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Effective containment in API and drug-product manufacturing encompasses a variety of process, equipment, and operational issues.
High-containment manufacturing, whether for an active pharmaceutical ingredient (API) or finished drug product, requires specialized approaches in facility design, equipment selection, and manufacturing processes to achieve the desired levels of containment and minimize operator exposure. As with pharmaceutical manufacturing overall, science- and risk-based approaches to reach those goals serve as a crucial framework for optimizing high-potency manufacturing as well for specific elements in the process.
Patricia Van Arnum
Powder handling is a specific consideration in high-potency API manufacturing. "The exposure risk matrix for highly potent APIs considers the duration of the task, the quantity of the toxic compound handled, and the physical form of the substance with an increasing order of exposure risk for liquids, wetted solids, and dry, dusty solids," explains Charlie Johnson, head of the high-potency business at Carbogen Amcis, a contract manufacturing organization (CMO) of highly potent APIs. The increased emphasis on particle-size distribution (PSD) affects high-potency manufacturing as well. "Finely ground APIs have an increased specific surface area, which translates into a higher bioavailability of the drug, so particle-size control and distribution are key parameters, particularly when the substance has a poor solubility profile or will be administered orally rather than intravenously or by injection," he says.
Carbogen Amcis has adopted in-line wet milling as a core particle-sizing technology and uses it as its preferred approach for particle-size reduction where technically feasible in high-potency API manufacturing. Johnson says the approach has been shown to be broadly applicable with the exception of very low average PSD ( i.e., <20 μ) or where a very tight PSD is needed (i.e., d10/d90 of <10 μ, an indication of the uniformity of the distribution of particle sizes). "In such cases, especially where tight control of polydispersity is necessary, flow-cell sonication milling is an option for the production superfine slurries," he explains. During sonication milling, the drug particles are subject to surface erosion due to intense microturbulences formed by cavitation. Typically, average PSD <10 μ can be achieved with a high degree of monodispersity, which may be required in certain specialized drug formulations. Generation of these superfine slurries also requires special isolation and drying techniques, such as spray-drying to recover the bulk product. Where wet milling or flow-cell sonication milling are not technically feasible, traditional dry milling techniques are used, such as pin-milling or jet micronization, which are operated within specially commissioned glove boxes for the safe handling of highly potent compounds.
Manufacturing a solid-dosage form that contains a high-potency compound requires specialized consideration to achieve the desired level of containment. Calum Park, drug-product manufacturing manager for Abbott's Ireland pharmaceutical operations, identifies several key criteria the company used in the selection, design, and qualification of a tablet coater in high-potency manufacturing at Abbott's Ireland facility that conducts contract services, including the development and manufacturing of small- and large-scale potent APIs and drug products.
"The coater design was focused on providing stringent containment levels during processing and cleaning operations," he says. Processing activities included tablet charging, tablet coating, sampling, and discharging for both potent cores and potent-coating suspensions. For tablet charging and discharging, an investigation was conducted of the split butterfly containment valves available, and industrial hygiene monitoring was performed before specifying the valves. The coater recipes were designed to facilitate charging through the containment valve to the coater pan under negative pressure, relative to the processing room. "A 100% tablet discharge using automated unloading was essential in the design of the coater," he adds.
The design of coating-suspension vessels allowed potent APIs to be added through a split butterfly valve. The suspension feed was designed to be recirculatory through the spray nozzles, so priming the spray nozzles and any interruptions to the process would not result in API sedimentation in the tubing. For processing, the coater was specified with a containment door system, and the pan-to-room pressure differential was monitored to ensure negative depressurization. The coater was designed to provide automated control of the spray gun to the tablet-bed distance and spray angle without intervention to the coating pan. Individual pressure monitoring of the spray nozzles was used to identify blockages in each spray nozzle. The spray nozzles were antibearding by design and fitted with remote nozzle-blockage clearance devices.
A manufacturing chemist in personal protection equipment attaching a hose to a powder-transfer system below a glove-box isolator on a Nutsche filter dryer. (FIGURE IS COURTESY OF SAFC)
Park notes that sampling is an important issue from a containment perspective. "From a research and development point of view, multiple samples may be taken throughout the process from multiple locations in the pan. The design of the system to allow this type of sampling was very complex," he explains. As an alternative, work was done to test and demonstrate the mixing efficiency of the coating pans and baffle systems. This approach was used to rationalize a system that sampled from a single, fixed point of the tablet bed due to the mixing efficiency of the selected coater. The sampling device was a simple mechanical device that removed tablet samples without stopping the coating process and discharging the tablets to a rapid transfer port though a containment valve. This sampling system needed to be fully cleanable through the clean-in-place (CIP) system.
Performance attributes for the coating process for a highly potent compound are generally similar to those for a nonpotent compound, with specialized considerations. "First, coating uniformity is important to minimize any variability in the tablet coating as this may contribute to elevated content uniformity results during finished-product testing," says Park. "Second, the process must be efficient to reduce losses of API to the exhaust plenum in the hot airflow. Also, sampling and cleaning of the coater requires significant consideration for highly potent compounds."
