Setting impurity limits for endogenous substances: Recommendations for a harmonized procedure and an example using fatty acids.

Endogenous substances, such as fatty, amino, and nucleic acids, are often purposefully used in parenterally pharmaceuticals, but may be present as impurities. Currently, no consensus guidance exists on setting impurity limits for these substances. Specific procedures are needed, as the amount and types of toxicity data available for endogenous substances are typically far less than those for other chemical impurities. Additionally, the parenteral route of administration of these substances is inherently non-physiological, resulting in potentially different or increased severity of toxicity. Risk Assessment Process Maps (RAPMAPs) are proposed as a model to facilitate the development of health-based exposure limits (HBELs) for endogenous substances. This yielded a framework that was applied to derive HBELs for several fatty acids commonly used in parenteral pharmaceuticals. This approach was used to derive HBELs with further vetting based on anticipated perturbations in physiological serum levels, impacts of dose-rate, and consideration of intermittent dosing. Parenteral HBELs of 100-500 mg/day were generated for several fatty acids, and a proposed class-based limit of 50 mg/day to be used in the absence of chemical-specific data. This default limit is consistent with the low toxicity of this chemical class and ICH Q3C value for Class 3 solvents.

Development of Duration-Based Non-Mutagenic Thresholds of Toxicological Concern (TTCs) Relevant to Parenteral Extractables and Leachables (E&Ls).

The threshold of toxicological concern (TTC), i.e., the dose of a compound lacking sufficient experimental toxicity data that is unlikely to result in an adverse health effect in humans, is important for evaluating extractables and leachables (E&Ls) as it guides analytical testing and minimizes the use of animal studies. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium, which consists of member companies that span biotechnology, pharmaceutical, and medical device industries, brought together subject matter expert toxicologists to derive TTC values for organic, non-mutagenic E&L substances when administered parenterally. A total of 488 E&L compounds from the ELSIE database were analyzed and parenteral point of departure (PPOD) estimates were derived for 252 compounds. The PPOD estimates were adjusted to extrapolate to subacute, subchronic, and chronic durations of nonclinical exposure and the lower fifth percentiles were calculated. An additional 100-fold adjustment factor to account for nonclinical species and human variability was subsequently applied to derive the parenteral TTC values for E&Ls. The resulting parenteral TTC values are 35, 110, and 180 µg/day for human exposures of >10 years to lifetime, >1-10 years, and ≤1 year, respectively. These parenteral TTCs are expected to be conservative for E&Ls that are considered non-mutagenic per ICH M7(R1) guidelines.

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.

Special endpoint and product specific considerations in pharmaceutical acceptable daily exposure derivation.

Recently, a guideline has been published by the European Medicines Agency (EMA) on setting safe limits, permitted daily exposures (PDE) [also called acceptable daily exposures (ADE)], for medicines manufactured in multi-product facilities. The ADE provides a safe exposure limit for inadvertent exposure of a drug due to cross-contamination in manufacturing. The ADE determination encompasses a standard risk assessment, requiring an understanding of the toxicological and pharmacological effects, the mechanism of action, drug compound class, and the dose-response as well as the pharmacokinetic properties of the compound. While the ADE concept has broad application in pharmaceutical safety there are also nuances and specific challenges associated with some toxicological endpoints or drug product categories. In this manuscript we discuss considerations for setting ADEs when the following specific adverse health endpoints may constitute the critical effect: genotoxicity, developmental and reproductive toxicity (DART), and immune system modulation (immunostimulation or immunosuppression), and for specific drug classes, including antibody drug conjugates (ADCs), emerging medicinal therapeutic compounds, and compounds with limited datasets. These are challenging toxicological scenarios that require a careful evaluation of all of the available information in order to establish a health-based safe level.

In silico approaches to predicting cancer potency for risk assessment of genotoxic impurities in drug substances.

The current risk assessment approach for addressing the safety of very small concentrations of genotoxic impurities (GTIs) in drug substances is the threshold of toxicological concern (TTC). The TTC is based on several conservative assumptions because of the uncertainty associated with deriving an excess cancer risk when no carcinogenicity data are available for the impurity. It is a default approach derived from a distribution of carcinogens and does not take into account the properties of a specific chemical. The purpose of the study was to use in silico tools to predict the cancer potency (TD(50)) of a compound based on its structure. Structure activity relationship (SAR) models (classification/regression) were developed from the carcinogenicity potency database using MultiCASE and VISDOM. The MultiCASE classification models allowed the prediction of carcinogenic potency class, while the VISDOM regression models predicted a numerical TD(50). A step-wise approach is proposed to calculate predicted numerical TD(50) values for compounds categorized as not potent. This approach for non-potent compounds can be used to establish safe levels greater than the TTC for GTIs in a drug substance.