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Single‐Use Equipment in Biopharmaceutical Manufacture: A Brief Introduction
Abstract
The acceptance of single‐use systems, which are obtainable for all stages of the biopharmaceutical production process up to the mid‐volume scale, has increased in the production of biotherapeutics in the past 10 years. This concerns, in particular, the development and manufacture of monoclonal antibodies, therapeutic hormones, as well as enzymes and vaccines which are mainly produced with continuous animal and human cell lines. This chapter introduces the reader to the area of single‐use technology. In addition to terminology, it describes advantages and disadvantages of existing single‐use devices. Based on a schematic of a typical production process for a protein therapeutic, the chapter presents an overview of currently available single‐use devices and a categorization approach. Moreover, it summarizes the main criteria for implementing single‐use systems in biopharmaceutical production processes, and explains current concepts concerning single‐use production facilities.
Continuous biopharmaceutical manufacturing is currently a field of intense research due to its potential to make the entire production process more optimal for the modern, ever‐evolving biopharmaceutical market. Compared to traditional batch manufacturing, continuous bioprocessing is more efficient, adjustable, and sustainable and has reduced capital costs. However, despite its clear advantages, continuous bioprocessing is yet to be widely adopted in commercial manufacturing. This article provides an overview of the technological roadblocks for extensive adoptions and points out the recent advances that could help overcome them. In total, three key areas for improvement are identified: Quality by Design (QbD) implementation, integration of upstream and downstream technologies, and data and knowledge management. First, the challenges to QbD implementation are explored. Specifically, process control, process analytical technology (PAT), critical process parameter (CPP) identification, and mathematical models for bioprocess control and design are recognized as crucial for successful QbD realizations. Next, the difficulties of end‐to‐end process integration are examined, with a particular emphasis on downstream processing. Finally, the problem of data and knowledge management and its potential solutions are outlined where ontologies and data standards are pointed out as key drivers of progress.
Rocking single-use bioreactors (SUBs) adopt an effective mixing mechanism based on the rocking movement of a platform on which a disposable bag-like container is placed. Non-typical liquid flow patterns make the hydrodynamical properties of rocking SUBs not yet well systematized. The aim of the study was to determine a quantitative characteristic of mixing time in a ReadyToProcess WAVE 25 system equipped with a 2-litre Cellbag disposable container, with the use of a sensor method and the Design of Experiment (DoE) methodology. The DoE-based approach has been used to screen significant operational parameters and evaluate their impact on the values of mixing time reached in the studied rocking SUB system. To quantify relations between operational parameters and important process quantities in rocking disposable bag-like containers of different sizes, a set of original formulas for generalization of experimental data and predicting mixing time values has been proposed. The set includes exponential correlations and a correlation involving a dimensionless filling level term and a modified Reynolds number expression. Comparisons between estimations and experimental data have shown satisfactory levels of accuracy within ± 30% of experimental values. The correlation involving dimensionless terms can be applied for disposable bag-like containers offered by different manufacturers and of various sizes.
Recent technological advances are enabling manufacturers to move away from equipment that must be sterilised or consumables that are recycled or pose a risk with their transfer into cleanrooms, towards the adoption of disposable and single-use sterile items. This article considers the advantages of implementing single-use technology and outlines a framework that can be used as a strategy for implementation.
The use of biopharmaceuticals dates from the 19th century and within 5–10 years, up to 50% of all drugs in development will be biopharmaceuticals. In the 1980s, the biopharmaceutical industry experienced a significant growth in the production and approval of recombinant proteins such as interferons (IFN α, β, and γ) and growth hormones. The production of biopharmaceuticals, known as bioprocess, involves a wide range of techniques. In this review, we discuss the technology involved in the bioprocess and describe the available strategies and main advances in microbial fermentation and purification process to obtain biopharmaceuticals.
