Source plasma apheresis and plasma-derived medicinal products: a historical review

Introduction

The history of plasmapheresis dates to the Second World War but has antecedents in the work of Emil Von Behring in the late 19^th century. Von Behring, recipient of the first Nobel Prize in medicine, had developed a diphtheria antitoxin which, in its time, saved many lives (1). The concept of using human serum with specific antibodies for infectious agents was explored further in the measles and influenza pandemic that swept across the world starting near the end of the First World War (2,3). Several laboratories produced antiserum from patients with influenza in hopes high level of antibodies to the virus would have therapeutic value. There was no significant impact on the pandemic, but physicians used that experience to promote convalescent plasma as a therapy for recent epidemics, including Ebola and coronavirus disease 2019 (COVID-19) (4,5). While convalescent plasma was not shown to be effective for Ebola patients, there is a suggestion that it was effective for a subset of COVID-19 patients (6,7). However, the efforts to produce an immune globulin with specific and effective activity against COVID-19 were not successful. Despite the origins of the therapy in antibody-specific therapy, only a few efforts to produce pathogen-specific products have been successful and this area of therapeutics has advanced in other, non-infection areas.

A review of the historical timepoints of the source plasma (SP) collection industry is crucial to understanding how today’s safety standards, collection technologies, and regulatory requirements were shaped by decades of scientific progress and responses to past challenges. We believe that this is the first published historical review of its kind.

This manuscript outlines the history of SP apheresis and medicines derived from human plasma known as plasma-derived medicinal products (PDMPs).

A literature review was conducted using historical documents from Plasma Protein Therapeutics Association (PPTA). Gaps in the timeline were supplemented by literature searches on PubMed.

The emergence of PDMP therapy

PDMPs began with a different therapeutic purpose other than targeting infections. In the years leading up to the Second World War, the United States (US) military collaborated with Edwin Cohn, a physical chemistry professor at Harvard University, with the goal of developing albumin as a volume expander that could be practical on the battlefield if concentrated in a small volume. Initial experiments with bovine albumin were abandoned due to severe reactions to bovine proteins in some recipients. Human albumin became the product of choice, and Cohn’s work led to the first infusion of a PDMP to victims of the 1941 Pearl Harbor attack.

Cohn developed a method to fractionate plasma that would yield purified plasma proteins. Protein concentration, pH, ionic strength, temperature, and ethanol concentration were the five critical variables of fractionation. Early studies showed fibrinogen, immunoglobulin G (IgG), globulins, and albumin could be contained in fractions I–V. A pilot plant was developed and used blood from the American Red Cross (ARC) (8). Under contract with the US Navy, multiple companies worked with Cohn’s lab at Harvard to produce albumin. Early collections of blood for the war effort were primarily to produce albumin from the plasma. John Oncley from Massachusetts Institute of Technology joined the effort and was able to develop a method to produce Igs from fractions II + III. The Cohn fractionation method has been the basis for producing PDMPs over the years, but modifications and improvements have been made by others. In 1962, Kistler and Nitschmann at the Swiss Red Cross published a method for further improvement of yield with lower volumes of ethanol (9). The contributions of Cohn, Kistler, and Nitschmann form the backbone of manufacture of PDMPs in the present time, but chromatographic and pathogen reduction methods have since been added to improve purity and safety, respectively (10).

In the years following the Second World War, albumin and Ig were the therapeutic PDMPs used clinically. At that time, Ig was administered intramuscularly (IM) because attempts at intravenous (IV) infusion led to untoward reactions in patients, such as hypotension, chills, and fever. The product was mainly used as prophylaxis before potential exposure to various diseases, due to the antibodies in the product, but was limited in its usefulness in immunodeficiency patients for two reasons. First, administering sufficient volume IM to raise their Ig levels was extremely painful and not very practical. Second, the absorption of Ig into the bloodstream was inconsistent. Thus, there was a major effort to develop an IV product that would be efficacious for immunodeficient patients. The primary cause of the reactions was later identified as complement activation by aggregates of 7S globulins. Modifications that were successful in minimizing this risk included ultracentrifugation, dissociation by treatment of low concentrations of pepsin, incubation at pH 4, and reduction and alkylation of disulfide bonds. Subsequently, mild reduction and alkylation, reconstitution in 0.3M glycine, and treatment at pH 4 with low concentrations of pepsin led to the first commercial IV products. The tolerability was enhanced by sugars as stabilizers, such as maltose and sucrose (11). Current Ig products are more than 95% pure Ig utilizing modified purification procedures which employ a single ethanol precipitation step with fatty acids, such as caprylate or medium chain alcohols, with depth filtration for the serial Cohn-Oncley ethanol steps (11). Anion exchange chromatography has also been added to increase the yield. IVIg became standard therapy by the late 1970’s with more purified products and subcutaneous products becoming available in the new millennium. The IM product is rarely used today but is still utilized for specific antibody preparations, such as Rh_o(D) (Rh) and rabies immune globulins (12).

