Cleaning validation: health based exposure limits in shared facilities

By Paolo Pescio, Eurofins BioPharma Product Testing Italy, PaoloPescio@eurofins.com

In shared facilities, the possible cross contamination between different active substances is an issue of concern. An active substance could contaminate the next product manufactured in the same facility; therefore, its presence should be restricted to a level that can be considered safe for all populations.

During cleaning validation some practical and arbitrary criteria are in place:

•  a relative limit considering a contamination lower than 1/1000th of the lowest clinical dose of any product in the maximum daily dose of the next product, or
•   an absolute limit of 10 ppm of the previous active substance in the next product manufactured.

These limits do not take account of the available pharmacological/ toxicological data and possible duration of exposure and may be too restrictive or not restrictive enough.

Threshold value (permitted daily exposure - PDE) or threshold of toxicological concern (TTC) should be used as actual limits for cleaning validation.

 Determination of a PDE involves:

•  hazard identification by reviewing all relevant data
•  identification of "critical effects"
•  determination of the No-Observed-Effect Level (NOEL) of the findings that are considered to be critical effects (if no NOEL is obtained, the Lowest-Observed-Effect Level or the benchmark dose could be considered)
• use of several adjustment factors to account for various uncertainties (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).

Eurofins can perform PDE and TTC evaluation on the basis of available pharmacological and toxicological data, including both non-clinical and clinical data as required by EMA guideline, "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities."

For more information on how Eurofins can help you with cleaning validation, visit www.eurofins.com.