Challenges for Plasma-Derived Medicinal Products Open Access

Plasma-derived medicinal products (PDMPs) are medicinal products derived from human plasma. The plasma is collected from donors at blood establishments and plasma collection centers and their plasma donations can be classified according to the method of collection. Plasma can be “recovered” as a by-product of whole blood processing into cellular components and plasma, or obtained as ‘source’ plasma by apheresis. This latter approach known as plasmapheresis is a process by which during the donation procedure a machine removes the red cells and platelets from whole blood and returns the cells to the donor while retaining the plasma. The allowed source plasma donation frequency per donor and the allowed donation volume per donation/donor are regulated by national authorities and differ per country (see Table 1). Most European blood establishments adhere to the guide of European Directorate for the Quality of Medicines and HealthCare (EDQM) [1].

Human plasma and its fractions and derivatives are used in biomedicine as plasma contains thousands of proteins. These constitute the largest and most diverse set of proteins that the human species can produce, performing a wide range of functions of which some are still unknown. Plasma has different qualities regarding protein content and concentration of clotting factors. The normal albumin level ranges between 35 and 55 g/L. The normal blood level for the clotting factor VIII (FVIII) is 100% with a range of 60–150% according to different factors such as genetic and environmental factors, blood group, disease, and stress response to injury. The normal immunoglobulin (IgG) level ranges between 7 and 16 g/L and the antibody profile depends on race, epidemiology of endogenous diseases, climate, vaccination programs, and prevalence of pathogens in different countries and regions [2]. The absence, deficiency, or dysfunction of a particular plasma protein can impair the homeostasis of the human body and be life threatening or disabling.

Currently, around 30 proteins are suitable for manufacturing to PDMPs. Since PDMPs are medicinal products, the source material for the manufacturing, plasma, needs to be qualified, and the collection process of blood and plasma compliant with Good (Manufacturing) Practices. The fractionation or other techniques used during manufacturing aim at high efficacy and quality, and maximum safety. Being designated as medicinal products, PDMPs are licensed by medicines agencies such as the US-Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of a great number of diseases and disorders. Purified plasma proteins are referred to as “biologicals” or “biological therapeutics.” Biologicals are distinguished from other medicines in that they are generally proteins purified from blood, living culture systems, or transgenic animals, whereas classic medicines are either made synthetically or purified from plants [3]. Because of these differences, biologicals are subject to separate regulations, tests, and controls as well as standard pharmaceutical regulations. The pathogens that may be present in donor blood require that safety is of high interest.

The World Health Organization (WHO) has underlined the importance of PDMPs for global clinical care by listing a number of PDMPs on the WHO Model List of Essential Medicines [4]. Normal IgG for intramuscular, intravenous or subcutaneous use, anti-D IgG, anti-rabies IgG, anti-tetanus IgG, coagulation factor VIII (FVIII), and coagulation factor IX (FIX) is designated as essential medicinal products. For some PDMPs, alternative products are on the market, such as recombinant factor products, monoclonal derived clotting factors, and by-pass products, or alternative treatments with gene therapy. For patients with hemophilia in many countries, these alternatives for plasma-derived FVIII or FIX concentrates are common practice. For specific indications, alternative products for IgG are under research development.

A great number of PDMPs are indicated for rare or orphan diseases as they are used for treatment or prevention of rare clinical conditions which affects no more than 5 out of 10,000 people [5]. This is one of the challenges for the development and availability of PDMPs because rare diseases are neglected conditions whose treatments are often not considered profitable due to the high costs of the development of medicines and the small size of the patient population.

