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:
- 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.