What are the main reasons for establishing health-based exposure limits (HBELs)?

The Acceptable Daily Exposure plays a crucial role in the pharmaceutical and chemical industries, particularly when it comes to ensuring the safety of drug products and workplace environments. Every manufacturer of medicinal or veterinary products needs to obtain and keep current health-based exposure limits, also known as ADE limits or PDE limits, for all their products.

ADE/PDE values help define safe levels of drug residues in manufacturing environments. By setting limits on the acceptable daily exposure to a given API, these values help ensure that there is no cross-contamination between products, which could lead to unsafe levels of the drug in other medicines or pose risks to patients. ADE/PDE values consider the potential risks to patients, particularly sensitive populations (e.g., children, elderly, or individuals with pre-existing conditions), by setting conservative limits that prevent harmful exposures through unintended contamination.

Establishment of PDE/ADE has become an integral part of cleaning validation program due to the risks of possible carryover contamination of residual active substances to comply with various Regulatory or GMP requirements. The PDE/ADE values are used in cleaning validation in manufacturing facilities to further determine the maximum acceptable carryover (MACO values).

Establishing the OEL for an API is a critical step in ensuring worker health and safety, meeting regulatory requirements, minimizing environmental impact, and maintaining safe, efficient manufacturing operations. Though not mandated for pharmaceuticals, the OEL calculation has been recommended by several Agencies including, Occupational Safety and Health Administration (OSHA), American Conference of Governmental Industrial Hygienists (ACGIH), National Institutes of Occupational Safety and Health (NIOSH), Japan Society for Occupational Health (JSOH) and European Chemical Agency (ECHA).

OELs are designed to prevent both acute and chronic health issues, such as respiratory problems, skin irritation, or long-term organ damage that could result from prolonged exposure to hazardous chemicals.

OELs play a crucial role in identifying and mitigating risks in the production environment. By setting exposure limits, companies can implement proper safety measures (e.g., ventilation, PPE, containment systems) to protect workers. Knowing the OEL of an API helps in designing workstations, setting up appropriate safety equipment, and structuring workflows to minimize worker exposure.

Key steps

PDE/ADE have to be determined for all APIs of human and veterinary medicinal products produced in multi-purpose facilities, according to EMA guidelines. Setting ADE/PDE values ensures that each batch produced meets the required quality standards without the risk of interference from traces of other APIs, thus safeguarding both product quality and patient safety. PDE/ADE calculation is in compliance with EMA/CHMP/CVMP/SWP/169430/2012 – Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.

The PDE/ADE/OEL calculation involves complex steps such as systemic hazard identification through organized, strategized literature search; identification of critical effects; establishment of NOEL (no observed effect level)/NOAEL (no-observed-adverse-effect level) for critical effects and application of adjustment factors including bioavailability correction factors for route-to-route extrapolation as per the EMA, 2014, ICH Q3C and ISPE.

Hazard identification is the qualitative appraisal of the inherent property of a substance to produce a pharmacologic/toxicologic effect. To improve the hazard characterization, it is important and necessary to conduct a comprehensive and systematic literature review aimed at identifying all available and relevant data on animals and humans for deriving ADEs. Each compound or set of compounds has complexities in the literature search process and no search is identical. If there are different routes of administration for active substances, a single ADE Report will be made which will include several ADE values for different routes of administration.

Objectives

• Minimizes Cross-Contamination Risks: The ADE value is an essential tool for assessing the risk of cross-contamination and ensuring that manufacturing facilities maintain proper controls. By setting ADE limits, laboratories can prevent contamination in multi-product environments, ensuring that substances do not interfere with other experiments or production processes, thereby safeguarding the integrity and safety of products and experiments.
• Supports Cleaning Validation Processes: Cleaning validation is a crucial aspect of pharmaceutical manufacturing, ensuring that cleaning procedures effectively eliminate residual compounds between production runs. ADE values help establish acceptable residue limits, playing a key role in defining and optimizing cleaning protocols.
• Supports Risk Assessments: ADE values play a crucial role in performing in-depth risk evaluations, ensuring exposure levels stay within safe boundaries. They help identify potential dangers in manufacturing settings that might otherwise be overlooked. With knowledge of the ADE, manufacturing facilities can adopt appropriate safety measures, such as enhanced ventilation, personal protective gear, and containment systems, to reduce the risk of exposure to harmful chemicals or pharmaceutical substances.
• Guarantees Safety Compliance: ADE values serve as a standard for evaluating whether manufacturing practices and facility controls adhere to safety regulations. This is especially crucial during inspections, where auditors must assess potential exposure risks for both workers and end users.