Securing commitment and control for the supply of plasma derivatives for public health systems. I: A short review of the global landscape

Abstract

The social market economies of the Western world considered the provision of plasma derivatives produced from publicly owned blood services as a legitimate state commitment and, until the last decades of the 20th century, many of the relevant jurisdictions maintained state‐supported fractionation plants to convert publicly collected plasma into products for the public health system. This situation started to change in the 1990s, because of several converging factors, and currently, publicly owned/subsidized, not‐for‐profit fractionation activity has shrunk to a handful of players. However, the collection of plasma from publicly owned blood services has continued and recent developments have increased the interest of state authorities globally to increase the volume of plasma collected to increase the level of strategic independence in the supply of crucial plasma‐derived medicines from commercial market pressures, particularly the global for‐profit fractionation sector with its dominance of source plasma from paid donors in the United States. This paper reviews the development of the plasma industry and the evolution of the pressures on the supply of plasma, which has led to a situation of scarcity of key plasma‐derived medicinal products (PDMPs).

Highlights.

• In the Western world, increasing demands for plasma‐derived medicinal products (PDMPs), particularly immunoglobulin, have increased the dependence of public health authorities on products sourced from commercial players in the United States.

• Part or all of this dependence can be offset by publicly collected plasma, which may be converted into PDMPs under contracts that return the products to the public health system.

• Achieving strategic independence in PDMPs can result in economic benefits and protects the supply of these products from the vagaries of the commercial market.

BRIEF HISTORY OF THE PLASMA INDUSTRY

Modern plasma fractionation has its inception in the work of Edwin Cohn and his group in Harvard University during the 1920s–1930s [1]. Cohn's process described eight separate potential therapeutics [2]. Albumin solutions were tested to treat the first patients in December 1941 [3]. Cohn controlled pharmaceutical manufacture through patents ensuring specification and quality [4]. After the war, most of the companies exited what was perceived as an unprofitable field [5, 6].

Demand for albumin reignited commercial interest by the early 1950s [4]. In the United States, the raw material base of paid donors was accessed by the fractionators. The industry evolved to a global presence and continues to depend on these donors. Cohn's method, as well as its variants [7], remains the main manufacturing process for albumin, although immunoglobulin (IG) is now the major plasma therapy in developed countries.

In tandem with the commercial industry, a number of fractionation facilities operating on a not‐for‐profit (NFP) basis started operations in Europe and parts of the English‐speaking world. The history of some of these agencies has been described [6]. These facilities drew on the voluntary blood donor sector for procuring plasma recovered from whole blood donations, while the commercial sector increasingly used plasma from apheresis procedures. The NFP sector operated arrangements ranging from competition with the commercial sector to monopolistic arrangements. These national plants started to come under increasing financial and regulatory pressures from the 1990s onwards. Most had lacked the necessary investment to ensure regulatory compliance as this evolved to include oversight of plasma‐derived medicinal products (PDMPs). This lack of investment led to the closure or commercialization of most of these plants. In some countries, blood and plasma public collectors moved to contract fractionation arrangements [8], or to sell their plasma [9]. In countries where former public/NFP plants have been privatized, the public collectors have mostly continued their relationship with the new entity. Today, public/NFP fractionation is limited to these companies included in the International Plasma and Fractionation Association (IPFA).

IPFA also represents several NFP plasma collectors. These have evolved since the inception of blood banking, with the supply of plasma for fractionation becoming a late addition to their operations. While some are funded directly by the state, others recover their costs through sales to hospital blood centres. These organizations face considerable challenges in supplying plasma in sufficient volumes compared with the for‐profit sector, whose vertically integrated plasma collection activities can achieve considerable relative efficiencies. The availability of a large population of paid donors, the exemption of source plasma from some of the safety measures required for recovered plasma collection, such as screening for certain pathogens [10], and the continuous introduction of non‐specific deferral measures for blood donors but not for source plasma donors all impede the efforts of public collectors. In certain jurisdictions, some NFP collectors have adopted measures historically associated with the private sector, for example, through agreements with their fractionator to collect plasma from paid donors to augment supply within their jurisdiction [11]. Measures to incentivize the voluntary donor base are also under review [12].

