When BD Rx introduced prefilled syringes to flush IV lines in 2005, it converted an existing facility to produce these integrated devices. Later, when the prefilled format was extended to four generic injectable drugs, BD designed a new manufacturing facility to meet the more stringent manufacturing and regulatory concerns.
The new facility integrated everything from drug formulation through manufacturing into a single plant. “Although vertical integration enabled us to do things never before done with sterile products, it also brought new challenges,” says Mark Sebree, president, BD Rx.
While the specifics of the plant and processes are proprietary, Sebree explained that about half of the products must be sterilized with pressure and heat, and the others manufactured aseptically. The ability to move the products in a notouch environment required the company to build handling processes that had never been seen before. Automating the plant so thoroughly that the syringes are handled without any human contact helps BD meet increasingly stringent regulatory requirements and also improves efficiency.
Sebree says similar efficiency would have been unlikely in a retrofitted environment. “The problem with retrofitting an existing building is the point of contact between the old and new environments,” he says. Retrofitting to meet current air handling requirements is an obvious issue, but temperature and humidity control also can be challenging in older buildings or in facilities designed for other uses, he says. “Temperature and humidity are hard to control to today’s standards in a building that’s 30 to 50 years old.”
Specific challenges vary according to the type of pharmaceutical product being made. “For sterile products, err on the side of building new facilities to avoid the point-of-contact issues,” Sebree advises. “But, if you’re making solid dosages, you wouldn’t have the same need.”
AGING FACILITIES CONTRIBUTE TO DRUG SHORTAGES
According to Maik Jornitz, co-chair of the PDA Aging Facilities Task Force, “Most of the facilities are product-dedicated. Therefore, the age of manufacturing facilities probably correlates closely with the age of the pharmaceuticals being produced.”
In fact, many of the recent drug shortages are caused by quality issues in manufacturing facilities rather than shortages in APIs. Sebree says, “As drug shortages grow, alternative ways of manufacturing must be applied, and the FDA must work with manufacturers more closely on infrastructure.”
The drug shortage is one of the reasons the PDA formed the Task Force on Aging Facilities. U.S. regulators and lawmakers recognize the correlation between aging facilities and the drug shortage, and Jornitz says this isn’t just a North American phenomenon; it’s a global issue.
“Aging facilities may run perfectly with trained staff and the right processes and systems in place when staff really understands the processes and owns them,” Jornitz says. “However, these staffers also are aging. As they retire, companies lose their expertise. Then, facilities experience more outliers and citations, and processes no longer run as they should.”
To put this in perspective, many pharmaceutical manufacturing facilities have expanded several times during multiple decades, cobbling on additional space for new processes. Eventually, once-streamlined workflows become convoluted and inefficient for materials management as well as human processes.
REGULATION STYMIES INNOVATION
The inability of companies to improve product lines without revalidation poses an additional barrier. Kevin O’Laughlin, a principal of KPMG’s Advisory Practice, says that after scale-up, regulations virtually lock a company into a process and into a facility. “It’s very costly to change manufacturing processes because you have to reopen the NDA (new drug application) and revalidate systems, which allows the FDA to challenge the formulation and other aspects of the drug.” Therefore, companies carefully evaluate which NDAs may be reopened when considering the pros and cons of modernizing or moving production lines or entire manufacturing facilities.
Political considerations may impact these decisions, too. “Especially in Europe, national health services may link registration in a national market to maintaining a production facility in that country. That’s often a reason aging plants remain in a company’s network,” O’Laughlin says.
TASK FORCE ADDRESSES ISSUES
PDA task force aims to be a platform for regulators, industry, and vendors to create solutions for aging facilities. “Technology has outpaced the regulations,” Jornitz says. “The life sciences industry needs to be able to optimize processes using state-of-the-art technology.” Doing so requires reducing the regulatory burden to make optimization economically feasible.
Part of that process involves encouraging regulators to examine their own requirements with an eye to outcomes rather than processes or technologies. The goal would be to develop outcomesbased strategies to meet regulatory requirements and allow new technologies to be added.