In general, treatments with PDMPs can be divided into four categories: replacement or substitution therapies with products such as pro- and anti-coagulant factor concentrates, polyvalent IgGs, specific or hyper-immune IgGs, albumin, alpha 1-antitrypsin, and C1-esterase inhibitor concentrate; immune-modulating therapies (polyvalent IgG, alpha 1-antitrypsin); anti-inflammatory therapies (polyvalent IgG, anti-thrombin, activated protein C); and therapies directed to plasma protein antagonist functions (prothrombin complex concentrate, activated prothrombin complex concentrate) [6]. These and other PDMPs are crucial for the prophylaxis and treatment of patients with bleeding disorders, immune deficiencies, autoimmune and inflammatory diseases and a variety of congenital deficiency disorders. While for some diseases the products can be lifesaving, for others they are disease mitigating. This matters in particular for high dose polyvalent immunoglobulin for intravenous administration which is also available in a more patient-friendly subcutaneous form (SC-IgG). Immunoglobulin for intravenous administration is manufactured from more than 1,000 donations, has a very broad antibody spectrum, and is essential for the treatment of patients with primary (PID) and secondary immune deficiencies. This product is originally developed for PID patients who while receiving an intramuscular administered IgG could not bear the painful required dose. In a high dose however, intravenous/subcutaneous immunoglobulin (IV/SC-IgG) has immune-modulating and anti-inflammatory therapeutic effects in an increasing number of immunological, neurological, hematological, and dermatological diseases, and many patients diagnosed with these disorders benefit from treatment with this product.

Guidelines recommend the use of IV/SC-IgG in diseases with often unknown pathology where the mechanism of action is mostly unclear or hypothetical. Based on the experiences as effective immunomodulatory medicine, many studies in this type of disease or with new dosage schemes are performed. In most cases, the clinical evidence is not sufficiently shown, for example, because of a not clear diagnosis, confirmation bias, self-limiting nature of the disease, too few patients studied, or retrospective studies. Because of lack of sufficient clinical evidence, the indication or new approaches of treatment cannot be granted by the medicines agencies. However, the publication of these reports does not prevent physicians to prescribe IV/SC-IgG for off-label indications or higher dosages per Kg/body weight because of the absence or lack of alternatives.

The demand for PDMPs is steadily growing driven by global increased access to medical care, new products and indications, more patient-friendly applications, and diagnostic advances. According to data of international patient organizations (IPOPI, AAT) and based on epidemiological studies, many patients around the globe are not yet diagnosed with diseases that require PDMP treatment [7, 8]. The patients depending on PDMPs and collaborating in the Platform of Plasma Protein Users (PLUS) consider more plasma collections and consequently more IgG products as the best option to safeguard their treatment. They prefer IV/SC-IgG above triage or choices for alternative products given the safety profile and low adverse event rate of IV/SC-IG and advocate that patient centered decision making should be included in decisions on sustainable access to safe PDMPs [9].

Prior to the SARS-CoV-2 pandemic, the global IV/SC-IgG demand had growth at rates averaging 8–9% per year. There are, however, significant regional variations in use of IgGs. The comparatively high consumption level in North America stems from longer experience with IV/SC-IgG, safety, efficacy and availability, doctors’ awareness, manufacturers’ promotion, reimbursement of many indications, and off-label use and good reimbursement prices [10]. In low- and middle-income countries, IV/SC-IgG is used mostly for acute medical conditions due to therapy cost and underdiagnosis of PID and other chronic diseases. This pattern is changing because of better diagnosis, product awareness, funding, patient organizations’ influence and improved health care services. Going forward, the consumption will grow faster in the emerging markets than in the most advanced countries which will reach maturity, as the number of new IV/SC-IgG indications dwindles and alternative therapies surface. As a result, more plasma will be needed as raw material for making increased quantities of IV/SC-IgG. In 2021, the WHO has published guidance to support this process [11]. For the near future, a number of challenges can be identified.

The global supply of plasma is dominated by the collection of source plasma in the USA, and the majority of this plasma comes from the US commercial plasma industry which historically has dominated international plasma markets. This plasma provides not only for the PDMPs’ needs of US patients but also for international export. Pre-pandemic of SARS-CoV-2 in 2019, the total collection volume of plasma globally was 69 mL of which 67% originated from the USA. 18% of the plasma source came from Asia-Pacific of which 75% from China. The contribution of Europe was 14%, but Europe is the largest supplier of recovered plasma [12]. Latin America and Africa account for a small proportion of the global plasma supply but have a rapidly growing demand for PDMPs [13]. In high-income countries, the volume of recovered plasma from blood establishments has declined in recent years including during the SARS-CoV-2 pandemic due to less clinical use of red cells following the implementation of patient blood management. Although US source plasma is crucial for meeting increasing international needs, the imbalance of the global supply of plasma and the reliance on a single country or region to supply the bulk of the world’s plasma raises significant concerns and is a challenge for the supply of PDMPs [14]. Because of the SARS-CoV-2 pandemic, the collections in the USA declined with 4–18% and in 2020, the overall volume of collected plasma in the world was 59 mL which is 14.5% less than 2019 [12].

