PLASMA-DERIVED BIOLOGICS - New Fractionation Process to Expand Availability of Plasma-Derived Treatments

INTRODUCTION

Plasma-derived therapeutics start from human blood plasma instead of the chemical or synthetic materials from which most pharmaceuticals are made. Human blood plasma is rich in proteins that boost the immune system, and fight infections and inflammation, making plasma-derived biologics useful in treating rare, chronic, and often genetic diseases like hemophilia. Among the proteins used are immunoglobulins, coagulation factors, alpha-1 antitrypsin, fibrin sealants, and albumin.

While there is no distinction biologically, human plasma donations come from two different processes. The first type of donation is called “source” plasma, wherein a donor undergoes a process called plasmapheresis. In this process, the plasma is separated from the other components (red and white blood cells and platelets) of the donor’s blood. The plasma is retained by the collecting facility, while the other components are returned to the donor’s blood stream. By this method, 600 to 800 milliliters of plasma can safely be donated at a time. The American Red Cross states that plasma donation can occur every month without harm to the donor.

The other type of donation is that of “recovered” plasma. In this type of donation, the donor gives whole blood, and the plasma is taken from it. This provides about 250 milliliters per donation. Whole blood donors should wait 8 weeks between donations.

Once the plasma is collected, it needs to be screened for disease (eg, HIV or hepatitis). Plasma that has passed such screening then undergoes “fractionation.” Thousands of plasma donations that have passed screening are pooled together, which ensures homogeneous batches, and the process begins to extract and purify the desired proteins. The process is called “plasma fractionation,” and the proteins are said to be “fractioned off.”

FRACTIONATION TODAY: COHN COLD FRACTIONATION PROCESS

All fractionation today is done via the Cohn Cold Fractionation Process, named after Dr. Edwin J. Cohn who developed it in the 1940s. The Cohn Process involves modifying the pH, ethanol concentration, and temperature to separate proteins through precipitation into five “fractions” (IV). The separated proteins then undergo an extensive purification process that includes cryoprecipitation, nanofiltration, solvent detergent treatments, and incubation to produce a sterile, virally inactivated protein product.

Plasma fractionation has been around since World War II, when it was used to create blood products, initially albumin, to help wounded soldiers and sailors suffering from burns and hemorrhagic shock. While human blood plasma contains hundreds of proteins that may have medicinal value, there are around 20 that are commercialized today. The main proteins, in chronological order of development include the following:

Albumin: Used since the 1940s as a volume expander for blood and fluid loss, septic shock, burn therapy, renal dialysis, and therapeutic plasma exchange. Albumin represents roughly 55% of the total protein volume in human plasma.

Hemophilia Factors: Used since the 1960s, first as cryoprecipitate to control bleeding, but later as individual anti-hemophiliac factors, such as Factor VIII (the most common factor deficiency) and Factor IX as methods of purification were developed.

Intravenous Immunoglobulins (IVIG): In the 1970s, the Swiss Red Cross further improved on the Cohn method by adding chromatography process to further extract and purify immunoglobulins. FDA-approved indications include some oncology indications, certain neurological conditions, and select hematological and dermatological conditions.

Alpha-1 Antitrypsin (AAT), Also Known as Alpha-1 Protease Inhibitor (A1PI): AAT is a protein that is made in the liver in healthy humans, and certain genetic defects diminish or eliminate the liver’s ability to make AAT. An AAT deficiency causes a variety of conditions, including emphysema, neonatal hepatitis, jaundice, and chronic obstructive pulmonary disease (COPD). Approximately 1 in 3,000 humans have this genetic deficiency, and it is estimated that over 300,000 people in North America and Europe are living with the deficiency, but less than 3% receive A1PI replacement therapy, which is lifelong and involves weekly infusions of A1PI of at least 60 mg/kg of body weight, or roughly 250 grams per year. Information on Alpha-1 deficiency, and resources provided by the patient advocacy group Alpha-1 Foundation, can be found at www.alpha1portal.org.

For albumin, the Cohn Process is perfectly adequate. With albumin accounting for 55% of all the proteins in plasma, it’s a target-rich environment for this 75-year-old process.

For AAT, the Cohn Process suffers from very low yields. It is believed the ethanol in the Cohn Process is very damaging to some proteins, negatively affecting the ability to get good commercial yields. AAT makes up 1.8 to 3.5 grams per liter of plasma, and the Cohn Process can only recover about 7% of it. When one considers the numerous potential uses for AAT, it is not beyond reason to worry about a shortage of the protein for patients who need it. Of the 300,000 potential patients with Alpha-1 deficiency, only about 10,000 are getting plasma-derived treatment. If the other 291,000 are to be identified and treated with replacement therapy, supplies will have to expand radically.