Some public collectors attain higher than average volumes of plasma collection when compared with the rest of the public NFP sector, for example, the Czech public hospital system generates 22 L/10³ population, compared with the European Union average of 10 litres of publicly collected plasma/10³ population [13], while Australia's pubic collector achieves 31.2 L/10³ population [14]. Although this is the world's leading public plasma collection rate, Australia still needs to augment the national supply with imported IG, due to the continuous increase in demand in this and other countries. In 2022, IG sales comprised 60% of the total 30.3 billion USD market of PDMPs compared with 20% in 1996 when the total market was only at 4.8 billion USD [15]. While some of this growth is due to price increases per gram of IG, estimates indicate that since 2022, growth by volume of product generated has been approximately 8%, while growth in the total value has been 8.1%, suggesting that growth is being driven more by volume than by price [16, 17].

A number of reviews on the factors contributing to IG demand are available [18, 19]. The frequent attribution of non‐evidence‐based ‘off‐label’ use is unlikely to be a factor in Australia, where a governance infrastructure‐based Level 1 clinical evidence indication ensures appropriate use [20]. Work on the latent therapeutic demand (LTD) for IG in such uncontroversial Level 1 indications suggests that the LTD for these approaches 230 g/10³ population [21, 22]. In addition, the potential demand arising from immunodeficiency resulting from the treatment of blood cancers is expected to continue and grow in the near future. The use of antibiotics in secondary immunodeficiency [23] and the possible use of alternative modalities for neuropathies [24] may assist in managing the intrinsically limited IG supply in the future.

ACCESSING RAW MATERIAL

The most recent data indicate that approximately 72 million litres of plasma was harvested from the US paid donor source sector in 2023 [15]. This donor population can donate legally a maximum volume of plasma of 1 L twice weekly, a limit imposed by the US Food and Drug Administration (FDA) [25], although most donors donate at lower frequencies. The number of US paid donors is estimated at around 3 million [26]. In Europe, paid plasma donation in Germany has a legal maximum of 60 donations yearly, but 70% of donors donate less than 20 times yearly [27]. High donation frequencies lead to depletion of IgG [28], with an uncertain effect on donor health [29]. Further clinical studies are called for [30, 31]. US studies conclude that monetary compensation is the primary motivator for these donors [32] who are drawn mostly from lower socio‐economic groups [33] and use the payment for donation to offset debts incurred for living expenses [26]. Approximately two‐thirds of the global supply of PDMPs is extracted from this donor population.

Plasma recovered as a by‐product from whole blood forms the main contributor from the public/NFP sector globally, although apheresis collection is growing. Because of the limitations in donation frequency and collection volume, the volumes collected are much lower than those collected by the source sector (Figure 1). Conversely, this recovered plasma contains higher amounts of IG than source plasma [28]. Hence recovered plasma finds ready buyers in the open market for plasma. Its dual identity as a transfusable component and a raw material for fractionation makes the management of this material complex. In the United States, it is not licensed for transfusion, but is overseen through short supply agreements, which include quality requirements [25].

FIGURE 1.

Global volumes of plasma used for fractionation (litres × 10³), supplied by the Marketing Research Bureau, with permission.

