Although therapeutic drivers are changing over the years, and innovative biotech products are continuously modifying the clinical landscape, there is an increasing need for plasma protein therapies obtained by the fractionation of human plasma. Plasma-derived protein products therefore continue to play vital roles in the therapeutic management of various immunological disorders, deficiencies in coagulation factors or protease inhibitors, viral or bacterial infections, and trauma. Plasma fractionation is a biotechnology industry that has increased in complexity over the last 30 years to ensure that plasma-derived protein therapies exhibit optimal quality and pathogen safety profiles. Plasma-derived products are among the safest biological therapies available; in industrialized countries they are strictly and efficiently regulated in all aspects of their production chain and clinical use. Conversely, due to some technological complexities and strict adherence to regulatory requirements, a substantial barrier to entry into the field of plasma fractionation exists. Although various plasma-derived protein products are on the WHO model list of essential medicines, dramatic shortages of these products exist, especially in low-/medium income countries, while at the same time more than 9 million liters of recovered plasma in these countries are wasted annually. Lack of plasma protein products results mainly from three factors: (a) cost of imported products, (b) insufficient local supply of quality plasma for fractionation, or (c) lack of domestic industrial fractionation capacity. As the understanding of critical quality and safety factors has dramatically improved over the years, there is a need to rethink how affordable, scalable, and reliable purification and virus inactivation technologies could be introduced in countries with poor relevant infrastructures and low-/medium income. Such technologies, when properly validated and implemented, could help ensure local availability of essential plasma protein therapies and gradually fill the gap in product supply, safety and affordability that exists relative to advanced economies.