HUMAN DRUG CGMP NOTES EXCERPT
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