ECONOMICS OF THE INDUSTRY

The fractionation process' ability to yield several potentially therapeutic proteins has underpinned its economics. For the first decades, albumin remained the main product extracted from plasma, determining the volume of plasma that needed to be collected. Albumin was the first plasma ‘driver’. Fractions rich in other proteins were also extracted by accessing other portions of the fractionation scheme and became increasingly important in bolstering industry revenue. In the 1960s, the exploitation of cryoprecipitation of freshly frozen plasma allowed the preparation of the first widely available concentrates of FVIII, improving greatly haemophilia A treatment. FVIII became the second driver. A number of modifications to the fractionation scheme allowed the purification of IG solutions, which could be administered intravenously, leading IG to become the third plasma driver in the 1980s. Concurrently, the demand for FVIII declined as recombinant factors became available. Demand for albumin continued, particularly in emerging markets such as China, although its traditional use has eroded and other, less prevalent, conditions have been explored [34].

The economics of the industry has also drawn on the concept of ‘first‐ and last‐litre’ economics. The eventual saturation of need for more niche products (currently represented by anti‐haemophilic factors, other proteins such as alpha one antitrypsin, C1 inhibitor and others)—‘first‐litre’ products—by an initial proportion of collections is such that once need is met, additional plasma is used only for production of high‐demand—‘last‐litre’—products. Thus, all the plasma collected, to the very last litre, is fractionated into IG, which is a ‘last‐litre’ product. For much of its history, albumin was also a last‐litre product. In the era when it was the dominant modality for treating haemophilia A, FVIII was a last‐litre product. This ‘First–Last litre’ concept is shown in fig. 2 from Reference [35]. Clearly, the first litres fractionated generate the most products and the highest revenue per litre fractionated. As the volume of plasma fractionated increases, less of the ‘first‐litre’ products are harvested, until the ‘last litre’ is reached. Using this concept, it is proposed that the extraction of all the IG from the available plasma is able to offset all the raw material and fractionation costs, and generate a small profit [35]. Any additional margin depends on the generation of saleable ‘early‐litre’ proteins. Albumin's position in this hierarchy has diminished over the years, with 76% of collected plasma being processed to albumin in 2010 shrinking to 56% in 2022 [36] (estimated from the reports of the Market Research Bureau) (Figure 2).

FIGURE 2.

Plasma industry economics viewed as ‘First’ and ‘Last’ litres fractionated. From ‘Production of Plasma Proteins for Therapeutic Use’ Ch 33 fig. 33.1. Wiley 2012. ISBN‐13: 9781118356791. FIX, FIX concentrate; FVIII, FVIII concentrate; GM, gross margin, HSA, human [serum] albumin; IgG, immunoglobulin.

IG is now the driver protein and, arguably, the sole remaining ‘last‐litre’ protein. The increasing dependence of the industry's economic fundamentals on IG influences the product's price. While one study [37] proposes that IG prices were stable during 2010–2017, prices during and after the COVID‐19 pandemic rose sharply, as the cost of plasma in the United States rose with the drop in donations [38]. The IG price varies between different geographies, and the companies strive for market approval in the highly priced US market first and foremost. As more ‘first‐litre’ products fade into insignificance, companies have attempted to source other proteins to generate more revenue per litre of plasma. These have included attempts at resurrecting previously redundant products such as fibrinogen, proposed for several acquired deficiencies despite a moderate evidence base [39], and prothrombin complex concentrates, proposed for a range of indications with, again, moderate clinical evidence [40]. High‐value proteins such as alpha 1 antitrypsin generate revenue for companies that have the product, although sales have not matched the levels expected by the disease's prevalence. The industry needs to continue to collect increasing volumes of plasma to, increasingly, satisfy the market for one protein. It is likely that the price of IG will have to rise further to cover the costs of plasma procurement and fractionation [41]. The industry is already characterized by a high cost of goods sold (COGS) (Table 1) [42] and continues to seek other proteins. As an example, the recent failure to demonstrate efficacy by an intravenous formulation of human apoA‐I, [43], following many years of pre‐clinical and clinical development, led to its abandonment as a commercial proposition [44]. This demonstrates the difficulties faced in trying to expand the range of therapeutic proteins from plasma. The difficulties for NFP agencies, unable to invest to the same level as the commercial sector, are commensurately bigger. These include the cost of the required research and development to develop a therapeutic hypothesis, the progression, through pre‐clinical and staged clinical phases, to a safe product capable of being tested for safety and efficacy in successive populations of patients, the required conformance to regulatory requirements and other requirements all posing formidable barriers for companies. It is also pertinent to reiterate the possible development of non‐plasma‐based alternatives, usually manufactured at lower costs than plasma‐derived proteins, for example, the bi‐specific monoclonal antibody emicuzimab has, within a short time span, practically obliterated the market for plasma‐derived FVIII, as well as other recombinant formulations [45], while other non‐plasma‐derived alternatives form part of the product range of companies also offering plasma‐derived equivalents, for example, anti‐haemophilic concentrates. While some NFP plasma companies have managed to enter the recombinant space [46], the factors listed above militate strongly to prevent these agencies, and other small companies still in the commercial sector, from developing significant commercial prospects using these technologies.

