Heparin Investigation Update By Baxter

As reported in previous updates, Baxter's sophisticated analytical procedures, including capillary electrophoresis and nuclear magnetic resonance spectroscopy, identified an unknown material in some lots of the active pharmaceutical ingredient (API) for heparin, which is supplied to Baxter by Scientific Protein Laboratories (SPL).

I. Further analysis of contaminant rules out proteins, dioxins and other chemicals

The heparin impurity that has been found in the API lots associated with adverse clinical events is chemically very similar to the heparin molecule itself. Heparin is called a polysaccharide because it is composed of many sugar-like units, and likewise, the impurity contains polysaccharides. One reason it has been difficult to determine the precise chemical structure of the impurity is because it is so similar to heparin, making it hard to separate the two in sophisticated chemical analyses.

Through its research to date, Baxter has ruled out protein impurities in the suspect heparin API. Therefore, bacterial-derived protein molecules such as pertussis, botulinum, shiga, diphtheria, cholera, and tetanus toxin, to name a few, can be ruled out as the heparin impurity. Other chemicals such as tetrodotoxin (from puffer fish), lead and dioxins (formed when hydrocarbons with chlorine are burned) also do not match the identified heparin impurity.

While Baxter's analysis is not complete, the company has evidence that the unknown material is a highly sulfated glucosaminoglycan-like (GAG-like) material. While heparinlike, the material is structurally different from naturally-occurring heparin. The unknown material has approximately the same molecular weight as heparin and is similar in other ways, which is why standard testing would not detect its presence.

II. Investigation focus turns to supply chain and determining causality of allergic reactions

"In this investigation, there are three key questions that we are trying to answer - what exactly is the contaminant, where in the supply chain was it introduced, and can we prove that this contaminant is in fact causing the reactions we've seen," explained Norbert G. Riedel, corporate vice president and chief scientific officer of Baxter International Inc.

Dozens of Baxter scientists, manufacturing and quality experts have been working seven days a week since late December 2007, when the company began to see the increase in heparin-related adverse event reports. More than 40 different laboratory methodologies and hundreds of different tests have been employed in these investigations, including state-of-the-art analytical instrumentation such as nuclear magnetic resonance spectroscopy, which Baxter is now using on a continuous basis.

III. No fatalities have been confirmed by medical evidence to be caused by allergic reactions to Baxter heparin

At this point in time, neither Baxter nor the U.S. Food and Drug Administration (FDA) investigations have confirmed that Baxter heparin has caused any fatalities as a result of an allergic reaction. Baxter has received reports of a number of deaths. The company determined that there are four cases in which patients received Baxter heparin and suffered an allergic-type reaction to heparin that may have contributed to the adverse outcome, though there is not yet enough medical data available to draw a firm conclusion that the reaction caused death. In each of these cases, the patient had multiple underlying complex medical conditions and patients in three of these four cases had either undergone, or were in the process of undergoing, invasive cardiac surgery.

The company has received approximately 600 heparin-related adverse reaction reports to date.

"Patient safety is Baxter's highest priority, and we take our responsibility to investigate any report we receive seriously," Riedel said. "The company investigates as thoroughly as possible, contacting the person or institution that reported the event, checking sales records, medical records, and visiting the institution for further inquiry when appropriate. Baxter will continue its diligent investigation into the reports it receives."

"The continued collaboration between Baxter, FDA and SPL, as well as the consolidators, workshops and other links in the supply chain, is critical to putting all of the pieces together and determining root cause," Riedel said. "Baxter remains committed to facilitating this collaboration and providing the technical expertise necessary to resolve this issue. We stand ready to assist SPL and regulatory authorities in implementing additional measures to ensure that this does not happen again."

"We are confident that through our quick actions, significant resources and technological capabilities, we have been able to materially assist the FDA and other countries' regulatory agencies in identifying and resolving this issue before it manifested itself more widely in the industry," concluded Riedel.