Single-use technology (SUT) is now available for all processing operations within the biopharmaceutical industry. It has the potential to reduce capital costs, improve plant throughput and reduce the risk of cross-contamination. However, there are no clear guidelines to aid the end-user on implementation of these technologies into a validated, good manufacturing practice (GMP) environment. This book is the first comprehensive publication of practical considerations for each stage of the implementation process of SUT, and covers the selection, specification, design and qualification of systems to meet end-user requirements. Serving as an introduction and practical reference to this growing area of application within the biopharmaceutical industry, this handbook presents: An approach for SUT implementation within an end-users facility with examples for bioreactors, tangential-flow filtration and fill-finish systems ; SUT within the context of regulatory guidance, such as ICH Q8, Q9, Q10 and GMP; Strategy for standardisation of single-use bag systems and assessment of extractables and leachables; Specifications of user requirements and design of specific SUT alongside process descriptions and flow diagrams; Strategies and tools to evaluate risk with examples of risk assessments applicable to design, processing and product quality; and Qualification approach for different SUT types. With the information presented in this book, engineers, researchers and professionals involved in biopharmaceuticals will be better prepared to plan and make effective decisions to design and implement SUT.
Plant cell suspension cultures have several advantages that make them suitable for the production of recombinant proteins. They can be cultivated under aseptic conditions using classical fermentation technology, they are easy to scale-up for manufacturing, and the regulatory requirements are similar to those established for well-characterized production systems based on microbial and mammalian cells. It is therefore no surprise that taliglucerase alfa (Elelyso®)—the first licensed recombinant pharmaceutical protein derived from plants—is produced in plant cell suspension cultures. But despite this breakthrough, plant cells are still largely neglected compared to transgenic plants and the more recent plant-based transient expression systems. Here, we revisit plant cell suspension cultures and highlight recent developments in the field that show how the rise of plant cells parallels that of Chinese hamster ovary cells, currently the most widespread and successful manufacturing platform for biologics. These developments include medium optimization, process engineering, statistical experimental designs, scale-up/scale-down models, and process analytical technologies. Significant yield increases for diverse target proteins will encourage a gold rush to adopt plant cells as a platform technology, and the first indications of this breakthrough are already on the horizon.
Since the first use of Chinese hamster ovary (CHO) cells for recombinant protein expression, production processes have steadily improved through numerous advances. In this review, we have highlighted several key milestones that have contributed to the success of CHO cells from the beginning of their use for monoclonal antibody (mAb) expression until today. The main factors influencing the yield of a production process are the time to accumulate a desired amount of biomass, the process duration, and the specific productivity. By comparing maximum cell densities and specific growth rates of various expression systems, we have emphasized the limiting parameters of different cellular systems and comprehensively described scientific approaches and techniques to improve host cell lines. Besides the quantitative evaluation of current systems, the quality-determining properties of a host cell line, namely post-translational modifications, were analyzed and compared to naturally occurring polyclonal immunoglobulin fractions from human plasma. In summary, numerous different expression systems for mAbs are available and also under scientific investigation. However, CHO cells are the most frequently investigated cell lines and remain the workhorse for mAb production until today.
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.
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.
A practical overview of a full rangeof approaches to discovering, selecting, and producing biotechnology-derived drugs. The Handbook of Pharmaceutical Biotechnology helps pharmaceutical scientists develop biotech drugs through a comprehensive framework that spans the process from discovery, development, and manufacturing through validation and registration. With chapters written by leading practitioners in their specialty areas, this reference: Provides an overview of biotechnology used in the drug development process. Covers extensive applications, plus regulations and validation methods. Features fifty chapters covering all the major approaches to the challenge of identifying, producing, and formulating new biologically derived therapeutics. With its unparalleled breadth of topics and approaches, this handbook is a core reference for pharmaceutical scientists, including development researchers, toxicologists, biochemists, molecular biologists, cell biologists, immunologists, and formulation chemists. It is also a great resource for quality assurance/assessment/control managers, biotechnology technicians, and others in the biotech industry.
