Immunoglobulins, polyclonal/polyvalent (IgG) and hyperimmune (H-IgG) are plasma derived medicinal products (PDMPs) produced by fractionation. Immunoglobulin replacement therapy (IgRT) began in 1952  with subsequent developments in intramuscular immunoglobulin (IMIg), intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg) and most recently, facilitated SCIg (fSCIg) routes .
Today Ig therapies are used in a wide range of indications with increasing demand and availability directly linked to supply of the raw material, human plasma. This article reviews plasma sourcing and manufacture alongside a global perspective to challenges in supply and new therapies, which may impact on some of the current indications for immunoglobulin therapy.
PLASMA COLLECTION AND IMMUNOGLOBULIN MANUFACTURE
Ig therapies are manufactured from plasma collected from a large number of donors to ensure diverse specificities of antibodies against a broad spectrum of pathogens [3,4]. Manufacture is a complex, strictly regulated process to ensure safety, quality, purity and potency of therapies [3–12].
Plasma is obtained either from whole blood donation by separating from cells (recovered plasma) or by direct plasma donation through plasmapheresis (source plasma) or co-collected during platelet apheresis. Plasmapheresis separates plasma by centrifugation while returning blood cells to the donor. Donor care is key both for the well being of the donor and quality of the plasma.
A unit of recovered plasma ranges from 100 to 260 ml (WHO)  and can be used as fresh frozen plasma (FFP), convalescent plasma therapy (CPT) as for COVID-19, or to manufacture PDMPs. Whole blood donors are usually only permitted to donate every 3 months to avoid anaemia.
Plasmapheresis (source plasma) yields more plasma (450–880 ml) (WHO)  depending on regulations in the country of collection [14▪▪,15,16]. In the United States donation frequency is twice weekly with 2 days between and maximally 104 donations annually  but only 0.3% donate more than 100 times, 14% more than 50 times, whereas 49% donated 10 times or fewer annually . In Europe, maximum annual donations range from 24 to 60. The European Directorate for the Quality of Medicines (EDQM) nonbinding recommendations advise a maximum of 33 plasma donations per year with at least 96 h between the donations . Compared with recovered plasma, plasmapheresis allows collection of much larger annual plasma volumes available for fractionation due a combination of higher donation frequency and a larger volumes per donation.
Manufacture by fractionation of Ig from up to tens of thousands of units of pooled plasma takes from 7 to 12 months and is based on cold ethanol precipitation of proteins developed by Cohn et al. in the 1940s [19–21] with additional dedicated steps to increase purity, yield, improve quality and enhance safety margins to prevent potential transmission of pathogens. These steps vary between brands and include plasma protein separation by precipitation and/or chromatography, protein purification using ion exchange or affinity chromatography, and steps (one or more) for the inactivation or removal of potential infectious agents, such as blood-borne viruses and prions [22–27].
INDICATIONS AND USES OF IMMUNOGLOBULIN THERAPIES
Ig therapies for primary immunodeficiency (PID) and Kawasaki diseases are on the WHO List of Essential Medicines [28,29] and are unique biological products with no single product or method of administration suitable for all patients . It is well established that the differences in manufacturing processes can affect individual tolerability, risk of adverse events, infusion rate and potentially efficacy  making access to a range of different Ig therapies vital.
Indications for Ig therapy vary depending on the region/country (Table 1) as does use in a wide range of other off-license indications [32–35].
Currently PID and secondary inmmunodeficiency (SID) are the major indications as exemplified from Australian National Blood Authority data  (Fig. 1) and the UK Database  with PID (1 514 760 g), CIDP (1 239 547 g) and SID (991 511 g). In the United States, PID represents roughly 30% (including some SID), CIDP 20%, myasthenia gravis 10%, ITP 9%, others 31%, (M. Hotchko, MRB Personal communication, 1 July 2020).
Overall global Ig demand has increased annually by 6–8% (Fig. 2), with a higher rate in emerging markets because of lower starting consumption levels .
Factors influencing annual growth in consumption are complex and not only include increasing use in SID and neurological conditions but also improved diagnosis for PID particularly in developed countries linked to increasing use of newborn and calculated globulin screening [39–41,42▪▪]. However, the reality of massive worldwide underdiagnosis for around 70–90% of PID patients persists . Encouragingly, disease-specific diagnostic tests for PIDs are now on the WHO List of Essential In-Vitro Diagnostics Tests  with 430 different PIDs identified in the latest IUIS classification .
Supply dynamics of PDMPs have historically been characterized by intermittent shortages with Ig therapies recently ranked third most frequent medicinal product facing shortages in the EU pharmacists report of medicinal products .
NEW THERAPIES WHICH MAY REDUCE IMMUNOGLOBULIN USE
Set against this growth are some potential areas of reduction for immunomodulatory indications because of new therapies.
Three evolving therapeutic approaches overlap with immunomodulatory mechanisms of action of Ig including – blockade of the neonatal Fc receptor (FcRn) and other Fc receptors (FcR), reducing autoantibody production, and complement inhibition [32,47–50,51▪▪,52▪▪].
The FcRn functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Maintenance of serum IgG levels is proportionally more dependent on recycling than production [49,50]. One mechanism by which hdIVIg reduces pathogenic autoantibodies is by saturation of FcRn receptors .
Several FcRn inhibitors (FcRni) rozanolixizumab, efgartigimod, orilanolimab, and nipocalimab selectively targeting IgG recycling are in clinical trials for CIDP, MG and ITP. These can reduce serum IgG by 45–80% [54–57], levels returning to baseline after 28 and 57 days depending on the FcRni [54–58]. FcRni have potential for future use in a much wider variety of antibody-mediated autoimmune diseases, which may reduce pressure for Ig on repertoire-dependent indications such as PID and SID.
