Navigating Health-Based Exposure Limits in Pharmaceuticals A Path to Safety and Compliance

In the pharmaceutical industry, health-based exposure limits are crucial for safeguarding against potential health risks. These limits have traditionally been used to protect workers in pharmaceutical manufacturing and are often derived from acceptable daily exposures (ADEs). However, there’s a growing interest in transitioning to ADEs and permitted daily exposures (PDEs) to ensure product quality. Recent regulatory attention has focused on preventing cross-contamination in equipment and facilities, particularly regarding residues of active pharmaceutical ingredients (APIs) present in subsequent medicinal products. APIs inherently possess biological activity, sometimes even at very low doses. Historically, empirical approaches, rather than data-driven methodologies, have been used to manage cross-contamination risks, including the requirement for dedicated facilities for specific compounds. However, these approaches lacked clarity and scientific basis.


To address these issues, recent guidelines from the International Society of Pharmaceutical Engineers (ISPE) and the European Medicines Agency (EMA) advocate systematic, scientifically defensible, health-based approaches for setting acceptable exposure limits. These approaches align with International Conference on Harmonisation (ICH) guidelines.

Although the terminology differs slightly between ISPE and EMA (ADE vs. PDE), both aim to determine a dose unlikely to cause adverse effects with daily exposure. Both involve reviewing relevant data, identifying critical effects, selecting a point of departure, calculating the ADE/PDE with adjustment factors, and transparently documenting the rationale.

Over the years, there have been multiple revisions to good manufacturing practices (GMPs) related to exposure limit setting. ICH has made efforts to harmonize risk assessment methodologies globally. Harmonization is essential to ensure consistency across companies and regulatory bodies.

While progress has been made in adopting scientifically sound methods for setting exposure limits, challenges remain. Existing guidelines leave room for interpretation, leading to potential variability in limit derivation, increased manufacturing costs, and human health risks.

It’s important to note that there’s no single correct ADE/PDE value, as it can vary based on factors like point of departure and adjustment factors. Innovative companies with comprehensive data may have higher ADE values, while generic manufacturers with limited data may have lower ones, but all ADE values must be determined by qualified toxicologists.

To address these issues, a workshop was convened in 2014 to discuss harmonization and best practices in ADE/PDE derivation. The workshop identified three main areas for harmonization: regulatory guidance, operations and process management, and ADE/PDE derivation methodology.

In regulatory guidance, differences in approaches to cleaning validation and cross-contamination prevention were noted. There’s a need for clearer, science-based approaches and more harmonized regulations.

Operations and process management require improved communication between companies and regulators, especially in shared facilities. Clearer guidelines and decision-making frameworks are needed.

ADE/PDE derivation methodology involves selecting a point of departure, handling pharmacokinetic issues, considering specific toxicological endpoints, and applying adjustment factors. Harmonization in these areas is essential.

In conclusion, harmonization of scientific principles and practices is crucial for consistent and science-based pharmaceutical risk assessments. It will enhance understanding among stakeholders, improve regulatory compliance, and ensure safer pharmaceutical manufacturing processes. For comprehensive solutions and expert guidance in navigating these challenges, consider partnering with RABT Global, a leading company specializing in pharmaceutical risk assessment and compliance. Our team of experts is dedicated to helping you meet industry standards and ensure the highest level of safety in your pharmaceutical operations.

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