ISPE Glossary of Pharmaceutical and Biotechnology Terminology

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Performance-Based Occupational Exposure Limits (PB-OEL)

A systematic method of assigning compounds to one of four categories based on potency, pharmacology, acute toxicology, therapeutic class, therapeutic dose, genotoxicity, and bench-marking. PB-OELs differ from OELs in that PB-OELs are established early in preclinical development before or at Investigational New Drug (IND) phase, they are order(s) of magnitude estimation of the OEL, provide guidance on engineering controls that will meet the OEL, protect the scientists and development engineers during product/process development, and enable companies to accelerate drug development. PB-OELs achieve containment primarily with engineering controls.

Airborne concentrations vary predictably with the process equipment utilized, transfers in and out of equipment, degree of containment, how equipment is cleaned, and whether the facility design includes airlocks and general ventilation. Based in these considerations a containment technology hierarchy has been established:

1. Category I > 100 µg/m³ - Low to moderate toxicity and pharmacological activity, no teratogens, mutagens, or carcinogens, low acute/chronic systemic effects, low potency, reversible effects, and first aid/simple medical treatment. - At this level, local exhaust and general ventilation are utilized, and adhering to normal cGMPs is usually enough protection for an operator, this should include hair and shoe covers and the requirement to change into a uniform that is laundered or replaced. For process areas, access to change/locker rooms and showers is required.

2. Category II > 100 µg/m³ - <20 µg/m³ ? Irritant; good warning properties, no teratogens, mutagens, or carcinogens, onset of symptoms is immediate, low acute/chronic systemic effects, low potency, reversible effects, and requires first aid/simple medical treatment. - This is the first category that requires the use of special equipment such as unidirectional laminar flow booths to create an additional separation between the operator and the materials being handled. Process areas must have adjoining change/locker rooms available.

3. Category III >20 µg/m³ - <5 µg/m³ - Moderate to high acute systemic toxicity, moderate chronic systemic toxicity, reversible effects, sensitizer, onset of symptoms immediate to delayed, weak mutagens, moderate degree of medical intervention may be required, compounds of unknown toxicity. - At this level the lower level of the capabilities of unidirectional laminar flow technology has been reached, and another level of control (barrier technology) such as Split Butterfly Valves (SBVs) must be used to separate the operator from the material being handled. Process areas must have adjoining change/locker rooms, and a decontamination area is strongly recommended.

4. Category IV <5 µg/m³ - Highly potent, high acute and/or chronic systemic effects, irreversible effects, extreme sensitizer, mutagen, developmental toxicity, reproductive toxicity or carcinogen, none or poor warning properties, immediate and delayed onset of symptoms, high degree of medical intervention needed. - At this level, the guaranteed limits of SBVs have been reached and to meet the containment requirements, Isolation Technology such as robotics, or glove boxes with Rapid Transfer Ports (RTPs) need to be used. Process areas must have adjoining change/locker rooms for production, maintenance, service, and decontamination. Decontamination required prior to entry to change/degowning room.

NOTE: Most manufacturers of potent compounds establish categories based upon the exposure limits of the products. The above-mentioned Categories (I through IV) and their limits in µg/m³ (micrograms per cubic meter) are an example of a standard based upon the equipment capabilities. It is a base to assist in the design of new solid dosage facilities, and to weigh the impact on existing facilities, and health and safety operational changes that may preclude capital investment.

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See also: Occupational Exposure Limits (OEL)

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