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

AI Article Synopsis

  • Endogenous substances like fatty acids, amino acids, and nucleic acids are often included in parenteral pharmaceuticals but can also appear as impurities, with no current guidelines on acceptable impurity levels.
  • Limited data exists on the toxicity of these endogenous substances compared to other chemical impurities, and administering them parenterally can lead to unique toxicity issues.
  • The proposal of Risk Assessment Process Maps (RAPMAPs) aims to establish health-based exposure limits (HBELs) for these substances, which generated specific limits for fatty acids ranging from 100-500 mg/day, and a general limit of 50 mg/day for cases lacking specific data.

Article Abstract

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.

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Source
http://dx.doi.org/10.1016/j.yrtph.2022.105242DOI Listing

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