Optimizing High-Potency Manufacturing

Effective containment in API and drug-product manufacturing encompasses a variety of process, equipment, and operational issues.
Jun 01, 2011

Patricia Van Arnum
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.

API manufacturing

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.

Solid-dosage manufacturing

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.

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)
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.

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:

  • Cleaning of both sides of the containment valves
  • CIP media passed through the suspension lines and the spray nozzles
  • Suspension vessels that could be washed and dried using a separate wash skid
  • Coating-pan cleaning using a high pressure CIP system (i.e., 70 bar)
  • External surfaces of the pan and coater housing fully covered by wash media from spray balls
  • Exhaust plenums fully cleaned by the CIP system.

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.