The development of processes to produce the IV preparations of Ig constitutes some of the downstream processing currently used to incorporate purification and pathogen reduction. Ion exchange, affinity chromatography, and ultrafiltration are examples. This has allowed for the development of additional PDMPs (11). Figure 1 shows an example of the diseases and the estimated number of patients in the US and Europe who need treatments with PDMPs (13-22).

Figure 1 Patients treated with PDMP in the US and Europe. PDMP, plasma-derived medicinal product; US, United States.

The origins of plasmapheresis

The demand for plasma for further manufacture into albumin and Ig led to plasmapheresis. Recovered plasma from whole blood donations could not meet the PDMP demand, although it continued to be utilized and became more available with the rise of component therapy in the 1970s. This led to a high percentage of whole blood collections being processed into red cells with plasma left over for either transfusion or further manufacturing.

The same innovation that allowed the development of component therapy was instrumental in the development of plasmapheresis to collect SP for further manufacture into PDMPs. John Jacob Abel was credited with being the first to use the word “plasmapheresis” in 1914 and it is derived from the Greek verb αφαιρώ (afairó), meaning ‘to withdraw’ (23). As described in a 1952 article by Dr. J. A. Grifols-Lucas, a donor’s whole blood is collected in glass bottle containing a mixture of acid-citrate-dextrose. The whole blood is centrifuged and refrigerated. The donor returns the following week for a second donation and the packed cells from the prior donation are returned (24). Later that decade, plastic bags replaced glass bottles for the collection of whole blood and plasma (25). This improvement allowed the bags to be readily centrifuged allowing components for transfusion as well as plasma separation. As a result, SP collection centers proliferated. In some cases, the manufacturers established plasma collection centers, but until consolidation in the industry in the late 1990s, independent companies predominated in the collection activities. These companies contracted with the PDMP manufacturers to sell their SP.

Unfortunately, manual plasmapheresis using plastic bags was both uncomfortable for donors and entailed greater risks than blood donation. Plasmapheresis involved the collection of a bag of whole blood which was removed and taken to a laboratory in the plasma center for centrifugation. While the centrifugation process was ongoing, the donor was infused with saline. The process was repeated so that plasma from two whole blood donations constituted the typical 500–600 mL donation. The plasma was retained, and the red cells were returned to the donor. However, if there were multiple people donating, there was a risk of infusing the red cells into the wrong donor. This safety issue could result in a serious transfusion reaction (i.e., hemolytic or infection) if the red cells were re-infused into a different donor from the one from whom they were collected. Despite efforts to prevent these errors, instances of renal failure, serious complications, and deaths occurred, albeit rarely. Even if the red cells given to the wrong donor were ABO-compatible, other transfusion reactions, such as hepatitis transmissions, were possible (26,27). In addition, the saline infusion was uncomfortable for many donors, and the procedure could take a long time.

The development of automated plasmapheresis was, therefore, a major advance in both the donor experience and the safety of the procedure. The procedure involved continuous collection and centrifugation, allowing for a more rapid procedure. Since the donor was connected to the device, only his or her own red cells could be reinfused (28). In the early 1970s, Haemonetics Corporation (Boston, MA, USA) developed a device using a collection bowl that spun at an appropriate speed. When the red cells filled the bowl, the device stopped collecting and returned the red cells to the donor. The bowl had been invented by Alan Latham and Edwin Cohn. Refinement of this technology continued to the present time. Fenwal Automated Systems, then a unit of Baxter Healthcare Corporation (Deerfield, IL, USA), introduced technology initially known as the Autopheresis-C system that used a reservoir that was centrifuged, collecting the plasma and returning the red cells to the donor. Today, an instrument that has evolved from the Autopheresis-C is manufactured by Fresenius Kabi (Lake Zurich, IL, USA) (29). By the early 1990’s virtually the entire collection industry had converted to automated collection. The volumes for collection were based on a nomogram from a 1992 US Food and Drug Administration (FDA) memorandum that established three collection volumes (up to 880 mL) based on the weight of the donor (30).

