Safety Thresholds

Although leachables represent a particular class of drug product impurity, current regulatory guidance for drug product impurities specifically considers leachables to be out of scope (5). Thresholds that have been specifically proposed for drug product leachables are based on either patient safety considerations or the current capabilities of analytical technology. Safety thresholds are particularly important in a leachables assessment because current analytical technology allows detection of trace organic and inorganic chemical entities at extremely low levels (i.e., ng/mL; ng/g). 

Identification and risk assessment (or qualification) of every individual chemical entity in a typical leachables profile at the limits of current analytical technology is neither necessary from a toxicological perspective nor feasible in a typical drug product. Safety thresholds allow for a science- and risk-based determination of acceptable levels of leachables and can be based on established toxicological information, as well as additional safety risk factors that consider, e.g., route of administration, daily exposure, and treatment duration. Because safety thresholds are derived from exposure data they are considered in terms of units of exposure, such as Total Daily Intake (TDI). 

Thus, any safety threshold must be converted into units of concentration (e.g., µg/mL) so that it can be applied as an analytical threshold in the laboratory. The analytical threshold is a guide as to which chemical entities in the leachables profile should be considered for chemical characterization (i.e., confirmed identification) and safety evaluation and qualification.

An example of a safety threshold concept that has been practically applied in pharmaceutical development is the Threshold of Toxicological Concern (TTC) approach (6). The TTC concept was adopted by the European Medicines Agency (EMA) to evaluate genotoxic impurities, using an excess cancer risk factor of 105 (1 in 100,000) (7). The EMA's proposed safety threshold for genotoxic impurities using the TTC approach is 1.5 µg/day TDI. Other examples of safety thresholds include the Product Quality Research Institute (PQRI) Safety Concern Threshold (SCT) and Qualification Threshold (QT), derived and proposed for individual organic leachables in Orally Inhaled Nasal Drug Products (OINDP) (2,8,9). The SCT is 0.15 µg/day TDI, and the QT is proposed at 5 µg/day TDI for an individual organic leachable. The development of the TTC approach provided a foundation, precedent, and guide for derivation of the PQRI SCT, which incorporates a 106 (1 in 1,000,000) risk factor rather than the 105 value used for the EMA threshold. 

This lower threshold was considered appropriate for leachables in OINDP because of considerations regarding the direct delivery of some of these dosage forms to diseased organs of a sensitive patient population, and assuming lifetime exposure. In addition, leachables are typically industrial chemicals with no direct structural relationship to any active ingredient or other formulation constituent. Below the SCT, identification and safety evaluation of leachables generally would not be required. Below the QT, leachables without structure alerts for carcinogenicity or irritation would not require compound-specific safety risk assessment. Note that neither the SCT nor the QT is a control threshold or safety-driven limit. Rather, they are leachables evaluation thresholds. The SCT in particular is designed to establish a threshold for characterization of unknown drug product leachables. Individual levels of safety concern, different from the SCT value, could be determined for known leachables and potential leachables (i.e., extractables).

For OINDP there are certain “special case” compounds and compound classes, that due to particular safety concerns (e.g., carcinogenic) were deemed to require lower thresholds based on the capabilities of specific analytical technologies and methods. These special case compounds for OINDP include: polyaromatic hydrocarbons or polynuclear aromatics (PAHs or PNAs), N-nitrosamines, and the individual chemical entity 2-mercaptobenzothiozole (see Orally Inhaled and Nasal Drug Products 1664.1).


Information Sharing


To successfully manage leachables throughout the drug product lifecycle, it is critical to establish close and regular communication among those stakeholders throughout the development and drug product lifecycle responsible for the quality of the drug product: chemists, toxicologists, packaging engineers, manufacturing operations, procurement, etc. With respect to leachables, communication between the analytical chemist and toxicologist is critical. 

For example, if a leachable is found to be above an accepted limit, or a new leachable is found, a safety evaluation will need to be performed. The chemist will need to provide the toxicologist with information that will help to qualify the leachable, including the identity of the leachable, which may include compound class or more specific information, such as chemical formula and structure; and the amount and concentration of the leachable in the drug product.

Information sharing between packaging component manufacturers/suppliers and drug product developers/manufacturers is also important in order to guide packaging component and materials of construction selection, provide knowledge of potential extractables and leachables, and facilitate leachables–extractables correlations via knowledge of packaging component chemical compositions, etc. (also see 1663).