An Overview of Risk Assessment Strategies for Extractables and Leachables

The author describes several approaches for risk assessment of extractables and leachables.
Jan 01, 2012
Volume 25, Issue 1

Several scientific, quality control, and regulatory approaches are used to control and assess the risk of foreign substances that are inadvertently added to products that humans consume. The term extractables describes substances that might leach from a material's surface into a solution while the term leachables describes substances that migrate from the material surface into the solution under the actual conditions of use.

In general, the following three possible negative effects result from the introduction of leachables into a pharmaceutical product stream.

  • The leachable is toxic and poses a health risk to the consumer
  • The leachable interacts with the drug product formulation so as to alter its stability and potency
  • The leachable interferes with an assay that is crucial to measuring an important property of the drug product.


The threshold of toxicological concern (TTC) defines a generic exposure threshold value for groups of chemicals below which no appreciable risk to human health exists. The TTC approach is based on the analysis of the toxicological or structural data of a broad range of chemicals and was developed as a substitute for substance-specific information. The concept proposes that such a value can be identified for many chemicals, including those of unknown toxicity, when considering their chemical structures. Several excellent reviews have been recently published that summarize both the history and the scientific approach that TTC brings to risk assessment of chemicals (1–3).

In 1978, Cramer proposed that many chemicals, excluding polymers, could be categorized into three classes of compounds with three different potentials for toxicological risk (4). The categorization was based on a series of yes or no questions pertaining to structural-activity relationships (SARs), metabolic mechanisms, chemical reactivity, and other relevant information. Cramer class I substances have simple chemical structures and predictable and efficient modes of metabolism that suggest a low order of toxicity. Cramer class III substances permit no strong initial presumptions of safety, and may suggest significant toxicity, because their chemical structure has similarities to those of known toxins. Cramer class II substances cannot be placed in class I or class III and are therefore intermediate in expected toxicology. Cramer did not identify safe daily intakes for the Cramer classes but rather calculated a protection index that could be used to establish priorities and the extent of appropriate toxicity testing.

Table I: Threshold of toxicological concern (TTC) summary. PDE is permitted daily exposure.
Table I presents a summary of the permitted daily exposures for the various classes of chemicals using the TTC approach.

The European Medicines Agency (EMA) has used the TTC approach to develop guidelines for genotoxic impurities (5). The Pharmaceutical Research and Manufacturers of America (PhRMA) has also detailed a rationale for dealing with potentially genotoxic impurities in pharmaceuticals employing the TTC approach (6).

Perhaps the most notable use of TTC was in the 1996 report issued by the Pharmaceutical Quality Research Institute (PQRI) working group on leachables and extractables in orally inhaled and nasal drug products (OINDPs) (7). The PQRI working group concluded that the TTC level for carcinogens of 0.15 µg/person-day would be the safety threshold concern (STC) level for leachables in OINDPs. The qualification threshold for noncarcinogenic or nongenotoxic impurities was recommended to be 5 µg/person-day, rather than the 18 µg derived in the above table for food, based on an analysis of data of respiratory toxicities from three toxicological databases. The recommended threshold reflects the commonly observed trend that respiratory toxicities are generally greater than systemic, such as oral, toxicities.

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