In 2023, a third device called the RIKA Plasma Donation System was introduced by Terumo BCT Inc. (Lakewood, CO, USA). This system used a separation chamber as the device centrifuge spins (31). It had its origins in a device initially developed by IBM (Armonk, NY, USA) and the National Cancer Institute for white cell collections. Around the same time, plasmapheresis collection systems were approved for an individualized continuous nomogram to replace the 1992 nomogram of the FDA, after Haemonetics published the initial study showing safety of the system. Instead of the three different collection volumes, the volume collected is continuously extracted from a specific donor’s estimated plasma volume based on weight, height, and hematocrit with the goal of collecting the same percentage of plasma volume from each donor (28.5% based on the mean collection percentage on the original FDA nomogram) with a maximum generally of 1,000 mL (32). This is anticipated to be a further advance in donor comfort and safety and the efficiency of the collection process.

PDMPs beyond albumin and IG

Until 1965, PDMPs were limited to albumin for IV administration and Ig for IM administration. Judith Pool’s discovery that allowing frozen plasma to slowly thaw overnight at 4 ℃ would result in a concentrate of human factor VIII resulted in specific therapy for hemophilia patients (33). However, the ideal of home therapy to spare patients from visits to emergency departments with every bleed was difficult to achieve with the blood bank product. The plasma industry soon introduced an initial cryoprecipitation step into the processing of frozen plasma for further manufacturing that resulted in a factor VIII concentrate that could be easily stored at home and infused as needed initially for bleeds and subsequently for prophylaxis. By the late 1970s, the demand for this product exceeded supply, thus making clotting factor VIII concentrates the driver of the volume of plasma needed for further manufacturing. The quality of life for the patient was so greatly improved that the known transmission of hepatitis (mostly non-A, non-B, since donors were tested for hepatitis B surface antigen) was considered an acceptable risk. This changed after human immunodeficiency virus (HIV) transmission from these products was identified in 1983 and resulted in a drive to supplant plasma-derived factor VIII with recombinant products which prevailed from the mid-1990s until non-replacement therapy became available. Factor IX concentrates were also developed from cryo-precipitate poor-plasma (10). However, demand for plasma for further fractionation continued to increase with the development of safe IVIg products and shortly thereafter subcutaneous Ig products. The era of Ig dominance of the plasma industry remains to this day.

A second significant new product was developed around the same time as the clotting factor concentrates known as Rh Ig. Rh Ig, or anti-D, was administered to women to prevent the sensitization that could result in hemolytic disease of the newborn in subsequent pregnancies (34,35). While anti-D is not the only antibody that can cause this disease, it is the most common due to the potency of the antibody and the frequency of Rh-negative women in white and black communities. Given the morbidity and mortality associated with hemolytic disease of the newborn and the cost of treatment, this was a very significant development to ensure safe outcomes for mother and baby. This was also a significant development in the link between plasmapheresis and PDMPs, as plasma from specific donors with the antibody was required. Initially women who had been sensitized were the donors, but as their numbers dwindled due to the success of Rh Ig treatment, there was a need for Rh-negative donors who were sensitized by mini doses of Rh-positive cells. This required collection of cells from blood donors who were Rh positive. The cells were frozen and then matched to ensure immunization without causing development of other clinically significant antibodies, such as Kell, Duffy, and Kidd (36). Specialty plasmapheresis centers with laboratory support were needed. Regulation by the US FDA assured the safety of the procedure for the donors. This activity was largely limited to the US, although pheresis of donors with pre-existing anti-D who were sensitized only by pregnancy or transfusion was utilized in other countries.

In the years that followed, scientists associated with research institutes and/or the companies producing PDMPs in the US and Europe developed additional products from the base fractionation of human plasma. These proteins are described in Figure 2 (37).

