Recent advances
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.
Future improvements
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, pvanarnum@advanstar.com
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