At 9:30 a.m. on May 23, 1997, Nancy Hogan gave birth to a beautiful baby girl. But at three months premature, Mary Grace tipped the scales at just over 2 pounds. She was highly susceptible to infection and in need of constant medical attention.
As a concerned father, Matt Hogan went to work every day wishing there was something more that he could do. But one day, as he read the fine print on the medications Mary Grace was receiving, he realized he already was.
An architect at Lockwood Greene's Spartanburg, S.C., office, Hogan was hard at work on Bayer Biological Products' next-generation Clayton, N.C., facility for producing intravenous immunoglobulin (IGIV),the same infection-fighting preparation that helped his daughter grow into the healthy six-year-old she is today.
Essentially a concentrated dose of antibodies derived from large pools of blood plasma donors, immunoglobulin (also called gamma globulin) is used to treat primary and secondary immune deficiencies as well as other conditions in which the immune system is compromised. And because it is derived from blood plasma, immunoglobulin is by definition a scarce commodity. Availability is often limited and shortages, common,troubling news for the many patients who need lifelong treatment and a safe, dependable source.
It was against this backdrop of global shortages that Bayer Biological Products commissioned its search for an entirely new production process that would overcome the limitations of the current state of the art, a process first pioneered in the 1950s and evolved over time to meet new safety threats to plasma-based preparations such as HIV, hepatitis C and the infections agents prions.
"Our scientists went back to basic principles," says Peter Clarke, PhD., director of Bayer Biological Products' new IGIV-C process.
As it turns out, the "C" moniker stands for "caprylate," the unpretentious salt of octanoic acid. (Organic chemistry refresher: Caprylate is an eight-carbon chain with acid functionality on one end.)
This relatively simple and proven safe molecule, Bayer scientists and engineers discovered, allowed them to streamline the manufacturing process by integrating essential viral inactivation, purification and stabilization steps into a far shorter and far more efficient process without compromising safety.
"Compared to the old process, we're down from 120 hours to 40 hours," Clarke says. Yields, too, already are up 30 percent compared to the old methodology. Perhaps most compelling, Bayer officials expect that because of the significantly gentler treatment and shorter processing times, the preparation's molecule conformance is better preserved--and efficacy may be improved.
Indeed, trials have been conducted that are expected to "demonstrate for the first time that different production methods lead to different clinical outcomes," says Gunnar Riemann, PhD, executive vice president, Bayer Corp., and president of Bayer Biological Products.
Even as this is written, commercial production is ramping up at the Clayton, N.C., and a final FDA green light is expected sometime in June. "With the approval process underway in three key markets [U.S., Europe, and Canada], there is growing anticipation about what's next in IGIV treatment," Reimann adds.
The Old Way
Current immunoglobulin manufacturing processes are based on technologies originally developed in the 1950s. The Cohn-Oncley cold-ethanol fractionation process, pioneered by Cutter (now Bayer BP) was initially developed for producing albumin, the protein portion of blood used in the treatment of shock, burns and protein blood loss.
As research progressed, immunoglobulins specifically for intravenous injection became a principal goal for plasma processors. Modifications over time added a multitude of steps for stabilization, purification and viral safety. While these additional steps insured the quality, safety and purity of the product, they also made the process complex and inefficient.
In a nutshell, the old way involved a complex series of precipitations and centrifugation, depth filtration, and separate solvent-detergent and low pH virus deactivation steps, followed by final formulation.
The key discovery by Bayer scientists was that sodium caprylate/octanoate, a naturally occurring, plant-derived substance with a long safety record as a stabilizing agent for albumin, deactivated viruses virtually instantaneously upon addition to the blood plasma fraction that is the process feedstock.
"Our team was pleased to find a new practical application for an agent with a 50-year-old track record that sets a high standard for current viral inactivation methods," says Marina Koneyeva, senior staff scientist, Pathogen Safety Research, Bayer BP.
Bayer scientists theorize that precise pH control allows the non-ionized lipophilic molecule, which is in equilibrium with the acid, to infiltrate the viral envelope, inactivating the virus immediately, . "Caprylate is on the verge of solubility, which allows it to penetrate virus envelopes," Clarke explains.
Filter press removal of solids is followed by two chromatographic separations to further purify the immunoglobulins. Final ultrafiltration and diafiltration steps remove any residual processing chemicals, yielding the final 10-percent immunoglobulin solution, which will go to market under the tradename Gamunex, Immune Globulin Intravenous (Human), 10%.
A key advantage of this new process is that once the paste feedstock is reconstituted, the immunoglobin stays in solution throughout the entire process, better preserving the conformation and biological activity of the compounds, according to Clarke.
Finally, the preparation also is stabilized at low pH, where immunoglobulins are naturally soluble and viral deactivation can continue. The old way of doing things required the addition of a sugar stabilizer at neutral pH, an additive that sometimes led to unwanted side effects. The neutral pH also obviated the bonus gain in viral deactivation that could continue,even while the finished preparation was in storage.
Process Drives Design
With this break-through conceptual process in hand; the Bayer team bucked the industry trend toward multiple-purpose facility design to build a new, highly automated and dedicated facility for immunoblobulin production. Even the personnel who run the new facility 24/7 work exclusively on the Gamunex line.
"We actually built this facility around the new process,we didn't create a process based on the limitations of an existing facility, which is the norm," Bayer's Clarke says. "And it's the automation that ensures consistency and gives us the high reliability we're achieving," Even clean-in-place sequences are highly automated.
Mary Kuhn, Bayer senior vice president of operations and Clayton site head, concurs, explaining that in biological product manufacturing "it's the process that really defines the product."
As primary design firm on the new unit and associated utilities, Lockwood Greene project manager Greg Karpick credits early involvement of the LG design team with Bayer personnel as key to the project's success. "From the laboratory phase forward, we worked hands on with the scientists, they helped us to understand the product and the process," he says.
For example, the team used AutoMod simulation software from Brooks-PRI of Chelmsford, Mass., to maximize process throughput and minimum labor requirements, resulting in the ultimate design of two parallel production trains. "This allows us to run and clean at the same time," Clarke explains. "Downtime is minimized."
Mix-proof valves from Tuchenhagen of Portland, Me., are used to advantage, replacing more complex, four-valve assemblies with an integrated approach.
Other key technology partners included automation system supplier ABB Industrial Systems, Rochester, N.Y.; Amersham Biosciences, Piscataway, N.J., which provided the chromatography subsystems; Millipore, Billerica, Mass., provider of the ultrafiltration and diafiltration technology; Seiberling Associates, Roscoe, Ill., for clean-in-place systems; Kinetics, Santa Clara, Calif., for sanitary piping; and general contractor Gilbane of Providence, R.I.
The facility that houses the process also embodies advanced concepts in contamination control. Different points of entry and exit are used for plasma, raw materials, personnel, finished product and waste. Two distinct production zones are provided. The product moves from one zone to the other only after viral inactivation. Reverse flow in not possible, thus minimizing the risk of cross-contamination.
"From previral to post viral [deactivation], the process follows a unidirectional route--you can't back up," Clarke explains.
Superimposed on this unidirectional process flow is a two-zone, unidirectional air flow in the opposite direction. This ensures that the quality of the air increases as the immunoglobulin is purified--the air becomes purer as the immunoglobulin becomes purer. Facility design is class D throughout, with isolated class C zones for solids addition. The modular building approach means that different functional areas are connected through environmentally controlled corridors, thus eliminating the need to exit the building to transfer product at different stages in the process.
All told, the facility represents a $250-million investment that should improve the quality and availability of immunoglobulin treatments to the patients who need them.
Mary Grace would be proud.