
Health-based exposure limits (HBEL) are vital for setting safe occupational exposure levels and provide the foundation for developing effective cleaning validation limits. HBELs utilize a risk-based approach that involves a structured scientific evaluation of toxicological and pharmacological data, including both non-clinical and clinical data, to derive a threshold value that is considered safe for all populations [1]. Typically, these limits are product-specific and may be expressed as either an Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE). Unfortunately, there is not always sufficient data available for every residue that may be encountered during the manufacturing process and poses a risk to patient safety to establish a compound-specific HBEL. This memo will discuss situations where it may be appropriate to use a default HBEL and why default limits are scientifically justifiable when a product-specific HBEL cannot be determined.
For genotoxic impurities, early clinical products, or monoclonal antibody intermediates, there is not always sufficient data to support the derivation of a compound-specific HBEL. Due to the large inherent uncertainty (e.g., composite factor applied is > 5000) of incomplete data sets, it may be appropriate to utilize a default HBEL approach [1, 3].
Genotoxic impurities are produced as a result of chemical synthesis or degradation during the drug manufacturing process. These impurities pose a patient safety risk due to their potential for mutagenic and carcinogenic properties and are classified into one of five categories. Class 1 impurities are known mutagens typically with positive carcinogenicity data and require derivation of a compound-specific acceptable intake limit [7]. However, for class 2 and 3 impurities, a default HBEL of 1.5 mg/day is recommended as it represents an acceptable intake for any unstudied chemical that will not pose a risk of significant carcinogenicity or other toxic effects [7]. These impurities are either known mutagens with unknown carcinogenic potential (i.e., class 2), or they have an alerting structure and are not verified to be non-mutagenic (i.e., class 3). Class 4 and 5 impurities have an alerting structure, but testing has demonstrated they are non-mutagenic, or there is sufficient data to demonstrate they are not mutagenic or carcinogenic in alignment with ICH M7 [6]. These impurities are treated as non-mutagenic, and a default limit of 1000 mg/day is considered acceptable in alignment with ICH Q3A [7].
Standardized methodology for setting default limits of small molecules drug substances where there is limited data available for the compound being assessed was originally proposed by Dolan DG in the Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations and has since been widely accepted in the industry and supported by several organizations including the American Society for Testing Materials (ASTM) International. It was originally adopted to evaluate genotoxic impurities but has since been expanded to include substances that are typically encountered in manufacturing, including early clinical. This approach establishes a threshold of toxicological concern (TTC) based on compiled toxicity data for representative compounds [2,3] to derive a default value, see Figure 1, Default HBELs for Small Molecule Drug Substances with Limited Data. For compounds that may be mutagenic with unknown carcinogenic potential, a default HBEL of 1.5 mg/day is recommended. For compounds that are considered potent or highly toxic but not mutagenic or carcinogenic, a default HBEL of 10 mg/day is recommended. For compounds that are not potent, highly toxic, or carcinogenic, a default HBEL of 100 mg/day is recommended. Lastly, for compounds that are reprotoxic or teratogenic, a default HBEL of 1.0 mg/day is recommended [3]. Prior to using any of the default limits mentioned, it is critical to have an expert (e.g., toxicologist) verify that the compiled toxicological data used to derive the default value is, in fact, representative of the compound in question. A risk assessment must be approved by the expert, justifying why the chosen default limit is appropriate.
Figure 1: Default HBELs for Small Molecule Drug Substances with Limited Data

In contrast, standardized methodology has not been developed for the establishment of default limits for biological products [3]. However, there are situations where the use of a default HBEL limit may be appropriate. Monoclonal antibodies (mAb) are prone to degradation, especially during cleaning where they are exposed to high temperatures and/or pH. These degraded product residues may have different chemical compositions, properties, or structures than those of the original product. Although the degradants are no longer biologically active, they do pose immunogenicity risks due to altered protein structures or epitopes that must be addressed during product changeover to control the risk of carry-over into the subsequent product. Thus, if the product fully degrades, the inactive protein fragments constitute the potential residue left on equipment surfaces after cleaning. An approach that has been proposed to establish a default HBEL utilizes a banding scheme where a toxicologist evaluates the risks associated with inadvertent exposure and potential immunogenicity concerns related to biologics as potential carryover impurities [4]. The risk assessment must be approved by the expert (e.g., toxicologist), justifying why the chosen default limit is appropriate.
If a default HBEL is established and more information becomes available later (e.g., early clinical products), the default limit should be updated based on the more robust data set or replaced with a compound-specific HBEL. Risk-assessed default HBELs can be scientifically sound and provide a conservative estimate of safe exposure levels.
References-
EMA. (2014). EMA/CHMP/CVMP/SWP/169430/2012. Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.
Dolan DG, Naumann BD, Sargent EV, Maler A, Dourson M (2005). Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations. Regul Toxicol Pharmacol, 43, 1-9.
ASTM. (2020). E3219-20. Standard Guide for Derivation of Health-Based Exposure Limits (HBELs).
Card, J.W., Fikree, H., Haighton, L.A., Blackwell, J., Felice, B., Wright, T.L., 2015. Proof of Concept for a banding scheme to support risk assessments related to multi product biologics manufacturing. Regul. Toxicol. Pharmaco. 73, 595-606.
Faria, E.C., Bercu, J.P., Dolan, D.G., Morinello, E.J., Pecquet, A.M., Seaman, C., Sehner, C., Weidman, P.A. (2016)., Using default methodologies to derive an acceptable daily exposure (ADE). Regel. Toxicol. Pharmaco. 79, 28-38.
ICH. (2023). M7 (R2). Guideline on assessment and control of DNA reactive (mutagenic) impurities in pharmaceutical to limit potential carcinogenic risk.
ICH. (2006). Q3A (R2). Impurities In New Drug Substances
Contributors: Joanna Joseph and Jenna Carlson