Viscosity of concentrated therapeutic protein compositions

Ježek, Jan; Rides, M; Derham, Barry K.; Moore, Jonathan D.; Cerasoli, Elenora; Simler, Robert; Pérez-Ramírez, Bernardo

doi:10.1016/j.addr.2011.09.008

Cited by 120 publications

(91 citation statements)

References 81 publications

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“…This significant reduction in injection volumes requires increase in formulation concentration to achieve the desired doses. 12 Higher concentrations can introduce significant burdens on the formulation and the device design space and often limit the types of approaches that can be used to provide an acceptable stability and delivery profile. At higher concentrations, enhanced attractive intermolecular protein-protein interactions (e.g., charge-charge and hydrophobic interactions) often increase the propensity of a molecule to undergo reversible self-association (RSA), a phenomenon in which native, noncovalent, and reversible oligomeric species are formed.…”

Section: Introductionmentioning

confidence: 99%

A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies

Esfandiary¹,

Hayes²,

Parupudi³

et al. 2013

Journal of Pharmaceutical Sciences

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In addition to controlling typical instabilities such as physical and chemical degradations, understanding monoclonal antibodies' (mAbs) solution behavior is a key step in designing and developing process and formulation controls during their development. Reversible self-association (RSA), a unique solution property in which native, reversible oligomeric species are formed as a result of the noncovalent intermolecular interactions has been recognized as a developability risk with the potential to negatively impact manufacturing, storage stability, and delivery of mAbs. Therefore, its identification, characterization, and mitigation are key requirements during formulation development. Considering the large number of available analytical methods, choice of the employed technique is an important contributing factor for successful investigation of RSA. Herein, a multitechnique (dynamic light scattering, multiangle static light scattering, and analytical ultracentrifugation) approach is employed to comprehensively characterize the self-association of a model immunoglobulin G1 molecule. Studies herein discuss an effective approach for detection and characterization of RSA during biopharmaceutical development based on the capabilities of each technique, their complementarity, and more importantly their suitability for the stage of development in which RSA is investigated.

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Section: Introductionmentioning

confidence: 99%

A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies

Esfandiary¹,

Hayes²,

Parupudi³

et al. 2013

Journal of Pharmaceutical Sciences

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show abstract

“…In particular, the irreversible aggregation and the reversible self-association of protein molecules are often accompanied by an increase in the solution viscosity [62,83]. This effect, which complicates the handling and the delivery of the drug product, is even more pronounced at the high protein concentrations that are typically encountered in therapeutic protein formulations [84][85][86].…”

Section: Occupied Volume Fraction To Correlate Aggregation With Viscomentioning

confidence: 99%

A multiscale view of therapeutic protein aggregation: A colloid science perspective

Nicoud

Owczarz

Arosio

et al. 2015

Biotechnology Journal

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The formation of aggregates in protein-based pharmaceuticals is a major issue that can compromise drug safety and drug efficacy. With a view to improving protein stability, considerable effort is put forth to unravel the fundamental mechanisms underlying the aggregation process. However, therapeutic protein aggregation is a complex multistep phenomenon that involves time and length scales spanning several orders of magnitude, and strategies addressing protein aggregation inhibition are currently still largely empirical in practice. Here, we review how key concepts developed in the frame of colloid science can be applied to gain knowledge on the kinetics and thermodynamics of therapeutic protein aggregation across different length scales. In particular, we discuss the use of coarse-grained molecular interaction potentials to quantify protein colloidal stability. We then show how population balance equations simulations can provide insights into the mechanisms of aggregate formation at the mesoscale, and we highlight the strength of the concept of fractal scaling to quantify irregular aggregate morphologies. Finally, we correlate the macroscopic rheological properties of protein solutions with the occupied volume fraction and the aggregate structure. Overall, this work illustrates the power and limitations of colloidal approaches in the multiscale description of the aggregation of therapeutic proteins.

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“…The main advantage of this method is that with a small gap between plates the volume required for a measurement is greatly reduced, and that very high shear rates can be achieved with the smaller gap size. Some of the problems that can occur with this method, such as errors in gap size for small gaps, are summarized by Jezek et al (2011).…”

Section: Rotational Rheometersmentioning

confidence: 99%

The molecular basis of high viscosity of monoclonal antibodies (mAbs) at high concentration

Shire¹

2015

Monoclonal Antibodies

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Viscosity of concentrated therapeutic protein compositions

Cited by 120 publications

References 81 publications

A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies

A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies

A multiscale view of therapeutic protein aggregation: A colloid science perspective

The molecular basis of high viscosity of monoclonal antibodies (mAbs) at high concentration

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