IV/SC-IgG, the most wanted PDMP, is the trigger for the volume of plasma to be collected. There is a delicate balance between plasma supply and the demand for PDMPs and any disruption in supply could devastate vulnerable patient populations such as those with coagulation or immune deficiency disorders. Over three decades, self-sufficiency has been advocated in order to bring plasma supply and PDMP use in balance, and it was defined that blood and plasma collected in a country or region should be used for the production of blood components and PDMPs to be used in that country or region. This concept of self-sufficiency, supported by the WHO, is defined in the preamble of the European Blood Directive stating that in respect of blood and blood components as a starting material of proprietary medicinal products, Member States should take measures to promote Community self-sufficiency in human blood or blood components and to encourage voluntary unpaid donations of blood and blood components [15, 16]. Not defined was which level of self-sufficiency should be aimed at. Neither whether self-sufficiency of PDMPs in the European Union would imply being manufactured from European plasma only and exclusion of products manufactured from non-EU plasma. This approach has not worked out well and the aim has not been reached because the European supply of plasma was never sufficient or could not be guaranteed.

As another approach, it is advocated to put plasma in a special position and consider plasma as a strategic resource. A strategic resource is a material which is critical for a region or a country and which is insufficient through domestic production and/or inability to guarantee supply through importation. It is important to national industries which are dependent on importation, particularly during periods of expanding market demand [14]. The concept of strategic resource is used for other rare resources such as rare metals, energy resources, or drinking water. For example, the imbalance in the supply of gas, a strategically vital energy resource, and the dependency on the gas supply from Russia has resulted in the current worldwide energy crisis and governments are taking drastic measures to balance the supply and demand of gas. A strategic resource emphasizes that a dependency from one country may imply risks on shortages which will harm industries. The origin of the advocacy of plasma as a strategic resource is the imbalance of the global plasma supply and the risk of lack of supply of plasma. The recent strongly reduced supply of plasma from the USA because of the corona crisis has shown that the dependency from one country has impacted indeed the global plasma supply and implicitly the supply of PDMPs worldwide. Besides outside the USA during the COVID pandemic, there was even a bigger concern that the global plasma supply would be affected by the “America first” mantra of the Trump administration and the threat of activation of the US Defence Act which prioritizes the USA. The current supply of plasma and PDMPs is also suffering from military conflicts (the war in Ukraine and the plasma supply in Ukraine), new emerging pathogens (SARS-CoV-2), economic and political factors including commercial consolidation and prioritizing markets (prioritizing albumin for China), changes in demand, and the transfer of medicines from countries with low prices to countries with high prices. For the benefit of patients, disruption of plasma supply should be prevented and strategies should be developed which mitigate the risks of regional and global shortages of PDMPs. The plasma shortage should be addressed by reducing the supply dependency on the USA, and an appropriate balance should be established between domestic supply and importation. It is encouraging that in Europe the European Commission has recognized the critical plasma dependency of Europe from the USA and has granted funds for the Supply Project with the aim to investigate opportunities for increasing the European plasma supply. In the Supply Project, special attention is given to ensure a high level of health protection for donors as well as for recipients and that plasma should be obtained from individuals whose health status is such that no detrimental effects will ensue as a result of the donation. For example, since the half-life of endogenous IgG is around 3 weeks, an interval of less than 3 weeks between two source plasma donations may negatively influence the remaining IgG concentration in the plasma of the donor. This physiological situation sets questions about a too high frequency of donation in relation to the immunological health of the donor and the safety of plasma donation. Solutions will be studied such as expanding of the donor pool in order to reduce the risk on too high frequency donations from the relatively small donor pool.

