The Impact of Inadequate Temperature Storage Conditions on Aggregate and Particle Formation in Drugs Containing Tumor Necrosis Factor-Alpha Inhibitors

When administered intravenously, various particles and nanomedicines activate complement, potentially leading to infusion reactions and other adverse drug reactions. Particles form within formulations of therapeutic proteins due to stresses incurred during shipping, handling, and administration to patients. In this study, IVIg solutions were stored in multiple types of vials and prefilled syringes and exposed to agitation and freeze-thaw stresses to generate particles. The stressed samples were added to human serum to determine whether these particles activated complement. Subvisible IVIg particles ranging in size between 2 and 10 microns activated complement in a fashion that was linearly dependent on the number of particles dosed, whereas little correlation was found between doses of larger particles (>10 microns) and complement activation. Activation of complement by subvisible particles of IVIg followed the alternative pathway, as shown by the release of complement cascade factor Bb and the production of the anaphylatoxins C3a and C5a without generation of C4a. The number and the morphology of subvisible particles formed depended on the applied stress, formulation, and on the container material. But the capacity of the 2-to 10-micron-sized particles to activate complement in human serum appeared to depend only on particle concentration.

Section: Discussionmentioning

confidence: 99%

Subvisible Particles in IVIg Formulations Activate Complement in Human Serum

Chisholm

Behnke

Pokhilchuk

et al. 2020

“…Subsequently, simulation studies were carried out in the laboratory and the possible impact on the physicochemical properties of the proteins under these conditions was established. 117 Clearly, this issue of proper storage and handling of biologics in real-life situations needs more attention in educational programs for health care professionals and more hard data are urgently needed to assess the real risk patients run.…”

Section: Handling Of Biologics In Real-life Situationsmentioning

confidence: 99%

Shifting Paradigms Revisited: Biotechnology and the Pharmaceutical Sciences

Crommelin

Mastrobattista

Hawe³

et al. 2020

“…In a follow-up study, a few commercial protein pharmaceuticals in prefilled syringes were exposed to similar freeze-thaw cycles as those that were experienced in patients' refrigerators; the authors observed that the applied stress caused measurable increases in particle levels. 80 Whether such changes in the impurity profile have an impact on the overall safety and efficacy of the products remains to be studied, but potentially, they could contribute to immunogenicity in the patients receiving a product mishandled in such a way.…”

Section: Temperature Excursions and Freeze-thaw Cyclesmentioning

confidence: 99%

Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues

Nejadnik

Randolph

Volkin

et al. 2018

The safety and efficacy of protein pharmaceuticals depend not only on biological activity but also on purity levels. Impurities may be process related because of limitations in manufacturing or product related because of protein degradation occurring throughout the life history of a product. Although the pharmaceutical biotechnology industry has made great progress in improving bulk and drug product manufacturing as well as company-controlled storage and transportation conditions to minimize the level of degradation, there is less control over the many factors that may subsequently affect product quality after the protein pharmaceuticals are released and shipped by the manufacturer. Routine handling or unintentional mishandling of therapeutic protein products may cause protein degradation that remains unnoticed but can potentially compromise the clinical safety and efficacy of the product. In this commentary, we address some potential risks associated with (mis)handling of protein pharmaceuticals after release by the manufacturer. We summarize the environmental stress factors that have been shown to cause protein degradation and that may be encountered during typical handling procedures of protein pharmaceuticals in a hospital setting or during self-administration by patients. Moreover, we provide recommendations for improvements in product handling to help ensure the quality of protein pharmaceuticals during use.