TABLE 1.

COGS as a percentage of revenue for all five manufacturers between 2019 and 2022.

Fractionator	2019 (%)	2020 (%)	2021 (%)	2022 (%)
A	54.1	57.8	60.9	63.2
B	69.3	73.1	84.3	77.1
C	75.7	76.5	78.2	80.0
D	43.8	43.1	44.1	52.3
E	64.6	64.9	67.8	70.0

Note: Extracted from Marketing Research Bureau Report titled ‘Plasma Fractionation: Benchmarking, Analysis & Trends. 2023’.

A NOTE ON THE PLASMA VALUE CHAIN

These economic factors may be illustrated by the value chain for plasma in the process of PDMP manufacture (Figure 3). Associated with each element in the figure are a number of factors that require inclusion in generating the chain. Many of these factors pose challenges for the industry, particularly for the NFP sector as discussed above. The formation of a stable and safe donor base for plasma generation is less costly for the vertically integrated source plasma sector than in the blood/plasma collection centres of many publicly funded blood systems, with limited ability to offer donor incentives and to generate cost‐savings through economies of scale, especially in the heavily decentralized systems of many European jurisdictions. The additional donor screening and testing requirements for recovered plasma also impose further limitations relative to the source plasma sector. The specific safety requirements required by regulatory authorities and the commercial industry's own standards [47] impose further barriers. Some of these industry standards, such as donor qualification for viral status, have been adopted by some parts of the public collection system, for example, in Italy [48], but most are difficult to implement and maintain in public blood services that provide a range of components compared with only plasma for fractionation from the source plasma sector. In particular, the 60‐day inventory hold period for frozen plasma prior to progression to fractionation is challenging for services providing components with short shelf lives from the same donations of whole blood. Some of the difficulties faced by the NFP sector should be offset by the higher intrinsic value of recovered plasma and plasma from low‐frequency plasmapheresis, which contain higher concentrations of IG, and therefore results in a substantially higher yield of IG in the final product than from high‐frequency‐donated source plasma [28]. This is not recognized in the value of plasma sold on the open market, where source plasma still attracts higher prices [38] (Table 2).

FIGURE 3.

The plasma value chain and its cost structure. PDMPS, plasma‐derived medicinal products.

TABLE 2.

Market price of plasma sold on the open market.

Type of plasma	Price	2021	2022	2023	2024
Source	$US	198	229	219	201
	Euro	139	168	158	160
Recovered	$US	135–142	152	189	192
	Euro	125	155	158	155

Note: Extracted from The International Blood and Plasma News (Market Research Bureau) Issues March 2021, March 2023 and February 2024.

Fractionation of the plasma, released for manufacture after these requirements are met, demands the establishment of capital‐intensive fractionation plants, subject to the additional formidable phalanx of regulatory requirements and the development of an infrastructure for product approval and marketing. All these factors have influenced the consolidation of the industry, as well as the quasi‐extinction of NFP fractionation activity, at least in the Western countries. A number of fractionation projects have been proposed outside these geographies, few of which have come to fruition, although the lower costs associated with construction and labour has probably enhanced the probability of success in the ventures described for Thailand [49], and a nascent endeavour in Indonesia [50].

