Before formal cleaning validation programs were instituted, visual inspection was the primary means of determining equipment cleanliness. The use of visual inspection is still typically a component of a cleaning validation program and for routine inspections of cleaning effectiveness, but the use of visual inspection as a sole criterion for equipment cleanliness has not been successfully implemented as a valid approach for cleaning validation.

A validated cleaning program based on quantitative visual inspections in conjunction with swab testing is possible. Acceptable visible-residue limits (VRLs) can be established in conjunction with and compared with swab results. Assuming the swab results demonstrated a validated cleaning procedure, if the results are in agreement, then the VRLs may be used going forward. A similar argument has been successfully used to defend the use of rinse sampling established in conjunction with swab results.

Cleaning validation is a critical consideration in the pharmaceutical industry. Inadequate cleaning can result in contamination of drug products with bacteria, endotoxins, active pharmaceuticals from previous batch runs, and cleaning solution residues. Such contaminants must be reduced to safe levels, both for regulatory approval and to ensure patient safety.

Although we commonly talk about "disinfectant validation," the US Food and Drug Administration validates only processes (1). Disinfectants themselves are qualified—that is, found to be effective in the context of a given process, just as we qualify the clean steam supply for an autoclave and then validate the steam sterilization process. The approach to disinfection should be similar, so that a working definition for disinfection process validation would be "establishing documented evidence that a disinfection process will consistently remove or inactivate known or possible pathogens from inanimate objects."

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Pharmaceutical plants must have visually clean equipment to operate according to good manufacturing practices. Formulators must visually inspect manufacturing equipment for cleanliness before formulation work begins (1). Manufacturers establish and perform visible cleanliness and analytical methods to ensure regulatory compliance. An analyst conducts a visual inspection and confirms visible cleanliness before taking swab samples for chemical analysis (2). The formulator of the subsequent batch conducts a visual inspection before manufacturing work begins. A correlation between available analytical data and visible cleanliness of manufacturing equipment over an extended period of time can expand the practice of performing visual inspections in lieu of swab sampling.

In the pharmaceutical industry, Good Manufacturing Practices (GMPs) require that the cleaning of drug manufacturing equipment be validated.1 Many different validation techniques can demonstrate that the manufacturing equipment is cleaned and essentially free from residual active drug substances and all cleaning agents.Common analytical techniques in the validation process include HPLC, spectrophotometry (UV/Vis), and TOC. HPLC and UV/Vis are classified as specific methods that identify and measure appropriate active and substances. TOC is classified as a non-specific method and is ideal for detecting all carbon-containing compounds including active species, excipients, and cleaning agent(s). 2,3,4,5.

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A fiber-optic, mid-IR spectroscopy probe combined with a grazing-angle reflectance sampling head can be used as a solvent-free in situ method for validating cleanliness with substantial improvement in accuracy.

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Destin A. LeBlanc
Cleaning Validation Technologies
Technical Consulting Services
Cleaning Memo for JULY 2004
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A swab-sampling method was developed for cleaning validation of a residual active pharmaceutical ingredient in samples collected after cleaning the sampling suite. A summary of the strategies and results of the method development is presented. The developed extraction method produced an acceptable level of recovery and precision.Cross contamination with active ingredients is a real concern. The Code of Federal Regulations (CFR) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official, or other established requirements” (1). Cleaning validation is required in the pharmaceutical field to avoid potential clinically significant synergistic interactions between pharmacologically active chemicals (2).

WHO- EDM Jan 02