Ceprotin

DRUG DESCRIPTION

CEPROTIN [Protein C Concentrate (Human)] is manufactured from human plasma
purified by a combination of filtration and chromatographic procedures, including
a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS:
Transmission of Infectious Agents .

The manufacturing process for CEPROTIN (protein c concentrate) includes processing steps designed to reduce the risk of viral transmission. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of CEPROTIN (protein c concentrate) is collected only at FDA-approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, plasma pools for manufacturing are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative.

To further improve the margin of safety, two dedicated, independent and effective virus inactivation steps (Polysorbate 80 [P80] treatment and vapor heating) have been integrated into the manufacturing process in addition to other purification steps such as immunoaffinity chromatography.

Comprehensive virus clearance studies have been performed for the following steps: P80 treatment alone or coupled with an ion exchange chromatography step (IEX I), immunoaffinity chromatography (IAX) and vapor heating. In each study, the validity of the downscaled process has been confirmed by measuring process and biochemical parameters and comparing these with data from the large-scale manufacturing process. Where applicable (i.e. for P80 treatment and for vapor heating), the robustness of virus clearance has also been investigated by adjusting critical process parameters to levels least favorable for virus inactivation (e.g. temperature and incubation time for vapor heating).

Virus clearance studies for CEPROTIN (protein c concentrate) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log10 virus reduction factors per virus and manufacturing step is presented in Table 2.

Table 2 Summary of Mean Log10 Virus Reduction Factors for the CEPROTIN Manufacturing Process
Manufacturing Step	HIV-1	HCV Model Viruses		PRV	HAV	MMV
		BVDV	TBEV
P80 Treatment	>5.1	>4.7	n.d.	2.5*	>3.8*	1.4*
IAX	5.7	n.d.	4.8	5.4	3.1	3.6
Vapor Heating	4.6	>5.9	n.d.	5.9	>4.2	1.2
*Coupled with IEX. I Abbreviations: IEX, Ion Exchange Chromatography; IAX, Immunoaffinity Chromatography; HIV-1, Human Immunodeficiency Virus Type I; TBEV, Tick-Borne Encephalitis Virus (model for hepatitis C virus); BVDV, Bovine Viral Diarrhea Virus (model virus for HCV and other small, enveloped RNA viruses); PRV, Pseudorabies Virus (model virus for enveloped DNA viruses, e.g. HBV, Hepatitis B Virus); HAV, Hepatitis A Virus; MMV, Mice Minute Virus (model for Human Parvovirus B19 and for non enveloped viruses); n.d., not done.

CEPROTIN (protein c concentrate) is supplied as a sterile, white or cream colored, lyophilized powder
for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower
than 240 mosmol/kg. One International Unit (IU) of protein C corresponds to
the amidolytically measured activity of protein C in 1 mL of normal plasma.
The potency (IU) is determined using a chromogenic substrate method referenced
against the World Health Organization (WHO) International Standard (86/622).