All costs must be recovered through sales, and a return on investment needs to be achieved for whichever entity, whether private or public, for re‐investment in facility maintenance and research and development. The evolution of IG as the dominant product in assuring the industry's economic viability has been discussed. Companies strive primarily to supply IG in the United States, and to sell albumin generated as a by‐product from the plasma fractionated to IG, most importantly in China. Factors that can increase the supply of IG, apart from increasing plasma collection, include modifying the original Cohn fractionation chemistry to improve the IG yield, measures that require investment and clinical development [51]. Albumin is still produced, in most plants, using purification of Cohn Fraction V, achieving yields that are more than adequate to satisfy the global need. The evidence base for albumin is still debated, and usage in the Western economies for the historical indications associated with acute blood loss has been significantly diminished. Newly proposed indications around a number of hepatologies still seek high‐level evidence [52]. The continued absorption of albumin, generated from US plasma and surplus to Western needs, by the Chinese market is an important component of the industry's viability, and the possible scrutiny of the poorly evidenced indications for most of the albumin use in China [53] should be kept in mind. Similar scrutiny in the United States and European Union, reflected in the relevant clinical guidelines, has diminished significantly albumin demand in these geographies.

We summarize the status of the industry's economics as being increasingly dependent on selling IG, generating a surplus of albumin that is largely absorbed in China. The industry's success in generating additional revenue by accessing other proteins has been modest, especially for companies that have not diversified their assets through investing in non‐plasma‐based therapies. The increasing costs of generating high‐quality plasma for fractionation and the substantial investments needed to establish and maintain fractionation plants pose formidable challenges for agencies seeking to maintain a presence in the industry, contributing to the consolidation, still ongoing [54], of the past 30 years.

RISKS FACING PUBLIC SYSTEMS

The continued dependence on IG sourced predominantly from the companies of the US commercial sector poses the risk that any disruption to this supply would have detrimental effects on patients. Such disruptions are not hypothetical. The regulatory compliance problems encountered in the 1990s–2000s by several US fractionation companies [55] had a significant effect on IG supply [56]. Similar shortages were experienced following product recalls due to Creutzfeldt–Jakob disease [57, 58]. These measures date from 25 to 30 years ago, and regulatory science, together with industry compliance, has progressed since then. Irrespective of their merits, it should be noted that the US authorities then contemplated directing IG from Europe to the United States to ameliorate these product shortages [56]. The opinion of their political leaders is reflected from the following intervention by a US legislator, many years before the current era of increasing commercial wars and trade protection:

Exports reduce the amount of immunoglobulin available to (American) patients. Blood and plasma donors provide a precious community resource with the expectation (their donations) will benefit their neighbours and countrymen, particularly in times of shortage. Yet exports of immunoglobulin made from US plasma held constant in 1997, at more than 20% of total production, even as domestic supplies fell by 10%. That is very troubling to many patients, and it is an issue that must be addressed by the manufacturers, regulators, and perhaps by Congress. Representative Christopher Shays, US Congress, 7 May, 1998 [59].

This risk may be ameliorated through contract fractionation type arrangements [8] between fractionators and public/NFP collectors, firmly committing plasma supplied by the latter to the provision of PDMPs channelled to public health facilities. Supply can only be assured through such arrangements, as the simple sale of publicly collected plasma to fractionators, whether sited within or outside the borders of the collecting country, is no guarantee to adequate provision of PDMPs from such domestic plasma, as will be discussed below.

A further risk to supply will ensue if the donor base is not sustainable. This is especially important in crisis situations, such as the COVID‐19 pandemic. By comparing the plasma supply before and during the pandemic, a recent study measured supply resilience across the private sector (donors are effectively remunerated) and public sector (non‐remuneration). Results showed that the plasma supply collected through the private sector decreased more drastically than the plasma supply collected through the public sector [60].