In order to keep the balance of supply and demand of PDMPs under control and to help the triage when decisions need to be made on lifesaving treatments and disease mitigating use of IV/SC-IgG in times of product shortage, “demand management” plans need to be established [17]. For 2025, it is projected that in Europe 67,368 kg of IgG is needed [18]. Currently, there is no alternative for IgG with the same broad antibody spectrum. Over the last years, countries such as United Kingdom, France, Romania, Cyprus, Greece, Latvia, Lithuania, and Portugal have suffered serious shortages of IV/SC-IgG because of an insufficient supply or supply instability, a reduction of products commissioned, cost containment, selection for the cheapest products only, and withdrawals from market. The shortage of IV/SC-IgG has caused cancellations of treatments and rationing which has affected patients seriously and resulting in deaths in PID patients. Even in countries with a high supply of commercial source plasma (Germany, Czech Republic, Hungary, and USA) shortages of IV/SC-IgG has occurred. In particular, the shortage of IV/SC-IgG in 2019 in the country with the highest plasma supply resulted in questions from the US Senate and the FDA. The concern of the general public was vocalized by critical articles in the Washington Post and Wall Street Journal. Other PDMPs have not encountered similar shortages because either the supply is sufficient or alternative treatments were available to replace the use of PDMP.

Commercial source plasma collection from paid plasma donors is taking place in the USA, Austria, the Czech Republic, Germany, Hungary, Ukraine, and China. For the WHO, voluntary non-remunerated blood donations from low-risk populations remain the foundation of safe, adequate, and sustainable blood supply for transfusion that also can support patient needs for therapies with PDMPs [19]. The donation of whole blood is not reimbursed and the procedure takes about 10 min. For a source plasma donation, the procedure takes around 45–60 min. This difference in time is reason for the commercial plasma collection industry to pay the donor. For reasons of safety and availability of blood and blood products, the WHO, International Red Cross, EDQM and International Society of Blood Transfusion (ISBT) promote voluntary, non-remunerated donation. Many arguments against paying for plasma donation are about the conception that paying for donation can exploit vulnerable people and that blood should not be treated as a commodity but be an altruistic behavior [20]. Target groups for plasma collectors are people from lower socioeconomic classes, students who need money for paying their studies, and in the USA, Mexicans who live across the border with the USA. In Europe, the absolute compensation in Euro’s differs between countries and ranges from 13 to 27 EUROs per donation. In the USA, plasma donations tend to pay between USD 20 and 50 per session, depending on the location. If the different donor compensations are expressed relatively to the median average hourly wage (%) per country, the percentages range from 163% (Austria) to 347% (Czech Republic) (see Table 2). As a consequence of the plasma shortage due to corona pandemic, first time donors in the USA are currently being offered between USD 825 and 1110 for their first eight donations, with returning donor paid an extra USD 15 and 20 depending on the location and demand where they are donating [21]. For some, the payment is a question of definition: compensation, incentivization, reimbursement, payment, or a reward [22]. However, in the proposal for revision of the EU Blood Directive, it is stated that “As a matter of principle, programmes promoting the donation of Substances of Human Origin (SoHOs) should be founded on the principle of voluntary and unpaid donation, altruism of the donor and solidarity between donor and recipient. Voluntary and unpaid SoHO donation is also a factor which can contribute to high safety standards for SoHOs and therefore to the protection of human health. It is also recognized, including by the Council of Europe Committee on Bioethics, that while financial gain should be avoided, it may also be necessary to ensure that donors are not financially disadvantaged by their donation. Thus, compensation to remove any such risk is acceptable but should never constitute an incentive that would cause a donor to be dishonest when giving their medical or behavioral history or to donate more frequently than is allowed, posing risks to their own health and to that of prospective recipients. Such compensation should, therefore, be set by national authorities, at a level appropriate in their Member State to reach such objectives” [23].

Crowding out is defined as buying and selling morally significant goods self-interest into a domain that should be governed by altruism or public spiritedness and that self-interest, once unleased, crowds out these more valuable motivations. When the difference between non-remuneration and payment increases, the risk could occur that altruism will be pushed out when a remunerated system will be introduced [24].

