Process analytical technology (PAT) for biopharmaceutical products: Part I. concepts and applications

Read, Erik K.; Park, J.T.; Shah, Rakhi B.; Riley, B.S.; Brorson, Kurt; Rathore, Anurag S.

doi:10.1002/bit.22528

Cited by 201 publications

(123 citation statements)

References 36 publications

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“…An ideal technique should also be fully automatable, thus reducing the requirement for scientific staff to be on hand for analysis/ interpretation. 5 …”

Section: Analytical Technologies In the Biopharmaceutical Industrymentioning

confidence: 99%

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

2017

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The production of active pharmaceutical ingredients (APIs) is currently undergoing its biggest transformation in a century. The changes are based on the rapid and dramatic introduction of protein-and macromolecule-based drugs (collectively known as biopharmaceuticals) and can be traced back to the huge investment in biomedical science (in particular in genomics and proteomics) that has been ongoing since the 1970s. Biopharmaceuticals (or biologics) are manufactured using biological-expression systems (such as mammalian, bacterial, insect cells, etc.) and have spawned a large (>E35 billion sales annually in Europe) and growing biopharmaceutical industry (BioPharma). The structural and chemical complexity of biologics, combined with the intricacy of cell-based manufacturing, imposes a huge analytical burden to correctly characterize and quantify both processes (upstream) and products (downstream). In small molecule manufacturing, advances in analytical and computational methods have been extensively exploited to generate process analytical technologies (PAT) that are now used for routine process control, leading to more efficient processes and safer medicines. In the analytical domain, biologic manufacturing is considerably behind and there is both a huge scope and need to produce relevant PAT tools with which to better control processes, and better characterize product macromolecules. Raman spectroscopy, a vibrational spectroscopy with a number of useful properties (nondestructive, non-contact, robustness) has significant potential advantages in BioPharma. Key among them are intrinsically high molecular specificity, the ability to measure in water, the requirement for minimal (or no) sample pre-treatment, the flexibility of sampling configurations, and suitability for automation. Here, we review and discuss a representative selection of the more important Raman applications in BioPharma (with particular emphasis on mammalian cell culture). The review shows that the properties of Raman have been successfully exploited to deliver unique and useful analytical solutions, particularly for online process monitoring. However, it also shows that its inherent susceptibility to fluorescence interference and the weakness of the Raman effect mean that it can never be a panacea. In particular, Raman-based methods are intrinsically limited by the chemical complexity and wide analyte-concentration-profiles of cell culture media/bioprocessing broths which limit their use for quantitative analysis. Nevertheless, with appropriate foreknowledge of these limitations and good experimental design, robust analytical methods can be produced. In addition, new technological developments such as time-resolved detectors, advanced lasers, and plasmonics offer potential of new Raman-based methods to resolve existing limitations and/or provide new analytical insights.

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“…An ideal technique should also be fully automatable, thus reducing the requirement for scientific staff to be on hand for analysis/ interpretation. 5 …”

Section: Analytical Technologies In the Biopharmaceutical Industrymentioning

confidence: 99%

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

2017

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“…Therefore, functional bioprocess control in TE bioreactors, in the sense that it allows direct control over the critical quality attributes (CQAs) of the TE construct, such as proliferation rate, extra-cellular matrix production, differentiation stage, construct permeability, etc., remains a challenge due to inadequate online, non-invasive, and cost-effective monitoring tools (Glassey et al, 2011;Koutinas et al, 2012;Placzek et al, 2009;Read et al, 2010;Vojinović et al, 2006). Depending on the bioreactor setup and cell carrier or scaffold design under consideration, this can be attributed to the high technicality and/or cost of direct, online and non-destructive measurement of TE construct CQAs.…”

Section: Introductionmentioning

confidence: 98%

Model‐based cell number quantification using online single‐oxygen sensor data for tissue engineering perfusion bioreactors

Lambrechts

Papantoniou

Sonnaert

et al. 2014

Biotech & Bioengineering

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Online and non-invasive quantification of critical tissue engineering (TE) construct quality attributes in TE bioreactors is indispensable for the cost-effective up-scaling and automation of cellular construct manufacturing. However, appropriate monitoring techniques for cellular constructs in bioreactors are still lacking. This study presents a generic and robust approach to determine cell number and metabolic activity of cell-based TE constructs in perfusion bioreactors based on single oxygen sensor data in dynamic perfusion conditions. A data-based mechanistic modeling technique was used that is able to correlate the number of cells within the scaffold (R(2) = 0.80) and the metabolic activity of the cells (R(2) = 0.82) to the dynamics of the oxygen response to step changes in the perfusion rate. This generic non-destructive measurement technique is effective for a large range of cells, from as low as 1.0 × 10(5) cells to potentially multiple millions of cells, and can open-up new possibilities for effective bioprocess monitoring.

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“…1 Its principles involve understanding both the product and the process highlighting those parameters critical to a well controlled process and being able to consistently manufacture product to the required specification. 2 The application of QbD approaches to biopharmaceutical processing is relatively difficult when compared with its implementation in the small molecule pharmaceutical industry.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 The first major processing decision in the manufacture of biologics is the harvest time of an upstream process. 1 Harvest point is the boundary between the upstream and downstream process, where the physical characteristics of the host cell and fermentation broth are critical to the sequence of downstream operations that follow. It can be particularly important for intracellular proteins and materials associated with membranes such as certain vaccines.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the manufacturability of Escherichia coli high cell density fermentations

Perez-Pardo

Ali

Balasundaram

et al. 2011

Biotechnology Progress

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The physical and biological conditions of the host cell obtained at the end of fermentation influences subsequent downstream processing unit operations. The ability to monitor these characteristics is central to the improvement of biopharmaceutical manufacture. In this study, we have used a combination of techniques such as adaptive focus acoustics (AFA) and ultra scale-down (USD) centrifugation that utilize milliliter quantities of sample to obtain an insight into the interaction between cells from the upstream process and initial downstream unit operations. This is achieved primarily through an assessment of cell strength and its impact on large-scale disc stack centrifugation performance, measuring critical attributes such as viscosity and particle size distribution. An Escherichia coli fed-batch fermentation expressing antibody fragments in the periplasm was used as a model system representative of current manufacturing challenges. The weakening of cell strength during cultivation time, detected through increased micronization and viscosity, resulted in a 2.6-fold increase in product release rates from the cell (as measured by AFA) and approximately fourfold decrease in clarification performance (as measured by USD centrifugation). The information obtained allows for informed harvest point decisions accounting for both product leakages during fermentation and potential losses during primary recovery. The clarification performance results were verified at pilot scale. The use of these technologies forms a route to the process understanding needed to tailor the host cell and upstream process to the product and downstream process, critical to the implementation of quality-by-design principles.

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Process analytical technology (PAT) for biopharmaceutical products: Part I. concepts and applications

Cited by 201 publications

References 36 publications

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

Model‐based cell number quantification using online single‐oxygen sensor data for tissue engineering perfusion bioreactors

Assessment of the manufacturability of Escherichia coli high cell density fermentations

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