Potential Issues With the Handling of Biologicals in a Hospital

Jiskoot, Wim; Nejadnik, M. Reza; Sediq, Ahmad S.

doi:10.1016/j.xphs.2017.02.029

Cited by 24 publications

(15 citation statements)

References 2 publications

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“…Subvisible particles are ubiquitous in formulations of therapeutic proteins, but their levels can be greatly increased by stresses encountered during shipping, handling, and storage. [42][43][44] Agitation stresses are incurred as a result of vibration during shipping and during routine handling of liquids. Although liquid formulations of therapeutic proteins are typically intended to remain in liquid form at controlled temperature, accidental freezing can occur, especially during shipping in containers cooled with gel packs, 38 or in formulations intended for home administration.…”

Section: Discussionmentioning

confidence: 99%

Subvisible Particles in IVIg Formulations Activate Complement in Human Serum

Chisholm

Behnke

Pokhilchuk

et al. 2020

Journal of Pharmaceutical Sciences

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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.

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Section: Discussionmentioning

confidence: 99%

Subvisible Particles in IVIg Formulations Activate Complement in Human Serum

Chisholm

Behnke

Pokhilchuk

et al. 2020

Journal of Pharmaceutical Sciences

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“…Recently, it is reported that, even under use-relevant stress conditions, subvisible particles in marketed factor VIII products are formed. 8 Moreover, vigorous shaking during reconstitution of lyophilized protein products by hospital pharmacists has been reported in published studies 9 and observed in unpublished studies.…”

Section: Introductionmentioning

confidence: 93%

“…These stresses include mechanical shock, agitation, freeze-thawing, exposure to high temperatures, light exposure, and other stresses arising during routine handling or mishandling. 9 Exposure to the one or more of the stresses can cause a loss of activity, promote aggregation and particle formation, or cause chemical degradation of the protein molecules in the drug products. [11][12][13][14] For therapeutic protein products that are commercialized as lyophilized formulations, a particular concern for product quality is mishandling during reconstitution.…”

Section: Effects Of Shaking During Reconstitution On Particle Levels mentioning

confidence: 99%

Effects of Product Handling Parameters on Particle Levels in a Commercial Factor VIII Product: Impacts and Mitigation

Ueda

Nakamura

Abe

et al. 2019

Journal of Pharmaceutical Sciences

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To reduce the risk of immunogenicity that may be caused by therapeutic protein products, it is important to properly characterize subvisible particles and to develop strategies to reduce the levels of particles delivered to patients. In the present study, by using state-of-the-art methods to quantify particle levels, we found that the factor VIII product, Kogenate FS, contained relatively high levels of protein particles and silicone oil droplets, the vast majority of which were submicron in size. In a test of effects of product mishandling, the Kogenate FS vial was shaken instead of swirled during reconstitution. Levels of silicone oil droplets and protein particles were increased. In contrast, these levels were greatly reduced by 2 mitigation strategies tested, using a nonsiliconized syringe for the diluent container or using submicron pore size syringe filters during simulated infusion. Thus, to avoid potential adverse effects due to mishandling-induced increases in particle levels, it is important to educate end-users about proper product handling. Furthermore, effective particle mitigation and reduction strategies should be developed for factor VIII, and other therapeutic protein products. Such efforts could lead to clinically useful approaches to reduce the levels of particles delivered to patients and to an associated reduction in adverse immunogenicity.

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“…Paul et al published on the stability of a diluted mAb in their hospital pharmacy and the same group studied the effect pneumatic tube transport on antibody stability. 112,113 Jiskoot et al 114 published observations on handling biologics in hospitals and listed a number of irregularities that could jeopardize the quality of the drug product. Nejadnik et al 115 then wrote a commentary summarizing the "state of the art" and actions to be taken.…”

Section: Handling Of Biologics In Real-life Situationsmentioning

confidence: 99%