Is it mandatory for the results to be 10 times smaller them the criteria, for the cleaning validation?
The acceptance criteria of cleaning validation studies should be based on HBEL Criteria, i.e. Health-Based Exposure Limits.
The procedure proposed for the determination of health-based exposure limits for the residual active substance is based on the method for establishing the so-called Permitted Daily Exposure (PDE) as described in Appendix 3 of ICH Q3C (R4) “Impurities: Guideline for Residual Solvents” and Appendix 3 of VICH GL 18 on “residual solvents in new veterinary medicinal products, active substances and excipients (Revision)”.
The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.
Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii)
identification of “critical effects”, (iii) determination of the no-observed-adverse-effect level (NOAEL) of
the findings that are considered to be critical effects, and (iv) use of several adjustment factors to
account for various uncertainties. Appendices 3 of the ICH Q3C and VICH GL 18 guidelines present the following equation for the derivation of the PDE:
NOAEL x Weight Adjustment
PDE = --------------------------------------
F1 X F2 X F3 X F4 x F5
The PDE is derived by dividing the NOAEL for the critical effect by various adjustment factors (also
referred to as safety-, uncertainty-, assessment- or modifying factors) to account for various
uncertainties and to allow extrapolation to a reliable and robust no-effect level in the human or target
animal population. F1 to F5 are addressing the following sources of uncertainty:
F1: A factor (values between 2 and 12) to account for extrapolation between species
F2: A factor of 10 to account for variability between individuals
F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks
F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity,
neurotoxicity or teratogenicity
F5: A variable factor that may be applied if the no-effect level was not established. When only a LOEL
is available, a factor of up to 10 could be used depending on the severity of the toxicity.
If several critical effects have been identified resulting in the calculation of more than one PDE value, a
decision with respect to the most appropriate PDE to be used for the cleaning validation process should be made with an appropriate justification. Usually, by default, the lowest PDE value will be used.
Reference guidelines: By EMA- Guideline on setting health-based exposure limits for use
in risk identification in the manufacture of different medicinal products in shared facilities
20 November 2014
EMA/CHMP/ CVMP/ SWP/169430/2012
Committee for Medicinal Products for Human Use (CHMP)
Committee for Medicinal Products for Veterinary Use (CVMP)
Thanks, we already use that but I was trying to find this statement somewhere…