New EMA Guideline on Dedicated Facilities and Exposure Limits for Cleaning Validation

The draft Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, published in January had already been discussed conclusively by EMA's Safety Working Party in December 2012. The new Guideline became necessary because of the more scientific approach of the Chapters 3 and 5 in the EU GMP Guideline. And the previous requirement for certain materials ("certain antibiotics, certain hormones, certain cytotoxic and certain highly active drugs") to be manufactured in dedicated facilities was not very scientific without taking into consideration specific toxicological/pharmacological data. The same applies to the definition of the 1/1000 dosage or the 10 ppm criterion in the cleaning validation.

This approach is now abandoned for active substances for which a safe threshold level is known or can be established in favour of an approach that calculates the PDE: Permitted Daily Exposure (elsewhere also referred to as ADE, Acceptable Daily Exposure). The PDE represents a dose that is unlikely to cause an adverse effect if an individual is exposed at this dose every day for a lifetime. This approach isn't new. The PDE concept is already used in the ICH Guideline Q3C (R4) Guideline for Residual Solvents. The PDE determination is carried out substance-specific on the basis of all available toxicological and pharmacological data from clinical, preclinical or toxicological studies by means of the NOEL (no-observed-effect-level). The NOEL is the highest dose at which no critical effect is observed. The critical effect can be a negative health impact (for instance seen in a toxicity study) or a therapeutic effect (clinical study). For all critical effects (elsewhere also referred to as lead effect) identified, the NOEL is established and the lowest value used for calculation of the PDE value. The PDE is derived by dividing the NOEL by various safety factors as described in the Guideline ICH Q3C (R4) mentioned above.

From this approach excluded are active substances with a genotoxic or a sentising potential. Since usually there is no discernible threshold for these active substances, which means that there does not exist a safe level of exposure so that any level of exposure carries a risk, the PDE approach cannot be chosen. For active substances with a genotoxic potential, EMA refers to the Guideline  "Limits of Genotoxic Impurities" and to the TTC concept (Threshold of Toxicological Concern). A threshold of 1.5 µg/person/day is established for genotoxic impurities. In contrast to impurities intrinsic to production, residual active substances principally are avoidable and therefore the EMA sets a stricter limit dose of 0.15 µg/person/day.
In the case of active substances with a sensitising potential for which no threshold values are known, point 3.6 of the updated EU GMP guideline is valid which requires the use of dedicated facilities.

In the cleaning validation practice this new way of determination of the threshold leads in most cases to less strict thresholds compared to the 1/1000 dosage or the 10 ppm criterion established so far. Merely in those cases in which the critical effect is not the pharmaceutically desired effect, this can result in drastically stricter limits.

Deadline for comments is 30 June 2013.

Please find more infromation in the draft "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities" der EMA.

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