In this episode, we will discuss the intricate process of producing immune globulin products, hereafter referred to as IG products.
Today, we have guest speaker Keith Berman. Keith has worked in the plasma therapeutics and blood therapies industry in a career spanning over three decades. He holds a bachelor’s degree in biological science from UC Berkeley, an MBA in marketing and an MPH in health services management from UCLA.
Beginning his career in the late 1980s, Keith started at what is now Takeda, where he supported IG product development and was involved in the successful U.S. launch of Gammagard. His knowledge and experience in IG development, usage and reimbursement have made him a trusted advisor in the industry.
In addition to his consultancy work, since 1989, Keith has served as editor and writer of International Blood/Plasma News, a monthly newsletter that covers the blood and plasma products industry.
In this episode, we will discuss the intricate process of producing immune globulin products, hereafter referred to as IG products.
Today, we have guest speaker Keith Berman. Keith has worked in the plasma therapeutics and blood therapies industry in a career spanning over three decades. He holds a bachelor’s degree in biological science from UC Berkeley, an MBA in marketing and an MPH in health services management from UCLA.
Beginning his career in the late 1980s, Keith started at what is now Takeda, where he supported IG product development and was involved in the successful U.S. launch of Gammagard. His knowledge and experience in IG development, usage and reimbursement have made him a trusted advisor in the industry.
In addition to his consultancy work, since 1989, Keith has served as editor and writer of International Blood/Plasma News, a monthly newsletter that covers the blood and plasma products industry.
Episode 10
From Plasma to Healing: The Intricate Journey of Producing Immune Globulin Medications
Hello and thank you for joining us today. My name is Abbie Cornett, and I am the patient advocate for IG Living magazine. This podcast is brought to you by IG Living magazine to give readers an opportunity to hear from healthcare experts on topics important to them.
In this episode, we will discuss the intricate process of producing immune globulin products, hereafter referred to as IG products.
Today, we have guest speaker Keith Berman. Keith has worked in the plasma therapeutics and blood therapies industry in a career spanning over three decades. He holds a bachelor’s degree in biological science from UC Berkeley, an MBA in marketing and an MPH in health services management from UCLA.
Beginning his career in the late 1980s, Keith started at what is now Takeda, where he supported IG product development and was involved in the successful U.S. launch of Gammagard. His knowledge and experience in IG development, usage and reimbursement have made him a trusted advisor in the industry.
In addition to his consultancy work, since 1989, Keith has served as editor and writer of International Blood/Plasma News, a monthly newsletter that covers the blood and plasma products industry.
Abbie: Keith, it is real pleasure to have you here today. I have followed your work for years and thought you would be the perfect person to have as my guest for today’s topic, “From Plasma to Healing: The Intricate Journey of Producing Immune Globulin Medications.” Before we start, why don’t you give our listeners a little background on yourself and how you became involved in plasma and blood therapies.
Keith: Thanks for inviting me, Abbie, and I always enjoy talking about IG therapies, which have been a big part of my career. My story really begins at UCLA Medical Center in 1981, where I was working as the lab research assistant for a young immunologist named Michael Gottlieb. I ran certain tests for him to evaluate immune function of infection-fighting cells isolated from hospitalized patients. One day, Dr. Gottlieb gave me the first of many samples from a few extremely ill patients with severe immunodeficiency and strange infections, and he cautioned me to handle them extra carefully. It turns out that these UCLA patients were the very first in the world to be diagnosed with AIDS, which Dr. Gottlieb and his colleagues reported to the Centers for Disease Control in mid-1981.
I moved on to graduate school in public health and business at UCLA, but that experience stayed with me. So when I saw an ad after graduation for a position working in marketing and product development for an L.A.-area company developing a new immune therapy, I ditched my plan to work in hospital administration and joined Baxter BioScience, now part of Takeda. That product was Gammagard, one of the first intravenous IG products (IVIG) launched in the 1980s, and I was hooked.
