Plasma-derived medicinal products: a narrative review of the multi-layered approach to ensuring pathogen safety

Introduction

Background

Following the earliest efforts to purify serum albumin from human plasma, plasma-derived medicinal products (PDMPs), including plasma proteins such as immunoglobulins, factor VIII, factor IX, and C-1 esterase inhibitors, have been used clinically since the 1940s (1). By the late 1970s, clotting factors were commonly used to treat patients with bleeding disorders (2). However, following the contamination events of the 1970s and 1980s, efforts focused on developing a multi-layer safety approach to reduce and prevent the risk of pathogen transmission via these products. The approach has been built on several complementary safety strategies composed of donor selection, testing, and pathogen reduction.

Rationale and knowledge gap

Following the coronavirus disease 2019 (COVID-19) pandemic and given the challenges posed by several disease outbreaks, a review of the historical development and current state of safety strategies offers an opportunity to reflect on future considerations. While several review articles have previously covered the safety aspects of PDMPs in general (3,4) or those of individual products (5,6), based on our assessment, this review captures the safety strategies used across several different PDMPs, with an up-to-date review of published literature demonstrating ongoing safety against established and emerging pathogens.

Objective

This literature review focuses on the safety of PDMPs from the perspective of the plasma industry that produces them and monitors patient safety. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-50/rc).

Methods

A literature search was conducted using PubMed and Google Scholar (Table 1).

Historical overview of the development of the safety strategies

PDMPs emerged in the 1940s following Edwin Cohn’s investigations commissioned by the United States (U.S.) military and were first used during World War II (7). PDMPs are biological pharmaceutical products manufactured from donated human plasma using a series of fractionation and purification steps that can take up to 7 to 12 months to yield a final product. Cohn’s investigations initially focused on human serum albumin for its potential as a plasma expander. Safety was a major concern of Cohn, who employed pasteurization to prevent the transmission of pathogens. Thus, albumin has had an exemplary safety record dating back to its origins (8). Immunoglobulin was the second product to be fractionated (9), and early on, it demonstrated a high level of safety without any pathogen reduction steps. This was partly attributed to the presence of neutralizing antibodies against any pathogens that might have been present. However, following the introduction of factor VIII and IX concentrates for hemophilia patients in the 1970s, a widespread transmission of hepatitis B virus (HBV) was observed (10). This was later followed by transmission of human immunodeficiency virus (HIV), and non-A non-B hepatitis, which was later identified as hepatitis C virus (HCV) (11). These events were not limited to clotting factors but, to a lesser degree, also included immunoglobulins. This period of widespread viral transmission triggered intense focus on the safety of PDMPs.

During this time, similar infections were also transmitted through transfusible blood components, such as red cells, platelets, and plasma. In contrast to PDMPs, these blood components are labile products that undergo minimal processing. However, because of the pooling of large numbers of plasma donations, PDMPs had a greater risk until new safety measures were introduced. In the 1980s, two innovations in particular resulted in immediate improvement in the safety profiles of PDMPs (12). First, Norbert Heimburger successfully stabilized the factor VIII molecule during pasteurization, which led to heat-treated factor VIII products (13). Second, Bernard Horowitz developed solvent-detergent treatments that inactivated enveloped viruses, such as HBV, HCV, and HIV (14). During the same time frame, other methods, including dry heat and a combined β-propiolactone-ultraviolet (BPL-UV) treatment (15,16), were also developed, but they were not as widely adopted as pasteurization and solvent-detergent treatments.

The development of additional safety measures came quickly based on lessons learned. Donor screening and testing of donations in the 1980s, followed by the use of pathogen reduction measures in manufacturing later, ushered in a period of enhanced safety for all PDMPs (6,17). These three safety measures are collectively referred to as the “safety tripod” (Figure 1), a commonly used term for the multi-layered approach to pathogen safety of PDMPs (3,18). These approaches have also been successfully adapted for the manufacture of other biological medicines. The effect of these measures has been supported by the industry’s pharmacovigilance (12).

