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Über dieses Buch

This book review series presents current trends in modern biotechnology. The aim is to cover all aspects of this interdisciplinary technology where knowledge, methods and expertise are required from chemistry, biochemistry, microbiology, genetics, chemical engineering and computer science.

Volumes are organized topically and provide a comprehensive discussion of developments in the respective field over the past 3-5 years. The series also discusses new discoveries and applications. Special volumes are dedicated to selected topics which focus on new biotechnological products and new processes for their synthesis and purification.

In general, special volumes are edited by well-known guest editors. The series editor and publisher will however always be pleased to receive suggestions and supplementary information. Manuscripts are accepted in English.

Inhaltsverzeichnis

Frontmatter

An Introduction to „Recent Trends in the Biotechnology Industry: Development and Manufacturing of Recombinant Antibodies and Proteins“

The production of the first therapeutic proteins in the early 1980s heralded the launch of the biopharmaceuticals industry. The number of approved products has grown year on year over the past three decades to now represent a significant share of the entire pharmaceuticals market. More than 200 therapeutic proteins have been approved, approximately a quarter of which are represented by monoclonal antibodies and their derivatives. In 2016, the list of the top 15 best-selling drugs included more than eight biologics and in 2020 the trend will continue, with more than 50% of the top 20 best-selling drugs predicted to be biologics. From 1986 to 2014 several first-in-class, advance-in-class, and breakthrough designated therapeutic options were approved, with advanced therapies such as immuno-oncology and cell-based therapies being approved for several indications.
Michael Pohlscheidt, Robert Kiss, Uwe Gottschalk

New Mammalian Expression Systems

There are an increasing number of recombinant antibodies and proteins in preclinical and clinical development for therapeutic applications. Mammalian expression systems are key to enabling the production of these molecules, and Chinese hamster ovary (CHO) cell platforms continue to be central to delivery of the stable cell lines required for large-scale production. Increasing pressure on timelines and efficiency, further innovation of molecular formats and the shift to new production systems are driving developments of these CHO cell line platforms. The availability of genome and transcriptome data coupled with advancing gene editing tools are increasing the ability to design and engineer CHO cell lines to meet these challenges. This chapter aims to give an overview of the developments in CHO expression systems and some of the associated technologies over the past few years.
Jie Zhu, Diane Hatton

Innovation in Cell Banking, Expansion, and Production Culture

Cell culture-based production processes enable the development and commercial supply of recombinant protein products. Such processes consist of the following elements: thaw and initiation of culture, seed expansion, and production culture. A robust cell source storage system in the form of a cell bank is developed and cells are thawed to initiate the cell culture process. Seed culture expansion generates sufficient cell mass to initiate the production culture. The production culture provides an environment where the cells can synthesize the product and is optimized to deliver the highest possible product concentration with acceptable product quality. This chapter describes the significant innovations made in these process elements and the resulting improvements in the overall efficiency, robustness, and safety of the processes and products.
Rashmi Kshirsagar, Thomas Ryll

Risk Mitigation in Preventing Adventitious Agent Contamination of Mammalian Cell Cultures

Industrial-scale mammalian cell culture processes have been contaminated by viruses during the culturing phase. Although the historical frequency of such events has been quite low, the impact of contamination can be significant for the manufacturing company and for the supply of the product to patients. This chapter discusses sources of adventitious agent contamination risk in a cell culture process, provides a semiquantitative assessment of such risks, and describes potential process barriers that can be used to reduce contamination risk. High-temperature, short-time (HTST) heat treatment is recommended as the process barrier of choice, when compatible with the process. A case study assessing the compatibility of HTST heat treatment with a cell culture medium is presented, and lessons learned are shared from our experiences over many years of developing and implementing virus barriers in mammalian cell culture processes.
Masaru Shiratori, Robert Kiss

Manufacturing of Proteins and Antibodies: Chapter Downstream Processing Technologies

Cell harvesting is the separation or retention of cells and cellular debris from the supernatant containing the target molecule Selection of harvest method strongly depends on the type of cells, mode of bioreactor operation, process scale, and characteristics of the product and cell culture fluid. Most traditional harvesting methods use some form of filtration, centrifugation, or a combination of both for cell separation and/or retention. Filtration methods include normal flow depth filtration and tangential flow microfiltration. The ability to scale down predictably the selected harvest method helps to ensure successful production and is critical for conducting small-scale characterization studies for confirming parameter targets and ranges. In this chapter we describe centrifugation and depth filtration harvesting methods, share strategies for harvest optimization, present recent developments in centrifugation scale-down models, and review alternative harvesting technologies.
Richard Turner, Adrian Joseph, Nigel Titchener-Hooker, Jean Bender