Figure 2 The cold ethanol fractionation process for plasma (Cohn method 6) with the fractions indicated that are the source of various therapeutic proteins. Proteins that are recovered from the cryosupernatant and Supernatant I fractions require specific adsorption using chromatographic resins (denoted by *). Adapted from Fig 22.1 in Brinkman N, McCann K, Gooch B. The purification of plasma proteins for therapeutic use. In: Simon TL, Gehrie E, McCullough J, et al., editors. Rossi’s principles of transfusion medicine. 6th ed. Chichester: Wiley Blackwell; 2022:218. Used with permission from John Wiley & Sons Ltd.

To the extent that plasma is utilized for some of these specialty products, there is potential not only to provide clinical benefit, but also to reduce the cost to recipients of albumin and Ig. In the pharmaceutical world, as demonstrated in Figure 3, PDMPs have a higher-than-usual cost for starting material, estimated to be approximately 68%, compared to 14% for traditional pharmaceuticals, and a long timeline from starting material to final product, estimated to be about nine to 12 months in most cases (38). Thus, the more products obtained from a liter of plasma, the more the cost of starting material and base fractionation can be shared among more products. In the world of PDMPs, the typical benefit of volume in manufacturing rarely applies.

Figure 3 Complex manufacturing of PDMP. PDMP, plasma-derived medicinal product.

The achievement of greater safety for donors and PDMPs

From 1985 to the present, industry has moved aggressively to achieve greater safety for donors and PDMPs. There have been two areas in which efforts have focused: the plasmapheresis process and the manufacturing process.

Since the US provided most of the plasma for further manufacture, many of the changes were concentrated there. The system for blood collection in the US had been fragmented since the Second World War. Europe had always been guided by a strong preference for unpaid donor collections, but the US had a hybrid system in which plasma donations were paid and FDA regulations allowed more frequent and higher volume donations on an annual basis compared to whole blood collections (39). There were commercial blood banks that paid donors, community blood centers that used a replacement requirement that required recipients to provide donors or pay a non-replacement fee utilizing a national blood exchange, and the ARC and some blood centers that used a voluntary, unpaid system. In the 1970’s the US federal government organized a push towards volunteer, unpaid blood donations with a regional system, although plasma collection was not included.

The plasma industry began moving towards industry-promulgating voluntary changes in the early 1970s. In 1971, the American Blood Resources Association (ABRA) served as the trade association for the US private sector plasma collection industry headquartered in Memphis, Tennessee. ABRA first established voluntary guidelines which paved the way for decades of safety (C. Izzi, personal communication, August 21, 2025). By 1978, ABRA opened offices in Annapolis, Maryland, and expanded to represent both collector and manufacturer interests, becoming a respected voice among regulators and policy makers. In the early 1990s, ABRA initiated the quality plasma program (QPP) which required adherence by its members. Notably, in 1993, the National Donor Deferral Registry was initiated, which was a database for donors who were permanently prohibited from donating plasma due to reactive testing for HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Concurrently, the International Plasma Products Industry Association (IPPIA) and the European Association of the Plasma Products Industry (EAPPI) were formed to focus on international and European challenges as the demand for targeted, international representation of the plasma industry emerged. In 2000, IPPIA and EAPPI merged to form PPTA. By 2002, ABRA merged with PPTA to form one global voice for the industry, focusing on access to PDMPs, favorable reimbursement practices, quality standards, raising awareness on plasma donation and PDMPs, and other global issues. The QPP rebranded to include International Quality Plasma Program (IQPP) for plasma collectors, and the Quality Standards of Excellence, Assurance and Leadership (QSEAL) were implemented for the manufacturing portion of the business.

Several new IQPP Standards that increased donation and product safety were created (40). First was the qualified donor standard which required two units with acceptable testing within a 6-month period before the donor’s plasma could be used for injectable product, the viral marker standard which requires viral marker data for HIV, HBV, and HCV to be tracked and trended to have rates below a cut-off and the requirement for nucleic acid amplification testing (NAT), and the Cross Donation Management System which notified companies if an individual attempted to donate outside of the US Federal Regulations (not less than two days apart or more frequently than twice in a seven day period) (41). Over the next decade, other IQPP and QSEAL standards were created including the community-based donor standard eliminating transient individuals as donors, the inventory hold standard initially for 60 days that delayed pooling of a donor’s plasma until no unacceptable history or test results appeared in prior 60 days, the donor education standard that assured donors understood the qualifications, and the quality standard for operations in a suitable facility. Later a fluid replacement standard and a donor adverse event standard were added for additional donor safety. An industry study in the late 1990s showed that the addition of the qualified donor standard and inventory hold resulted in a residual risk of a pathogen from plasma from paid donors that was similar to the risk from volunteer blood center donors (42). By 2014, models were calculated to define the process limits for epidemiological data based on margin of virus safety for final products (43). The inventory hold standard was recently updated, reduced from a 60-day hold to a 45-day hold, when NAT became available, reducing the window period (i.e., the period between infection occurrence and a test becoming positive) that existed with serology testing alone. IQPP standards are reviewed periodically and updates are shared for public input. All changes made to existing IQPP standards, or the development of new IQPP standards, are done by consensus.

