Fickle formulations

National report - Slight changes in the biologic manufacturing process can significantly alter efficacy and safety, manufacturers say.

Differences between the two were "small enough that our scientists believed the materials were interchangeable. But when we did a clinical trial, we discovered there was a major difference in efficacy."

"To this day," he says, "we still don't know what caused the difference in efficacy between the Xoma and Genentech materials."

Similarly, Johnson & Johnson's experience with its biologic product Eprex was timely in that it occurred just as European regulatory authorities were considering a pathway for the approval of biosimilars, says Johnson & Johnson executive director Audrey Phillips, Ph.D. Eprex is the company's international version of the same protein sequence used in the erythropoietin products Procrit (Ortho Biotech) and Epogen (Amgen), she says.

After Eprex had been on the market for 10 years without incident, European authorities asked all biologic manufacturers to remove human products, including the stabilizer human serum albumin, from formulations, she says.

"We replaced it with polysorbate 80, another very common stabilizer," she says, but soon noticed an increased incidence of pure red cell aplasia.

"In rare cases," Dr. Phillips says, "patients developed antibodies not only to Eprex, but also to their own hormonal erythropoietin." After a four-year investigation, she says, "We determined that the polysorbate 80 was leaching a chemical out of the rubber stopper in the syringe and acting as an adjuvant."

This case "serves as a reminder that all proteins are immunogenic, and speaks to a very important difference between small molecules and biologics," she says. "A biologic from one manufacturer can be significantly different in terms of immunogenicity" than another manufacturer's version of the same formulation.