ESTER LOVSIN BARLE*¹, MARGARET AMELIA CUDD², ROLAND LOOSER¹, RUDOLF BECHTER¹, GIAN CHRISTIAN WINKLER²
*Corresponding author
1. Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland
2. Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland

Abstract

The point-of-departure for calculating a carryover limit (toxicity and pharmacology) can be the same as the one used for calculating occupational exposure limits (OEL). We calculated carryover limits with three different approaches for the purpose of comparing them to their respective OELs and assessing possible correlations. We selected several drug substances with different mechanisms of action. Calculating carryover limits from LD50 (LDDE) resulted consistently in much higher values than with other methods. Comparison of the OELs and permissible daily exposures (PDEs) has revealed no constant relation between the values, because there was a difference in the point-of-departure used for calculation, as well as in the use of different safety factors for different target populations (e.g. patients, employees). Looking at the log values we found a significant correlation (calculated after Pearson) between PDE and OEL and PDE and carryover value (COV). LDDE has shown the least similarity to all other values. Most similarities were found between PDE and COV.

INTRODUCTION
Carryover contamination in shared pharmaceutical manufacturing facilities may pose a risk for patients. Production of highly active drugs in separate self-contained facilities has been required for a long time. Over the past 20 years, a number of approaches have been proposed to calculate allowable carryovers for shared pharmaceutical manufacturing facilities. Some of them use rigid calculation models such as a residue maximum of 1/1000 of the minimal daily therapeutic dose (1), termed Carryover Values (COV) in this study. Another example is the calculation model for LDDE (Lethal Dose Daily Exposure), using the median lethal dose (LD50 values) from acute toxicology studies (2). Originally designated Allowable Daily Intake (ADI) by the authors (2), we termed it LDDE in this paper to prevent confusion with the ADI (Acceptable Daily Intake) parameter used for residual limits in food. Most recently EMA, the European Medicines Agency, has issued a draft guideline on setting exposure limits, termed Permitted Daily Exposure (PDE), for use in risk identification in the manufacture of different medicinal products in shared facilities (3). Basically a ...