Special Issue "Biopharmaceutical Process Development"

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A special issue of Bioengineering (ISSN 2306-5354).

Deadline for manuscript submissions: closed (30 September 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Christoph Herwig

Department of Chemical Engineering, Research Area Biochemical Engineering, Vienna University of Technology, Austria
Website | E-Mail
Interests: integrated bioprocess development; monitoring; modeling and control of bioprocesses; data–information–knowledge; scale down models

Special Issue Information

Dear Colleagues,

Process development for the industrial production of biopharmaceutical drug substances is still time consuming. In addition, the process continues to have a high risk to fail at the manufacturing scale, due to high variability of biological origin and of the various input materials.

Not long ago, the regulatory bodies launched the Quality by Design (QbD) initiative, which proposes a systematic, science driven and risk based approach to process development. However, the current interpretation of QbD is mainly data driven, using statistical approaches, identifying correlations (“How” parameters and attributes are correlated), without emphasizing “Why”. Therefore, QbD is perceived to be laborious and does not reach the full potential of its intention.

The current special issue emphasizes scientific and risk based methods to accelerate bioprocess development while allowing a mechanistic approach for process understanding and safe scale up. As a consequence, it is reviving QbD also as a new business opportunity.

We look forward to receiving your contributions to these cutting edge issues.

Prof. Dr. Christoph Herwig
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Bioengineering is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. For the first couple of issues the Article Processing Charge (APC) will be waived for well-prepared manuscripts. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • integrated bioprocess development
  • microbial and mammalian host organisms
  • biopharmaceutical drugs
  • upstream and downstream processing
  • scale up, scale down models
  • multivariate explorative analysis
  • mechanistic modeling
  • hybrid modeling
  • bioprocess control

Published Papers (5 papers)