IntroductionNormal-Flow Versus Tangential-Flow FiltrationUltrafiltration Membranes: Chemistry, Pore Size and CharacterizationUltrafiltration DevicesUltrafiltration Operation and Process DevelopmentUltrafiltration Principles and TheoryConcentration Polarization and Membrane FoulingUltrafiltration Control StrategiesMembrane Cleaning and SanitizationEmerging Technologies for Protein ConcentrationSummaryReferences
Quality management systems are, as a rule, tightly defined systems that conserve existing processes and therefore guarantee compliance with quality standards. But maintaining quality also includes introducing new enhanced production methods and making use of the latest findings of bioscience. The advances in biotechnology and single-use manufacturing methods for producing new drugs especially impose new challenges on quality management, as quality standards have not yet been set. New methods to ensure patient safety have to be established, as it is insufficient to rely only on current rules. A concept of qualification, validation, and manufacturing procedures based on risk management needs to be established and realized in pharmaceutical production. The chapter starts with an introduction to the regulatory background of the manufacture of medicinal products. It then continues with key methods of risk management. Hazards associated with the production of medicinal products with single-use equipment are described with a focus on bioreactors, storage containers, and connecting devices. The hazards are subsequently evaluated and criteria for risk evaluation are presented. This chapter concludes with aspects of industrial application of quality risk management.
Graphical Abstract
The growing demand for biotherapeutics and, in particular, antibodies has resulted in an increasing use of disposables over the last ten years. This concerns both, process development and commercial manufacturing, where animal cells are grown in suspension or on microcarriers. The use of disposable devices have been implemented in all three stages of biotechnological production processes: (i) upstreaming, (ii) downstreaming as well as (iii) final formulation and filling. The majority of applications are to be found in upstream processing. Here, disposable expendable laboratory items, simple peripheral elements, and equipment for unit operations are well‐established. Among the components listed, disposable bioreactors have achieved the highest growth rate over the last year.
Following an introduction in which the term “single‐use” is defined, a general overview of single‐use devices in antibody production processes is given. We focus on frequently used disposable bioreactor types, their characteristics, and obtainable results, and discuss apparent trends for disposables in antibody manufacture.
IntroductionFormulationLyophilization of BiologicalsFreeze Drying Cycle DesignResidual MoistureFunctional ActivityEquipment and Processing IssuesConclusions
AcknowledgementReferences
Biotechnology is gaining in increasing importance in pharmaceutical production processes by replacing chemical production procedures for economical and ecological reasons and in the development and commercialization of novel therapeutic principles. To fully exploit the potential of biotechnological production methods, an integrated process design will be necessary considering the downstream processing requirement during the design of upstream operations and vice versa. This chapter aims is to give insights into the typical issues and problems encountered in the manufacture of biopharmaceuticals, to mediate general ideas and current strategies on how to proceed in the design and development of biotechnological processes.
Over the past two decades terms such as 'biopharmaceuticals' and 'biotechnology medicines' have crept into the pharmaceutical vocabulary. Such terms often have different meanings for different people and it is perhaps time that they were more formally defined.
This paper presents an overview of large-scale downstream processing of monoclonal antibodies and Fc fusion proteins (mAbs). This therapeutic modality has become increasingly important with the recent approval of several drugs from this product class for a range of critical illnesses. Taking advantage of the biochemical similarities in this product class, several templated purification schemes have emerged in the literature. In our experience, significant biochemical differences and the variety of challenges to downstream purification make the use of a completely generic downstream process impractical. Here, we describe the key elements of a flexible, generic downstream process platform for mAbs that we have adopted at Amgen. This platform consists of a well-defined sequence of unit operations with most operating parameters being pre-defined and a small subset of parameters requiring development effort. The platform hinges on the successful use of Protein A chromatography as a highly selective capture step for the process. Key elements of each type of unit operation are discussed along with data from 14 mAbs that have undergone process development. Aspects that can be readily templated as well as those that require focused development effort are identified for each unit operation. A brief description of process characterization and validation activities for these molecules is also provided. Finally, future directions in mAb processing are summarized.
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