Identifying nonhazardous substances in pharmaceutical manufacturing and setting default health‐based exposure limits (HBELs)

Abstract

Contract Development and Manufacturing Organizations (CDMOs) that manufacture large, diverse portfolio of chemical and pharmaceutical substances require pragmatic risk-based decisions with respect to the safe carry-over between different chemical entities, as well as for worker protection. Additionally, CDMOs may not have access to primary study data, or data are generally lacking for a specific substance. While pharmaceuticals require the establishment of health-based exposure limits (HBELs) (e.g., occupational exposure limits [OELs] and permitted daily exposure [PDE] limits), the limits for nonhazardous substances could be set in a protective and pragmatic way by using default values, when internally required. Because there is no aligned definition provided by authorities, nor agreed default values for nonhazardous substances, we provide a decision tree in order to help qualified experts (such as qualified toxicologists) to identify the group of nonhazardous substances and to assign default HBEL values for specific routes of exposure. The nonhazardous substances discussed within this publication are part of the following subgroups: (I) inactive pharmaceutical ingredients, (II) pharmaceutical excipients or cosmetic ingredients, (III) substances Generally Recognized as Safe (GRAS), and (IV) food ingredients, additives, and contact materials. The proposed default limit values are 1 mg/m 3 for the OEL and 50 mg/day for the PDE oral and intravenous (IV) route.

Bioinformatics‐based identification of hepatocellular carcinoma‐associated hub genes and assessment of the restorative effect of tannic acid in rat liver exposed to monosodium glutamate

“…8,69 Some authors argue that this paradigm has emerged because GRAS determination criteria and methodologies, especially for experience-based procedures, have not been updated in accordance with today's toxicity determination tests and technologies. [70][71][72] To date, a large number of independent studies have conducted numerous studies on Tannic acid (TA), a plant-derived polyphenol, and shown that TA has pharmacological effects such as antioxidant, antimicrobial, anti-inflammatory, anticarcinogenic, and antimutagenic. In addition to its multifunctional biological potential, TA has attracted great attention because it is cheap, easily accessible, and can be taken in the daily diet.…”

“…Although international regulatory agencies (US Food and Drug Administration; FDA, the European Food Safety Association; EFSA, and Joint FAO/WHO Expert Committee on Food Additives; JECFA) evaluate MSG as a GRAS (generally recognized as safe) substance with established limits, 67,68 mentioned preclinical studies emphasize that MSG exposure, especially with chronic consumption, causes many different organ toxicities and therefore poses a real health risk 8,69 . Some authors argue that this paradigm has emerged because GRAS determination criteria and methodologies, especially for experience‐based procedures, have not been updated in accordance with today's toxicity determination tests and technologies 70–72 …”

“… 8 , 69 Some authors argue that this paradigm has emerged because GRAS determination criteria and methodologies, especially for experience‐based procedures, have not been updated in accordance with today's toxicity determination tests and technologies. 70 , 71 , 72 …”