There are several approaches available to evaluate the risk posed by a leachable. The first approach, used for known compounds,
is to compare the concentration of the leachable to published limits. A good first source of published limits is Q3C (R3)
Impurities: Guidelines for Residual Solvents from the International Conference on Harmonization (ICH). The document separates solvents into three groups:
- Class I: Solvents to be avoided—five solvents that should be avoided due to either toxicological concerns or environmental
- Class II: Solvents to be limited—26 compounds that should be limited because of their inherent toxicity. The allowable concentrations
range from 50 PPM to 4840 PPM.
- Class III: Solvents with low toxic potential—28 solvents that should be limited by GMP or other quality-based requirements.
The ICH limit for Class III solvents is 5000 PPM.
Another source of acceptable limits is published by FDA, Office of Food Additive Safety (OFAS). This publicly available database
lists cumulative estimated daily intakes (CEDI) and acceptable daily intakes (ADI) for a large number of substances (6).
A second approach to evaluating risk for a known compound is to calculate an ADI or permitted daily exposure (PDE) concentration
(see Equation 1). FDA calculates the ADI by dividing a no observable effect level (NOEL) concentration by a safety factor
(usually 100). The safety factor takes into account that the NOEL was determined from an animal study and for variability
among humans. Alternatively, ICH calculated the allowable residual concentrations based on PDE. PDE is similar to ADI except
for a few variations in the equation (see Equation 2). If NOEL values are not available, then lowest observable effect level
(LOEL) values can be used, but with an additional safety factor incorporated.
Sources for NOEL values include the Chemical Carcinogenesis Research Information System (CCRIS), Integrated Risk Information
System (IRIS) and the International Toxicity Estimates for Risk (ITER).
An approach for evaluating the risk associated with unknown compounds is to use the threshold of toxicological concern (TTC).
The TTC is a concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical-specific
toxicity data, below which there would be no appreciable risk to human health. The TTC approach is based on the analysis of
the toxicological or structural data of a broad range of different chemicals and has been developed as a substitute for substance-specific
In 1978 Cramer proposed that many chemicals could be categorized into three classes of compounds with three different potentials
for toxicological risk based on structural activity relationships (SARs), metabolic mechanisms, chemical reactivity, and other
relevant information (7). Cramer Class I substances are those with simple chemical structures and predictable and efficient
modes of metabolism that suggest a low order of toxicity. Cramer Class III substances are those that suggest significant toxicity
because their chemical structures have similarities to known toxins. Cramer Class II substances are those that cannot be placed
in Class I or Class III and are therefore intermediate in expected toxicology. This tier classification was later expanded
by the International Life Sciences Institute (ILSI Europe) and its TTC Task Force to include a class for select organophosphates
(which have neurotoxicity) (8). Table I summarizes the PDE for the various classes of chemicals using the TTC approach.
Table I: Daily permitted exposures for various classes of chemicals.
In assessing the risk of leachables, no single method needs to be used. Instead a combination of all three methods previously
listed can be implemented as shown Figure 2.
Figure 2: Flowchart for assessing the risk of leachables. ICH is International Conference on Harmonization, IRIS is Integrated
Risk Information System, PQRI is Product Quality Research Institute, and QC is quality control.