Company creates first GMP operational clinical sterile continuous process isolation facility in the United States

When Bristol-Myers Squibb conceptualized its new, more than $90 million pharmaceutical development center at its New Brunswick, New Jersey campus, the idea was to bring early and late phase clinical manufacturing and development scale-up together in a single facility, and enhance compliance, productivity and technical innovation to meet its existing and contemplated drug development pipeline needs—while helping to speed products to market.

Two-Phase Project – Designed For Flexibility

The new facility encompasses a $54 million Clinical Supplies Manufacturing operation and a $37 million Drug Product Technology Center Project. “This was essentially a two phase project, and during the course of construction in phase one, we had a formal lessons learned process that informed and benefited the second phase,” says Anthony Consolo, Project Director.

Phase one entailed the expansion of a state-of-the-art clinical supply manufacturing facility, which included full containment for expanded oral solid dose (OSD) operations and “the most flexible clinical-scale continuous barrier line in the United States for sterile products,” according to the company. The facility was designed to make OSD batches of up to 400 Kg and parenteral liquid fill batches up to 250 L.

“The goal was to create a flexible facility capable of performing multi-product clinical scale manufacturing and processing solvent-based and potent compound operations. The new facilities provide BMS with the capacity and capabilities to deliver supplies for increasing clinical demands according to current good manufacturing practices (cGMP). The first phase consisted of approximately 93,110 ft² including processing, manufacturing, support and mechanical space,” according to BMS literature.

Phase two built on the technologies in the first phase and added processing space and scale to the OSD clinical operation and a new stand-alone Product Technology Center (PTC) for development scale-up activities. The addition to OSD operations allows for the manufacture of long term stability batches within the Clinical Supply Operations facility of at least one-tenth commercial scale. The PTC was designated to perform both process development and scale-up. Batch sizes for the PTC range from 20 Kg-100 Kg and are manufactured using many different unit operations. The second phase consists of 39,300 ft² of PTC and additional CSO process, manufacturing, support and mechanical space, according to the BMS 2008 FOYA submission.

Design and development work started on the clinical supplies project in March 2004, and construction lasted from June 2004 to October 2005. OSD validation was in February 2006 and parenteral validation in February 2007.

For the drug product technology project, design and development was initiated in November 2004. Construction started in March 2006 and was completed in June 2007.

The facility was selected by an independent blue-ribbon panel of judges as the 2008 Equipment Innovation category winner in the annual Facility of the Year Awards (FOYA), sponsored by the International Society for Pharmaceutical Engineering (ISPE), INTERPHEX, and Pharmaceutical Processing magazine.

Market Demands Create Need For Expansion

With headquarters in New York, BMS’s worldwide activities include R&D, licensing, manufacture, marketing, distribution, and sale of pharmaceuticals and other health care products. Annual revenues are estimated at around $20 billion.?Its pharmaceutical product offerings include cardiovascular agents, such as Plavix, Pravachol, and Coumadin; virology products Reyataz, Sustiva, and Baraclude; oncology products Erbitux, Taxol, Sprycel, and Ixempra; affective and other psychiatric disorder products, such as Abilify; and immunoscience products such as Orencia, among others.

BMS’ nutritional products operation (Mead Johnson) makes and sells infant formulas like Enfamil, and other related products. Its ConvaTec segment manufactures, distributes, and sells ostomy, wound and skin care products primarily to hospitals, professional medical practices, and medical suppliers.

The expansion project at the New Brunswick campus was implemented to meet the demands of a growing pipeline and to buttress aging facilities while ensuring compliance, according to Sarah Doshna, Associate Director of Clinical Manufacturing.

“Our solid dose capability here in New Brunswick was small, and relied heavily on operator protection in order to protect ourselves from potent compounds, which were becoming an increasing part of our portfolio.

“This project was basically designed to improve our compliance posture and to expand our operations because we knew that the pipeline was expanding, and we wanted to ensure that when our discovery compounds reached the development stage, we would be in a position to make them for the clinic,” says Doshna.

“Concern about closing the gap between R&D size batches and commercial scale batches was another driver for the project,” says Consolo.

Focusing on the rationale for the project, Consolo says, “We investigated a number of options, and considered whether to even build a new facility or look at other existing facilities that could be modified for these purposes.

“It turned out that this facility, Building 115, in New Brunswick was built for sterile injectable products years ago, so we had the opportunity to go in and make use of that shell almost immediately.

“Some demolition work, which took about six months, had to be done inside but the facility already had a number of usable utilities. That helped financially and also facilitated an earlier start, compared to if we had to build a grassroots facility,” says Consolo.

The New Brunswick campus has been in continuous operation since BMS first purchased the land in 1905, and currently spans approximately 100 acres.

“By locating the facility here, we could create a center of excellence for pharmaceutical development orientation and have the scientists and clinical manufacturing staff under one roof, which facilitates the kind of interaction that will enable us to be a more a nimble and flexible organization,” says Doshna.

In-House Concept Leads To Cooperative Effort

“The facility is currently a fully commissioned and operational GMP building. We had our first OSD batch in August 2006 and our first development batch out of the PTC facility in May 2007,” says Consolo.

“We have a number of in-house engineers who do conceptual work, so we orchestrated a team made up of our engineers, staff from the clinical supplies group as well as our various support groups—QA, validation, EHS, maintenance and utilities and purchasing, among others—and we developed the concept. We then presented the concept for competitive bidding,” says Consolo. IPS Inc. (Lafayette Hill, PA) won the bid for engineering and design on the project, he added.