Currently, the US-FDA bans non-US plasma for the products authorized for the US market. This ban prevents EU companies to enter the US market with their own products if manufactured from non-US plasma. The reason was that after the appearance of human immunodeficiency virus in the 1980s resulting in an historic interruption of blood services, the detection of a novel transfusion-transmissible pathogen in the United Kingdom in 1996, a prion causing variant Creutzfeldt-Jakob disease, resulted in termination of all plasma collections in the United Kingdom and Ireland and necessitated plasma importation from the USA to meet UK patient needs [25]. The US-FDA acted to protect US patients by prohibiting US distribution of all PDMPs manufactured from non-US plasma, further amplifying the imbalance in global plasma supplies. While in the UK and Australia, the source plasma collection has restarted, still due to transatlantic regulatory differences on collection practices, donor deferral practices and donor risk assessments, testing processing and viral marker test kit licensing, storage, and distribution standards for source plasma non-US collected plasma and PDMPs is still banned from the USA [26, 27]. Removing acceptance of both origins and removing trade barriers for plasma and PDMPs to make it easier to trade between the two continents would improve the aim of achieving sustainable patient care in the two regions. For plasma as a strategic source it is important that development of a regulatory pathway for USA, regulatory acceptance of source plasma collected in Europe is a top tier priority for Europe.

Over the last three decades, the number of manufactures both in the commercial and the not-for-profit sector has decreased, while the manufacturing of human plasma into PDMPs has evolved into a mature pharmaceutical industry. The scale of operations, the quality of the source material, the collection of plasma, the plasma volumes that are processed and the markets that are being served have increased significantly. The quality of the final products in particular with respect to viral safety has reached a high level. The number of commercial fractionators has been reduced as a result of mergers or take overs and the size of the companies has significantly grown while products are marketed worldwide. Commercial plasma collection centers in the USA and Europe have been integrated into fractionator’s companies in order keep the supply of plasma under control. It is a challenge whether a smaller number of manufacturers will have a positive effect on the supply of plasma and on the demand and the availability of sufficient PDMPs for patient treatments in a growing world market. There is concern that with a small number of manufacturers a risk of a production breakdown might have a significant effect on the PDMP supply. In other industries, a smaller number of manufacturers and thus less competition enhance monopolistic behavior with higher prices, less innovations, and fewer products available. There is also a risk that the companies choose for selected markets with non-introduction and withdrawals in case of governmental decisions. This risk should consider given the experience of the Rumanian IVIG crisis in 2018 when IVIG was withdrawn from market by the companies due to a clawback tax set by government. Most not-for-profit manufacturers are of a smaller size compared to the commercial companies and have a particular focus on and commitment to serve home markets. A challenge for these manufacturers is to achieve a scale of operation sufficiently large to render their business and produce the products at an economically viable level. To achieve such viability, not-for-profit fractionators are specializing in international co-operation and toll manufacturing and are establishing strategic alliances. For all manufacturers, operations cannot be based on a relatively small product portfolio as the increasing cost of a sustainable plasma supply and manufacturing needs to be borne by a broad product base in order to keep the costs under control. Development of new products in addition to new clinical indications for existing products and expanding markets is essential to avoid that the driver of the plasma supply (currently IV/SC-IgG) would become overly expensive. It seems, therefore, clear that for the treatment of patients with rare diseases, a free market of PDMPs has its limitations.

Another challenge regarding the reducing number of manufacturers and the future pricing of PDMPs might be when for patient treatment alternative products for PDMPs will become the products of choice. The main question might be what will happen if the number of products manufactured from plasma will be that small that only IV/SC-IgG will be left as almost the only PDMP to cover the costs of the whole manufacturing chain. The answers are not given yet, but for the increasing costs of treatment of patients, this might be of concern.

The future of treatments with PDMPs for patients with coagulation disorders, immune deficiencies, autoimmune and inflammatory diseases, and other disorders depends on the supply of plasma. The challenges are mainly related on a balanced and sufficient supply in order to help the patients in need. Challenges at different level should be addressed in order to safeguard the treatment with these essential lifesaving and disease mitigating medicines.

The author has not conflicts of interest to declare.

The author has no funding sources to declare.