Challenges in setting Permitted Daily Exposure (PDE) Limits for pharmaceuticals: A review

BACKGROUND: When more than one drug is manufactured at a shared facility or equipment in pharmaceutical manufacturing, the potential carry-over of the retained residue of existing drug product on product contact parts of the equipment to the next product can be a source of cross contamination. Permitted daily exposure (PDE) is derived based on the complete nonclinical and clinical data available and is a dose that is unlikely to cause adverse effects if an individual is exposed, by any route, at or below this dose every day over a lifetime. OBJECTIVE: The objective was to present a comprehensive review of available scientific knowledge for derivation of PDE. METHODS: PubMed and ScienceDirect databases were searched using keywords “PDE” and “pharmaceuticals” and all the relevant literature up to March 2021 was reviewed. We have also calculated PDEs for Tobramycin (CAS No. 32986-56-4) and Acetyl Salicylic Acid (ASA, CAS No. 50-78-2). RESULTS: This research will be useful for scientists working in the PDE domain. The given examples emphasize the importance of use of human data in calculating PDE. CONCLUSION: The duty of the risk assessor entrusted with setting PDEs is to derive a data driven, scientifically justified value that is safe for patients, while avoiding unjustified conservativeness that puts unnecessary burden on manufacturing.

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

A workshop entitled “Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis” was held at the 2018 Genetic Toxicology Association annual meeting. The objectives of the workshop were to provide an educational forum and use case studies and live multiple-choice polling to establish the degree of similarity/diversity in approach/opinion of the industry experts and other delegates present for some of the more challenging decision points that need to be considered when developing a compound-specific exposure limit (ie, acceptable intake or permissible or permitted daily exposure). Herein we summarize the relevant background and case study information for each decision point topic presented as well as highlight significant polling responses and discussion points. A common observation throughout was the requirement for expert judgment to be applied at each of the decision points presented which often results in different reasoning being applied by the risk assessor when deriving a compound-specific exposure limit. This supports the value of precompetitive cross-industry collaborations to develop compound-specific limits and harmonize the methodology applied, thus reducing the associated uncertainty inherent in the application of isolated expert judgment in this context. An overview of relevant precompetitive cross-industry collaborations working to achieve this goal is described.

Fuzzy probabilistic approach for risk assessment of BOT toll roads in Indian context

Purpose The built-transfer and operate (BOT) toll model has been a common approach for highway construction in India. Due to large amount of investment, many stakeholders and long concession period, Indian BOT toll roads become susceptible to different risks. Risk assessment is one of the essential and difficult steps of risk management that enables professionals to quantify and analyze the risks that may hamper the BOT toll project performance in terms of cost, quality, safety and time. The purpose of this study is to identify and assess the risk factors by the fuzzy probabilistic model. Design/methodology/approach The comprehensive literature review has been carried out for identification of Indian BOT toll roads projects' risk factors. A structured questionnaire was prepared which was then filled by contractors, government officers, academicians, project managers and consultants. For risk assessment, a systematic quantitative-based fuzzy probabilistic model is proposed with the help of lab-view, as a risk assessment technique to simulate the impreciseness of human judgment and to improve the assessment accuracy. Findings The risk assessment is one of the difficult tasks because BOT toll roads have complex structure. In this study, total 71 risks have been identified and categorized under 14 risk factors on a basis of case studies of Indian toll roads and literature review. All risks have been assessed by the fuzzy probabilistic model by lab-view. The land acquisition is the most crucial risk of BOT toll roads project which is subsequently followed by construction time and cost over-run. Also, Indian BOT toll roads are facing the traffic shortfalls critically, which became a reason toward declination trend for investment in BOT toll projects by the private players. Other risks like political risks, contractual and social risk badly are affecting the project performance. Early risk identification and assessment can be beneficial for the project, which is required to prepare the risk response strategy before the project commencement. Originality/value This study throws light on comprehensive risk assessment and framework modeling of the risk assessment for the BOT toll roads project in India. This comprehensive risk assessor model can be used for BOT toll roads in Indian scenario for prioritization of the critical risk. It is important for the public and private sectors to establish an effective risk assessor model for public–private partnership (PPP) projects to achieve win-win condition for both.