Evaluating Risk Using Acceptable Daily Exposure (ADE)/Permitted Daily Exposure (PDE) and Setting Limits based on Statistical Process Control

CPCI has been a strong advocate for changing the current approach to setting Cleaning Validation Limits. The 20 year old approaches of setting Cleaning Validation limits as a fraction of the lowest therapeutic dose, or the Median Lethal Dose (LD50), or 10 ppm have been shown to be wildly inaccurate from a patient safety standpoint and have been causing major issues with manufacturing operations for years. These old approaches should be replaced by an ADE / PDE (Acceptable / Permitted Daily Exposure) that is derived by a Qualified Toxicologist and Maximum Safe Carryover values (MSCs) may then be determined (see our Publications page for several articles on these topics).

CPCI has retained highly qualified Toxicologists who can quickly deliver ADEs to CPCI for your projects. Using these ADEs/PDEs, CPCI can then assist you in calculating MSCs.

However, these MSCs should not be used specifically as Cleaning Limits: they should only be used for the assessment of Risk. Cleaning data collected can  be used to determine the Process Capability (Cpk, Ppk) of the Cleaning Process using the MSCs as the specification. The Cpks/Ppks derived are a direct measurement of the degree of exposure and consequently can be used to evaluate Risk.

Finally, in line with the FDA's 2011 Guidance of Process Validation, we believe limits should be based on process derived data. Data on Cleaning Processes should be collected and limits should be statistically derived from the data using Statistical Process Control techniques.

This approach focuses Cleaning Validation efforts where they are most important and provides operational relief where the risks are shown to be low.

CPCI has years of experience using this approach and can guide you in implementing this Cleaning Validation for the 21st Century approach and defending it with regulators.