Downstream Processing Technologies/Capturing and Final Purification

Opportunities for Innovation, Change, and Improvement. A Review of Downstream Processing Developments in Protein Purification
Increased pressure on upstream processes to maximize productivity has been crowned with great success, although at the cost of shifting the bottleneck to purification. As drivers were economical, focus is on now on debottlenecking downstream processes as the main drivers of high manufacturing cost. Devising a holistically efficient and economical process remains a key challenge. Traditional and emerging protein purification strategies with particular emphasis on methodologies implemented for the production of recombinant proteins of biopharmaceutical importance are reviewed. The breadth of innovation is addressed, as well as the challenges the industry faces today, with an eye to remaining impartial, fair, and balanced. In addition, the scope encompasses both chromatographic and non-chromatographic separations directed at the purification of proteins, with a strong emphasis on antibodies. Complete solutions such as integrated USP/DSP strategies (i.e., continuous processing) are discussed as well as gains in data quantity and quality arising from automation and high-throughput screening (HTS). Best practices and advantages through design of experiments (DOE) to access a complex design space such as multi-modal chromatography are reviewed with an outlook on potential future trends. A discussion of single-use technology, its impact and opportunities for further growth, and the exciting developments in modeling and simulation of DSP rounds out the overview. Lastly, emerging trends such as 3D printing and nanotechnology are covered.
Nripen Singh, Sibylle Herzer

Fully Disposable Manufacturing Concepts for Clinical and Commercial Manufacturing and Ballroom Concepts

The availability and use of pre-sterilized disposables has greatly changed the methods used in biopharmaceuticals development and production, particularly from mammalian cell culture. Nowadays, almost all process steps from cell expansion, fermentation, cell removal, and purification to formulation and storage of drug substances can be carried out in disposables, although there are still limitations with single-use technologies, particularly in the areas of pretesting and quality control of disposables, bag and connections standardization and qualification, extractables and leachables (E/L) validation, and dependency on individual vendors. The current status of single-use technologies is summarized for all process unit operations using a standard mAb process as an example. In addition, current pros and cons of using disposables are addressed in a comparative way, including quality control and E/L validation.
The continuing progress in developing single-use technologies has an important impact on manufacturing facilities, resulting in much faster, less expensive and simpler plant design, start-up, and operation, because cell culture process steps are no longer performed in hard-piped unit operations. This leads to simpler operations in a lab-like environment. Overall it enriches the current landscape of available facilities from standard hard-piped to hard-piped/disposables hybrid to completely single-use-based production plants using the current segregation and containment concept. At the top, disposables in combination with completely and functionally closed systems facilitate a new, revolutionary design of ballroom facilities without or with much less segregation, which enables us to perform good manufacturing practice manufacturing of different products simultaneously in unclassified but controlled areas.
Finally, single-use processing in lab-like shell facilities is a big enabler of transferring and establishing production in emergent countries, and this is described in more detail in 7.
Berthold Boedeker, Adam Goldstein, Ekta Mahajan

Trends in Process Analytical Technology: Present State in Bioprocessing

Process analytical technology (PAT), the regulatory initiative for incorporating quality in pharmaceutical manufacturing, is an area of intense research and interest. If PAT is effectively applied to bioprocesses, this can increase process understanding and control, and mitigate the risk from substandard drug products to both manufacturer and patient. To optimize the benefits of PAT, the entire PAT framework must be considered and each elements of PAT must be carefully selected, including sensor and analytical technology, data analysis techniques, control strategies and algorithms, and process optimization routines. This chapter discusses the current state of PAT in the biopharmaceutical industry, including several case studies demonstrating the degree of maturity of various PAT tools.
Marco Jenzsch, Christian Bell, Stefan Buziol, Felix Kepert, Harald Wegele, Christian Hakemeyer

Next Generation Biopharmaceuticals: Product Development

Therapeutic proteins show a rapid market growth. The relatively young biotech industry already represents 20 % of the total global pharma market. The biotech industry environment has traditionally been fast-pasted and intellectually stimulated. Nowadays the top ten best selling drugs are dominated by monoclonal antibodies (mABs).
Despite mABs being the biggest medical breakthrough in the last 25 years, technical innovation does not stand still.
The goal remains to preserve the benefits of a conventional mAB (serum half-life and specificity) whilst further improving efficacy and safety and to open new and better avenues for treating patients, e.g., improving the potency of molecules, target binding, tissue penetration, tailored pharmacokinetics, and reduced adverse effects or immunogenicity.
The next generation of biopharmaceuticals can pose specific chemistry, manufacturing, and control (CMC) challenges. In contrast to conventional proteins, next-generation biopharmaceuticals often require lyophilization of the final drug product to ensure storage stability over shelf-life time. In addition, next-generation biopharmaceuticals require analytical methods that cover different ways of possible degradation patterns and pathways, and product development is a long way from being straight forward. The element of “prior knowledge” does not exist equally for most novel formats compared to antibodies, and thus the assessment of critical quality attributes (CQAs) and the definition of CQA assessment criteria and specifications is difficult, especially in early-stage development.
Roman Mathaes, Hanns-Christian Mahler

Continuous Manufacturing of Recombinant Therapeutic Proteins: Upstream and Downstream Technologies

