In-use physicochemical and microbiological stability of biological parenteral products

Ricci, Margaret Speed; Frazier, Michelle; Moore, Jamie; Cromwell, Mary; Galush, William J.; Patel, Ankit R.; Adler, Michael; Altenburger, Ulrike; Grauschopf, Ulla; Goldbach, Pierre; Fast, Jonas; Krämer, Irene; Mahler, Hanns‐Christian

doi:10.2146/ajhp140098

Cited by 27 publications

(18 citation statements)

References 36 publications

(39 reference statements)

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“…187 However, this consensus is an improvement in the analytic rigor of studies, but the meaningful acceptance criteria are often undefined and reference standards absent, making method validation a challenge. 85 In complement to this consensus, British recommendations indicate that one should at least assess visual aspect, pH, particulates, physical stability, chemical stability, and biological activity. Freshly reconstituted drug formulation should be used as the reference material, and set acceptance criteria as a 5% maximum loss in active protein and a maximum increase of secondary species of 2%.…”

Section: Methods For Investigating Mab Stabilitymentioning

confidence: 99%

“…188 Analysis of physicochemical stability during simulated administration is also warranted, given that additional surfaces come into contact with the protein, the drug product formulation may be diluted, including dilution of critical excipients required for protein stability, and environmental stressors may be present during use. 85 U.S. Pharmacopeia described a series of analytical techniques to be used in the analysis of monoclonal antibodies, including SEC, CE-SDS, and HPLC with fluorescence detection. 189 A wide panel of techniques used in physicochemical stability studies is presented in Table 1.…”

Section: Methods For Investigating Mab Stabilitymentioning

confidence: 99%

“…Contact of the drug with various surfaces can affect stability and drug recovery and can lead to unacceptable product loss, decreased potency, and potential underdosing. 81,85 Adsorption has been shown to be concentration-dependent with saturation occurring at some point. It is function of various other parameters such as the number of protein layers, pH, and ionic strength, but when it occurs, desorption of adsorbed mAbs can lead to denaturation and aggregation.…”

Section: Interfacesmentioning

confidence: 99%

“…The dilution of excipients that stabilize the protein (e.g., surfactants) and the use of destabilizing vehicle solutions (e.g., dextrose solution that may lead to protein glycosylation) can result in protein instability, especially when the drug formulation is added to an infusion bag. 17,29,85,126 For example, bevacizumab and trastuzumab diluted in 5% dextrose were shown to undergo rapid aggregation when mixed in vitro to human plasma. However, the aggregation mechanisms involved seemed to be linked to pH-dependent precipitation of plasma proteins, secondarily causing antibody aggregation.…”

Section: Excipientsmentioning

confidence: 99%

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Physicochemical Stability of Monoclonal Antibodies: A Review

Basle

Chennell

Tokhadzé

et al. 2020

Journal of Pharmaceutical Sciences

281

162

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Monoclonal antibodies (mAbs) are subject to instability issues linked to their protein nature. In this work, we review the different mechanisms that can be linked to monoclonal antibodies instability, the parameters, and conditions affecting their stability (protein structure and concentration, temperature, interfaces, light exposure, excipients and contaminants, and agitation) and the different analytical methods used for appropriate physicochemical stability studies: physical stability assays (aggregation, fragmentation, and primary, secondary, and tertiary structure analysis), chemical stability assays and quantitative assays. Finally, data from different published stability studies of mAbs formulations, either in their reconstituted form, or in diluted ready to administer solutions, was compiled. Overall, the physicochemical stability of mAbs is linked to numerous factors such as formulation, environment, and manipulations, and must be thoroughly investigated using several complementary analytical techniques, each of which allowing specific characterization information to be harvested. Several stability studies have been published, some of them showing possibilities of extended stability. However, those data should be questioned due to potential lacks in study methodology.

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Section: Methods For Investigating Mab Stabilitymentioning

confidence: 99%

Section: Methods For Investigating Mab Stabilitymentioning

confidence: 99%

Section: Interfacesmentioning

confidence: 99%

Section: Excipientsmentioning

confidence: 99%

See 2 more Smart Citations

Physicochemical Stability of Monoclonal Antibodies: A Review

Basle

Chennell

Tokhadzé

et al. 2020

Journal of Pharmaceutical Sciences

281

162

View full text Add to dashboard Cite

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“…Therefore, physicochemical stability, microbial proliferation, and recovery of activity after dilution are typically evaluated during drug development process. 12 This provides the rationale for the recommendation of in-use time in the PI.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical stability of pembrolizumab admixture solution in normal saline intravenous infusion bag

Sundaramurthi

Chadwick²,

Narasimhan

2019

J Oncol Pharm Pract

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Introduction Pembrolizumab is an anti-PD-1 monoclonal antibody, approved and under development for numerous indications in oncology. It is available as either lyophilized powder for reconstitution or ready-to-use solution. Both are required to be diluted in saline or dextrose solution prior to intravenous infusion. After dilution, the recommendation per summary of product characteristics is 24 h at 2–8℃ and 6 h at room temperature. The purpose of this study was to investigate the physicochemical stability of pembrolizumab diluted solution (1 mg/mL) at both refrigerated and room temperature conditions for an extended period. Methods Under aseptic conditions, pembrolizumab was diluted in 250 mL of saline injection in polyolefin bags to obtain the final protein concentration of 1 mg/mL. Thus, prepared bags were then stored at either 5℃ ± 3℃, refrigerator exposing the product to ambient light or room temperature (20℃ ± 3℃) on the benchtop. Results Using several analytical methods, it was demonstrated that pembrolizumab solution for infusion, diluted in normal saline can be stored in polyolefin infusion bags for at least 1 week at 5℃ or RT with no evidence of chemical or physical instability. No aggregation was observed. Conclusion Thus, the practical use of aseptically prepared diluted pembrolizumab in saline can be safely extended to optimize the workload of centralized preparation units and to minimize costs. However, it is the responsibility of the end-user to maintain overall quality of prepared admixture solution that is administered to patient, by following aseptic compounding process as recommended in the packaging insert.

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