Cleaning Validation: Detergent Removal


Hello good people of the world! Today’s blog post is about verification of detergent removal in cleaning validation. As we know, cleaning validation is concerned with leaving process equipment clean; that means not residual API, excipients, or detergents. One unique problem with detergents is that, while we typically know in detail the composition of APIs and excipients, detergent composition may be proprietary and not available to the end-user.

It its 1993 Guide to Inspections: Validation of Cleaning Processes, the FDA set the expectation that removal of detergents be included in cleaning validation scope.

Besides possibly not knowing what’s in them, testing for removal of API may be problematic because the acceptable carryover limit can not by calculated using traditional means using lowest therapeutic dose, since there is no therapeutic dose for detergents. Some proposed alternatives:

The Hall Approach (1999)

Dr. Hall presented an approach that used the No Observable Effect Level (NOEL), calculated as:

NOEL = LD50 x 0.0005

where LD50 is the lethal dose required to kill 50% of a population and 0.0005 is a constant derived from a large toxicology database (according to the article)

then the Acceptable Daily Intake (ADI) become


where SF is a safety factor, tyipcally 100 for oral and 5,000 for intravenous routes of administration.

In 2000, the CEFIC/APIC Guide was updated and presented the following approach:

NOEL = LD50 (g/kg) x 70 (kg a person) / 2000

and calculated the Maximum Allowable Carryover (MACO) as:


where MBS is the minimum batch size for the next product/batch and TDD_NEXT is the largest normal daily dose for the next product/batch. The CEFIC/APIC gives a safety factor of 200 for oral and 1,000-10,000 for parenterals, depending on substance.

PDA’s 1999 edition of Technical Report 29 (not available for free unfortunately) has:

NOEL = LD50 x Empirical Factor

and ADI = NOEL x AAW x SF

where the empirical factor is derived from animal model developed by Layton, et al., and AAW is the average adult weight

How do you calculated the ADI for cleaning agents in your process(es)?

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