Human Plasma Products: Two Decades of Unsurpassed Safety

“Quality is never an accident; it is always the result of intelligent effort.”

— John Ruskin

THANKS TO DONOR screening and blood testing, the risk of a potentially serious infection from transfused blood is lower today than it has ever been. Bacteria transmitted through platelet transfusions now account for the most meaningful risk; a non-negligible proportion of the approximately one in 3,000 contaminated units result in sepsis or death. At the other extreme, the theoretical risk of acquiring an HIV infection through blood transfusion is estimated at one in 1.5 million; the last reported case of HIV acquired from a blood transfusion was in 2008.¹ While the U.S. Centers for Disease Control and Prevention characterizes most of these risks as “rare,” “extremely rare” or “extremely remote,” the agency still cautions that “a wide variety of organisms, including bacteria, viruses, prions, and parasites, can be transmitted through blood transfusions.”²

With this in mind, consider the safety record of human plasma derivatives — immunoglobulins, coagulation factor concentrates, albumin, fibrin sealants and others. Those familiar only with the fact that each of these is purified from many thousands of pooled units of donor plasma may be surprised to learn that we are fast approaching two decades without a single reported infection* transmitted to any U.S. patient through any licensed plasma-derived product.

The significance of this extraordinary safety record should particularly resonate with those who practiced in the 1970s.

In those days, hepatitis B and C viruses would eventually infect most persons with severe hemophilia through contaminated factor VIII and IX concentrates. Then, in the early 1980s, HIV, a previously unknown lipid-enveloped virus, found its way into transfused patients through the blood supply and infected nearly half of all persons with severe hemophilia, again through contaminated factor concentrates.

How did the entire plasma products industry turn this grim situation around? How, since the early 1990s, has this industry supplied vast quantities of dozens of therapeutic proteins administered to millions of patients with a completely unblemished pathogen-related safety record?

The “Safety Tripod”

The answer lies in a continuing collaboration between industry and drug safety regulators to innovate, validate and, finally, incorporate measures that collectively have driven down pathogen contamination risks to extraordinarily low levels. Because they conveniently fall into three categories, these measures are known as the “safety tripod” (see Figure 1).

Selection of starting material. Before plasma is accepted for further processing, the potential donor is subjected to a screening questionnaire to try to assure that he or she is in good health and to rule out personal or medical history associated with increased risk of exposure to one of the “big three” viruses (HIV or hepatitis B or C) or to the infectious prion thought to be responsible for about 200 cases of variant CreutzfeldtJakob disease (vCJD) in Europe.

Pathogen testing. Testing occurs in two successive stages (see Table 1). First, individual donor plasma units are screened for HIV and hepatitis B and C viruses using conventional viral antigen and antibody screening tests. Plasma units are then aggregated into minipools and tested again for the “big three” viruses, as well as the non-enveloped viruses hepatitis A and parvovirus B19, using nucleic acid amplification testing (NAT). NAT can detect exceedingly small numbers of viral particles in the rare event that a plasma unit that tested negative by serological tests was collected during the very brief “window period” following donor infection and prior to appearance of enough antiviral antibody or antigen load to be detected by routine serological tests.

Once each donor plasma unit is “released” by passing these screening tests, each plasma unit is pooled with thousands of other units into a single production batch, which undergoes further processing into purified therapeutic proteins.

While donor selection and pathogen testing dramatically reduce the chance of a contaminated unit entering the plasma pool, just as importantly, these two steps act to assure that only a very minimal amount, or “load,” of any pathogen might conceivably escape testing and end up in the plasma pool. Unlike blood and blood components intended for transfusion, the goal here of donor screening and plasma testing is not merely to mitigate infectious risks. These two legs of the safety tripod most importantly act to limit any potential pathogen load that slips through so that downstream inactivation and removal steps can readily and completely eliminate it.

Pathogen inactivation and removal. Over more than 60 years of widespread clinical use — including four decades prior to the availability of pathogen screening — human albumin has never transmitted hepatitis. Nor has a single case of HIV ever been associated with albumin administration, even in the early 1980s before HIV had even been identified.

The reason for this perfect pathogen safety record traces back to World War II, when stabilizers were added to albumin to improve the protein’s physical integrity during military shipment to hot desert regions. It was soon recognized that albumin stabilization would allow the application of heat to inactivate infectious agents present in donor plasma. Numerous subsequent studies confirmed that heat treatment of the final albumin solution bottles at 60 degrees Celcius for 10 hours — simple pasteurization — eliminated any risk of jaundice, later understood to be caused by hepatitis viruses.³

It was not until the early 1980s that scientists identified ways to stabilize factorVIII and factor IX concentrates so that heat treatment could similarly be employed to inactivate hepatitis viruses. Before the introduction of this first virus inactivation procedure in 1984, most persons with severe hemophilia eventually acquired hepatitis B and hepatitis C (then called “non-A, non-B hepatitis”) through infusions of factor concentrates.

