swabbing of the equipment surfaces, and/or (2) sampling of the final rinse fluid. A third technique that is sometimes discussed but is not recommended [2] as the preferred choice is manufacture of a placebo batch in the cleaned equipment, and then testing for contamination in representative samples from this batch.

The validity of the sampling strategy is a key element of performing a meaningful cleaning validation test. Irrespective of the sampling technique chosen, it is essential to verify that the contaminant is thoroughly extracted from this sampled surface. Furthermore, it is equally important to ensure that the contaminant is fully recovered from the sampling medium (swab, solution, or placebo) prior to the analysis.

Swabbing of equipment surfaces is usually performed with some appropriate swab material to wipe a defined area that has been exposed to the product. Test results for the swabbed area are then used to calculate the level of cleanliness for the total surface area of the equipment. Suitable swab materials include cotton, paper, or other cellulosic material, and synthetic materials such as polyester. The swabs are used dry, moistened with water, or saturated with an appropriate solvent. Among the advantages of using the swab technique is that one can be more assured of recovering any surface residue that could not be adequately washed and/or rinsed from the area that is being wiped. In addition, it affords the ability to sample difficult-to-clean areas. The downside is that extrapolation of the test results on small, poorly accessible areas may transpose into exaggerated levels of residue for the total equipment surface.

The sampling of rinse fluid is operationally an easier technique. However, a major disadvantage is that the residue(s) may be insufficiently soluble in the rinsing fluid, thus giving erroneously low results. It is also quite possible that the rinse fluid will not come into contact with all of the equipment surfaces that are contacted by product during a manufacturing process. It follows, therefore, that combined testing of both swab samples and rinse fluid samples will provide the highest level of assurance that an equipment module has been adequately cleaned. The decision tree reproduced in Fig. 1 provides for a systematic means of simplifying the sampling procedure [3]. Through this controlled evaluation of both swab-sampling and rinse-sampling, one can determine if the simpler rinse-sampling technique used alone will provide assurance of an acceptable cleaning process. However, in order to shorten development times for cleaning validation assays, it may be preferable to utilize swab sampling by default and not investigate other options unless the swab test cannot be validated.

A third technique for sampling equipment for the presence of contaminants is to process a placebo batch using the equipment of interest and then testing the batch for contaminant levels. This technique is operationally a costly one and, as indicated in the U.S. Food and Drug Administration (FDA) Inspection Guide [2], there is no assurance that any contaminants will be uniformly distributed throughout the placebo batch. This procedure is also more demanding from an analytical testing point of view, since any low level contaminant must be determined in the presence of a complex matrix. This may require a more elaborate sample preparation scheme and/or the use of a more selective and sensitive analytical technique.

Figure 11.1. Decision tree for evaluating sampling methods (Adapted from Ref. [3])

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