Subvisible (2-100 μm) Particle Analysis During Biotherapeutic Drug Product Development: Part 1, Considerations and Strategy

Narhi, Linda O.; Corvari, Vincent; Ripple, Dean C.; Afonina, Nataliya; Cecchini, Irene; DeFelippis, Michael R.; Garidel, Patrick; Herre, Andrea; Koulov, Atanas V.; Lubiniecki, Tony; Mahler, Hanns‐Christian; Mangiagalli, P.; Nesta, Douglas P.; Pérez-Ramírez, Bernardo; Polozova, Alla; Rossi, Mara; Schmidt, Roland; Simler, Robert; Singh, Satish K.; Spitznagel, Thomas M.; Weiskopf, Andrew; Wuchner, Klaus

doi:10.1002/jps.24437

Cited by 66 publications

(32 citation statements)

References 53 publications

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“…In solutions for injection supplied in containers with a nominal content of less than 100 mL, particles !10 mm and !25 mm are controlled by a light obscuration (LO) method at or below 6000 particles/container and 600 particles/container, respectively. In addition to LO, various methods such as flow imaging, qLD, resonance mass measurement, and nanoparticle tracking analysis are reported to be useful for detection and quantification of subvisible particles of less than 10 mm in size, [34][35][36][37] although it remains unclear what type of subvisible particles should be controlled for and where to set the optimal cutoff for the number of allowable subvisible particles in a product.…”

Section: Discussionmentioning

confidence: 99%

Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

Tada

Aoyama

Ishii‐Watabe

2020

Journal of Pharmaceutical Sciences

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Protein aggregates are a potential risk factor for immunogenicity. The measurement, characterization, and control of protein aggregates in drug products are indispensable for the development of biopharmaceuticals, including therapeutic mAbs. In this study, Fcg receptor (FcgR)-expressing reporter cell lines were used to analyze the FcgR-activation properties of mAb aggregates. Comparison of aggregates of mAbs harboring different IgG subclasses revealed that the FcgR-activation profiles of the mAb aggregates were dependent on IgG subclass. In addition, aggregates of Fc-engineered mAb with enhanced FcgRactivation properties exhibited stronger activation of FcgRs than was observed in the wild-type aggregates, whereas aggregates of Fc-engineered mAb with decreased FcgR-activation properties showed reduced activation. These results suggest that FcgR activation by mAb aggregates depends greatly on the Fc functions of the native (nonaggregated) mAbs. We also showed that aggregates of mAbs smaller than 1 mm in size have the potential to directly activate FcgRs. Unintended immune cell activation can be induced on account of FcgR activation by mAb aggregates and such FcgR activation may contribute to immunogenicity, and therefore, analysis of the FcgR-activation properties of mAb aggregates using FcgR-expressing reporter cell lines is a promising approach for the characterization of mAb aggregates.

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Section: Discussionmentioning

confidence: 99%

Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

Tada

Aoyama

Ishii‐Watabe

2020

Journal of Pharmaceutical Sciences

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“…The current specifications require that particles >10 µm and 25 µm in size are reported (United States Pharmacopoeia < 788 >). Particles <10 µm in size are currently not required to be monitored; however, their significance in autoimmune responses and product quality is an area of significant debate . The emergence of technologies such as MFI enables monitoring of particles as small as 1 µm in size, and we therefore report SVPs in the range 1–100 µm in size.…”

Section: Resultsmentioning

confidence: 98%

Application of ER Stress Biomarkers to Predict Formulated Monoclonal Antibody Stability

Talbot

Mead

Davies³

et al. 2019

Biotechnology Journal

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For a therapeutic monoclonal antibody (mAb) to reach the clinic, the molecule must be produced at an appropriate yield and quality, then formulated to maintain efficacy and stability. The formation of subvisible particles (SVPs) can impact product stability and is monitored during formulation development; however, the potential of a mAb to form such species can be influenced throughout the whole bioprocess. The levels of intracellular endoplasmic reticulum (ER) stress perceived by Chinese hamster ovary (CHO) cell lines, the day of mAb harvest, and the relationship with subsequent product stability of two mAbs (denoted A and B), as determined by the SVP content after accelerated stability studies, are reported here. Here, it is shown that the propensity of mAb A to form SVPs can be predicted by transcript expression of biomarkers of cellular ER stress, heavy/light-chain transcript and polypeptide amounts, and harvest day. Further, mAb A material harvested on day 9 of culture was more stable, in terms of SVP formation, than material harvested on day 13. These data suggest that ER stress perceived by CHO cells can reflect the stability of a mAb, and that biomarkers of such stress could help define culture harvest time as a tool to control SVP formation in formulated mAbs.

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“…Protein pharmaceuticals can degrade via multiple chemical and physical processes, and detailed knowledge of these processes is critical to prevent degradation and to maintain stability of formulations . The last years have witnessed significant progress in our understanding of physical degradation processes, for example leading to aggregation and particle formation, in part due to the development of new analytical methodology and the critical evaluation of its potential and limitations . In contrast, the characterization of chemical degradation processes is far from complete, for the most part due to the continuous discovery of new reaction pathways and products, which can be unique to specific protein sequences.…”

Section: Introductionmentioning

confidence: 99%

Novel chemical degradation pathways of proteins mediated by tryptophan oxidation: tryptophan side chain fragmentation

Schöneich

2017

Journal of Pharmacy and Pharmacology

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Objectives This minireview focuses on novel degradation pathways of proteins in solution via intermediary tryptophan (Trp) radical cations, which are generated via photo-induced electron transfer to suitable acceptors such as disulfide bonds. Methods Gas-phase mass spectrometry studies had indicated the potential for Trp radical cations to fragment via release of 3-methylene-3H-indol-1-ium from the side chain. HPLC-MS/MS analysis demonstrates that analogous fragmentation reactions occur during the exposure of peptides and proteins to light or accelerated stability testing. Key findings The light exposure of selected peptides and monoclonal antibodies leads to the conversion of Trp to glycine (Gly) or glycine hydroperoxide (GlyOOH), where GlyOOH could be reduced to hydroxyglycine, which undergoes subsequent cleavage. Product formation is consistent with C a -C b fragmentation of intermediary Trp radical cations. For the peptide octreotide and specific glycoforms of IgG1 Fc domains, Trp side chain cleavage in aqueous solution is indicated by the formation of 3-methyleneindolenine (3-MEI), which adds to nucleophilic side chains, for example to Lys residues adjacent to the original Trp residues. Conclusions Trp side chain cleavage leads to novel reaction products on specific peptide and protein sequences, which may have consequences for potency and immunogenicity.

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Subvisible (2-100 μm) Particle Analysis During Biotherapeutic Drug Product Development: Part 1, Considerations and Strategy

Cited by 66 publications

References 53 publications

Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

Application of ER Stress Biomarkers to Predict Formulated Monoclonal Antibody Stability

Novel chemical degradation pathways of proteins mediated by tryptophan oxidation: tryptophan side chain fragmentation

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