Plasma Therapies: IG in the Driver’s Seat

by Ronale Tucker Rhodes, MS and Kris McFalls

The market for plasma protein therapies continues to offer lifesaving treatments for a growing number of individuals who suffer from a variety of diseases. Still, the intricacy of meeting the increasing demand for these therapies is often misunderstood. The reason is that manufacturing plasma protein therapies — how they are developed, in what quantities and at what cost — is perhaps one of the most perplexing production models because it differs significantly from traditional pharmaceutical manufacturing processes. Plasma pharmaceuticals rely solely on the proteins present in human blood, rather than on chemical processes that can be developed and/or improved for traditional pharmaceuticals. In further contrast, considerably fewer patients are treated with plasma products, and the cost of production is much higher due to the challenges of the manufacturing process.

The Facts of Plasma

Most plasma is collected at the 380 U.S. Food and Drug Administration (FDA)-licensed and International Quality Plasma Program (IQPP)-certified plasma collection centers located throughout the United States.¹ The centers (owned almost exclusively by plasma therapy manufacturers) pay between approximately $15 and $40 for a donation of plasma, which, through a process known as plasmapheresis, is extracted as whole blood and then put into a centrifuge to separate the plasma. According to Patrick Robert, president of the Marketing Research Bureau Inc., an independent market research firm specializing in blood and plasma products, U.S. donors are the source of 47 percent of the world’s plasma.

Worldwide, the total annual demand for plasma by pharmaceutical companies that manufacture plasma-based therapies is about 23 million to 28 million liters.² The amount collected by plasmapheresis in commercial plasma industry facilities is roughly 11 million liters from more than 15 million donations. And, the remaining liters are recovered from whole blood donations at community or American Red Cross (ARC) blood banks around the world.³

Once collected, plasma — 92 percent water and 8 percent proteins — must go through a fractionation process that separates and collects the individual proteins. According to Mary Kuhn, executive vice president of production at Talecris Biotherapeutics, of these proteins used to manufacture plasma pharmaceuticals, 64 percent are albumin, 20 percent are immune globulin, 2.5 percent are alpha-1 antitrypsin, less than 1 percent are clotting factors, and 13.5 percent are others, such as antithrombin, protein C, C1 esterase inhibitor, etc.

Fractionation: Making Therapies from Proteins

As part of the industry’s voluntary international standards program for manufacturers, known as the Quality Standards of Excellence, Assurance and Leadership (QSEAL), all plasma is held in inventory for 60 days before it can enter the manufacturing process.¹ This allows for rigorous testing to identify, retrieve and destruct plasma donation from donors who are disqualified for various reasons, such as having received a tattoo or piercing at the time of the original donation or failing to report foreign travel.

Once the plasma is released from inventory, it is ready for fractionation. During the fractionation process, plasma is pooled from multiple donations, purified and processed in a specific order to extract specific plasma proteins that have a proven health benefit.¹ The steps and regulations required to collect donated plasma and complete the manufacturing process that ultimately results in the final therapies takes between seven and nine months. Between weeks 0 and 4, the plasma is collected. Then, between weeks 4 and 12, it is batched and transported to the fractionation plant, where it is stored from weeks 12 through 16. During this period, “it is the combination of time, temperature, pH and alcohol concentration [that] allows the extraction of the specific therapeutic proteins.”¹ At that point, the plasma is inspected and released for production. Production occurs between weeks 20 and 24. Then, between weeks 24 and 28, internal testing of the therapeutic proteins takes place, and the therapies are then released by the FDA and shipped between weeks 28 and 32 to the wholesalers and end users.

Manufacturing Costs of Plasma Therapies

The high cost of plasma, plasma testing and the lengthy production process boost the manufacturing costs for plasma protein therapies — much higher than chemical pharmaceuticals. Manufacturing costs for plasma products are about 65 percent of the price, compared with 20 percent to 25 percent for traditional pharmaceutical products.⁴ And the costs have continued to rise due to changes in demand for therapies, new technologies and changes to regulatory measures introduced to improve the safety of plasma therapies.

Over the years, what has driven the amount of plasma collected — in order to meet the volume required for each therapy — has evolved. For instance, 30 years ago, the need for albumin determined how many liters of plasma were needed. Then, 20 years ago, it was the need for plasma-derived factor VIII. Today, the growing demand for immune globulin (IG) has put it in the driver’s seat.⁴

With IG in highest demand, manufacturers have to produce greater amounts of the therapy, which results in proportionately greater amounts of the other protein therapies. For instance, the U.S. needs about 40 million grams of IG to treat patients with a variety of conditions. But, producing 40 million grams of IG results in about 250 million grams of albumin — far exceeding current demand. Fortunately, worldwide demand for albumin is increasing, particularly in China, Japan and Europe.

Further impacting the cost of production is regulation. Since the 1980s, the national and international “agencies regulating the plasma fractionation industry have developed a comprehensive set of measures to ensure the viral safety of plasma products.”² These include multiple levels of regulatory oversight to ensure overlapping safeguards against the risks of transmitting bloodborne infectious agents. However, these rigid regulations, combined with the complex changes in technology to ensure the greatest progress in product purity and quality, have resulted in decreased yield for most proteins, apart from albumin.

Manufacturers, in turn, have expended substantial research and technology investments to increase the yield and to identify additional enhancements that can create even more effective therapies.¹

A Promising Outlook for Plasma

While the process of manufacturing plasma protein therapies is complex, patients have benefited greatly. Not only are there more therapies to treat diseases, but these therapies are also safer than ever before.

But today’s promising outlook doesn’t alleviate the need for improvements. Despite strides in regulations, “regulatory disharmonies exist in the areas of donor acceptance, testing, Good Manufacturing Practices-related issues, batch release, documentation, clinical trial requirements and probably more.”⁴ By better harmonizing regulatory issues, the costs of production could be lowered and supply could be increased. In addition, discovering new uses for excess product and developing new therapies derived from plasma proteins with still unknown functions could also reduce manufacturing costs.

RONALE TUCKER RHODES, MS ,is the editor of BioSupply Trends Quarterly magazine. KRIS MCFALLS is the patient advocate for IG Living magazine, directed to patients who rely on immune globulin and to their caregivers.