Figure 1 The pathogen safety of PDMPs is built on the safety tripod. This consists of donor selection to identify low-risk donors, testing of donations for highly relevant pathogens, and pathogen reduction to inactivate or remove any contaminating pathogens. At each step, the necessary requirements listed must be met before plasma is used to manufacture PDMPs. DHQ, donor history questionnaire; NAT, nucleic acid-amplification testing; PDMP, plasma-derived medicinal product.

Donor selection

Donor selection was the earliest intervention used to reduce infection risk. The donor selection process involves assessment of a donor’s medical and social history using a standardized donor history questionnaire (DHQ) and a brief physical examination (19). Donors with risk factors for disease transmission are deferred, leaving eligible healthy donors who are low risk for infectious diseases that could pose a risk to the safety of the product. The DHQ consists of questions that are aimed at identifying daily activities and travel history that could result in potential exposure to HIV, hepatitis viruses, or other pathogens. Examples are recent receipt of blood products, allogenic tissues or transplant, injection drug use, risky sexual practices, such as unprotected anal sex, needle stick, or blood exposure (20). In addition, other questions focus on medications the donor is using or any recent live-virus vaccines that may pose a risk to the recipient of PDMPs. Specific approach to donor selection can vary depending on the country. An example of the donor selection process is provided from the U.S., where donors can donate plasma by plasmapheresis, called source plasma (SP), which is specifically used for PDMP manufacture (21). To assess eligibility for SP donation, an extensive questionnaire is used for applicant donors (first and second donations) and annually for long-term donors. For repeat donors, a shorter questionnaire focuses on any changes since the prior donation, including changes in medication use, and goes through a risk poster summarizing behaviors that might increase infectious disease risk (20).

Over the years, the donor selection process has evolved, reflecting advances in scientific knowledge on disease transmission, testing methods, and manufacturing processes. While the DHQ used for plasma for PDMP manufacture has similarities to those used for blood collection, certain questions regarding diseases transmitted by red cells, such as malaria and babesiosis, are omitted (22). In contrast, unlike transfusible blood components that are only used in the country where they are collected, PDMPs can be distributed globally. As a result, the DHQ used by SP collectors could include additional questions to ensure compliance with the regulatory requirements of other countries. Additionally, in recent years, several regulatory decisions around the world employed a risk-based approach to deciding donor eligibility. Some notable recent examples include the implementation of individual assessment of risk of infections due to unsafe sexual practices, regardless of sexual orientation, and the lifting of donor deferral against the geographic risk of variant Creutzfeldt-Jakob disease (vCJD) (23-26).

Testing

Screening of blood donations for potential infection transmission began in the 1950s with syphilis testing (27). Although it is recognized that Treponema pallidum, the causative agent of syphilis, is not transmissible by PDMPs due to freezing of plasma before manufacture, the U.S. Food and Drug Administration (FDA) has maintained the requirement for syphilis testing primarily as a public health measure as well as a potential surrogate for sexual activities that could increase risk of transfusion-transmitted infections of concern (28). Screening tests can be either Treponemal (TP) or non-TP tests. TP tests can indicate either recent or distant infection, whereas non-TP tests are more specific for active or recent infections and become negative with treatment (28).

Testing for HBV was introduced in the 1970s (29), and the testing strategy later evolved to include HIV in 1985 and HCV in 1990, with more sensitive second-generation HCV starting in 1992 (30-32). These are viruses that can have continued subclinical presence after acute infection and have been found to be transmissible by blood and plasma infusion. Early testing was done by serological methods that detect either antigen (HBV) or antibody (HIV and HCV). Initially, the radioimmunoassay was used, but this methodology was supplanted by the enzyme immunoassay (EIA) or the enzyme-linked immunosorbent assay (ELISA). Since such tests only become positive when the donor has reacted immunologically to the infection, they are associated with a significant window period, i.e., the time during which the virus is present in the donor’s blood or plasma, which could result in transmission, but the test is negative (33).

