Setting health-based residue limits for contaminants in pharmaceuticals and medical devices.

A procedure for determining health-based residue limits for impurities in drug substances and medical devices is described. The procedure is based upon the concept of setting residue limits that correspond to the intended usage of the drug or device, i.e., short-term use, prolonged use, and/or lifetime use. Data pertaining to chemical and physical properties, occurrence and use, biodisposition, pharmacology, toxicology, and effects in people are used. After evaluation of these data, acceptable daily intake (ADI) values are derived using a safety margin approach for short-term and prolonged exposure limits. The safety margin approach combines the use of safety factors and professional judgment. ADI values for lifetime exposure are calculated using the safety margin approach for noncarcinogens and for some carcinogens, and they are calculated using risk assessment procedures that provide ADI values corresponding to no more than a 1 in 10,000 excess lifetime cancer risk based upon maximum likelihood risk levels for other carcinogens. A weight-of-evidence test determines the use of each approach. Finally, ADI values from relevant routes and endpoints are compared and a residue limit or residue limits are estimated. The standard is expressed in terms of maximum dose per exposure period and/or dose per day and is applicable to medical products intended for short-term use, for prolonged use, and/or for lifetime use as a major clinical indications dictate.