Further strategies targeting FcR in autoimmune disease are multimerization of recombinant Fc portion of antibodies and modification of Fc by hyper-sialylation [59▪▪] (M254). Recombinant fragment crystallizable (rFc) multimers primarily target Fcγ receptors (FcγRs) but may also affect the complement system [60,61▪].
Significant advances have also been made in terms of targeting B cells predominantly for hematological malignancies, such as CD19 (Ineblizumab), CD22 (Epratuzumab), CD38 (Daratumumab, Isatuximab) as well as proteasome inhibitors. Future indications in autoimmune and inflammatory disease as with rituximab are likely, impacting indications for hdIVIg, such as neuromyelitis optica (NMO) .
There is also increasing interest in complement inhibition in autoimmune and inflammatory diseases with novel inhibitors (eclulizumab, tesidolumab and ravulizumab) targeting C5 and the C5a blocking antibody (IFX-1) noting that complement inhibition is another mechanism of action of hdIVIg .
ENSURING SUFFICIENT FUTURE GLOBAL SUPPLY
Ensuring sufficient global supply and stability requires both increased plasma supply and improved fractionation technology to optimize yield from each litre of plasma alongside a vibrant R&D platform for novel PDMPs.
There are significant regional differences in collected volumes of recovered and source plasma. In 2017, the United States supplied 65% of world plasma for fractionation (Fig. 3), and 71% of all source plasma, whereas Europe was the largest supplier of recovered plasma with only 10% of source plasma . Latin America and Africa currently account for a very small proportion of global plasma supply and have a rapidly growing demand. The United States has the highest global Ig sales at 46% (Fig. 4) but is in fact a net exporter with 65% of the world plasma collection.
Strategies to attract and retain more blood and plasma donors, especially source plasma donors given that in 2015, recovered plasma accounted for only 13% of fractionated plasma worldwide , are key alongside harmonization of best practice in donation frequency and volume limits to ensure the safety of donors and quality of final products.
In the United States and some EU countries, such as Germany, Austria, the Czech Republic and Hungary, source plasma donors are compensated for their donations. However, in most other EU countries, plasma donor compensation is currently not authorized with reliance on unpaid donations. Germany, Austria, the Czech Republic and Hungary collect proportionally a much higher plasma volume than any other European country (three times higher). In 2017, whilst the nonprofit public sector collected 55% of European plasma used for fractionation, the commercial sector collected 45% but from just four countries with a population of 112 million (European population 743 million) (M. Hotchko, MRB. Personal communication, 1 July 2020).
Could both compensated and unpaid co-exist and contribute together towards increased plasma collection? From a viral safety perspective, it is well established that PDMPs made from compensated plasma donations are just as well tolerated as those made from unpaid donations . There is the need for a re-evaluation  of this growing disparity in collections across Europe to ensure future global supply based on more regionally balanced plasma collection.
Today's reality is that the United States contributes the large majority of the world's plasma supply (Fig. 3), making other regions, such as Europe highly dependent on American (largely compensated) plasma donors, creating an imbalance, which could jeopardize access to life-saving Ig therapies. The past has shown us that national sources of plasma can become unusable from 1 day to the next, such as with the variant Creutzfeldt--Jakob disease (vCJD) crisis in the UK in the 1990s. There has been significant inertia in evidence-based decisions concerning the ability to fractionate UK plasma again despite growing national and global need. The costs have been high in terms of opportunity, loss of sovereign fractionation capacity, supply shortages and the exposure to rising global price. Additionally, the COVID-19 pandemic is likely to lead to further strains on immunoglobulin supply as plasma donations have declined in 2020 (https://www.pptaglobal.org/media-and-information/ppta-statements/1081-ppta-repeats-appeals-for-plasma-donations). Stay-at-home and social distancing measures have led to reductions in regular attendances at donor centres whilst the urgent need for SARSCoV2 antibody-positive plasma for CPT and H-IgG has been an ongoing priority. This highlights the need for universal and international access to PDMPs (including CPT and H-IgG) and for collecting more plasma. In the UK and other countries, response times to the pandemic for CPT would have been markedly quicker had an existing national network for plasma donation at scale already been in place.
There has been significant and year on year growth of around 6–8% in the requirement for immunoglobulin for predominantly Immunology, Neurology and Hematology indications. Major drivers include increases in SID, better recognition and diagnosis of PID albeit on a background of massive underdiagnosis globally.
Novel therapies such as FcRn inhibitors may reduce demand in some of the current immunomodulatory indications for Ig. However, to meet demand there needs to be an increase in plasma collection with reduction in the current imbalance of 65% of plasma coming from the US towards a much more regionally balanced collection and with a view to attain global sufficiency in PDMPs. In addition, transparent and collaborative discussions concerning the regulatory framework to allow the coexistence of both unpaid and compensated plasma donation need to progress and should be patient-centred. The underpinning rationale should be the needs of patients for these life-saving therapies, the care of donors and the safety of plasma and PDMPs.
We would like to gratefully acknowledge the expertise and help of Larisa Cervenakova especially in relation to details of plasma collection and manufacture.
Financial support and sponsorship
Conflicts of interest
S.J. declares Advisory Board, Speaker, Conference, Clinical Trial, DSMB, or Projects with CSL Behring, Shire, Takeda, Thermofisher, Swedish Orphan Biovitrum, Biotest, Binding Site, BPL, Octapharma, Sanofi, LFB, Pharming, Biocryst, Zarodex, Weatherden and UCB Pharma.
J.P. is the Executive Director of the International Patient Organisation for Primary Immunodeficiencies (IPOPI). IPOPI regularly receives support from a broad range of companies involved in the manufacture of immunoglobulin therapies and the field of primary immunodeficiencies. For an updated list please visit www.ipopi.org.
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