Hepatitis B surface antigen (HBsAg) testing began in 1971 (29). The assay has evolved over the years and currently uses chemiluminescent labels. Confirmation of a positive test is done by a neutralization step, adding anti-hepatitis B surface antibody and repeating the assay. Reduction in activity indicates a true positive (34). HCV antibody is tested by a third-generation EIA. With EIA, peptides of HCV are bound to the solid phase, and an enzyme-linked anti-immunoglobulin is the detection system. Current tests use recombinant HCV antigens representing four viral sequences (35). Supplemental (confirmatory) test uses an alternate EIA. HIV antibody testing uses recombinant antigens, including HIV-1, HIV-2, and HIV group O. Currently, a combined antigen/antibody test is used, which also detects HIV p24 antigen (36). A supplemental HIV test is also available for confirmation.

If a donor’s positive serology is not confirmed, the FDA allows specific re-entry protocols (23,37-39). Because of their complexity, some plasma companies do not allow re-entry. All positive results in the U.S. are entered into the National Donor Deferral Registry (NDDR) so that once an individual has tested positive for the aforementioned three viruses, that individual cannot donate at any SP center, a donation center specialized in the collection of SP (40). If re-entry is successful, the donor’s name can be removed by the company responsible for the donor’s testing. In the European Union (EU), the availability of a specific re-entry protocol is determined by the national authorities of each member country (41,42).

To reduce the window period and improve both the sensitivity and specificity of testing, nucleic acid-amplification testing (NAT) was introduced in the late 1990s. Initially, testing used polymerase chain reaction (PCR), but later transcription-mediated amplification (TMA) was introduced (43). Implementation of NAT shortened the diagnostic window periods to about 38 days for HBV, 9.1 days for HIV, and 7.4 days for HCV (44). Nevertheless, occult HBV infections may be difficult to detect due to low viral loads below the assay limit of detection.

Testing is performed at both the individual donation stage and the first homogeneous pool used for manufacturing. Serology testing is commonly used on individual donations to test for HBV, HCV, and HIV. Individual donations that are non-reactive for serology are then tested with NAT using a mini-pool testing strategy (45). Mini-pool testing is carried out by pooling samples from a defined number of individual donations. Larger mini-pools consisting of 96 donations are used compared to the smaller mini-pool strategy employed in blood donation testing, as the test sensitivity takes into consideration the subsequent pathogen reduction steps in manufacturing. In addition to the required NAT for HIV, HBV, and HCV, the voluntary industry standard set by the Plasma Protein Therapeutics Association (PPTA) recommends the inclusion of hepatitis A virus (HAV) and parvovirus B19 (B19V) NAT for the mini-pools, while requiring these additional tests for the manufacture pools (45). These tests were introduced following the transmission of HAV and B19V, two non-enveloped viruses, from PDMPs that were treated with solvent-detergent. While solvent-detergent treatment was effective at removing enveloped viruses, it was not as effective against non-enveloped viruses such as HAV and B19V (46,47). These tests are considered “in-process tests” as donors who test positive are only deferred for specific periods rather than permanently, since these viruses are not present over the donor’s lifetime. Additionally, in the EU, PDMP manufacturers are required by the regulators to provide risk assessment for all five viruses (48).

While only units testing negative for HCV, HAV, HIV, and HBV are used to assemble a manufacturing pool, B19V testing follows a different strategy. As B19V has been shown to be resistant to some of the common reduction methods, limiting the viral load in the manufacturing pool is necessary before validated pathogen reduction methods can effectively remove B19V below a specific threshold (49-51). B19V threshold for manufacture pools is set to not exceed 10⁴ IU/mL. Therefore, the mini-pool testing strategy takes into consideration this threshold and the size of the mini-pools to determine a permissible testing threshold. When a mini-pool tests positive for one of the four viruses or exceeds the B19V threshold, resolution testing is performed to identify and discard individual positive units (45).