In further elaborating on considerations for a tablet coater in high-potency manufacturing, Park noted from his case study that the coater had to be fully cleaned in situ without manual intervention. "The focus was to provide engineering solutions rather than rely on single-use technology," he said. Several areas were important to achieve a fully automated and comprehensive CIP system. They included:
The support equipment for the coater also was a factor for cleaning and reducing the risk of potential cross-contamination. The exhaust ductwork was designed to ensure that powder dust could not blow back from the duct to the process in an unplanned event. The CIP system was designed to clean part of this ductwork to minimize the risk further. The dust-collection system was designed with washable, safe-change filters and a continuous liner system to prevent any exposure to the potent products during maintenance or waste removal.
Although approaches to optimize manufacturing and achieve the desired level of containment are specific to a given project and process, industry members point to recent gains in overall equipment, operations, and facility design in high-potency manufacturing. Important technological developments include more efficient integration of equipment within containment technology, including both hard-walled isolators and flexible containment, says John Farris, president and CEO of Safebridge Consultants, an occupational health and safety services firm. Newer isolator designs include bolt-on equipment panels, where isolator shells can accommodate various equipment types instead of an isolator for each individual piece of equipment. He also says flexible containment approaches have evolved to include combination technologies with ventilation controls, such as ventilated enclosures and more innovative designs of large flexible systems for entire processes.
"Facility designs also are still evolving and certain elements are becoming more standardized through the industry," adds Farris. He points to developments, such as establishing one-way traffic flow into and out of high-potency suites through the use of airlocks, installation of misting showers to decontaminate operators before entry to the degowning airlock, and pass-through chambers strategically located to allow sample transfers without having to either gown and enter the suite or degown and leave the suite.
Dave Bormett, Madison–Verona site director with SAFC, a provider of high-potency API manufacturing, points to the development of engineering controls and containment equipment for the manufacture and handling of large-scale potent compound batches, such as in the yield of batch sizes in the hundreds of kilograms. "Along with greater recognition of compound potency and proper handling techniques has come the need to produce potent compounds in annual volumes exceeding a metric ton," he says, which in turn, has necessitated that facility and equipment-containment design requirements be applied in larger-scale manufacturing plants. "Although the philosophies and requirements for handling remain the same as small-scale development laboratory, kilo laboratory, or pilot-plant production, certain challenges exist for charging and moving hundreds of kilograms of potent compounds that must be addressed in a large-scale high-potency manufacturing facility," says Bormett.
He says that in SAFC's recent expansion of large-scale high-potency API manufacturing at its facility in Verona, Wisconsin, the company was able to achieved this outcome by working with multiple vendors to coordinate engineering specifications, equipment design, and facility requirements as part of an overall strategy for maintaining a high level of containment for large-scale production. At its Verona facility, Bormett says the company developed a powder-transfer system to eliminate open handling of product by ensuring that final product and intermediates are either transferred into a reactor or into final containers using a system that collects all dry product and maintains containment.
Despite gains, there still are technology hurdles to overcome in high-potency manufacturing. "An important improvement for the use of high-containment equipment in API manufacturing would be a technology that fulfills industrial hygiene and quality assurance (QA) requirements," says Richard Denk, director of the pharmaceutical department at the equipment provider Hecht Technologie. "Proper industrial hygiene requires containment control for the operator, and QA ensures product production without any risks of cross-contamination and product impurities." With this in mind, the hygienic design of the critical product-contact parts is increasingly important, but related improvements in process technologies have been slow in coming.
"Process technologies, such as centrifuges, filter dryers, or Nutsche filters are very complex technologies with a lack of hygienic design on the product-contact parts," he explains. "Large flange connection and large surfaces often are attached with additional features, such as choppers, which make CIP, especially for highly active or highly hazardous substances often impossible. The process equipment must be opened and manually cleaned on the critical areas, which is an additional risk to contaminate the room and the operator. The focus for the future should be an appropriate design of process equipment for high-containment production." He points to disposables with appropriate containment-transfer systems used in biomanufacturing as a good model for such improvement in API manufacture.
Many of these same issues relating to containment and cleaning for API manufacture also apply to oral solid-dosage manufacturing. "Large, very complex, and not easy-to-clean process equipment requires a high demand on cleaning and containment around the process equipment," says Denk. "The containment of a process equipment should be designed from inside to outside, and at the moment, it is designed from the outside to the inside," pointing to what he sees as limitations in installing isolators around critical areas in a tablet press. "It only shifts the problem from industrial hygiene staff to QA," he says.
Denk adds that large product-contact surfaces also are an issue as surfaces are exposed to mechanical forces during manufacturing. "Take for example, high-shear mixers with their integrated agitator," says Denk. "After a short period of time, you will first find small scratches and then larger ones. This is a high-contamination risk in the same process system because cleaning can't be performed as needed, and residues often will not be detected in the scratches. A refurbish of the surfaces is needed, which means sending the equipment back to the vendor for restoration of the required surface quality. This is not easy to handle with large equipment."
Farris sums up the importance of continuous improvement in high-potency manufacturing. "As drug development shifts to more targeted and pharmacologically active products, the challenge of controlling occupational exposure and preventing cross-contamination becomes more acute."
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org.