In 1988, Cholestyramine Resin USP finished drug product (a cholesterol medication) was recalled due to cross-contamination with low levels of an agricultural pesticide. The contamination was a result of a lack of validated cleaning procedures and inadequate control of recovered solvent drums. This recall reinforced the need for validated cleaning procedures to prevent cross-contamination.
The FDA provides detailed information regarding equipment cleaning validation such as 21 CFR 211.67, Equipment Cleaning and Maintenance and 21 CFR 211.182, Equipment Cleaning and Use Log. To summarize:
- FDA expects firms to have written general procedures on how cleaning processes will be validated.
- FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.
- FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.
- FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.
- FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an “acceptable level.”
What is Clean?
When the FDA expects a final validation report indicative of primary contaminants and residues to be reduced to an “acceptable level,” what does that mean? Modern manufacturers use a risk-based approach when setting cleaning limits. A few points to consider when taking a risk based approach to acceptance criteria and limits during cleaning validation:
- What is the product or process intermediate being prepared (i.e. potential contaminant) within the unit of operation (e.g., fermenter, buffer tank, chromatography column) used for?
- What is the final dose of the product or process intermediate being prepared within the unit of operation? What are the size of batches that will be produced on the same equipment after cleaning?
- How toxic are the potential contaminants?
- Is the cleaning process effective for the equipment design (can it clean manifolds, gauges, probes, etc.?)
In closing, the path to a validated cleaning process can be a winding one and is not always clear or straight-forward depending on the complexity of your process. If cleaning validation is a gap or concern at your organization or for your product, don’t hesitate to reach out to Kymanox for a quick, no obligation discussion.
Pharmaceutical Process Validation, International 3rd Edition, Revised and Expanded (R. A. Nash, A. H. Wachter) 2003 Marcel Dekker Inc.
U.S. Food & Drug Administration, Inspections, Compliance, Enforcement, and Criminal Investigations, Validation of Cleaning Processes (7/93), http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074922.htm.
U.S Food & Drug Administration, Guidance for Industry, Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients, .
Regulations and You, Disposable Technology, K. S. Cleaves, https://pubs.acs.org/subscribe/archive/tcaw/12/i10/pdf/1003regulations.pdf.