In recognition of the window periods, the plasma industry employs an inventory hold of plasma for a set period of time (52). Plasma units are not pooled for manufacturing until the hold period has elapsed. This allows manufacturers to remove any plasma units suspected to be positive but within the window period, based on follow-up information received about donor. This information includes positive serology or NAT for HBV, HCV, or HIV at subsequent donations or other information about a donor that indicates that the donor should have been deferred due to possible risk for the product. The success of the inventory holds in reducing residual risk led the FDA to incorporate the hold into its regulations, initially as a 60-day hold, which was lowered to 45 days during the COVID-19 pandemic. In the U.S., with the frequency of permitted donations, the inventory hold has been successful in ensuring SP is highly unlikely to contain viruses (53).

After assembly of the manufacture pool, a combination of serology testing and NAT is carried out to ensure that only pools that meet specific testing requirements, set by the national pharmacopoeia and the voluntary industry standards, are used for further manufacturing. Only pools that test non-reactive for HBsAg and anti-HIV-1/2 antibodies by serology, NAT negative against HCV, HAV, HIV, HBV, and contain less than 10⁴ IU/mL B19V are qualified to be used for further manufacture of PDMPs.

Pathogen reduction

The greatest impact on the safety of PDMPs has been the universal adoption of pathogen inactivation and removal methods during PDMP manufacture, collectively referred to as “pathogen reduction”, resulting in a safety advantage over transfusible blood components (4). There has been no known transmission of HIV, HBV, or HCV to hemophilia patients since 1990 and no known transmission to any patient since 1994 (54-56). PDMP manufactures employ multiple orthogonal pathogen reduction steps that have been validated for robustness and reproducibility to effectively remove any remaining pathogens. The importance of using multiple pathogen reduction steps has been acknowledged by regulatory authorities and guidelines (48,57,58).

The importance of pathogen reduction steps in manufacturing is underscored by the nature of the fractionation process, which begins with large pools of human plasma (approximately 2,000–4,000 L) containing donations from many donors. Compared to the single donor transfusible blood components, the pooling process of PDMPs can magnify the potential risk of contamination. Intermediates from multiple plasma pools may be combined such that a final container could include proteins from as many as 50,000 donors. One factor that reduces the risk of contamination is the dilution factor in both the pooling and pool testing. However, pathogen reduction is the most important factor in achieving the current safety record of these products (3).

Validation of pathogen reduction is performed in a laboratory separate from the manufacturing facility. This process relies on scaled-down models that replicate key process parameters used during the manufacturing. The biochemical characteristics of the output material from the small-scale process must be comparable to those of the production scale process. Robustness experiments assess the impact of extreme production characteristics on the virus reduction capacity, measured as log₁₀ virus reduction factors (LRFs) and the possibility of transmission estimated based on the highest level of possible virus present in the plasma used (58). These calculations have ensured the safety of the product, as testing the final container is not suitable to demonstrate safety.

Test viruses used in validation studies must be the same as or similar to the viruses of concern and represent the range of physicochemical properties of various pathogens. In addition, they must be able to replicate in cell cultures in order to be assayed by in-vitro infectivity methods (57). For example, HIV and HAV meet these requirements and are used in validation studies. However, for viruses of concern that cannot be grown in cell culture, there are many model viruses that can be used in place. For HCV, model viruses such as bovine viral diarrhea virus (BVDV) or Sindbis virus are employed.

Pathogen reduction can be divided into pathogen inactivation and pathogen removal. The choice of specific pathogen reduction method depends on various factors, such as the physicochemical characteristics of the plasma protein of interest, the pathogens of concern, the pathogen reduction capacity of other steps used, and compatibility with the manufacturing steps. Table 2 summarizes studies on pathogen reduction methods that are used in PDMP manufacture.

In manufacturing, partitioning steps used to purify the desired products may also contribute to pathogen reduction (59,77). However, as they are designed and validated to isolate the protein of interest, their reduction capacity can be limited, unless they are also validated for their reduction capacity. Whatever steps are introduced into manufacturing must be demonstrated by analytical methods to have no impact on the integrity of the therapeutic product (48).

