Because of recent advances in genomics and other fields of science, biopharmaceutical companies and CMOs are producing medications that are much more potent than their predecessors. As a result, both industry and the federal Occupational Safety and Health Agency (OSHA) are focusing more on the safety of workers in pharmaceutical manufacturing.
However, protecting employees from exposure to toxic drug substances during the pharma manufacturing process began many decades ago, noted Glenn Herring, VP of manufacturing at Halo Pharmaceutical. During the early years of the birth control pill, manufacturing staff members, most of whom were male, worked rotating schedules within the factory to minimize their exposure to product APIs.
Today the therapeutic area requiring the most potent medications — and thereby posing the greatest safety risk for pharmaceutical manufacturing workers — is oncology. “Unfortunately cancer can’t be effectively treated with just an aspirin,” Stephen Richard, manager, mechanical systems and processors at Bristol-Myers Squibb (BMS), said in explaining the need for powerful, targeted drugs for cancer patients. The manufacture of these innovative drugs requires that personnel work with APIs that are highly toxic, particularly in the large amounts that are stored in liquid or dry powder form in pharmaceutical and CMO warehouses.
“Workers often must scoop these very dusty powders from big drums during dispensing operations,” said Richard. To prevent skin and inhalation exposure to these powders, technicians typically wear coveralls, gloves, and boots and use powered air-purifying respirators (PAPRs) outfitted with HEPA filters connected to a hood and shroud. By the time the medication reaches the patient, however, the amount of API in the drug, while based on the therapeutic dose, is relatively microscopic, because the dosage form will typically include one or more biologically inactive substances, or excipients. “Potent therapy drugs can have great benefit for patients when used in proper regimens, where doses are controlled and risks are minimized. But, they also can have serious consequences to the workers who handle, dispense, mix, apply, and dispose of them without proper controls and training,” said John Howard, M.D., director of the National Institute of Occupational Safety and Health.
Selecting Barrier/Containment Technologies
During the manufacturing process, exposure, even at the lowest levels, to some APIs can produce such toxic effects as cancer, reproductive and developmental problems, and allergic reactions, according to OSHA. The protection of pharma manufacturing workers has spawned a robust industry with numerous companies whose products range from personal protective equipment (PPE) to containment systems that physically separate workers from the drugs’ ingredients. One of these companies designed the space suits for NASA and is applying its expertise in safeguarding astronauts to protecting pharma manufacturing employees.
Unlike space suits, barrier and containment systems for pharmaceutical manufacturing “come in different shapes, sizes, and materials,” said Herring. Although their primary purpose is employee safety, these systems also reduce human contamination, an increasingly important requirement for the aseptic filling of potent products.
Herring explained that the selection of barrier/containment technologies depends on several factors, chief of which is the potential toxicity of the material being handled and the resultant occupational exposure limit (OEL). API manufacturers will develop a material safety data sheet (MSDS) that identifies safe handling practices and disposal of the components as well as an appropriate OEL. The OEL is typically calculated based on data generated during preclinical and clinical toxicology studies.
In pharmaceutical manufacturing, containment structures often are referred to as isolators. But, some industry leaders refer to structures that keep contaminants away from products as “isolators,” and use “containment” to describe strategies or systems that keep toxic or potent products from workers. The Parenteral Drug Association (PDA) uses “aseptic isolator” and “containment isolator,” respectively, to describe the same technologies.
Isolators come in two varieties: open and closed. In aseptic pharmaceutical filling, isolators enable continuous or semicontinuous ingress and/or egress of materials, while maintaining a level of protection over the internal environment. Open isolators are becoming popular in fill areas because they protect products while allowing vials to enter and exit the workspace.
Closed isolators, according to PDA, are “capable of levels of separation between the internal and external environment unattainable with other technologies.” Nothing goes in or out of closed isolators during their operation except for air, whose direction distinguishes aseptic closed isolators from containment closed isolators. While the former uses positive pressure to keep germs and particles out, the latter operates under negative pressure to keep toxic or potent materials away from workers and their workspace.
According to PDA, a barrier technology is “an open system that can exchange contaminants with the surrounding area, and cannot be decontaminated to the extent possible in an isolator.” Containment refers to closed isolators such as the physical structures that separate employees from hazardous substances. These include glove boxes that enable personnel to safely handle materials as well as plexiglass windows that allow them to view their work.
Three-sided downflow booths are an example of a barrier technology used in pharmaceutical manufacturing. Equipped with airflow equipment that draws particulates away from the worker’s breathing area, downflow booths prevent the inhalation of unsafe levels of dust during material handling. Because they enable workers to move freely, downflow booths are regarded as ergonomically friendly.
Some companies have begun to use downflow booths as the primary engineering control for containment. The amount of time required for cleaning is much less with a downflow booth than it is for containment systems. Thus, downflow booths are regarded as cost-effective.
Key Advances In Containment Technology
Recent advances in containment or isolation technology include the use of flexible containment materials as an alternative or supplement to the traditional containment structures that are constructed from stainless steel and other hard materials. Flexible containment technologies include bulk bags and super sacks as well as glove bags, isolators, flooring, and soft-wall clean rooms. The containment capabilities of flexible and rigid materials are reportedly comparable.
Flexible containment technologies have two advantages over rigid systems, said Herring. First, the initial purchase price for flexible technologies is lower than the capital investment required for rigid containment systems. Another advantage: These technologies are disposable, while rigid containment requires time-consuming setup and cleanup. Setup, which can take as long as 8 hours for rigid systems, can be reduced to minutes with single-use containment. The time required for changeover from one product operation to another is reduced from days or weeks to hours with single-use technologies.
Restricted access barrier systems (RABS) are also regarded as an efficient alternative to clean rooms and containment or isolator technologies that completely enclose the aseptic working area. RABS are mini environments with rigid walls that provide a physical and aerodynamic barrier between staff and the sterile drug manufacturing process enclosed within the production environment. In both RABS and isolators, materials are introduced and leave through mouse holes, rapid transfer ports, and pass-throughs. Glove ports and half suits also are used to separate staff from the RABS’ sterile interior.
A New Approach To Barrier Technology
In collaboration with barrier/containment company Walker Barrier Systems, BMS’ Richard has designed and installed a barrier device within a downflow booth as an added engineering control to further reduce dependency on PPE (see photo on page 28). The device, a 3’ x 4’ adjustable plexiglass screen, is designed to provide a physical separation between the worker’s breathing zone and the task being performed — dispensing of dusty powders from large drums. Personnel can manipulate the screen by hand while working in a downflow booth to place it in the most ergonomically effective position. Richard said that his initial studies indicate that the barrier provided a 10x protection factor to workers from inhalation and skin exposure to the APIs, in addition to being operator-friendly. Richard plans to conduct more studies on the device.
“The most impressive step I have noted in containment technology is the change to small equipment isolators and the move away from reliance on clean rooms,” said Dr. Wolfgang Kramp, senior manager of quality assurance at Fischer Clinical Services GmbH, at a recent International Society for Pharmaceutical Engineering (ISPE) conference. One application for such smaller containment areas is the solidcapsule filling process, during which the generation of particulates is unavoidable. Isolators enable the biopharma companies and CMOs to minimize the containment area and increase worker protection.
No doubt the dispensing, formulation, filling, and packaging of the next generation of pharmaceuticals will continue to generate new approaches to safeguard the health of the personnel essential to bringing these drugs to patients.