Johnson & Johnson will seek alternative stabilizers for its erythropoietin Eprex in response to reports of pure red cell aplasia following the removal of human serum albumin from the product formula.

"We are developing new analytical method and exploring other stabilizers to ensure continued quality of our finished product," R&D Pharmaceuticals Chair Per Peterson, MD/PhD, said during a Bear Sterns-sponsored conference call on Procrit /Eprex Sept. 10.

J&J removed human serum albumin from Eprex (epoetin alfa) in 1998. Since that time, 141 cases of PRCA are suspected to be associated with the product. J&J markets epoetin alfa as Eprex outside the U.S. and as Procrit in the U.S., where it is manufactured by Amgen.

"When we subjected the two formulations to rigorous stress conditions, we discovered that the formulation free of human serum albumin was less stable than the human serum albumin-containing formulation," Peterson said.

J&J believes three issues caused the increased incidence of PRCA: the removal of HSA from the Eprex formulation, an increase in subcutaneous administration, and inappropriate storage and handling of the drug. "These are three factors working together. No single factor explains this disease," Peterson said.

"We are now conducting additional studies to better understand whether and how physical stresses, such as elevated temperature, exposure to light and extreme shaking might affect Eprex."

J&J recently changed Eprex EU labeling to remove statements that subcutaneous injection is preferred over intravenous administration and distributed "Dear Doctor" letters in the EU, Switzerland and Canada (¹ Also see "J&J Eprex EU Label Changed; FDA Investigating Manufacturing Fraud" - Pink Sheet, 22 July, 2002., p. 11).

The company also "developed educational material to reinforce proper Eprex storage and handling," Peterson said. The patient and physician materials will be distributed in countries where Eprex is marketed.

Peterson called on other manufacturers to take similar steps. "In light of PRCA, this is a particularly prudent action that we hope other manufacturers of erythropoietin will follow," he declared.

Amgen, which manufactures darbepoetin alfa under the brand name Aranesp in the U.S., maintains that PRCA is not a class effect, and is linked to J&J's manufacturing process for Eprex.

Amgen said it has not received any reports of PRCA in Aranesp patients. Amgen's Epogen (epoetin alfa) is linked to four cases of PRCA. Roche's NeoRecormon (epoetin beta) has one confirmed case; Roche is also investigating a "handful" of recent reports.

J&J argued that the relatively low incidence of PRCA indicates that its manufacturing process is not the cause. "A single batch of bulk makes about a million syringes, and if you're putting a million syringes out in the marketplace that had a problem, then you would expect to see a much higher frequency than what we're seeing here," Centocor Senior VP-Worldwide Supply Chain Robert Sheroff said.

"Basically, for the patient population we're looking at, we're seeing statistics on the order of 1 per 10,000 and those patients, in a given year, will take roughly 156 syringes. So this is a defect in the 1 per million range, and you wouldn't expect that to be something coming from the bulk process," he said.

"What we're most likely seeing is that the removal of HSA, the formulation is not as robust, and we've put it in the marketplace which has gone more Sub-Q...and then combining that with perhaps not as careful of care in the supply chain by patients...drug exposed to warmer temperatures is a good possibility, we may, on an occasion, get that one in a million defect."

Peterson suggested more PRCA cases would be linked to other drugs if a common definition was agreed upon. "Other companies that manufactured erythropoietins have different definitions for their PRCA cases, and they have chosen to eliminate cases that may have confounding factors such as autoimmunity," he said. "Manufacturers have to agree on a common definition of PRCA such that apples may be compared to apples."

J&J has received "a relatively stable rate of reports" of PRCA, Pharma R&D Global Medical Leader Jan Smiell, MD, said. "Approximately six to 12 months down the road, we may see what changes we've made today have some effect on the rate of reports. It's not clear whether this will ever go to zero."

J&J Eprex Stability Improvements Planned In Response To Aplasia Incidence

More from Archive

More from Pink Sheet