Cleaning validation
Article 57
1. Cleaning procedures shall be validated. Cleaning validation shall be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to active substance quality. 2. Validation of cleaning procedures shall reflect actual equipment usage patterns. Where various active substances or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or active substance may be selected for cleaning validation. This selection shall be based on: (a) the solubility of the intermediate or active substance; (b) the difficulty of cleaning; (c) the calculation of residue limits based on potency, toxicity, and stability. 3. The cleaning validation protocol shall describe: (a) the equipment to be cleaned; (b) the procedures; (c) the materials; (d) the acceptable cleaning levels; (e) the parameters to be monitored and controlled; (f) the analytical methods to be applied; (g) the type of samples to be obtained and how they are collected and labelled. 4. Sampling shall include swabbing, rinsing or alternative methods (e.g. direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used shall allow the quantitative measurement of the levels of residues remaining on the equipment surfaces after cleaning. 5. Validated analytical methods sensitive to detect residues or contaminants shall be applied. The detection limit for each analytical method shall be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level shall be established. Residue limits shall be practical, achievable, verifiable and based on the most deleterious residue. Limits may be established based on the minimum known pharmacological, toxicological, or physiological activity of the active substance or its most deleterious component. 6. Equipment cleaning or sanitisation tests shall address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the active substance, or for other processes where such contamination could be of concern (e.g. non-sterile active substances used to manufacture sterile products). 7. Cleaning procedures shall be monitored at appropriate intervals after validation to ensure that those procedures are effective when applied during routine production. Equipment cleanliness may be monitored by analytical testing and visual examination, where feasible. Visual inspection may allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling or analysis.