Additionally, Jornitz says, “Regulators must ask themselves why such levels of scrutiny are needed when companies are motivated to improve their processes. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, agrees we need a better way to allow industry to improve processes.” The ability to apply more effective technology to drug development is one of the reasons the generics industry is so successful. In addition to getting drugs off patent, newer technology helps companies further lower their prices, Jornitz maintains.
Bipartisan discussions are under way with Congress to support the rapid development of the life sciences industry in the U.S., but more education and discussion is needed as regulators rethink current regulations.
In addition to Congress, the PDA task force itself is looking at regulations and technologies. The subgroup for analytics, for example, is assessing new qualitycontrol technology, including sensors, sample analysis, and assay validation. The facilities subgroup is addressing infrastructure, focusing on utilities and cleanroom standards. Air changing systems also are being evaluated in terms of reducing particulate load rather than rate of air change.
RETROFITS REQUIRE GUTS
As pharmaceutical manufacturers look outside the suburbs to locations within cities, “Old spaces with high ceilings are perfect for retrofits,” says Carol Patterson, senior partner at Zetlin & DeChiara LLP, a law firm that specializes in construction law. There are many examples of small molecule manufacturers gutting and using existing manufacturing facilities.
“These are ideal assets,” Jornitz says, “because they already have much of the infrastructure — power, utilities, chillers, water purification, compressed air, etc.” However, “You can’t convert from one to the other.” Cleanrooms, for example, have issues with drywall, epoxy coatings, mold, and cleaning regimens. Instead, companies must take a smart approach and be able to gut the building to its shell and add a new cleanroom structure. “It can’t be a gradual changeover because small molecule manufacturers usually can’t use the same equipment as large molecule manufacturers.”
Challenges extend beyond equipment to include process flow and, potentially, decontamination. New, high-efficiency biotech process designs may not fit architecture designed for a different process flow. “Plants were mothballed because they were designed for specific products,” Jornitz points out. So the costs of gutting, cleaning, and retrofitting often don’t make economic sense.
From a product flow standpoint, single use technology can overcome those challenges. “There’s increasing interest in modular components, which are making projects more efficient and opening spaces that otherwise wouldn’t be considered workable,” Patterson says.
But, Jornitz adds that single-use systems require a different mindset than steel systems. “They are also a bit more risky,” and can be less productive. For example, recent research reports the cytotoxic compound bisphosphate leaches from some single-use bags, reducing cell growth. Steel systems don’t have this challenge.
Another alternative, Jornitz says, is to install drop-in, premanufactured cleanroom pods inside an existing building. With this method, bioprocesses can be up and running in about 12 months, compared to the two to four years required to permit and build a traditional building.
GREENFIELDS AND COLLABORATION
In mature markets like the U.S., Canada, and EU, building new is somewhat unusual for pharmaceutical firms, but less so for biotech. “Biotechs are managed differently from pharma, and they have different systems and processes,” O’Laughlin points out, so there’s little incentive for those companies to retrofit existing manufacturing facilities. Instead, they tend to build from the ground up.
O’Laughlin says a quick look at KPMG data shows a 100,000-square-foot biologics plant may cost $80 to $120 million. “Biologics plants are much more complex and expensive to build and outfit. It is not unusual for plants to cost $150 million to $500 million, depending on size and the complexity of the production process.” A typical cost to build the same size secondary packaging facility for traditional pharmaceuticals ranges between $35 million and $65 million, excluding the cost of the land, “although I’m certain there are new plants outside this range,” he says.
For new builds, Patterson strongly recommends taking a collaborative design approach as a smart way to save money and increase overall project efficiency. “In an integrated development approach, the contractor is part of the design team from day one. The advantage is that construction difficulties can be resolved early at the most cost-effective phase.”
The environment that has suppressed technological innovation in existing product manufacturing lines is finally being challenged.Regulators and industry leaders are rethinking processes to enable life sciences companies to integrate state-of-the-art technologies into existing processes. The result will provide companies with reasons to look more broadly at their own infrastructure as they determine the relative merits of retrofitting or building new manufacturing facilities.