Pharmalucence To Launch Bosch Fill-Finish Isolator Line

The drug manufacturer sets up as a CMO with a new Boston BioTech Cluster-based facility.
Pharmalucence (www.pharmalucence.com) is building a barrier isolated aseptic fill-finish facility as it further develops its business segment in contract manufacturing.
The isolator line will support fill-finish of Pharmalucence’s manufactured radiopharmaceuticals, while providing expanded capacity for contract services the company projects will grow 10% annually for ten years.
Bosch Packaging Technology (www.boschpackaging.com) is supplying the MLF2020 Isolator Line for Vial Production, and the VRT1020 overseal capping machine for restricted access barrier (RABS) capping of liquid and lyophilized fill vials.
“This integrated line marries the newest filling and isolator technologies for liquid and lyophilized path fill-finish processing. Isolator and filler were designed and built in the same shop within the same team and project management,” says Mike McGown, regional sales manager, Bosch Packaging Technology.
The units will be delivered in mid-2012 to a new 70,000-sq-ft facility in Billerica, MA, with lab and production assets that will support product development and new business, says Glenn Alto, Pharmalucence’s president.
The facility increases five-fold lab and production space currently housed at the firm’s Bedford, MA, plant. Pharmalucence anticipates all Bedford-based drug production will transfer to the new site by September 2013. The new facility footprint includes 50,000 sq ft for inspection, labeling, and packaging suites; space for up to two isolator-based clean suites; and labs for quality control, analytical methods development, and formulation
development.
REVIEWING OPTIONS
In planning its management-led buyout, executed in 2007, the company reviewed three options for a business that possessed production assets approaching the end of their useful life, Alto says.
They included outsourcing to a CMO, renovating the 15,000-sq-ft Bedford plant, or constructing a new drug production facility. The case was made to build a new plant as a base for growth; and to set up as a CMO, competing for fill-finish business that has trended in recent years to offshore contractors.
“We found that the new facility option would support higher levels of growth than competing options, allow us to avoid product supply interruption and worker layoffs that would occur with a renovation, and support a strategic design with optimized work flows,” Alto says.
 
 The Bosch MLF2020 Isolator Line For Vial Production features an expedited decontamination cycle, with a combo filling system.
“When we solicited certain CMOs to manufacture our products, some said that we were too small for them. This experience supported our view of an unmet need for small-batch commercial production and clinical trial manufacturing in the CMO market. Since that time, we have been able to confirm existence of demand in this segment,” Alto says.
“As the pharmaceutical market transitions from a focus on ‘blockbusters’ toward personalized medicine, which targets therapies at genetically defined patient subsets, smaller-market populations are created that translate to small-batch production,” he adds.
The company believes it can leverage its pharmaceutical manufacturing expertise to compete with offshore markets, where highly skilled scientists are available at lower cost.
COMPETING GLOBALLY
“First, the direct labor cost of any given unit of manufacture is a small percentage of the cost of goods. In our case, we are staffed to manufacture our radiopharmaceutical products and can engage efficiencies that we can apply to the contract side of the business, eliminating any labor cost advantage. [In addition] we offer over 20 years of commercial parenteral drug production experience coupled with advanced automation and isolator technology previously unavailable in the CMO market,” Alto says.
The company evaluated isolator versus RABS technology with two consultant firms as it worked to understand aseptic processing trends. The solution Pharmalucence sought had to meet current and future expectations of regulators.
“There is a strong movement toward elimination of human interface with aseptically processed product. Regulatory bodies worldwide encourage use of technologies that limit the presence of people in the same environment as the open product formulation. It is accepted that one of the most prevalent means of product contamination is vectored from manufacturing personnel. In evaluating RABS versus full isolation, we rejected RABS because it is not fully sealed and can allow operator intervention. We wanted to build a facility at the true state-of-the-art that could be operated for the next 20 years,” Alto says. “We selected Bosch because of its excellent reputation for pharmaceutical equipment. It offered us a fully integrated solution with isolated vial washing, depyrogenation, product filling, and a RABS capping station in a predesigned package. It was important to us from a project management perspective to work with one vendor.”
The Bosch equipment and the automated load/unload lyophilizer supplied by IMA Edwards will be delivered in July. Final construction and facility turnover from the architectural and construction firm is planned for September. Pharmalucence is targeting an FDA prior approval inspection during the summer of 2013.
Initial production will be in one cleanroom suite with the isolator line and one IMA Edwards lyophilizer. The line can accommodate two IMA units to double lyophilization capacity. All isolator operations including filling occur in an ISO 5 critical process zone. The isolator is housed within an ISO 8 standard, Class C EU standard cleanroom.
ADVANCED FEATURES
The Bosch isolator features enhancements for flexible handling of small batches with a variety of vial configurations. Batch sizes can range from 1,000 up to 30,000 10-cm³ vials, says Bosch’s McGown.
“We make use of a small footprint and an easy-to-clean and changeover format. This combined with an expedited decontamination cycle for the isolator allows us to make quicker batch turnarounds in tandem with the highest sterility assurance available today,” McGown says.
The faster decontaminating cycle is achieved by heating the air in the preconditioning stage when vaporized hydrogen peroxide (VHP) is introduced into the chamber, says Dan Pratt, director of engineering, Pharmalucence.
“Decontamination consumes a lot of time when you are just changing the environment with ambient temperature air. By heating the air, they are speeding the aeration process [removal of the vapor after decontamination]. [In addition,] the process gets you down to lower levels of residual hydrogen peroxide after aeration. We are reaching 0.5 ppm and even lower levels of residual hydrogen peroxide, well below the standard requirement of one part per million,” Pratt says.
Change over is further supported by modular change parts.
The line is fully automated after the vials are introduced into the washer. The glass vial is singulated, washed, and depyrogenated by hot air. It is then singulated, filled, the stopper is applied, and it is automatically loaded into the lyophilizer, if the formulation is to be freeze-dried. After the cycle is complete, the vial is automatically unloaded from the lyophilizer, singulated again, and automatically conveyed to the RABS ISO 5 laminar flow environment for capping. Liquid fill vials are conveyed directly from the isolator to the capping station.
COMBO FILLING
The Bosch vial filling system is designed to accommodate both peristaltic and rotary piston pumps for meeting different applications. “In traditional high-speed filling, stainless-steel piston pumps are well known, super-reliable, and very accurate,” Pratt says. “If you have a very expensive product such as a monoclonal antibody, you will have less waste with peristaltic pump filling. Peristaltic filling is ideal for clients that want a disposable option. You can bring in the disposable sterilized tubing and run the product right away without a cleaning cycle. Millipore (www.millipore.com) provides the tubes and filters in the disposable fill path for feeding the filler,” Pratt adds.
Control over vial fill volumes is achieved with 100% checkweighing of empty and filled vials. The checkweigh function is integrated with the filling system with feedback for pump adjustment. Camera systems inspect for stopper and cap placement and raised stoppers.
The IMA Edwards-built loading system inside the isolator uses push-rods to advance filled vials to a belt for conveyance through the lyophilizer door.
The system fills 120 10-cm³ vials per minute. The lyophilizer capacity is 30,000 vials per batch.
“Accuracy and repeatability are of paramount importance for this line as they are for all sterile fill-finish lines,” says McGown.
“Production information and data are managed in a fashion that is consistent with both the Bosch design-and-build effort and Pharmalucence’s internal processes. The line integrates with Pharmalucence’s SOPs to achieve best-in-class cGMP manufacturing, with world-wide compliance and the highest level of quality assurance,” he adds. 
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