In addition to the risk to supply, the possible effects of product price increases merit consideration. It is an established practice for companies to allocate product based on the price attainable, sometimes irrespective of contractual arrangements under tenders. Several companies have withdrawn from a number of countries in the past years, on the basis of corporate profitability [61]. In addition, increased prices for commercially available IG put a strain on health care budgets, as exemplified by the increase of 43% of publicly tendered IG in Sweden over 2019–2024 [62]. In Italy, reimbursement of IG products is now at a historic high, and has doubled over the past 10 years [63].

Collaborative agreements for contract manufacture can blunt these price pressures on health care budgets. As an example, the 20 Italian regions, which collected publicly donated plasma through their health authorities, have formed four separate consortia [64] in order to generate a critical mass of plasma for fractionation. Each consortium requests offers for fractionation services for its plasma through public tender. The consortium pays for the manufacture of products for the plasma according to an agreed schedule, to whichever company wins the tender. This system has led to all the major fractionators being present in Italy through these contracts, generating products for the individual consortium, which, however, can be supplied to other consortia in the event of shortages. The Italian Blood Centre, which monitors and coordinates this activity, reports to the Italian Health Ministry on the outcomes attained across the country. Using data extracted from its data collecting activity [65], the Italian National Blood Centre has derived the following data extracted from [65] for the outcomes from this system for 2022:

1. Market value of all PDMPS produced by contract fractionation = 339,746,130 Euro.

2. Cost of all the four contract fractionation agreements for 2022 = 98,082,249 Euro.

3. Costs of plasma collection = 100,260,951 Euro.

Savings = [1] − [2] − [3] = 141,402,930 Euro.

As a converse example, in the Czech Republic (CR), 21.1 L/10³ population of plasma collected by public hospitals and 58.8 L/10³ collected by private establishments are all sold to fractionation companies outside the CR, without any apparent arrangement to provide products from this plasma to the Czech Health system [66]. Despite producing enough publicly collected plasma to cover the national usage of IG in 2021, the CR still experienced a shortage of IG during this period [67, 68] (statement by Rehacek in [66]). This suggests that a need exists to link the provision of plasma to fractionators with the provision of PDMPs to the public health system. Statements about the CR's self‐sufficiency in plasma [69, 70] are incomplete without the recognition that usage of IG in the CR is well below the EU average (Figure 4), and below the LTD for evidence‐based indications [22]. We note that during the COVID‐19 pandemic, the CR authorities considered mandating a commitment from the fractionation industry to ensure that a certain quantity of IG was available for CR patients before the CR plasma was shipped for conversion to commercial products [71].

FIGURE 4.

European average immunoglobulin consumption by country—2020—g/10³ population. Supplied by the Marketing Research Bureau, with permission.

CONCLUSIONS: THE ROAD TO SUPPLY

This work has described the evaluation of a global system for PDMP provision, which has resulted in the concentration of the industry into a small number of large, multinational companies with vertically integrated plasma collection capacities. Public collection of plasma continues and requires an adequate framework to provide a level of strategic independence and minimize the effect of shortages as a result of commercial vagaries. Increasingly, this has involved shortages and price increases in the supply of IG, the industry's dominant protein and its economic underpinning. An awareness that several such frameworks are in place globally led a group constituted within a Work Package of the Supply Project to assess these frameworks and their position within the national, regional and global supply chains for PDMPs, as described in this work. An accompanying paper describes an exercise to derive the salient features of these frameworks (Vox Sanguinis submitted 2024).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

von Bonsdorff L, Farrugia A, Candura F, O'Leary P, Vesga MA, De Angelis V. Securing commitment and control for the supply of plasma derivatives for public health systems. I: A short review of the global landscape. Vox Sang. 2025;120:114–123.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.