Development of a quantitative mass spectrometry multi-attribute method for characterization, quality control testing and disposition of biologics

Rogers, Richard S.; Nightlinger, Nancy S.; Livingston, Brittney; Campbell, Phil; Bailey, Robert W.; Balland, Alain

doi:10.1080/19420862.2015.1069454

Cited by 191 publications

(207 citation statements)

References 29 publications

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“…Similarly, MAM can facilitate the monitoring of host cell proteins (HCPs) with immunogenicity or safety risks, and for any HCPs at unacceptable levels, MAM can aid the optimization of purification processes for greater clearance (32). In addition to being an excellent formulation screening tool, MAM is now widely used to monitor specific oxidation, deamidation, isomerization, and/or succinimide formation events that can impact product potency and establish appropriate product expiries to mitigate their impact (8,10,(12)(13)(14)32,33).…”

Section: Mam Implementationmentioning

confidence: 99%

A View on the Importance of “Multi-Attribute Method” for Measuring Purity of Biopharmaceuticals and Improving Overall Control Strategy

Rogers

Abernathy

Richardson

et al. 2017

AAPS J

126

122

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Abstract.Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner. Recently, a liquid chromatography-mass spectrometry (LC-MS) multi-attribute method (MAM) has been developed and designed for improved simultaneous detection, identification, quantitation, and quality control (monitoring) of molecular attributes (Rogers et al. MAbs 7(5): 2015). Based on peptide mapping principles, this powerful tool represents a true advancement in testing methodology that can be utilized not only during product characterization, formulation development, stability testing, and development of the manufacturing process, but also as a platform quality control method in dispositioning clinical materials for both innovative biotherapeutics and biosimilars.KEY WORDS: biotherapeutic; mass spectrometry; multi-attribute method; quality by design.To date, multi-attribute method (MAM) has been applied to several early stage clinical programs with different classes of protein therapeutics and compared to current practices. This experience shows that the MAM technology can be utilized for different types of protein therapeutics delivering highly specific and quantitative information, which is invaluable during process development and essential for molecular characterization. Data has also been generated to support its use for release and stability in alignment with Quality by Design (QbD) principles. Utilizing recent advances in the technology, research, and development labs, in industry, has generated convincing data that MAM would be highly beneficial in a cGMP environment. This article will summarize the advantages of MAM relative to conventional product testing approaches. We recommend that MAM, unlike conventional purity methods, be used to specifically monitor and quantify molecular product quality attributes and product/process-related impurities. This increased specificity for attributes with increased relevance to safety and efficacy can lead to better product/process understanding, shorter process and product development timelines, and an improved control strategy by improving specificity of the measurement. MAM OVERVIEWReduced LC-MS-based peptide mapping methods have been used in academia and the industry for several decades. Biopharmaceutical companies are increasingly using quantitative LC-MS-based peptide mapping methods for clinical material characterization, as well as release and stability testing (1-7). Quantit...

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Section: Mam Implementationmentioning

confidence: 99%

A View on the Importance of “Multi-Attribute Method” for Measuring Purity of Biopharmaceuticals and Improving Overall Control Strategy

Rogers

Abernathy

Richardson

et al. 2017

AAPS J

126

122

View full text Add to dashboard Cite

show abstract

“…In contrast, a single LC-MS based MAM can assess many PQAs simultaneously, including many post-translational modifications (PTMs). Results have shown that data generated using either the LC-MS MAM or conventional analytical methods are comparable [20]. Thus, MAM can decrease the number of assays used during the drug development and potentially reduce costs.…”

mentioning

confidence: 76%

“…The LC-MS MAM approach can be applied to all stages of a therapeutic protein development, including candidate selection, process development, stability and comparability assessment, quality control, and drug disposition. For example, LC-MS MAM has been used for characterization and relative quantification of amino acid modifications and glycoform distribution of monoclonal antibodies [20]. LC-MS MAM can also be used to monitor lysine glycation of mAb in bioreactors.…”