Most modern manufacturing processes incorporate two steps that are effective in reducing any potential lipidenveloped virus load that might slip past donor selection and donation testing. The industry defines effectiveness as resulting in a minimum of four logs of viral reduction (i.e., at least a 10,000-fold reduction). Thus, two such steps together achieve at least a 100 million-fold viral reduction potential. It is this extraordinary designed-in margin of safety that ultimately accounts for plasma products’ unblemished safety record with respect to HIV, hepatitis B and C and other lipid-enveloped viruses.⁴

These inactivation and removal steps (see Table 2) can vary for different products. Some of these, including pasteurization and affinity chromatography, effectively clear both lipidenveloped and smaller non-enveloped viruses, while others better target one or the other. For all products, these as well as other steps throughout the protein purification process have been carefully validated to show how each contributes to getting the job done (see Figure 2).

Today, the manufacturing processes for every licensed therapeutic protein derived from human donor plasma include definitive pathogen reduction steps that have all but eliminated every known threat to our blood supply. This is the leg of the safety tripod that is properly credited for the extraordinary safety record of plasma products over the last two decades.

But What About the Unknown Pathogen?

With the safeguards currently in place, the risk of being infected through a licensed plasma product by known blood-transmissible viruses now arguably compares favorably with the chance of being struck by lightning. But what happens when a virus or other type of “emerging pathogen” comes along that we don’t yet know of, or for which we don’t have a valid test to screen donors?

In fact, this important question has already been put to the test.

Endemic to Africa and the Middle East for decades before the initial U.S. outbreak in 1999, the lipid-enveloped West Nile virus (WNV) is an avian zoonosis transmitted to humans through a mosquito vector. Roughly one in every 140 infected people progresses to develop encephalitis, meningitis or acute flaccid paralysis. A handful of WNV infections through a blood transfusion have been reported, beginning in 2002 when 23 cases were confirmed in patients transfused with platelets, red blood cells or fresh frozen plasma from 16 viremic blood donors. While national blood donor screening was initiated in 2003, it has not eliminated the risk of WNV transmission through transfusions.⁵

Each year during its transmission season, thousands of Americans are infected with WNV. A few of these individuals might inadvertently donate plasma during the early viremic phase before they become symptomatic. But through testing and experience, we also know this: 1) WNV is efficiently inactivated by pasteurization, solvent-detergent treatment and other validated virus inactivation methods, and 2) in the 12 years since that first outbreak, no cases of WNV infection have been reported through administration of a plasma product.

For these two reasons, the U.S. Food and Drug Administration (FDA) exempts source plasma intended for fractionation from the WNV screening requirement that applies to transfused blood components, which cannot be similarly subjected to dedicated pathogen inactivation.

The confidence of the FDA in this principle of preemptive pathogen reduction to eliminate WNV is supported by the lack of a single reported infection after more than a decade and millions of doses of plasma products.

Preemptive Pathogen Reduction: Powerful Protection

For a second equally compelling example of the preemptive pathogen reduction principle, consider the prion responsible for vCJD, a uniformly fatal neurodegenerative disease first identified in the United Kingdom in 1996 and contracted directly through consumption of cattle sick with bovine spongiform encephalopathy. Epidemiologists have concluded that three of the 217 cases of vCJD reported worldwide were linked to blood transfusion from an infected donor.⁶ To this day, there is no mass screening test available for blood or plasma donors, yet not a single case of vCJD has ever been traced to administration of a U.S.-licensed human plasma product. Manufacturer-conducted studies in which prion-infected material was spiked into various process intermediates have documented how individual protein purification steps — precipitation, filtration and affinity chromatography, for example — each contribute to prion clearance and reduction in infectivity.^7,8,9 Similar studies are conducted with both enveloped and non-enveloped viruses.

It is uncertain whether the infectious prion responsible for vCJD has ever found its way into a plasma pool sent for fractionation. All we know is that, consistent with the prion study findings, there has never been a single documented instance of the transmission of either vCJD or classical CJD by any therapeutic human plasma-based product.

The capability of preemptive pathogen reduction built into each plasma product manufacturing process will undoubtedly be challenged again by future emerging pathogens. But with the combination of this proven, robust preemptive pathogen reduction and constant vigilance by industry and drug regulators, it’s safe to say that plasma products can be prescribed with more confidence than ever.

*In 1995, a single production lot of a factor VIII concentrate was implicated in the infection of three hemophilia A patients (Morbidity and Mortality Weekly Report, 1996 Jan 19;45[2]:29-32). The FDA is not aware of a definitive cause of that contamination event (personal communication, R. Chapelle, FDA/CBER, Feb. 17, 2012)