IPOPI regularly receives support from a broad range of companies involved in the manufacture of immunoglobulin therapies and the field of primary immunodeficiencies. and PDMPs. Keywords: convalescent plasma, fractionation, immunoglobulin, plasma, plasmapheresis INTRODUCTION Immunoglobulins, polyclonal/polyvalent (IgG) and hyperimmune (H-IgG) are plasma derived medicinal products (PDMPs) produced by fractionation. Immunoglobulin replacement therapy (IgRT) began in 1952 [1] with subsequent developments in intramuscular immunoglobulin (IMIg), intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg) and most recently, facilitated SCIg (fSCIg) routes [2]. 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 Alofanib (RPT835) a global perspective to challenges in supply and new therapies, which may impact on some of the current indications for immunoglobulin therapy.? Open in a separate window Box 1 no caption available 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 [3C12]. 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) [13] 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 (450C880?ml) (WHO) [13] 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 [9] but only 0.3% donate more than 100 times, 14% more than 50 times, whereas 49% donated 10 times or Rabbit Polyclonal to Cyclin D3 (phospho-Thr283) fewer annually [17]. In Alofanib (RPT835) 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 [18]. 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 in the 1940s [19C21] 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 [22C27]. INDICATIONS AND USES OF IMMUNOGLOBULIN THERAPIES Ig therapies for primary immunodeficiency (PID) and Kawasaki Alofanib (RPT835) 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 [30]. It is well established that the.