Insight

Human Intravenous Immunoglobulin (IVIG) plays a vital role in humoral immunity. It recognizes and neutralizes pathogens or toxins, activates the complement system, enhances the phagocytic capacity of phagocytes, regulates allergic reactions and alleviates transplant rejection. As an indispensable biological agent in clinical treatment, IVIG is commercially available in two specifications: 5% and 10% concentration.

The cold ethanol fractionation process for separating albumin and globulin was developed in the 1950s–1960s, and globulin was initially administered via intramuscular injection.

In the 1960s, intravenous formulations with a concentration of 3% were developed through enzymatic digestion, representing the first-generation IVIG.

In the 1970s, chemical modification was adopted to remove anticomplementary activity (ACA), raising the product concentration to 5%–6%. Most products were presented as lyophilized preparations, marking the second-generation IVIG.

In the 1980s, manufacturing processes were further upgraded. Precipitation and purification technologies enabled the production of intact native IgG molecules, while viral inactivation procedures were optimized to mitigate potential viral risks. Products were formulated with low pH and supplied predominantly in liquid form, known as the third-generation IVIG.

Entering the 21st century, chromatography and multi-step viral inactivation/removal technologies have been widely applied to further reduce clinical medication risks and improve product quality. These technologies efficiently remove impurities such as IgA, IgM, anti-A agglutinins and anti-B agglutinins, and the product concentration has been increased to 10%, forming the fourth-generation IVIG.

The Technical Guidelines for Research on Production Site Changes of Licensed Blood Products (Trial), issued on May 19, 2025, has formulated more detailed and targeted regulations on the management of production site changes for licensed blood products. The guidelines explicitly encourage marketing authorization holders to upgrade and optimize production processes during site relocation, and to adopt chromatographic technologies to improve product purity and remove harmful residues, related substances (e.g., IgA, aluminum ions) and other blood protein impurities.

Against the backdrop of continuously upgraded quality requirements, chromatography has gradually become the mainstream manufacturing process for IVIG.

The ultra-large pore anion exchange media developed by Sino Bioengineering can serve as a cost-effective alternative to imported chromatographic media including Sepharose DEAE FF and Nuvia HP-Q. Featuring a high-rigidity polymer matrix, the media can process samples with moderate viscosity and deliver stable scale-up performance.

IgG is purified via single-step anion exchange flow-through mode, while relevant impurities are retained. The service life of the media exceeds 200 cycles.

A three-step flow-through process combining two rounds of anion exchange chromatography and one round of affinity chromatography is adopted for 10% IVIG purification.

Step 1: Anion Exchange Chromatography for Removal of IgA and Albumin

HPDEAE anion exchange media is applied here. With a high-rigidity polymer matrix and high-performance ligands, it efficiently binds and removes IgA and albumin, allowing the target IgG to flow through. HPDEAE is a reliable substitute for imported media such as Capto Q and Fractogel DEAE.

Step 2: Anion Exchange Chromatography for Adsorption of IgM

GPQ ultra-large pore anion exchange media is used to replace imported equivalents including Capto Q XP, Nuvia HP-Q and Fractogel TMAE. Its unique pore structure enables high-efficiency adsorption of macromolecular impurities like IgM, further elevating product purity while ensuring high processing capacity.

Step 3: Affinity Chromatography for Specific Removal of Anti-A/Anti-B Agglutinins

Anti-A and Anti-B affinity chromatography media are adopted as alternatives to Eshmuno P anti-A and Eshmuno P anti-B. Supported by specific polysaccharide antigen ligands, the media specifically adsorbs anti-A and anti-B agglutinins in plasma.

Remarkable purification results are achieved after the three-step chromatographic process: the removal rate of IgA reaches 98.95%, the removal rate of IgM exceeds 99.96%, and the titers of anti-A and anti-B agglutinins are reduced by 8 dilution units, yielding high-purity final products.