Continuous biomanufacturing of recombinant therapeutic proteins offers several potential advantages over conventional batch processing, including reduced cost of goods, more flexible and responsive manufacturing facilities, and improved and consistent product quality. Although continuous approaches to various upstream and downstream unit operations have been considered and studied for decades, in recent years interest and application have accelerated. Researchers have achieved increasingly higher levels of process intensification, and have also begun to integrate different continuous unit operations into larger, holistically continuous processes. This review first discusses approaches for continuous cell culture, with a focus on perfusion-enabling cell separation technologies including gravitational, centrifugal, and acoustic settling, as well as filtration-based techniques. We follow with a review of various continuous downstream unit operations, covering categories such as clarification, chromatography, formulation, and viral inactivation and filtration. The review ends by summarizing case studies of integrated and continuous processing as reported in the literature.
Rohan Patil, Jason Walther

Platforms for Manufacturing Allogeneic, Autologous and iPSC Cell Therapy Products: An Industry Perspective

As cell therapy processes mature from benchtop research protocols to industrial processes capable of manufacturing market-relevant numbers of doses, new cell manufacturing platforms are required. Here we give an overview of the platforms and technologies currently available to manufacture allogeneic cell products, such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), and technologies for mass production of autologous cell therapies via scale-out. These technologies include bioreactors, microcarriers, cell separation and cryopreservation equipment, molecular biology tools for iPSC generation, and single-use controlled-environment systems for autologous cell production. These platforms address the challenges of manufacturing cell products in greater numbers while maintaining process robustness and product quality.
Eytan Abraham, Behnam Baghbaderani Ahmadian, Kathryn Holderness, Yonatan Levinson, Erika McAfee

Gene Therapy

Gene therapy refers to a rapidly growing field of medicine in which genes are introduced into the body to treat or prevent diseases. Although a variety of methods can be used to deliver the genetic materials into the target cells and tissues, modified viral vectors represent one of the more common delivery routes because of its transduction efficiency for therapeutic genes. Since the introduction of gene therapy concept in the 1970s, the field has advanced considerably with notable clinical successes being demonstrated in many clinical indications in which no standard treatment options are currently available. It is anticipated that the clinical success the field observed in recent years can drive requirements for more scalable, robust, cost effective, and regulatory-compliant manufacturing processes. This review provides a brief overview of the current manufacturing technologies for viral vectors production, drawing attention to the common upstream and downstream production process platform that is applicable across various classes of viral vectors and their unique manufacturing challenges as compared to other biologics. In addition, a case study of an industry-scale cGMP production of an AAV-based gene therapy product performed at 2,000 L-scale is presented. The experience and lessons learned from this largest viral gene therapy vector production run conducted to date as discussed and highlighted in this review should contribute to future development of commercial viable scalable processes for vial gene therapies.
Barb Thorne, Ryan Takeya, Francesca Vitelli, Xin Swanson

High-Throughput Process Development for Biopharmaceuticals

The ability to conduct multiple experiments in parallel significantly reduces the time that it takes to develop a manufacturing process for a biopharmaceutical. This is particularly significant before clinical entry, because process development and manufacturing are on the “critical path” for a drug candidate to enter clinical development. High-throughput process development (HTPD) methodologies can be similarly impactful during late-stage development, both for developing the final commercial process as well as for process characterization and scale-down validation activities that form a key component of the licensure filing package. This review examines the current state of the art for HTPD methodologies as they apply to cell culture, downstream purification, and analytical techniques. In addition, we provide a vision of how HTPD activities across all of these spaces can integrate to create a rapid process development engine that can accelerate biopharmaceutical drug development.
Abhinav A. Shukla, Shahid Rameez, Leslie S. Wolfe, Nathan Oien

A Different Perspective: How Much Innovation Is Really Needed for Monoclonal Antibody Production Using Mammalian Cell Technology?

As biopharmaceutical companies have optimized cell line and production culture process development, titers of recombinant antibodies have risen steadily to 3–8 g/L for fed-batch mammalian cultures at production scales of 10 kL or larger. Most new antibody products are produced from Chinese Hamster Ovary (CHO) cell lines, and there are relatively few alternative production hosts under active evaluation. Many companies have adopted a strategy of using the same production cell line for early clinical phases as well as commercial production, which reduces the risk of product comparability issues during the development lifecycle. Product quality and consistency expectations rest on the platform knowledge of the CHO host cell line and processes used for the production of many licensed antibodies. The lack of impact of low-level product variants common to this platform on product safety and efficacy also builds on the established commercial history of recombinant antibodies, which dates back to 1997.
Efforts to increase titers further will likely yield diminishing returns. Very few products would benefit significantly from a titer greater than 8 g/L; in many cases, a downstream processing bottleneck would preclude full recovery from production-scale bioreactors for high titer processes. The benefits of a process platform based on standard fed-batch production culture include predictable scale-up, process transfer, and production within a company’s manufacturing network or at a contract manufacturing organization. Furthermore, the confidence in an established platform provides key support towards regulatory flexibility (e.g., design space) for license applications following a quality-by-design strategy.
These factors suggest that novel technologies for antibody production may not provide a substantial return on investment. What, then, should be the focus of future process development efforts for companies that choose to launch antibody products using their current platform? This review proposes key focus areas in an effort to continually improve process consistency, assure acceptable product quality, and establish appropriate process parameter limits to enable flexible manufacturing options.
Brian Kelley, Robert Kiss, Michael Laird

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