Even more dramatic in enhancing PDMP safety were the development of specific pathogen reduction strategies in manufacturing. The ability to apply pasteurization to factor VIII concentrates and use of enhanced purification and solvent detergent methods had eliminated the risk of HIV, HBV, and HCV from factor VIII and IX products by 1987. Ig products have always been considered safe largely due to antibodies in the product neutralizing any risk, but the second-generation testing for HCV antibodies in the early 1990s led to some breakthrough infections with HCV in Ig recipients. Therefore, the pathogen reduction technologies were applied to these products, rendering them safe from HIV, HBV, and HCV by 1994 (44). In the late 1990’s breakthrough infections with hepatitis A virus (HAV) occurred in some hemophilia patients who were treated with solvent-detergent pathogen reduced products, which did not act on non-enveloped viruses such as HAV and parvovirus (45,46). NAT for HAV and parvovirus soon reduced this risk as well. Addition of virus removal by virus (or nano) filtration and the use of two orthogonal risk reduction methods in all but a few products further achieved high degrees of safety that characterize PDMPs today. Currently in use, the virus inactivation methods include the classical pasteurization, dry heat (80 ℃ for 72 hours or 100 ℃ for 30 minutes), vapor heat, solvent-detergent treatment, such as Tween 80, octanoic acid (caprylate) treatment, low pH, and ultraviolet irradiation. In addition to dedicated virus removal by virus filtration or nanofiltration, some protein purification steps contribute to virus removal along with chromatography (47). While transmission is theoretically possible and there are lingering concerns about emerging viruses, to date the current processes have been demonstrated to be effective against every new virus of concern. Prion safety has also been achieved by these multiple manufacturing steps (38).

Conclusions

This historical review provides essential context for understanding the current landscape of plasma collection and manufacturing of PDMPs. Modern collection practices, such as the use of automated plasmapheresis devices, donor qualification standards, and pathogen-reduction methods, did not develop in isolation but emerged in response to scientific discoveries, evolving therapeutic needs, and the experience gained from managing transfusion-transmitted infections. Challenges do remain for the future. One is to develop methods to extract proteins for clinical use that are more efficient and cost-effective than the current fractionation procedures. This should help bring down the cost to patients. A second one is to isolate additional components of plasma with clinical potential and conduct clinical trials to gain regulatory approval. This would be another step in potential cost reductions to payers, since the more products that are produced from a liter of plasma, the more the cost of fractionation can be spread out among multiple products. A third challenge is to have greater global acceptance of the paradigm for plasma collections in the US that has resulted in the US providing approximately 70% of the plasma used to produce PDMP globally (48). This should be accompanied by ever increasing efforts to make these essential products more available throughout the world.

We believe that this is the first historical review using information and documents from the global trade group of collectors and manufacturers of PDMPs. However, a limitation is that a systematic review of literature was not conducted.

In conclusion, the journey from Cohn’s fractionation of plasma to achieve a safe and effective albumin product to the current array of PDMPs from SP collected by newer and safer plasmapheresis methods has demonstrated the strength of the industry in responding to changing clinical needs and safety challenges. Hopefully, technological advances in the future will continue that journey to achieve even safer and effective collection methods for donors and PDMP therapies for greater numbers of patients.

Acknowledgments

The authors would like to acknowledge the support of Rachel Liebe at PPTA for her assistance in designing the figures in this manuscript.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Jan Hartmann) for the series “Source Plasma” published in Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-42/prf

Funding: This study was supported by the Plasma Protein Therapeutics Association.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-42/coif). The series “Source Plasma” was commissioned by the editorial office without any funding or sponsorship. M.F. is an employee of PPTA. T.S. serves as a paid consultant to PPTA since January 2024 and as an employee of CSL Behring prior to retirement in January 2024. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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