According to draft guidance from the European Medicines Agency (EMA), manufacturers should determine either the permitted daily exposure (PDE) or the threshold of toxicological concern (TTC) through an evaluation of all pharmacological and toxicological nonclinical and clinical data. The TTC represents the genotoxic impurity exposure level associated with a theoretical cancer risk of 1 additional cancer in 100,000 patients exposed over a lifetime.
The PDE is 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. If several critical effects have been identified resulting in 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. The PDE should be determined by:
- Hazards identified after reviewing contamination data;
- Evaluation of “critical effects”;
- Determination of a no-observed-effect level of the findings that are considered to be critical effects; and
- Other adjustment factors to account for uncertainties.
Previously certain drug classes — such as some antibiotics, hormones, cytotoxic and highly active drugs — had to be manufactured in separate, self-contained facilities because cross-contamination could not be accurately calculated during contamination evaluations.
As far as active substances, unintended effects in patients caused by contaminations may constitute a hazard so clinical pharmacological data should be considered when identifying the critical effect, the EMA says. In addition, manufacturers should consider to what extent the active substance in question has been associated with critical adverse effects in the clinical setting.
The draft guideline also outlines how data on the TTC and PDE threshold values should be presented in a risk assessment report. A rationale for choosing specific endpoints of concern and the dose that is used in the calculation of the PDE should be included in the report. And to provide an overview to GMP inspectors, the initial page of any prepared risk assessment report should be in the form of a summary of the assessment process, the EMA adds.
Comments will be collected on the draft guideline until June 30.