Abbie: Keith, we know that IVIG and subcutaneous IG (SCIG) are important therapeutics produced from plasma, but could you start out by giving our listeners the 30,000-foot view?
Keith: Abbie, I know this podcast is all about how IG is produced, but I’d like to take a moment to mention just how unique these products are. When I started in the mid-1980s, IVIG was prescribed to people with primary immunodeficiencies who needed regular infusions of IgG antibodies for protection against serious bacterial infections. And it was used also to treat a rare autoimmune disorder that wipes out our blood platelets called ITP.
Thirty years and literally thousands of clinical studies and case reports later, IG is prescribed to treat or prevent literally dozens of disorders that range from autoimmune neuropathies such as CIDP and myasthenia gravis, to autoimmune inflammatory disorders such as dermatomyositis and stiff person syndrome, to secondary immunodeficiency disorders caused by powerful drugs like Remicade that suppress the patient’s ability to produce infection-fighting antibodies.
So as we’ve learned about more and more conditions that IG can effectively treat, the demand for IVIG and SCIG products has just kept growing. The very first IVIG product was approved in the early 1980s. By 1990, the industry produced a little less than 7 million grams. By 2010, demand had increased six-fold to 42 million grams. And today, the yearly U.S. demand for IVIG and SCIG together has nearly tripled again to more than 115 million grams.
No other licensed class of drugs or biotherapeutics has ever seen this kind of growth over a period stretching almost 40 years. It’s unheard of. But there’s a very simple reason: the IVIG or SCIG product that your listeners use or prescribe isn’t really a drug or a single protein such as insulin for diabetics or factor VIII for management of hemophilia. IG is actually thousands of different IgG antibodies purified from the plasma of many thousands of healthy donors. While it’s actually one of five major types of immunoglobulins present in our blood and tissues, IgG accounts for about three-quarters of all our circulating immunoglobulin, and it’s the most important of them for fighting infections and regulating our immune function.
So it’s really not surprising IG usage has steadily grown for nearly 40 years, because it’s much more than just a drug or biological. One can think of IG as almost half of the healthy human immune system concentrated in glass vials.
Of course, other important therapeutic proteins are also purified from donor plasma, including C1 esterase inhibitor for treatment of a rare condition called hereditary angioedema, albumin for patients with severe liver disease or to replace blood volume in major surgeries, and alpha-1 antitrypsin for people with hereditary emphysema. But the product that dictates how much plasma needs to be collected and processed is IG — about 85 percent of which is made into IVIG products and 15 percent is made into SCIG products. Of course, other than their concentration and delivery route, IVIG and SCIG are the same thing — IgG antibodies purified from donor plasma.
Abbie: How important are IVIG and SCIG to the manufacturers of plasma proteins? Today, IG products alone account for two-thirds of the industry’s total revenues from plasma processing, or what’s known generally as plasma fractionation. All the other plasma proteins together add up to the remaining one-third of revenues.
Keith: Close to a quarter-million Americans of all ages will receive or self-administer an IG product this year. So just like any therapeutic, product safety is of paramount importance to patients, ordering physicians, manufacturers and the U.S. Food and Drug Administration (FDA). As I’ll get into in a moment, the industry and FDA have very successfully partnered for many years to assure the safety of every licensed IG product.
Abbie: Thank you for that information. My next question is about plasma donation. Can you please tell our listeners where donations come from and what’s done to assure their viral safety?
Keith: Well, just as IG demand has grown year after year, so has the need for the donor plasma that it’s made from. Each roughly pint-and-a-half plasma donation yields around 3 grams of IgG antibody, which means that, today, IG manufacturers collectively need more than 35 million individual plasma donations to produce enough IG to meet our domestic needs. To put this into context, that’s around three times the number of whole blood donations that the Red Cross and independent blood banks collect each year.