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Research

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Open AccessArticle Modeling of Filtration Processes—Microfiltration and Depth Filtration for Harvest of a Therapeutic Protein Expressed in Pichia pastoris at Constant Pressure
Bioengineering 2014, 1(4), 260-277; doi:10.3390/bioengineering1040260
Received: 20 October 2014 / Revised: 28 November 2014 / Accepted: 3 December 2014 / Published: 8 December 2014
Cited by 1 | PDF Full-text (552 KB) | HTML Full-text | XML Full-text
Abstract
Filtration steps are ubiquitous in biotech processes due to the simplicity of operation, ease of scalability and the myriad of operations that they can be used for. Microfiltration, depth filtration, ultrafiltration and diafiltration are some of the most commonly used biotech unit operations.
[...] Read more.
Filtration steps are ubiquitous in biotech processes due to the simplicity of operation, ease of scalability and the myriad of operations that they can be used for. Microfiltration, depth filtration, ultrafiltration and diafiltration are some of the most commonly used biotech unit operations. For clean feed streams, when fouling is minimal, scaling of these unit operations is performed linearly based on the filter area per unit volume of feed stream. However, for cases when considerable fouling occurs, such as the case of harvesting a therapeutic product expressed in Pichia pastoris, linear scaling may not be possible and current industrial practices involve use of 20–30% excess filter area over and above the calculated filter area to account for the uncertainty in scaling. In view of the fact that filters used for harvest are likely to have a very limited lifetime, this oversizing of the filters can add considerable cost of goods for the manufacturer. Modeling offers a way out of this conundrum. In this paper, we examine feasibility of using the various proposed models for filtration of a therapeutic product expressed in Pichia pastoris at constant pressure. It is observed that none of the individual models yield a satisfactory fit of the data, thus indicating that more than one fouling mechanism is at work. Filters with smaller pores were found to undergo fouling via complete pore blocking followed by cake filtration. On the other hand, filters with larger pores were found to undergo fouling via intermediate pore blocking followed by cake filtration. The proposed approach can be used for more accurate sizing of microfilters and depth filters. Full article
(This article belongs to the Special Issue Biopharmaceutical Process Development)
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Open AccessArticle Characterization and Application of a Disposable Rotating Bed Bioreactor for Mesenchymal Stem Cell Expansion
Bioengineering 2014, 1(4), 231-245; doi:10.3390/bioengineering1040231
Received: 11 September 2014 / Revised: 18 November 2014 / Accepted: 25 November 2014 / Published: 27 November 2014
PDF Full-text (7164 KB) | HTML Full-text | XML Full-text
Abstract
Recruitment of mesenchymal stromal cells (MSC) into the field of tissue engineering is a promising development since these cells can be expanded vivo to clinically relevant numbers and, after expansion, retain their ability to differentiate into various cell lineages. Safety requirements and the
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Recruitment of mesenchymal stromal cells (MSC) into the field of tissue engineering is a promising development since these cells can be expanded vivo to clinically relevant numbers and, after expansion, retain their ability to differentiate into various cell lineages. Safety requirements and the necessity to obtain high cell numbers without frequent subcultivation of cells raised the question of the possibility of expanding MSC in one-way (single-use) disposable bioreactors. In this study, umbilical cord-derived MSC (UC-MSC) were expanded in a disposable Z 2000 H bioreactor under dynamic conditions. Z was characterized regarding residence time and mixing in order to evaluate the optimal bioreactor settings, enabling optimal mass transfer in the absence of shear stress, allowing an reproducible expansion of MSC, while maintaining their stemness properties. Culture of the UC-MSC in disposable Z 2000 H bioreactor resulted in a reproducible 8-fold increase of cell numbers after 5 days. Cells were shown to maintain specific MSC surface marker expression as well as trilineage differentiation potential and lack stress-induced premature senescence. Full article
(This article belongs to the Special Issue Biopharmaceutical Process Development)
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Open AccessArticle An Integrated Downstream Process Development Strategy along QbD Principles
Bioengineering 2014, 1(4), 213-230; doi:10.3390/bioengineering1040213
Received: 31 July 2014 / Revised: 18 September 2014 / Accepted: 17 October 2014 / Published: 24 October 2014
PDF Full-text (939 KB) | HTML Full-text | XML Full-text
Abstract
The development, optimization, and analysis of downstream processes are challenged by a high number of potentially critical process parameters that need to be investigated using lab-scale experiments. These process parameters are spread across multiple unit operations and potentially show interactions across unit operations.
[...] Read more.
The development, optimization, and analysis of downstream processes are challenged by a high number of potentially critical process parameters that need to be investigated using lab-scale experiments. These process parameters are spread across multiple unit operations and potentially show interactions across unit operations. In this contribution, we present a novel strategy for bioprocess development that considers the risk of parameter interactions across unit operations for efficient experimental design. A novel risk assessment tool (interaction matrix) is introduced to the Quality by Design (QbD) workflow. Using this tool, the risk of interaction across unit operations is rated. Subsequently, a design of experiments (DoE) across unit operations is conducted that has the power to reveal multivariate interdependencies. The power of the presented strategy is demonstrated for protein isolation steps of an inclusion body process, focusing on the quality attribute inclusion body purity. The concentration of Triton X-100 in the course of inclusion body (IB) purification was shown to interact with the g-number of the subsequent centrifugation step. The presented strategy targets a holistic view on the process and allows handling of a high number of experimental parameters across unit operations using minimal experimental effort. It is generically applicable for process development along QbD principles. Full article
(This article belongs to the Special Issue Biopharmaceutical Process Development)
Open AccessArticle Biopharmaceutical Process Optimization with Simulation and Scheduling Tools
Bioengineering 2014, 1(4), 154-187; doi:10.3390/bioengineering1040154
Received: 29 July 2014 / Revised: 9 September 2014 / Accepted: 22 September 2014 / Published: 29 September 2014
Cited by 3 | PDF Full-text (1637 KB) | HTML Full-text | XML Full-text
Abstract
Design and assessment activities associated with a biopharmaceutical process are performed at different levels of detail, based on the stage of development that the product is in. Preliminary “back-of-the envelope” assessments are performed early in the development lifecycle, whereas detailed design and evaluation
[...] Read more.
Design and assessment activities associated with a biopharmaceutical process are performed at different levels of detail, based on the stage of development that the product is in. Preliminary “back-of-the envelope” assessments are performed early in the development lifecycle, whereas detailed design and evaluation are performed prior to the construction of a new facility. Both the preliminary and detailed design of integrated biopharmaceutical processes can be greatly assisted by the use of process simulators, discrete event simulators or finite capacity scheduling tools. This report describes the use of such tools for bioprocess development, design, and manufacturing. The report is divided into three sections. Section One provides introductory information and explains the purpose of bioprocess simulation. Section Two focuses on the detailed modeling of a single batch bioprocess that represents the manufacturing of a therapeutic monoclonal antibody (MAb). This type of analysis is typically performed by engineers engaged in the development and optimization of such processes. Section Three focuses on production planning and scheduling models for multiproduct plants. Full article
(This article belongs to the Special Issue Biopharmaceutical Process Development)

Review

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Open AccessReview Trends in Upstream and Downstream Process Development for Antibody Manufacturing
Bioengineering 2014, 1(4), 188-212; doi:10.3390/bioengineering1040188
Received: 1 August 2014 / Revised: 12 September 2014 / Accepted: 29 September 2014 / Published: 1 October 2014
Cited by 24 | PDF Full-text (538 KB) | HTML Full-text | XML Full-text
Abstract
A steady increase of product titers and the corresponding change in impurity composition represent a challenge for development and optimization of antibody production processes. Additionally, increasing demands on product quality result in higher complexity of processes and analytics, thereby increasing the costs for
[...] Read more.
A steady increase of product titers and the corresponding change in impurity composition represent a challenge for development and optimization of antibody production processes. Additionally, increasing demands on product quality result in higher complexity of processes and analytics, thereby increasing the costs for product work-up. Concentration and composition of impurities are critical for efficient process development. These impurities can show significant variations, which primarily depend on culture conditions. They have a major impact on the work-up strategy and costs. The resulting “bottleneck” in downstream processing requires new optimization, technology and development approaches. These include the optimization and adaptation of existing unit operations respective to the new separation task, the assessment of alternative separation technologies and the search for new methods in process development. This review presents an overview of existing methods for process optimization and integration and indicates new approaches for future developments. Full article
(This article belongs to the Special Issue Biopharmaceutical Process Development)

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