Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides

Bercu, Joel P.; Galloway, Sheila M.; Parris, Patricia; Teasdale, Andrew; Masuda-Herrera, Melisa; Dobo, Krista L.; Heard, Pamela L.; Kenyon, Michelle; Nicolette, John; Vock, Esther; Ku, Warren W.; Harvey, James S.; White, Angela; Glowienke, Susanne; Martin, Elizabeth A.; Custer, Laura; Jolly, Robert A.; Thybaud, Véronique

doi:10.1016/j.yrtph.2018.02.001

Cited by 38 publications

(39 citation statements)

References 62 publications

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“…• Studies with one only dose group should not be used for TD 50 modelling; Bercu et al, (2018) 6 suggested a minimum of three dose groups be present;…”

Section: Discussionmentioning

confidence: 99%

“…5 A similar process utilising TD 50 values was used to derive acceptable intakes for the (only) two mutagenic impurities described in a recent pharmaceutical industry study, as well as a class-specific limit for alkyl bromides. 6 The calculation of TD 50 values is described in some detail in several publications, the most well-known being Cox (1972), 7 Peto et al (1984) 8 and Sawyer et al (1984); 9 however, these methods require the use of 'lifetable' data where tumour incidence is tracked over time. Such data are rarely available given current experimental protocols.…”

Section: Introductionmentioning

confidence: 99%

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Generation of TD50 values for carcinogenicity study data

Thresher¹,

Gosling

Williams³

2019

Toxicology Research

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Carcinogenic potency is a key factor in the understanding of chemical risk assessment. Measures of carcinogenic potency, for example TD50, are instrumental in the determination of metrics such as the threshold of toxicological concern (TTC), acceptable intake (AI) and permitted daily exposure (PDE), which in turn impact on human exposure. The Carcinogenic Potency Data Base (CPDB) has provided a source of study information, complete with calculated TD50 values. However, this is no longer actively updated. An understanding of carcinogenic potency, which can be derived from dose–response data, can be used as part of human risk assessments to generate safety thresholds under which cancer risk is judged to be minimal. The aim of this paper is to produce a transparent methodology for calculating TD50 values from experimental data in a manner consistent with the CPDB. This was then applied across the same data as used in the CPDB and analysis done on the correlation with the CPDB TD50 values. While the two sets of values showed a high level of correlation overall, there were some significant discrepancies. These were predominantly due to a lack of clarity in the CPDB methodology and inappropriate use of a linear model in TD50 calculation where the data was not suitable for such an approach.

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“…• Studies with one only dose group should not be used for TD 50 modelling; Bercu et al, (2018) 6 suggested a minimum of three dose groups be present;…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Generation of TD50 values for carcinogenicity study data

Thresher¹,

Gosling

Williams³

2019

Toxicology Research

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“…Bercu et al, 2018 is also another resource which has developed PDEs and AIs for common reagents and impurities in pharmaceuticals using methodology described in ICH Q3C(R6), ICH Q3D, and ICH M7 (R2) [29]. The publication also contains Supplementary Materials which describe the toxicity data and scientific process by which all toxicology limits were established.…”

Section: Generating Limits For Impurities With Established Toxicity Datamentioning

confidence: 99%

Establishing Patient Centric Specifications for Drug Substance and Drug Product Impurities

et al. 2018

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In this paper, we remind readers of several ICH guideline documents such as ICH Q3A, Q3B, Q3C, Q3D, Q6A, Q6B, M7, and ICH S9 which are related to the drug substance and drug product impurity limit setting. In particular, ICH Q6A clearly states that "specifications should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug substance and drug product"; however, recent negotiations between health authority and applicants (company) related to proposed marketing applications show that on a global level, batch experience, even when limited, plays an overwhelming role in developing impurity acceptance criteria rather than clinical relevance. The drawback of such practice and the great need to establish patient centric specifications (PCS) are highlighted. Secondly, this paper proposes approaches on how to establish patient centric criteria for drug substance and drug product impurity limits based on the principles outlined in ICH guideline documents and scientific literature. Three case studies are presented to illustrate the challenges in establishing PCS and the divergence of regulatory acceptance to such specifications. We propose some approaches that can be considered for specification setting based on clinical relevance in the drug development, registration and post-approval phases of a product life-cycle. Lastly, we give thoughts on the future perspective of this movement and offer recommendations to foster discussions between regulatory agencies and pharmaceutical industry on getting medicinal products that are safe and effective to the patient sooner to meet unmet medical needs without supply interruption concerns.

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“…Phosphine, the simplest phosphorus(III) compound, is a volatile toxic gas that is utilized in the agricultural industry as a fumigant [1,2]. Alkylphosphines and alkylphosphites also have acute toxicologies similar to phosphine [3][4][5]. Alkylphosphinites are listed as Schedule 1 compounds under the Chemical Warfare Convention as restricted precursors for the nerve agent VX, and alkylphosphites are listed as Schedule 3.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, phosphorus(III) compounds have been widely used in organic synthesis and the pharmaceutical industry, where a diverse number of new phosphorus(III) ligands with unknown toxicologies have been used in cross-coupling reactions, which remain a predominant synthetic tool [6,7]. However, though the toxicology of triphenylphosphine has been studied, with a permitted daily exposure (PDE) of 250 µg reported recently [5], only a few studies have explored the toxicity of less common aryl-and alkylphosphine ligands. In the absence of accurate toxicology, there remains a requirement to detect low-level concentrations of these potentially toxic analytes.…”

Section: Introductionmentioning

confidence: 99%

An Organophosphorus(III)-Selective Chemodosimeter for the Ratiometric Electrochemical Detection of Phosphines

2019

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The high toxicity of phosphine and the use of organophosphines as nerve agent precursors has provoked the requirement for a rapid and reliable detection methodology for their detection. Herein, we demonstrate that a ferrocene-derived molecular probe, armed with an azidobenzene trigger, delivers a ratiometric electrochemical signal selectively in response to organophosphorus(III) compounds and can be accurately measured with an inexpensive, handheld potentiostat. Through an intensive assay optimization process, conditions were found that could determine the presence of a model organophosphine(III) nerve agent precursor within minutes and achieved a limit of detection for triphenylphosphine of just 13 ppm. Due to the portability of the detection system and the excellent stability of the probe in solution, we envisaged that this proof-of-concept of work could easily be taken into the field to enable potentially toxic organophosphorus(III) compounds to be detected at the point-of-need.

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Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides

Cited by 38 publications

References 62 publications

Generation of TD50 values for carcinogenicity study data

Generation of TD50 values for carcinogenicity study data

Establishing Patient Centric Specifications for Drug Substance and Drug Product Impurities

An Organophosphorus(III)-Selective Chemodosimeter for the Ratiometric Electrochemical Detection of Phosphines

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