About 10 percent of plasma acquired by manufacturers is actually recovered plasma separated from whole blood given by healthy volunteer donors at local blood donation centers and blood drives around the country. Plasma fractionators purchase this “surplus” recovered plasma that’s above and beyond what hospitals need for direct transfusion into surgical and other patients. The other 90 percent of the plasma supply is called “source plasma,” which comes from healthy compensated individuals who donate at more than 1,000 licensed plasma collection centers across the U.S. So the industry heavily relies on compensated plasma donors to produce the IG products needed by patients both here and abroad.
But whether it’s source or recovered plasma, before it’s ever delivered to manufacturers to be pooled with other units and processed into IG, two key events happen at the outset to ensure its viral safety. These first two safety pillars are donor selection and testing for viral pathogens.
Each potential plasma or whole blood donor is asked to complete a screening questionnaire to verify 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: hepatitis B, hepatitis C and HIV. Anyone who has donated blood or platelets is very familiar with this first safety pillar. But this is unquestionably just the start, because donor selection reduces the risk of possible pathogen transmission by only about ten-fold.
The second pillar of IG safety is direct testing of the donor plasma itself, in two phases. First, each plasma unit is tested for hepatitis B, hepatitis C and HIV 1 and 2 using conventional viral antigen and antibody screening tests. Then, a number of plasma units are combined into mini-pools and tested again for these same viruses plus parvovirus B19 and hepatitis A using a special technology called nucleic acid amplification testing, or NAT. These are the same steps used by blood suppliers such as the Red Cross to increase the level of assurance that donated blood and platelets are free of these blood-transmissible viruses before they’re released to hospitals for transfusion. After this testing is completed, the risk that a unit of plasma is contaminated with any of the hepatitis viruses or HIV is well under one in a million.
Each plasma unit is then frozen and held in quarantine for 60 days to allow what’s called “lookback” to assure that the subsequent donation from that same individual doesn’t test positive for one of these viruses. This further reduces any risk that the would-be donor gave plasma just days after contracting a viral infection, or what’s called the “window period” during which even NAT testing may not be sensitive enough to detect just a few circulating viruses.
And finally, any prospective donor who does test positive for any of these viruses is added to a National Donor Deferral Registry, which is a database of permanently deferred plasma donors. In other words, these individuals are barred from ever donating plasma for fractionation into IG.
Abbie: So, Keith, after the plasma is tested and goes to the manufacturer for processing into IG, what happens next?
Keith: So all these tested units of plasma are frozen and shipped to manufacturers, where they’re thawed and pooled into huge batches for fractionation or separation into different proteins, including IG. I should mention that pooling all these units also provides a very important protective benefit for patients with primary and secondary antibody immunodeficiencies. Because every IG product is prepared from plasma from many thousands of donors, they and their physician can be confident that it includes significant quantities, or titers, of IgG antibodies against the widest possible spectrum of serious infection-causing bacteria.
Now the process to make IG and other therapeutic proteins begins. We can think of it as a sequence involving two basic activities: crude separation of proteins by precipitation from the solution, followed up by further protein purification. There are differences from one manufacturer to the next, but most start by doing a freeze-thaw step that removes a rich concentrate of fibrinogen and other clotting factors called cryoprecipitate. That fibrinogen may be purified into fibrinogen concentrate or used to make fibrin sealants. The cryoprecipitate-depleted plasma contains everything else, including IgG.
Next comes the protein fractionation steps first developed by a Harvard biochemist named Edwin Cohn back in the 1940s. The cryoprecipitate-depleted plasma is mixed with cold ethanol — the same alcohol that we enjoy in wine, beer and spirits — at a specific temperature and acid-base conditions to precipitate IgG and other immunoglobulins from the liquid phase. This precipitate is called “Fraction II + III.” A second precipitation step using a different concentration of ethanol and temperature brings down “Fraction II,” which mostly contains our IgG. Some processes do this differently and actually precipitate everything else and leave the IgG in the solution, or what’s called the supernatant.
What follows also varies by product and manufacturer, but virtually all processes take advantage of a method called anion exchange chromatography to capture and remove impurities from the IgG-rich Fraction II that’s been re-suspended in solution. It’s basically a column with a material attached to it that has a strong affinity for molecules with negative surface charges. And since IgG has a positive surface charge, it flows through the column, while those impurities are captured and stay behind.
