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Risk management guides decisions in facility design and operation for highly potent drugs.
Risk management is always a priority in pharmaceutical manufacturing. With highly potent drugs, the level of risk management required is even higher. For oral solid dosage forms based on highly potent APIs, rigorous care must be taken throughout the production process (granulation, mixing, tableting, etc.) to ensure the highest level of quality. Shielding operators from exposure to these highly potent drugs is paramount. Initially, for operator protection, the emphasis was placed on the use of extensive personal protective equipment (PPE), but more recently, it has shifted to the use of contained equipment and automation.
Most large pharmaceutical companies in general are well prepared in terms of providing developmental and commercial manufacturing capabilities to support their pipelines of highly potent drugs, according to Clemens Stief, team leader/PPD development for Pfizer's Freiburg, Germany facility, which is part of Pfizer Global Supply (PGS). The requirements for the handling of highly potent drugs are quite demanding with respect to environmental, health, and safety considerations, and the necessary investment for appropriate facilities is significant. Some CMOs, however, have identified the capabilities required for handling highly potent drugs, and there are a few companies out there offering containment capabilities, he adds.
Automation has big impact
With exposure of operators a real concern, separating them from the drug product is critical. “The real equipment breakthrough for the manufacture of highly potent solid dosage drugs in terms of both safety and efficiency has come in the form of automation,” says Stief. “With automation, it is possible to achieve a 100% remotely controlled manufacturing facility with no human interaction during the manufacturing process,” he notes. Stief points to the fully automated solid-dosage form manufacturing suites used for large-volume products such as smoking cessation drugs as prime examples.
These benefits can be harder to realize with smaller-volume products, which are often oncology drugs. Automated equipment is often not designed for smaller-scale operation. Thus, it may only be a solution if platform technologies are applied to a variety of compounds, such as dry granulation followed by capsule-filling for more than just one product in the portfolio, according to Stief. Here, of course, the issue of cross-contamination must then be addressed.
Although single-use and disposable systems have not yet penetrated the solid dosage manufacturing sector to the degree of their usage in liquid and aseptic manufacturing, the idea of using disposable parts is promising. “The use of such systems could allow for a tremendous reduction in cleaning verification and validation efforts as well as related analytical method development work. In addition, it could minimize the potential for contamination of operators and/or the environment,” he observes.
A choice for hard-wall isolation
Although disposable systems have advantages in certain applications, the CDMO Metrics elected to install purpose-built, hard-wall isolation technologies in the dedicated potent and cytotoxic facility it constructed in 2008, according to director of pharmaceutical development Joe Cobb. “Local ventilation and laminar/down-flow technologies are versatile and comfortable, but they are quite dependent on work practice. Similarly, flexible barrier solutions are practical and achieve good containment, but pose challenges from a cleaning standpoint, or, if disposable, a cost-of-goods standpoint,” he explains.
With a limited physical footprint at its site, Metrics could not house each piece of manufacturing equipment (granulators, mills, blenders, etc.) in its own customized isolator. The company thus engineered a series of multi-use, hard-wall isolators that can accommodate up to three individual pieces of processing equipment, for a total of eight individual equipment bays. Standard processing equipment was modified by installing it through a metal baffle, which fits into any bay on any isolator. “As a result, we have general-purpose isolators that can be customized to meet any client request or operation. That flexibility is very appealing to pharmaceutical companies,” Cobb comments.
The isolation barriers for its purpose-built potent facility have performed so well that Metrics has worked closely with its vendors to design similar isolation barriers for use elsewhere in its operations in order to provide an extra measure of safety for its employees even when projects don’t require that level of protection. “We are taking the concepts of containment that we successfully engineered for our potent facility and pushing them out elsewhere in development and manufacturing to make those operations as safe as possible for our operators,” says Cobb.
Need for well-designed containment
Little has changed over the last couple of years regarding the design principles for containment facilities, according to Steif, with the leading paradigm being ‘technical solutions first’ for commercial facilities. “Containment and isolator technology are the technologies of choice, followed by PPE, laminar-flow booths, or restricted access barrier systems (RABS), with only some exemptions in development facilities. This approach means that there is nothing like well-designed containment for individual pieces of equipment and/or manufacturing suites,” he asserts.
Meanwhile, negative-pressure and respective-pressure cascades continue to be considered the state-of-the-art. Separately, the shift to smaller batch size is product-related and applies mostly to oncology drugs with highly selective working principles.
With that key emphasis on well-designed containment equipment comes the challenge, according to Cobb. “While the pharmaceutical industry has a good handle on the technology of isolation (Metrics’ hard-wall containment systems are rated down to occupational exposure levels (OEL) of 30 nanograms per cubic meter of room air), the size and scale of the equipment needed for commercial production can be an issue. In addition, there is a real need for containment-related vendors with first-hand knowledge of the needs and opportunities of the pharmaceutical industry,” asserts Cobb.
When constructing its high-potent facility, the company had to adapt the technologies of vendors that provided equipment for the production of dangerous substances, such as biologicals and hazardous dusty materials. “The onus was on us to seek out vendors who specialized in containment systems for dangerous substances and encourage them to apply their knowledge to our needs within pharmaceutical development and formulation. It would be helpful to have vendors who better understand the pharmaceutical industry and can present ideas for containment advances to us, instead of the other way around,” Cobb says.
Manufacturers of highly potent solid dosage drugs are also dealing with the issue of segregation and the need to comply with stricter regulations introduced by several regulatory authorities, according to Stief. “Such requirements not only influence the facility layout and HVAC design, they also trigger activities related to industrial hygiene and monitoring and have an impact on overall equipment efficiency, thus, making the containment business even more challenging and expensive.”
Potential for PAT
Process analytical technology (PAT) can definitely make a difference, according to Stief, because it provides many opportunities for preventing operator exposure to highly potent drugs and drug products. These techniques are also attractive because they are mostly noninvasive and support process monitoring without direct product contact or sampling procedures. He points to the use of Raman analysis for compound identification, which can be achieved through a polyethylene bag. “Near-infrared (NIR) methods are also available for online blend uniformity measurement in blending operations, and NIR assays may eventually even support a real-time release strategy,” he notes.
Flexibility for success
Both Cobb and Stief believe that the flexibility of their highly potent solid dosage manufacturing facilities provides a real benefit to the industry. “With our custom-engineered, hard-wall isolators, clients have the flexibility to select only those capabilities needed for their particular projects,” explains Cobb. He notes that such flexibility is proving increasingly important as greater numbers of APIs (active pharmaceutical ingredients) are becoming increasingly more potent. “In addition, many of the new APIs are more difficult, challenging, and hard to handle, which means those of us who work with them need to be nimble and flexible in order to respond appropriately.”
The DevCon Facility (Development Containment) for Product and Process Development at Pfizer´s Launch Site in Freiburg, Germany can cover batch sizes from 10 to 150 kg and provides full GMP compliant services. This flexibility of scale is important in the development arena, according to Stief. He adds that the facility can also be used for the production of launch and commercial quantities of small volume products. PGS is also currently evaluating investment in additional laboratory-scale equipment in response to the urgent need to have GMP-compliant lab-scale equipment in a containment environment to cover the initial phases of the development cycle, according to Stief.