Determination of critical quality attributes for monoclonal antibodies using quality by design principles

Alt, Nadja; Zhang, Taylor Y.; Motchnik, Paul A.; Taticek, Ron; Quarmby, Valerie; Schlothauer, Tilman; Beck, Hermann; Emrich, Thomas; Harris, Reed J.

doi:10.1016/j.biologicals.2016.06.005

Cited by 218 publications

(134 citation statements)

References 52 publications

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“…This raises the question whether current critical quality attribute approaches 62,63 , which focus on assessment of low level alterations in chemical modifications (single digit % abundance range) in formulation, realistically add value to maintaining product quality from a patient’s safety perspective.…”

Section: Discussionmentioning

confidence: 99%

Assessment of susceptible chemical modification sites of trastuzumab and endogenous human immunoglobulins at physiological conditions

et al. 2018

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The quality control testing of chemical degradations in the bio-pharmaceutical industry is currently under controversial debate. Here we have systematically applied in vitro and in vivo stress conditions to investigate the influence of protein degradation on structure-function. Extensive purification and characterization enabled identification and functional assessment of the physiological degradation of chemical modification sites in the variable complementarity-determining regions (CDRs) and conserved region of trastuzumab. We demonstrate that the degradation of the solvent-accessible residues located in the CDR and the conserved fragment crystallizable region (Fc) occurs faster in vivo (within days) compared to the levels observed for bio-process and real-time storage conditions. These results hence question the rationality of extreme monitoring of low level alterations in such chemical modifications as critical patient safety parameters in product quality control testing, given that these modifications merely mirror the natural/physiological aging process of endogenous antibodies.

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Section: Discussionmentioning

confidence: 99%

Assessment of susceptible chemical modification sites of trastuzumab and endogenous human immunoglobulins at physiological conditions

et al. 2018

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“…Since both events are critical components of the FcRnIgG interaction, they should be included in a comprehensive analytical strategy as part of the candidate selection, quality control of therapeutic monoclonal antibodies (mAbs) or during quality by design studies [7][8][9]. Binding of IgG antibodies at low pH to FcRn is often characterized by surface plasmon resonance (SPR) binding assays [10][11][12][13].…”

mentioning

confidence: 99%

Evaluation of an Fcrn Affinity Chromatographic Method for Igg1-Type Antibodies and Evaluation of Igg Variants

Cymer

Schlothauer²,

Knaupp³

et al. 2017

Bioanalysis

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Aim:The neonatal Fc-receptor (FcRn) mediates long serum half-life of therapeutic IgG-type antibodies. This interaction represents a critical quality attribute in terms of pharmacokinetics and should be covered by respective quality control strategies. Antibodies are taken up by cells unspecifically and can bind to FcRn in early endosomes preventing lysosomal degradation and allowing release back into circulation. Reflecting this complex cycle in an in vitro assay strategy represents a challenging task. Methodology: We report the qualification of an FcRn affinity chromatographic method and, for the first time, establish a noncriticality window. We analyzed different IgG-type antibodies, subtypes, glycoforms as well as mutants. Conclusion: The FcRn affinity chromatographic method allows the assessment of mAb samples with respect to their pH-dependent FcRn interaction. Furthermore, the method's capabilities and current limitations are discussed.

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“…As a result, they are critical to the safety, efficacy, and pharmacokinetics of the drug. Characteristics important to these parameters are known as "critical quality attributes" [17]. These include the chemical structures, which are determined by the DNA template used, the cell line, and the manufacturing process.…”

Section: Critical Quality Attributesmentioning

confidence: 99%

A Primer on Biosimilars: FDA-Approved and those in the Pipeline

Pillai¹,

Malcom²,

Cox³

2017

SOJPPS

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Biologics have made groundbreaking treatments possible, for several difficult to treat conditions. However, they are very expensive, and biosimilars are expected to push prices down like the generics of small molecule drugs did in the past, replacing more costly brandname drugs. Biosimilars are not just generic replacement for brand name biologics, and their effect on cost reduction will be much more modest. Biologics, made from living organisms, are much larger in size and complex molecules than small molecule drugs which are easily synthesized, characterized and copied. Biosimilars may be highly similar to the original licensed biologic product but not a fingerprint copy; therefore, some differences are expected. This article describes the criteria for establishing similarity and interchangeability, current regulations and the clinical and pharmacoeconomic aspects of the four FDA approved biosimilars in 2015 and 2016.

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Determination of critical quality attributes for monoclonal antibodies using quality by design principles

Cited by 218 publications

References 52 publications

Assessment of susceptible chemical modification sites of trastuzumab and endogenous human immunoglobulins at physiological conditions

Assessment of susceptible chemical modification sites of trastuzumab and endogenous human immunoglobulins at physiological conditions

Evaluation of an Fcrn Affinity Chromatographic Method for Igg1-Type Antibodies and Evaluation of Igg Variants

A Primer on Biosimilars: FDA-Approved and those in the Pipeline

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