mentioning

confidence: 99%

LC-MS multi-attribute method for characterization of biologics

Xu¹,

Qiu²,

Li³

2017

J Appl Bioanal

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Biologics, such as therapeutic monoclonal antibodies (mAbs), are complex protein molecules produced from mammalian tissue culture cells through recombinant DNA technology. As a result of naturally-occurring molecular heterogeneity as well as chemical and enzymatic modifications during manufacture, process, and storage, there are many product quality attributes (PQAs) presenting in therapeutic proteins. These PQAs can potentially include: product-related structural heterogeneity related to glycosylation profile, disulfide bond pattern, and higher order structure; product-related degradants and impurities, such as deamidation, oxidation, sequence variants; and process-related impurities and residuals, such as host cell protein (HCP), host cell DNA, and residual protein A [1]. Regulatory agencies have recently recommended a Quality by Design (QbD) approach for the manufacturing of therapeutic molecules [2][3][4][5], which requires in-depth understanding of these PQAs at the molecular level to ensure that the drug products meet the desired safety and efficacy profiles [6]. The QbD guidelines require development of a quality target product profile (QTPP) that identifies critical quality attributes (CQAs) and implementation of control strategies to ensure that the QTPP is achieved. QTPP is a prospective summary of the quality characteristics of a drug product to be achieved to ensure the desired quality, safety and efficacy [2]. QTPP describes the design criteria for the product and forms the basis for determination of the CQAs, critical process parameters (CPPs), and control strategy. A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality [2]. A CQA is identified based on the severity of harm to a patient resulting from failure to meet that quality attribute. Analytical methods to identify and quantify these PQAs, especially CQAs, are essential for the development of QTPP and implementation of control strategies. Conventionally, a panel of analytical techniques such as size-exclusion chromatography (SEC), ion-exchange chromatography (IEX), hydrophobic-interaction chromatography (HIC), or capillary electrophoresis (CE) is typically used to monitor product quality consistency as well as product variants and impurities at the intact protein level [7][8][9]. Although these chromatographic and electrophoretic methods widely are used as release assays for biologics [10], they cannot directly monitor biologically relevant PQAs at the molecular level, which does not align with QbD principles. The complexity of biologics attributes and the implementation of QbD strategies demand a multi-attribute method (MAM) that can monitor multiple biologics PQAs at the molecular level in a single assay. Coupling liquid chromatography (LC) to high resolution and high accuracy mass spectrometry (MS) techniques, LC-MS based peptide mapping has become a MAM approach that can identify and quantify multiple ...

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“…[25][26][27] Mass spectrometry yields information rich datasets when utilized to optimize bioprocessing. 28 This technique has made its way into routine use in production processes and has been a major addition to the CGT research and development, despite the high initial costs of setup. 25 The wealth of data provided by this technique has facilitated the bioprocessing of the existing generation of biologics immensely and a similar advance in monitoring technology could augment CGT manufacturing.…”

Section: The Current State-of-art Of Sensory Technologymentioning

confidence: 99%

Enhancing cell and gene therapy manufacture through the application of advanced fluorescent optical sensors (Review)

Harrison

Chauhan

2017

Biointerphases

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Cell and gene therapies (CGTs) are examples of future therapeutics that can be used to cure or alleviate the symptoms of disease, by repairing damaged tissue or reprogramming defective genetic information. However, despite the recent advancements in clinical trial outcomes, the path to wide-scale adoption of CGTs remains challenging, such that the emergence of a “blockbuster” therapy has so far proved elusive. Manufacturing solutions for these therapies require the application of scalable and replicable cell manufacturing techniques, which differ markedly from the existing pharmaceutical incumbent. Attempts to adopt this pharmaceutical model for CGT manufacture have largely proved unsuccessful. The most significant challenges facing CGT manufacturing are process analytical testing and quality control. These procedures would greatly benefit from improved sensory technologies that allow direct measurement of critical quality attributes, such as pH, oxygen, lactate and glucose. In turn, this would make manufacturing more robust, replicable and standardized. In this review, the present-day state and prospects of CGT manufacturing are discussed. In particular, the authors highlight the role of fluorescent optical sensors, focusing on their strengths and weaknesses, for CGT manufacture. The review concludes by discussing how the integration of CGT manufacture and fluorescent optical sensors could augment future bioprocessing approaches.

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Development of a quantitative mass spectrometry multi-attribute method for characterization, quality control testing and disposition of biologics

Cited by 191 publications

References 29 publications

A View on the Importance of “Multi-Attribute Method” for Measuring Purity of Biopharmaceuticals and Improving Overall Control Strategy

A View on the Importance of “Multi-Attribute Method” for Measuring Purity of Biopharmaceuticals and Improving Overall Control Strategy

LC-MS multi-attribute method for characterization of biologics

Enhancing cell and gene therapy manufacture through the application of advanced fluorescent optical sensors (Review)

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