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Containment of High-Potency Products in a GMP Environment
Trevor Calkins
BioProcess International, Vol. 8, No. 8, September 2010, pp. 14–18

Many modern medicines are highly potent, with only tiny doses required to achieve a therapeutic effect. But a nanomolar medicine poses extra hazards during manufacturing, whether the product is a biologic or a small molecule. These issues have to be evaluated and addressed in the design of a manufacturing facility for such products. Not only is it vital that the product not become contaminated, but employees and the general public must be protected from the product. Exposure to just a small quantity of a highly potent compound can pose significant health risks.

Highly potent products have their individual manufacturing requirements. But the issues pertaining to safe handling are often common and not product specific. Potency is often a function of structural class, but it cannot be predicted for new molecules or new biological products without sufficient testing. A dramatic increase in development of new drugs, particularly in oncology, is more likely to require engineering controls for containment. My company tends to err on the conservative side and handle each product as potent, then relax restrictions as more information is gathered during a its development cycle. Proper handling of these materials involves specialized facilities that are carefully designed to minimize containment risks.

Facility Design

Some facility design requirements are common to all product types. Most significant is process isolation: ensuring that all product remains within its manufacturing equipment and process piping, including during cleaning procedures. Enclosed equipment such as sealed reactors and dryers are key here, as are product transfer systems for moving materials through a process train. A facility should also be designed with equipment such as isolators, laminar flow hoods, and local exhaust ventilation appropriate for potent compound handling.

Airflow within the facility should be single pass to prevent cross-contamination or concentration of materials. Exhaust air should be filtered to ensure that escaping product is captured before its release to the external environment. In addition, proper air-pressure differentials must be established to keep potent compound–handling areas negative to all adjacent vestibules or airlocks. Equipment and facility engineering controls apply not only to the manufacturing areas, but also support areas such as process development and quality control laboratories.

Even with extensive engineering controls, personnel working with potent compounds should wear suitable personal protective equipment (PPE), including respiration equipment for those working around the most potent products. Proper training on procedures for operation and maintenance of containment and isolation equipment is critical. Staff members must understand why the use of engineering controls is crucial for a manufacturing process.

Product Categories

Before work begins on any drug product, it must be evaluated and characterized to assess potential hazards. For contract manufacturers, the first call is clearly to the customer, who should have information about a product's safety and toxicology. Other information can be gleaned by making comparisons with similar products with known toxicological properties. The drug is then categorized according to its potential hazards so correct handling procedures can be established.

The performance-based exposure control limits (PBECL) categorization system links compound toxicity and potency to procedures for safe handling practices. This system was established in the late 1980s by health and safety departments within large pharmaceutical companies working on development projects for which insufficient data were available to determine occupational exposure limits (OELs). The industry uses many different categorization systems — including three, four, and five-tier systems — but this most common system has four categories.

Category 1 compounds are low potency with higher dosage levels. They have minimal acute or chronic health effects and good warning properties. These products will have no genic effects and will not be sensitizers. Absorption will be slow, and no medical intervention will be required following exposure to them.

Category 2 compounds have moderate acute or chronic toxicity, but their effects are reversible. They may be weak sensitizers. Most have fair warning properties, a moderate absorption rate, and no genic effects, but medical intervention may be required after exposure to them.

Category 3 compounds have elevated potency, with high acute or chronic toxicity. These effects may be irreversible. The products may be moderate sensitizers, and their warning properties are likely to be poor or absent. Their absorption rates may be rapid, they may have suspected or known genic effects, and moderate to immediate medical intervention will be required. At SAFC Pharma, we consider this to be the default category.

Category 4 compounds have high potency and extreme acute and chronic toxicity. They cause irreversible effects and are likely to be strong sensitizers, with poor or no warning properties and a rapid absorption rate. These products will have known genic effects and require a higher degree of medical intervention. They may also affect sensitive subpopulations to a greater extent than the public overall.

All potent products fall into category 3 or 4, depending on their cumulative risk factors. Requirements for containment and protection vary among the categories, and the precise ways they are put into practice differ. The details depend on whether a product is an infectious biologic such as a viral vector or vaccine, a highly potent small molecule (made by chemical reaction or fermentation), or an antibody drug conjugate that links a biologic to a potent small molecule.

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