Pasteurization is one of the main pathogen inactivation methods and involves heating in aqueous solution at 60 °C for 10 hours. This method, which was originally developed by Cohn for albumin, was later optimized for other proteins such as fibrinogen, c1 esterase inhibitor, factor VIII, and immunoglobulins (8,60,61,80,81). The composition of the solution and stabilizers used is critical to protect proteins and reduce neoantigen formation. Use of glycine and sucrose is important for use with labile proteins, such as factor VIII (62,63). In addition to pasteurization, dry heat (80 °C for 72 hours or 100 °C for 30 minutes) has been successfully used when residual moisture is adequately controlled (75,76). Vapor heat is an additional heat-based inactivation method that has also been utilized (61,74).

Solvent/detergent (S/D) methods, pioneered by Horowitz, disrupt the lipid membranes of enveloped viruses and render them unable to bind to and infect cells. A common method uses 0.3% tri(n-butyl) phosphate (TNBP) and 1% ionic detergent (such as Tween-80 or Triton X-100) at 24 °C for 4–6 hours (61,67,82,83). The intermediate must be filtered to eliminate viruses trapped in gross aggregates. The reagents are then removed downstream by chromatographic or precipitation steps. While Triton-X-100 is highly effective, its use has recently been restricted in the EU due to environmental concerns (84). Thus, there are ongoing efforts to identify additional S/D substitutes (85,86). For the manufacture of PDMPs, S/D methods must be supplemented with another method that is effective against non-enveloped viruses.

Octanoic acid (caprylate) treatment similarly disrupts the envelope of certain viruses. Its concentration, along with pH, temperature, and protein concentration, must be controlled for effectiveness (63,71). Low pH has been successfully used as a pathogen reduction method for many immune globulin products, as it inactivates enveloped viruses and certain non-enveloped viruses, including B19V. Its success depends on pH, temperature, type, and concentration of excipients (61,64,68,70,87).

Dedicated pathogen removal using nanofiltration has made considerable progress in recent years and serves as a size-based removal mechanism (59,73). Successful filtration depends not only on pore size but also on hydrodynamic forces, adsorption of the virus to the filter surface, and removal of virus that has aggregated with antigen-antibody or lipid complexes (88,89). When shear forces are appropriately controlled to prevent damage to the manufactured protein, this is a robust method that is complementary to virus inactivation (3).

Following the outbreak of mad cow disease in the United Kingdom (UK) and spread to humans in the 1990s, the scope of pathogen reduction was expanded to investigate the prion removal capacity of PDMP manufacturing steps. Prions are non-viral infectious agents made of misfolded proteins that cause diseases such as Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (BSE) (also known as “mad cow disease”), and chronic wasting disease (CWD). As there are no available diagnostic tests for prions, the prion safety of PDMPs has relied on donor selection and pathogen reduction. Pathogen reduction is provided by a combination of manufacturing steps, such as polyethylene glycol (PEG) precipitation and affinity chromatography, and dedicated pathogen reduction steps such as virus filtration, octanoic and caprylate precipitation (59,72,78,79). Although there was one reported case of vCJD transmission in a patient who received clotting factors, the cause of transmission could not be directly linked to the clotting factors due to the patient’s history of repeat blood transfusions (90). In light of the well-established prion removal capacity of PDMPs and based on the current epidemiological and clinical evidence, several regulatory decisions lifted deferrals for blood and plasma donors who resided in the UK during the mad cow disease outbreak (24,25,91).

While studies referenced above provide the published data on the validation of pathogen reduction, demonstrating the effectiveness of each method, pharmacovigilance activities carried out by the manufacturers and the regulators have confirmed the effectiveness of these methods in the real world, by monitoring and assessing any potential adverse events that are caused by these medicines (12,92-94).

In the last decade, the effectiveness of current pathogen reduction methods has been further tested following several outbreaks with new pathogens. Early during the COVID-19 pandemic, once the structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, was available, PDMP manufacturers evaluated findings from earlier validation experiments and carried out new experiments using similar model viruses, demonstrating the effectiveness of currently used validated methods against SARS-CoV-2 and highlighting the importance of using model viruses (62,68,95). This was an important aspect of pathogen safety against SARS-CoV-2. Early in the pandemic, identifying low-risk donors and testing donations were not feasible. Additionally, due to the broad-spectrum nature of pathogen reduction steps and the use of various model viruses, PDMPs have continued to maintain their safety against other emerging pathogens such as the Zika virus (64-66,96), Chikungunya virus (83,97), West Nile virus (61,63), and Monkeypox virus (63,69,75).