In the particular case of Gamunex and Privigen, a chemical called caprylic acid is introduced to Fraction II + III to precipitate impurities, followed by anion exchange chromatography to further purify the IgG. With Gammagard, cation exchange chromatography is additionally used to bind the IgG and allow impurities to flow through before the anion exchange chromatography step. I think you get the idea.
Abbie: Thank you, Keith. You mentioned the three safety pillars. Is this where the third pillar comes in?
Keith: Yes, and as important as the first two are for product safety, this is by far the most robust of the three safety pillars. And it’s actually a combination of a number of individual virus removal and inactivation steps. Each cold ethanol or caprylate precipitation, filtration and chromatography step along the way to our final IgG product works to separate any viruses that might have been introduced by a donor unit that somehow escaped detection through testing. Every IG production process also includes a special nanofiltration step, which allows the IgG to pass through tiny filter holes but catches and blocks viruses that are too big to pass through.
Then for good measure, each IG manufacturing process incorporates a potent viral inactivation step: either solvent/detergent treatment to dissolve the lipid coat on lipid-enveloped viruses or a very low pH incubation step that denatures viral proteins.
Abbie: OK, can you now take us through the last steps to formulate and bottle these IG products and get them to clinics and home infusion providers?
Keith: So no preservatives are added to the final sterile IgG concentrate, but a stabilizer is added to keep the IgG antibodies happily intact and free from clumping. The stabilizer of choice for most products is glycine, an amino acid that’s a protein building block. One IG product uses L-proline, a different amino acid, and one product uses maltose, a disaccharide made up of two glucose molecules. A few products also incorporate polysorbate 80, a surfactant used in numerous pharmaceuticals and foods. The IgG concentrates finally go to the filling line, where they’re aseptically added to vials or prefilled syringes. It sounds simple, but the filling line involves state-of-the-art technology for accurate fills and absolute assurance of sterility.
The vials are then sealed, labeled and packaged in containers that include features designed to make them tamper-evident to the user. Privigen, Gammagard Liquid, Gamunex-C and Gammaked, for example, all have a tamper-evident cap. Some products additionally come with a tamper-evident shrink band. To reduce the chance of product counterfeiting, several manufacturers actually laser-etch their IG vials with identifying numbers and the barcode.
Now the products are ready to ship. Most product is sold to major distributors such as FFF Enterprises, but it gets sold and shipped directly to the end hospital or specialty infusion provider.
The end customers for most SCIG products are specialty pharmacies such as Nufactor, which are responsible for managing the supply that goes to each patient for self-infusion and billing insurers. These days, roughly 40 percent of IVIG goes to hospitals, where it’s mostly administered in outpatient infusion clinics, and a similar share goes to specialty pharmacies. The balance is purchased and administered by non-hospital clinics and infusion centers.
Abbie, I left the best part of the IG manufacturing story for last. As I mentioned at the outset, the pathogen safety of these products is and always will be paramount for this industry and the FDA regulators responsible for its oversight. The three pillars of safety we talked about earlier have stood the test of time. Over the last 30 years and millions of infusions, there have been no reports of infection or viral transmission of any kind associated with any licensed IVIG or SCIG product. That’s a record that provides assurance to providers and peace of mind to everyone who relies on an IG therapy.
Abbie: Keith, it has been a pleasure to have you as our guest today. Thank you again for joining us to explain the Intricate process of producing IG medications. I am sure our listeners found it highly informative.
Listeners, thank you again for joining us today. Additional information regarding this podcast can be found on our website at www.igliving.com. If you have a question that was not answered, please contact me at acornett@igliving.com.
Look for the next IG Living podcast announcement on our website for the opportunity to submit your questions.
IG Living Advocate is a copywrite production of IG Living magazine, published by FFF Enterprises, the only magazine for the immune globulin community comprised of patients who suffer from chronic illness and their caregivers.