Destin A. LeBlanc

Cleaning Validation Technologies

Technical Consulting Services

2ND QUARTER 2001

Should equipment be as clean as the best possible method of residue detection or quantification? Must a firm quantify the amount of residue on equipment surfaces in support of validating the cleaning procedure? Should lab glassware be included in a firm's equipment cleaning validation program?

No, no, and mostly no. The CGMPs require that equipment be cleaned to prevent contamination that "would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements" (see 211.67(a». The preamble indicates that this phrase was added to account for the fact that absolute cleanliness is neither valuable nor feasible in many circumstances for multi-use equipment. The answer to the question "how clean is clean?" cannot, therefore, be "it depends on the method of detection." If the method of detection determined levels of contamination, advances in the sensitivity of detection methods would necessitate correspondingly ever-lower limits and ever-increasing wash cycles. So, how clean should equipment be? It should be as clean as can reason- ably be achieved, to a residue limit that is medically safe and that causes no product quality concerns (other than the fact of the contaminant's presence), and that leaves no visible residues. Reason- ably avoidable and removable contamination is never acceptable.

In validating the original cleaning procedure, a firm need not quantify the level of chemical contamination remaining after manufacturing a product and before cleaning during validation exercises. The firm must, however, ensure that they validate the proposed cleaning procedure as for routine use, and not pre-clean or otherwise attempt to make it easier for the procedure being validated to meet its cleaning objectives. For example, batches significantly smaller than full-scale would not offer sufficient assurance that the cleaning procedure could reliably remove residues to below acceptable levels after full-scale production. A validated cleaning procedure may be relied upon as long as the material being cleaned was manufactured at similar scale and manner as during validation. Also, equipment stored unclean for a longer time than during validation should be sampled to demonstrate that the cleaning procedure was effective. Once cleaned by a validated procedure, a firm generally should not be expected to analytically examine equipment surfaces to demonstrate cleanliness (see the Dec. 1998 Notes article). Hand cleaning methods may be an exception to this general rule because of inherent variability in operator compliance and abilities. Usually, visual inspection of equipment surfaces, including hard to clean nooks and crannies, along with rinse water testing would suffice.

Do not expect lab glassware to be included in the processing equipment cleaning validation program. Glassware must, of course, be clean and the CGMPs consider lab equipment to be included in the scope of 211.67. The assurance of cleanliness is best assessed by inspecting laboratory procedures for the use of non-dedicated glassware and other equipment, method validation (ruggedness, e.g.), and the absence of extraneous or interfering data in the results of sample analyses. Lab cleaning procedures may include repetitive rinses with the solvent used to prepare the analyte and oven drying. The equipment need not be swabbed or otherwise tested to ensure removal of potentially contaminating residues. A firm may elect to sample its glassware for residual contamination to exclude or explore the possibility of interference in the case of particularly sensitive analyses or highly difficult to clean compounds. The possibility of carryover contamination affecting a method's performance or integrity of the results is generally considered to have a low risk to product or consumers. Contaminated lab equipment, however, should not be a frequent excuse for rejecting or discarding aberrant results. We expect that firms maintain lab equipment in a clean and sanitary manner so as to provide confidence in the results of analysis.

References:

- Preamble to the Good Manufacturing Practices for Human and Veterinary Drugs, Federal Register, September 29, 1978, pages 45040-1, paragraphs 167-175  http://www.fda.gov/cder/dmpq

- 21 CFR 211.67

- Guide to Inspections of Cleaning Validation, 1993

- Human Drug CGMP Notes editions Dec. 1998, Sep. 1998, Sep. 1997, Jun. 1995