The team developed a statement of requirements, basis of design (BOD) and detailed design, and then sent the construction drawings out to a few potential construction management (CM) firms, which responded with their capabilities and pricing, says Consolo. Torcon, Inc. was selected as the CM, and the Red Bank, NJ firm provided construction management services, including commissioning and start-up, with a hands-on approach through project completion.

BMS, IPS and Torcon utilized a cooperative team approach to expedite the overall design/build/commissioning/qualification process for the project. The IPS team on the site was spearheaded by John Gilroy, Director of Operations for Engineering, and Andrew Haines, Design Manager. A number of senior construction executives from Torcon were also integrally involved in the project.

Ease Of Integration Main Reason For Equipment Selection

“We did the same thing with the equipment vendors as well. A team comprised of end users, members of the engineering group that interfaced the equipment with the building, and the quality and environmental safety group was assembled to address user requirements for the equipment.

“Once the user requirements lists were put together, we went to bid. We picked the best vendors for the lists based not only on pricing and the best fit for our requirements but also on how well the equipment could work with each other,” says Doshna. She explains that that all the equipment and structures in the building required some level of integration.

Turning to the two phased construction approach, Doshna says, “We did a lot of work with equipment integration in phase one of the project, which we did not have to redo in phase two.

“We learned a lot from our initial efforts to isolate equipment and being already on the floor and in production before some of the phase two activities were done, we could easily roll in what we learned from testing the equipment, but also from hands on use of the equipment on the floor,” she says. “The development facility for PTC was a hundred percent leveraged from the OSD. Very few modifications were needed.”

Key Accomplishments Industry Firsts

Focusing on the key accomplishments of the project, Doshna says, “This is BMS’s first isolator line. From a critical facility perspective, this is the first GMP operational clinical sterile continuous process isolation facility in the United States. This is also the most flexible barrier process line currently in use.

“Definitely, we are the first to integrate all the elements that we included within the sterile line. We even heard from our vendors that clinical facilities are very flexible and there was a necessity to mix and match equipment all the time. We were told that our approach did not necessarily lend itself to barrier technology because the perception at the time was that barriers were very rigid and that they would only work for certain sizes, and that all of those parameters must be specified at the start,” says Doshna.

She explains that in the end they were able to derive all the safety and quality benefits from the technology while at the same time preserving the clinical flexibility that was needed. “That was a big milestone for us. That we did it was in a way less important than the fact that we proved it could be done, and changed mindsets both within the company and without.

“We have shown this facility to a lot of people looking to build their own lines in other companies, and there has been a considerable interest among them in replicating this within their own operations,” says Doshna.

“I don’t think we left anything on the table. By that I mean that we have cutting edge technology throughout the facility. I don’t believe that there is any facility in the industry that is any further along technologically than what we have put in place here,” says Consolo.

Among other leading edge technologies, Consolo points to the facility’s wireless process and analytical technology (PAT) and validated 21 CFR Part 11 related data gathering and storage functions enabling flexibility and the maneuverability of process equipment from all rooms. The facility’s wireless process control system delivers key benefits including paperless batch records, recipe driven instructions for operations with built in checks, data capture and/or transfer of processing parameters, the ability to review historical processing data for analytical comparison and data interchange for materials transactions, and the ability to perform multiple process operations in all processing rooms.

He says, “We have the capability to produce as many as six products at a time, which is unprecedented for us, from a clinical standpoint.”

Safety And Environmental Considerations

The facility boasts a number of efficiency boosting systems including premium efficiency motors and high energy lighting wherever possible, says Consolo. Energy conservation measures were incorporated into the design, as well as the annual quality, environment, and health and safety departmental reviews. “We also have a provision in the future for energy recovery, which will have to be a separate project, but there are provisions in our system that will allow us to do that if it is deemed favorable later on.”

Furthermore, the company’s choice to renovate and expand an existing building resulted in lessened impact to the environment. Throughout the design process, the project team focused on multiple aspects of environmental performance, specifically protecting the quality and availability of water and reducing greenhouse gas emissions through energy conservation. As a result all processes were designed and installed incorporating equipment to control the discharge of air contaminants, contaminated wastewater and solid waste. “When we made decisions throughout the facility, the green aspects were always central considerations,” says Doshna.

Consolo says that safety issues were given top priority at this facility, as they are throughout BMS. “From BMS’s perspective, safety issues are considered from the first pencil line on a piece of paper by an engineer and are continued all the way through production. Our people work in these facilities every day and it is important that they are able to work safely. From an engineering and construction standpoint, that is a very important part of what we do everyday.

”Both Consolo and Doshna attribute the 2008 FOYA award to a high level of integration in the facility. “If you take any of our equipment innovations by themselves, they are nice but when you take them altogether they produce a truly impressive facility, and that’s what puts us ahead of our competitors,” says Doshna.

“That embodies the overall technical scope and complexity of the project. We were able to integrate all our operations successfully in one facility in a timely basis and met all our goals including staying within budget,” says Consolo.

Focusing on what the award means for BMS, Consolo says, “This award strengthens our belief that strategically we are on target with our commitment as a company in the biopharmaceutical arena. There has always been a strong relationship between the BMS technical staff and ISPE, and this award allows us to share our success with respect to lessons learned with the rest of the industry through ISPE. That will surely help communications and relationships into the future.”