One of the main issues with the Cohn Process is its reliance on ethanol combined with changes in pH, ionic strength, and temperature in a lengthy multi-step process to bring about the separation of proteins. The use of ethanol poses two problems: it tends to have denaturing effects on plasma proteins when they are exposed for a long time, and ethanol is volatile, making commercial use of the Cohn Process capital intensive for safety reasons. A process that could fractionate the proteins without the use of ethanol would, therefore, be a step forward.

IN WITH THE NEW: SALT DIAFILTRATION PROCESS

About 10 years ago, researchers began development of the Salt Diafiltration Process (SDF). The SDF Process uses salt as the precipitant at neutral pH, followed by salt removal by diafiltration, followed by the use of state-of-the-art chromatography for final separations and purification. The efficacy of the process has been confirmed in pilot-scale batches in independent laboratories. PlasmaTech Biopharmaceuticals has initiated a three-phase process of scaling up its process, validating it for required FDA filings, and ultimately running the process at production scale to enable the clinical trial product to be produced.

Over the years, research has established that several salts work. However, sodium citrate is now the preferred salt for the SDF process because of its ‘‘friendliness’’ to biologics, having been long used as an FDA-approved protectant and preservative of whole blood and blood plasma. With the SDF process utilizing sodium citrate, yields from plasma fractionation have gone from 7% recovery of AAT with the Cohn Process to 70% with the SDF, or approximately a 1000% increase in yield.

Moreover, the SDF process is quite capable, according to research done to date, of delivering other fractionated proteins. Intravenous Immune Globulin (IVIG) extracted from human plasma contains a broad spectrum of Immunoglobulin G (IgG) antibodies, and it is used to treat, among other conditions, primary immune deficiencies of genetic origin (estimated 10 million potential patients worldwide; 60,000 currently treated with IVIG), chronic lymphocytic leukemia, idiopathic thrombocytopenia, pediatric HIV, allogeneic bone marrow transplantation, kidney transplantation, and Kawasaki syndrome. The SDF process improves IVIG yields by roughly 20% and is expected to extend half-life in circulation due to reduced denaturation.

Further the short, two-step salt precipitation process, in contrast to the highly denaturing Cohn process, may also enable the extraction of several additional plasma biologics by means of downstream affinity and/or ion-exchange chromatography, thus potentially further improving revenues and process economics available from the same starting plasma. Examples of these additional therapeutic proteins are C-1-Esterase Inhibitor, Protein C, Antithrombin III, Transferrin, and Haptoglobin, all of which are used as treatments for low-incidence genetic deficiencies that could qualify them as Orphan Drugs.

THE FUTURE OF PLASMA-DERIVED TREATMENTS

A final advantage plasma-derived treatments have is a regulatory one. Because of concerns about product availability and because human-derived plasma biologics are considered to be “bio-identical,” as opposed to bio-similar as is the case of recombinant or transgenic products, the FDA’s Center for Biologics Evaluation and Research (CBER) approval process can be much shorter and less costly. Depending upon the specific protein being evaluated, CBER may only require clinical trials to demonstrate safety and bioequivalence of the protein in circulation.

The global market for human-plasma derived therapeutics is estimated at $15 billion, and is growing at more than 10% per year. With the clinical indications and uses for these proteins ever expanding, there is a real risk of potential shortages or shortfalls in the future due to limitations inherent to the Cohn process. SDF offers real innovation in an industry that has relied on the Cohn process for roughly 75 years. As uses for these proteins expands, SDF is well positioned to meet growing supply needs.

Jeffrey B. Davis earned his BS in Biomedical Engineering from Boston University and his MBA from The Wharton School, University of Pennsylvania. Mr. Davis has held a variety of c-level executive positions in the biotechnology industry, and is currently a Director and Chief Operating Officer of PlasmaTech Biopharmaceuticals, Inc. He was previously CEO of Access Pharmaceuticals, Inc., and has previously served in a variety of senior investment banking and management positions. Mr. Davis was an investment banker with various Deutsche Bank AG banking organizations, both in the US and Europe, and also served in senior marketing and product management positions at AT&T Bell Laboratories, where he was also a member of the technical staff, and at Philips Medical Systems North America. All inquiries are to be directed to: Andre’a Lucca – Director of Communications Office: 212.786.6208, alucca@plasmatechbio.com.
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