A case study
Understanding the requirements for HPAPI manufacturing and related costs is critical for a CMO or pharmaceutical company interested
in expanding or adding HPAPI capacity. The CMO SAFC (St. Louis, MO) went through this decision-making process in several recent
expansions. The company has invested $75 million during the past 18 months to expand its HPAPI capacity. These investments
include: a $4.5-million project to add a CGMP pilot plant and kilo-laboratory capacity at its Madison, Wisconsin, facility,
completed in early 2008; a $29-million investment to expand bacterial and fungal fermentation-derived HPAPI capacity at its
site in Jerusalem, Israel, due for completion in early 2010; and a $30-million investment to build a new commercial-scale
HPAPI facility at Madison, due to be completed by year-end 2009. SAFC also commissioned a conjugation suite for HPAPIs in
September 2008. It invested $12 million for expanding its viral manufacturing capacity (Biosafety Level 2-compliant at its
facility in Carlsbad, California. This expansion is to become operational in the second half of 2009.
Small-molecule HPAPI manufacturing
. SAFC is building a new commercial-scale HPAPI plant in Madison following several expansions at its facility there. "We made
the decision to expand our services by building from scratch rather than acquiring another building or CMO since there would
have inevitably have been a great deal of retrofitting necessary," says Dave Backer, director of business development and
marketing at SAFC Pharma. "When it comes to HPAPI facility design, SAFC has always felt that it is better to build a facility
with the type of products to be manufactured in that facility rather than to try and build into existing facilities, which
may not have the containment principles in place already."
Growth in oncology drugs
SAFC made two previous expansions at its Madison HPAPI facility, but needed additional capacity for large-scale and commercial
capabilities. Construction began in the fall of 2008 and will be completed by the end of 2009. The new facility will be capable
of manufacturing, handling, and transferring large volumes of product up to 4000 L. This capacity will allow for batches of
potent compounds to be manufactured in the range of hundreds of kilograms. The material-handling systems are being designed
for full containment on a large scale. The company is adding a milling and micronization area in the facility for potent compounds.
The facility is designed to adhere to Category IV standards, as defined by SafeBridge Consultants. SAFC's existing facility
in Madison is certified by SafeBridge, and the company intends to seek certification for the new facility upon its completion.
"Safety and consistency are paramount, and it is important to note that in addition to very careful facility design that SAFC
has work processes and very experienced staff," which the company uses in its small- and large-scale HPAPI manufacturing,
. SAFC recently received SafeBridge certification for its high-potency antibody–drug conjugation suite in St. Louis to complement
such certification for its high-potency manufacturing facilities in Madison. "For the high-potency conjugation suite in St.
Louis, we wanted to take the best practices that we had in facility design, operator training, and operator safety that has
been in operation for years at our Madison plant, and marry it to the conjugation and biologics capabilities and expertise
already employed at our St. Louis facility," continues Backer.
SAFC's high-potent conjugation facility was designed from its inception as a containment facility. Some key factors in designing
such a facility are room-pressure differentials, with appropriate monitoring and verification, to ensure that the pressure
of the major handling area is negative to its surrounding airlocks and vestibules. Single-pass air is used with temperature,
humidity, and particulate controls. Misting showers are part of the degowning and exit process for operators and equipment.
The suite also has filtration and capture equipment, both with the isolators and with the exhaust system of the heating, ventilation,
and air-conditioning system. Isolators and fume hoods are used for certain operations as are biologic safety cabinets. Other
facility designs such as unidirectional flow and restricted access are consistent with most recently built biologics facilities."
"Traditional biologics facilities that produce proteins and antibodies in mammalian-cell-culture or bacterial fermentation
are designed to have the suites where purification occurs be positive to their surroundings. However, when working with potent
products, such as viruses or biologics that are conjugated to highly potent APIs, processes are performed in a suite negative
to the surrounding rooms to ensure the potent compounds are contained within the working environment," explains Backer. "Protection
of the operators is also an absolute requirement. The operators are well trained in operating with protective garments and
wear respirators," he adds. "Training in the handling of high-potent products is ongoing and essential. Changeover processes
are validated and in place."
SAFC employs this negative-room-pressure concept at its facilities for viral-vaccine manufacturing in Carlsbad, its small-molecule
HPAPI manufacturing facility in Madison, and its potent antibody–drug conjugation suite in St. Louis. The company is also
including this approach at its fermentation facility in Jerusalem, which will target potent and cytotoxic molecules, and at
the company's new large-scale, small-molecule HPAPI commercial manufacturing facility in Wisconsin.
As with all HPAPI facilities, operator safety is key. "Demonstrating that controls are in place to ensure the highest levels
of safety to workers and the environment is an important consideration," says Backer. "The operators are well trained in operating
with protective garments and wear respirators. Training in the handling of high-potent products is ongoing and essential.
Changeover processes are validated and in place." He adds that SafeBridge certification adds assurance that there will not
be interruptions in manufacture due to safety concerns.