Guidance for establishing acceptable daily exposure limits (ADE) to enable risk-based pharmaceutical product manufacturing

Acceptable daily exposures (ADEs), or health-based limits for active pharmaceutical ingredients (APIs), are required by the pharmaceutical industry and are used to derive acceptance limits for cleaning validation and cross-carryover analysis. ADEs are defined as a dose of an API that is unlikely to induce adverse effects if an individual is exposed to it every day, by any route, for a lifetime.

ADEs must be established in keeping with ICH Q9 and other scientific approaches for determining health-based limits that assist in the management of risks to product quality and operator safety during the manufacturing of pharmaceutical goods. Previous methods for establishing acceptance limits in cleaning validation processes have been regarded as arbitrary, and they have generally ignored clinical and toxicological data for a medicinal substance. The ADE is more holistic and consistent with other quantitative risk assessment purposes such as the derivation of occupational exposure limits since it uses all available pharmaceutical data and applies scientifically acceptable risk assessment techniques. Hazard identification, dose response assessment, uncertainty factor analysis, and documentation processes are all addressed.

Highlights

-Cleaning validation limits for medicinal items are determined using ADEs.

-The term (ADEs) refers to the amount of radioactivity a patient is exposed to on a daily basis.

-For any route and for lifetime exposure, ADEs are defined.

-Guidance for establishing ADEs, which is required to maintain industry consistency.

Introduction

The pharmaceutical industry’s increased focus on quality risk management has required the development of additional guidelines and tools for pharmaceutical product quality control. In its Q9 document (ICH, 2005), the International Conference on Harmonization (ICH) described a systematic method for assessing, controlling, communicating, and reviewing risks to the quality of medicinal products. In support of this process, the International Society for Pharmaceutical Engineering (ISPE) developed a Baseline Guide titled Risk Mobilizing for Action through Planning and Partnerships (MaPP) or Risk-Based Manufacture of Active Pharmaceutical Products, which detailed a scientific approach to managing risks to both product quality and operator safety during the manufacture of pharmaceutical products (ISPE, 2010). Risk assessment is identified as the risk management process in the ISPE Risk Mobilizing for Action through Planning and Partnerships (MaPP) Guide, which follows the ICH Q9 process.

The identification, analysis, and evaluation of risks are all part of the Risk Mobilizing for Action through Planning and Partnerships (MaPP) risk assessment process. The identification of hazards and the assessment of dose response relationships are all part of the risk identification stage, which leads to the development of health-based limitations (ISPE, 2010). This method is similar to one that has been used in the past and was first recorded in the National Research Council’s “Red Book” risk assessment guide (NRC, 1983).

An acceptable daily exposure, or ADE, is the health-based limit set in the Risk Mobilizing for Action through Planning and Partnerships (MaPP) Baseline Guide. It reflects a dose that is unlikely to cause harm if an individual is exposed to it at or below this level every day for the rest of their lives (ISPE, 2010). The ADE is used to calculate acceptable limits for cleaning validation and cross contamination evaluation. Prior to the discovery of ADEs, acceptability limits were mostly arbitrary, such as 1/1000th of the clinical dose, or 10 ppm.

These restrictions did not take into account the active pharmaceutical ingredient’s toxicological, pharmacological, and clinical data (API). As a result, even though it was assumed, such arbitrary limits could not be shown to be health-protective. Penicillins, cephalosporins, and other antibiotics with a beta-lactam ring have been excluded from the Risk Mobilizing for Action through Planning and Partnerships (MaPP) method since it is unclear whether a safe limit can be calculated. These compounds’ risk assessment will not be discussed here.

While the process of determining ADEs for quality risk management is new, the pharmaceutical industry has a long history of assessing risks of occupational exposure and determining occupational exposure limits (OELs) for APIs (Sargent and Kirk, 1988, Galer et al., 1992). The ICH Q3C guidance on residual solvent impurities provides additional direction for the calculation of ADE-like values (ICH, 1998). Permissible daily exposures (PDEs) for residual solvent impurities in APIs and medicinal products are defined by ICH Q3C. The goal of this research is to examine the scientific knowledge gained through the industry’s experience with OELs, PDEs, and other quantitative risk assessments, as well as their use and application in the development of ADEs.

Calculation of an ADE

The equation used to generate the ADE, which is similar to that used to derive OELs for pharmaceuticals and most chemical substances: ADE = acceptable daily exposure (mg/day); NOAEL = no-observed adverse effect level (mg/kg/day); UFC = composite uncertainty factor; MF = modifying factor; PK = pharmacokinetic adjustments; UFC = composite uncertainty factor; NOAEL = no-observed adverse effect level (mg/kg/day); UFC = composite uncertainty factor; MF = modifying factor; PK = pharmacokinetic adjustments.

When the POD comes from a clinical trial and the doses have already been represented as a therapeutic dose, the numerator is used.

Summary

ADEs are a significant step forward from present hazard identification and risk management practises. Previously used in the development of acceptance limits in cleaning validation processes, generically determined limits were regarded arbitrary and mainly ignored the available clinical and toxicological data for a drug substance. The ADE is more holistic since it uses all available pharmaceutical data and applies scientifically approved risk assessment methods.