|Regarding the cleaning acceptable criteria limits, FDA does not intend to set acceptance criteria in cleaning validation or methods for determining whether a cleaning process is suitable or validated.
But, some limits that have been mentioned by the industry include analytical detection levels such as 10 PPM or less, biological activity levels such as 1/1000 or less of the normal therapeutic dose, and organoleptic levels.
Check the manner in which the acceptance criteria in cleaning validation is established.
Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, incipients, detergents, etc) bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified.
In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove.
There are circumstances where TLC screening, in addition to chemical analyses, may be needed.
In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if the equipment is not dedicated.
The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.
Worst cases should include in the selection of the acceptance criteria in cleaning validation:
– Evaluation of the medicinal products with the highest toxicity
– Consideration of the lowest solubility of drugs in cleaning solvents
– Evaluation of medicinal products with characteristics that make them difficult to clean
– Swabbing equipment places the most difficult to clean
FDA expectative to establish the acceptance criteria in cleaning validation 21 CFR 211.67
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 the conclusion that residues have been reduced to an “acceptable level.”
STATUTORY AND REGULATORY REQUIREMENTS OF ACCEPTANCE CRITERIA IN CLEANING VALIDATION
GMP Regulations (Part 133.4) stated as follows “Equipment … shall be maintained in a clean and orderly manner .” A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products.
FDA expects firms to have written general procedures on how to define the acceptance criteria in cleaning validation processes that will be validated.
Validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following:
“… a drug (including a drug contained in a medicated feed) shall be deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirement of the act as to the safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”
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PIC/S Guideline to Validation – PI -006-3 (2007)
ICH Guideline Q7 “GMP for APIs
Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide