Less Is More

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.

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%.