For the future safety of PDMPs, continuous monitoring of emerging pathogens and the use of model viruses are essential for preparedness. Over the years, public health organizations, such as the World Health Organization, have established monitoring systems for continued surveillance of pathogens that might pose risks to public health. Additionally, several non-profit organizations have dedicated expert groups to assess any emerging threats and their potential impact on the safety of blood components or PDMPs, based on available evidence (98-100). Data collected by these surveillance systems allows the manufacturers to regularly re-evaluate the effectiveness of specific pathogen reduction steps against emerging threats and adapt their methods accordingly.

While pathogen reduction ensures the safety of PDMPs, immunoglobulins administered to immunodeficient patients themselves play a role in providing protection against infectious diseases due to the presence of a broad spectrum of neutralizing antibodies. In some countries, regulators can require that immunoglobulins to meet specific lot release criteria, such as the U.S. FDA requirement for measles neutralization. In the case of measles antibodies, measurable protective levels have fallen as the vaccine-induced immunity produces lower antibody levels compared to what was observed with disease-induced immunity (101,102). This has required lowering this specific antibody requirement (103). In contrast, vaccination against SARS-CoV-2 combined with natural infection has resulted in the potential for increased protection by immunoglobulin (104).

Discussion and conclusions

Advances in safety measures have been greatly influenced by the lessons learned. The current safety strategy is built on the three pillars of the safety tripod: donor selection, testing, and pathogen reduction. In this review, the activities related to each pillar are reviewed from a historical and industry perspective, considering patient and physician concerns. The evolution of safety measures for PDMPs has been presented from collection through product release, focusing on reducing the risk of pathogen transmission and an up-to-date review of the published pathogen reduction studies. However, as this is not a systematic review, it has its limitations. The methodology used might have led to the omission of certain pertinent publications due to an incomplete search of the literature. Additionally, due to the manuscript’s word limit, the authors were unable to cover all the pathogen reduction methods and instead highlighted the most commonly used methods.

While each pillar provides an overlapping layer of safety, they have continued to evolve in light of new scientific evidence and technological innovation, with reduced residual risk and greater safety. This has been further supported by data collected through pharmacovigilance. Advances made in manufacturing, particularly in pathogen reduction, have provided well-documented protection against known pathogens.

Current analysis of the literature shows that there has been no known transmission of HIV, HBV, or HCV from clotting factors since 1990 and no known transmission from immunoglobulins since 1994. In the late 1990s and early 2000s, transmission of HAV and B19V, respectively, resulted in the evaluation of the commonly used methods and highlighted the need for additional safety measures against non-enveloped viruses. Since the implementation of these measures, there has been no known transmission of HAV or B19V from PDMPs. Furthermore, the publications referenced in this review provide evidence on successful protection against many emerging pathogens in recent years. It is true that the theoretical risk of disease transmission still remains. However, pharmacovigilance monitoring by the manufacturers and the regulators has provided real-world evidence that the residual risk is very low.

While many unknown pathogens can pose challenges to the public health system in the future, the continued resilience of PDMPs and other biological medicines will depend on ongoing surveillance, scientific vigilance, periodic evaluation of methods and model viruses, and technological advances to adapt these safety measures against future threats. The industry that produces these products is committed to maintaining vigilance in the laboratory and the clinic to ensure continued progress in risk reduction.

Acknowledgments

None.

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.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-50/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-50/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-50/coif). The series “Source Plasma” was commissioned by the editorial office without any funding or sponsorship. H.T. is a full-time employee of the Plasma Protein Therapeutics Association (PPTA), which is an industry association representing manufacturer of plasma-derived medicinal products (PDMPs) and private collectors of plasma used for PDMP manufacture. T.S. retired from CSL Behring and is self-employed as a medical consultant now. He has provided services to PPTA and CSL Plasma/CSL Behring. 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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