Topical otic drugs in a multi-purpose manufacturing facility: a guide on determination and application of permitted daily exposure (PDE)

Wiesner, Lisa; Prause, Maarten; Barle, Ester Lovšin

doi:10.1080/10837450.2017.1334665

Cited by 7 publications

(3 citation statements)

References 24 publications

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“…There can be instances where an alternative route of administration leads to higher toxic potentials. Further insight into this topic is not part of this work, and PDE determination for special routes, for example, ocular, otic, and others, has been explained elsewhere (Lovsin Barle et al, 2018, 2019; Wiesner et al, 2018) and should be consulted in the relevant cases.…”

Section: Methodsmentioning

confidence: 99%

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

Wiesner

Araya

Barle

2022

J of Applied Toxicology

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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.

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Section: Methodsmentioning

confidence: 99%

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

Wiesner

Araya

Barle

2022

J of Applied Toxicology

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“…A hazard that indicates a potential risk in the case of exposure is a prerequisite for conducting a risk assessment. Consequently, risk is associated with exposure to a hazard (Wiesner, Prause, Barle, 2018). In the context of cross- contamination, a hazard may be a source, situation, or event that has the potential to compromise patient health due to the lack of control measures to mitigate the risk of cross-contamination between products when the acceptable limit according to the permitted daily exposure (PDE) is exceeded (Sehner et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Permitted daily exposure from preclinical studies of Ginkgo biloba L. dry extract

Lamb,

Rodrigues,

Saraiva

et al. 2023

Braz. J. Pharm. Sci.

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Resolution 658/2022 of the Brazilian Regulatory Agency requires the determination of the permitted daily exposure (PDE) of pharmaceutical agents. Ginkgo biloba L. is used therapeutically to treat memory deficits and other brain diseases. However, published results indicate that more studies are needed to confirm the safety of Ginkgo biloba. This study aimed to evaluate the dry extract of Ginkgo biloba L. leaves PDE as an ingredient in an oral pharmaceutical product in preclinical studies using mice. Acute oral toxicity and repeated dose experiments were performed based on OECD guidelines, as well as genotoxicity tests. The results indicate that Ginkgo biloba L. has low acute toxicity, no liver toxicity, and does not alter blood glucose levels. No changes in weight gain were observed, but food intake decreased in males during the first week of treatment at the highest dose. Hematological parameters were not altered in males, whereas females presented lower leukocyte and lymphocyte counts and higher neutrophil counts at the highest dose. The lipid profile was not altered in males, whereas total cholesterol was increased in females. The estimated PDE was 0.1 mg/day and, when related to the maximum residual concentration, indicates that the cleaning process used is safe and does not require reassessment.

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“…Due to their inherent toxicity [ 3 ], volatile amines need to be effectively purged from intermediates or final products to ensure safety of the administered product. Their allowable residual levels are regulated by ICH guidelines [ 4 , 5 ], or are specifically calculated based on the daily dosage of active pharmaceutical ingredient (API) [ 6 , 7 ] and the permitted daily exposure (PDE) limit for each substance. The purge and determination of residual amines in intermediates or APIs not only reflect the effectiveness of purification procedures but also ensure product quality.…”

Section: Introductionmentioning

confidence: 99%

Development of a rapid GC-FID method to simultaneously determine triethylamine, diisopropylamine, and 1,1,3,3-tetramethylguanidine residues in an active pharmaceutical ingredient

Shou

Qiu

2021

Journal of Pharmaceutical Analysis

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A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine (TEA), 1,1,3,3-tetramethylguanidine (TMG), and diisopropylamine (DIPA) in the synthetic route of an active pharmaceutical ingredient (API). Due to the severe absorption of amines on GC stationary phases, GC columns with various stationary phases were evaluated for optimal peak shape and reproducibility. The final conditions used the Agilent CP-Volamine column to resolve the three amines in 12 min. Various inlet liners were also screened to further improve the sensitivity of the analysis. The Restek Siltek® liner was selected to achieve the desired detectability for the method. The quantitation limits were 4, 3, and 4 μg/mL for TEA, DIPA, and TMG in the presence of API, respectively. All three amines showed good linearity ( r > 0.999) and recoveries (> 90%) over the concentration range of 3 to 16 μg/mL. The testing of residual amines was initially performed at the penultimate stage of the synthesis. However, this work demonstrates that TMG can act as a proton sponge to react with salicylic acid, the counter ion of the penultimate, to form a volatile component that elutes at a different retention time. Consequently, in the final method, these three amines were monitored in the final API to circumvent the matrix interference. Key parameters of the method were qualified per method validation requirements in ICH guidelines. The method was successfully applied for batch testing during development and implemented as an in-process control procedure at manufacturing sites.

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Topical otic drugs in a multi-purpose manufacturing facility: a guide on determination and application of permitted daily exposure (PDE)

Cited by 7 publications

References 24 publications

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

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

Permitted daily exposure from preclinical studies of Ginkgo biloba L. dry extract

Development of a rapid GC-FID method to simultaneously determine triethylamine, diisopropylamine, and 1,1,3,3-tetramethylguanidine residues in an active pharmaceutical ingredient

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