Cross Contamination: Helpful Information for the Calculation of ADE/PDE Values

Authorities have responded to the request of the industry not to set a general requirement for dedicated facilities regarding certain products. The old 10 ppm provision disappears because of the amendments made to Chapters 3 and 5 of the EC GMP Guide and particularly because of the new EMA Guideline on setting scientifically-based limits (we reported).

Dedicated facilities are required for substances for which no lowest threshold level is known or it can't be proven that it can be cleaned under the PDE- based (permitted daily exposure) limit. Certain product categories are still excluded such as Beta-Lactam antibiotics (News on final FDA Guidance). Shared facilities remain here not possible.

For the calculation of the PDE, the NOEL is divided by various correction factors. The NOEL (no-observed-effect-level) is the highest dose which is known from scientific studies to have no critical effect observed. The correction factors serve the conversion of data from animal testing, compensate the differences between the various population groups or express the criticality of one effect.

Now in practice, considerable problems arise both by searching or establishing the NOEL and by setting the correction factors. In many cases, there is no alternative but asking a toxicological expert to be able to allocate the actual wished scientifically-based approach.
Yet, some documents and databases may be helpful to use EMA's PDE formula:

• FDA document with conversion factors animal to human (middle column, table 1, page 7)
• Access to a range of databases (subject to fees): not only for pharmaceuticals but also for chemicals in general
• Medicines Compendium of Switzerland®: all package leaflets including a version for physicians
• American drugs list: Physician's desk Reference
• EMA EU Public Assessment Reports for medicinal products