Guidance on the establishment of acceptable daily exposure limits (ADE) to support Risk-Based Manufacture of Pharmaceutical Products

Sargent, Edward V.; Faria, Ellen C.; Pfister, Thomas D.; Sussman, Robert

doi:10.1016/j.yrtph.2012.12.007

Cited by 23 publications

(17 citation statements)

References 25 publications

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“…Furthermore, they are generally established for a nominal 40‐h working week (5 days/week) and for a working lifetime of 40 years. In pharmaceutical manufacturing, the potentially exposed populations are healthy workers, both women and men, of all races (Sargent et al, 2013). For calculation purposes, the accepted average body weight of workers was assumed to be 70 kg (Association of British Pharmaceutical Industry [ABPI], 1995).…”

Section: Occupational Exposure Limitmentioning

confidence: 99%

“…A large amount of data is collected from healthy human volunteers and patients during development and post‐approval of a drug, which supports the efficacy and safety profile of the drug. Human data are of greater relevance than animal data for the same endpoints, such as the PKs, pharmacological effects, and dose dependence of adverse effects (Sargent et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Approaches for setting occupational exposure limits in the pharmaceutical industry

Ahuja

Krishnappa

2021

J of Applied Toxicology

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The use of pharmaceutical drugs has provided a cure for many diseases. However, unintended exposure to drugs in the manufacturing workplace can cause significant health hazards to workers. It is important to protect the workforce from these deleterious effects by limiting exposure to an acceptable level, the occupational exposure limit (OEL). OEL is defined as airborne concentrations (expressed as a time‐weighted average for a conventional 8‐h workday and a 40‐h work week) of a substance to which nearly all workers may be repeatedly exposed (for a working lifetime) without adverse effects. Determination of OELs has become very challenging over time, requiring an overall assessment of the preclinical and clinical data of the drug being manufactured. Previously, to derive OEL values, toxicologists used animal no‐observed‐adverse‐effect level (NOAEL) data, which have been replaced with the overall assessment of animal and human data, placing a higher emphasis on human health‐based data. A major advantage of working with human pharmaceuticals is that sufficient clinical data are available for them in most cases. The present manuscript reviews the latest knowledge regarding the derivation of occupational exposure limits as health‐based exposure limits (HBELs) for pharmaceuticals. We have provided examples of OEL calculations for various drugs including levofloxacin (CAS No. 100986‐85‐4), dienogest (CAS no. 65928‐58‐7), and acetylsalicylic acid (ASA, CAS no. 50–78‐2) using human data. This report will benefit professionals in the OEL domain in understanding this highly important, growing, and challenging field.

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Section: Occupational Exposure Limitmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Approaches for setting occupational exposure limits in the pharmaceutical industry

Ahuja

Krishnappa

2021

J of Applied Toxicology

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“…21, No. 1, 2015 283 cleaning validation limits (Dolan et al 2005;Naumann and Sargent 1997;Sargent et al 2013). The intent of an ADE is to establish an estimated concentration that would not be expected to cause harm from chronic exposure or a point of departure (POD) and dividing by a sum of uncertainty factors (UF total ).…”

Section: Acceptable Daily Exposuresmentioning

confidence: 99%

The Cumulative Risk to Human Health of Pharmaceuticals in New Jersey Surface Water

Roden

Sargent

DiFerdinando

et al. 2014

Human and Ecological Risk Assessment: An International Journal

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Surface water in New Jersey is used by many residential drinking water facilities. Like many water sources it is contaminated by upstream industrial and residential sources, including pharmaceutical residues. This research examines the concentrations of 18 pharmaceuticals in 30 New Jersey locations, their acceptable daily exposures (ADE), and potential drug-drug interactions (DDI). The surface water data was provided by the U.S. Geological Survey (USGS). ADEs for human health were set for each pharmaceutical in the study. The pharmaceuticals were evaluated for known adverse health interactions and their potential health impact. These factors were brought together using a cumulative hazard index (HI) risk assessment calculation to assess the overall risk of pharmaceuticals in NJ surface water to human health. When examining the potential for DDI in this assessment, the risk increased but not appreciably. The HI for the sample locations ranged from <0.00001 to 0.01 with the DDI adding less than 1.2× increase to the overall risk. The calculated risk of these mixtures was also increased to an extreme DDI of 7 times per interaction. A noticeable increase in the calculated risk was seen, but in no cases did it reach a level of concern.

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“…A qualified toxicologist proficient in the field of hazard assessment is needed to accurately collect and analyze all available physicochemical, preclinical, and human data in order to determine critical effect(s) for the calculation of an OEL. The critical effect is often that which occurs at the lowest dose (most sensitive adverse effect) if it is to be considered relevant to the target population (Naumann and Sargent, 2007;Sargent et al, 2013). For a DS with a narrow therapeutic index, one of the critical effects is often the minimal recommended therapeutic dose needed to achieve the intended pharmacological activity.…”

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confidence: 99%

“…Adjustment factors (AFs) are applied to each selected POD to account for uncertainties and pharmacokinetic adjustments are made for inhalation exposure (Reichard et al, 2016). Frequently applied AFs are those accounting for interspecies variability, study duration, intraspecies variability (also referred to as interindividual variability), LOAEL-to-NOAEL conversion, the severity of effect, and database completeness (EMA, 2014;ICH, 1998;ISPE, 2010;Sargent et al, 2013;Sussman et al, 2016;U.S. EPA, 2002;WHO, 2005).…”

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confidence: 99%

Setting Occupational Exposure Limits for Genotoxic Substances in the Pharmaceutical Industry

et al. 2016

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In the pharmaceutical industry, genotoxic drug substances are developed for life-threatening indications such as cancer. Healthy employees handle these substances during research, development, and manufacturing; therefore, safe handling of genotoxic substances is essential. When an adequate preclinical dataset is available, a risk-based decision related to exposure controls for manufacturing is made following a determination of safe health-based limits, such as an occupational exposure limit (OEL). OELs are calculated for substances based on a threshold dose-response once a threshold is identified. In this review, we present examples of genotoxic mechanisms where thresholds can be demonstrated and OELs can be calculated, including a holistic toxicity assessment. We also propose a novel approach for inhalation Threshold of Toxicological Concern (TTC) limit for genotoxic substances in cases where the database is not adequate to determine a threshold.

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Guidance on the establishment of acceptable daily exposure limits (ADE) to support Risk-Based Manufacture of Pharmaceutical Products

Cited by 23 publications

References 25 publications

Approaches for setting occupational exposure limits in the pharmaceutical industry

Approaches for setting occupational exposure limits in the pharmaceutical industry

The Cumulative Risk to Human Health of Pharmaceuticals in New Jersey Surface Water

Setting Occupational Exposure Limits for Genotoxic Substances in the Pharmaceutical Industry

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