As stated in 21 CFR 211.67 (a), Equipment cleaning and maintenance, “Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized 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.”

Similarly, 21 CFR 111.27 (d) states: “You must maintain, clean, and sanitize, as necessary, all equipment, utensils, and any other substances used to manufacture, package, label, or hold components or dietary supplements.”

Likewise, 21 CFR 820.70 (e) states: “Contamination control. Each manufacturer shall establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.”

Although it may sound impossible to prove that equipment and utensils are 100% clean, FDA has recognized that there are effective cleaning and sanitizing protocols to prevent cross contamination in the production of drugs. Modern cleaning validation procedures, including laboratory procedures and manufacturing optimization, must be implemented to prove that the equipment is reasonably free of any residue that is documented to be safe, causes no product quality concerns, and the process is contaminant-free in accordance with FDA, cGMPs, and USP guidelines.

FDA does not provide extensive guidance on conducting cleaning validation but does recommend consulting guidelines published by various trade and professional associations for additional information (e.g., International Society for Pharmaceutical Engineering, Parenteral Drug Association).

The effectiveness of the cleaning process should include a combination of subjective observation and qualitative analysis through visual inspection as well as quantitative analysis through direct and indirect methods of sampling. Indirect method, using rinse water, is most useful in analyzing the large surface area and inaccessible areas. Direct method, with the use of swabs, can remove contaminants that may adhere to the surfaces. The swab technique typically involves moistening a polyester swab with contaminant-free purified water acidified with phosphoric acid to wipe a measured area in a systematic manner.

According to the 1993 FDA guideline for cleaning validation for sampling, “There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.”

The appropriate method for analyzing a cleaning validation sample is as important as the sampling techniques. In determining an analytical method, consider if the instrument is clean and if the instrument meets required detection limits. Then, investigate the method for precision, accuracy, limit of detection, limit of quantification, specificity, range, linearity, and ruggedness. Common analytical techniques for clean-in-place applications include: visual analysis, gravimetric analysis, pH, conductivity/resistivity, light microscopy, titration, spectroscopic techniques, Thin Layer Chromatography, capillary zone electrophoresis, ELISA, High Performance Liquid Chromatography, ion chromatography, and TOC.

Of these methods, HPLC is most commonly used because the technique can accurately determine the specific compounds, monitor, and set control limits for a particular process. However, non-specific tests like TOC, pH, and conductivity are gaining popularity because they can quickly detect a range of contaminants with minimal development. The use of TOC analysis has many advantages. TOC has low level detection, rapid analysis times, can detect all carbon-based residuals, and costs less compared to other methods. Many pharmaceutical firms use a combination of HPLC and TOC to characterize and monitor the cleaning process.

TOC can be an acceptable method for monitoring residues routinely and for cleaning validation. In order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions. This is an important exercise because some organic compounds cannot be reliably detected using TOC.

TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit ‘background’ carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample holding time on accuracy and limit of quantitation.

For Additional Information, please contact:  Conchita Mendoza