Monoclonal Antibodies: Beyond the Platform in Manufacturing
The vast majority of monoclonal antibody (MAb) production processes are based on fed-batch Chinese hamster ovary (CHO) cell culture and protein A affinity column chromatography capture. Increasing cost-consciousness — among innovator companies as well as biosimilar makers — has many companies looking “beyond the platform” for less expensive alternatives that may provide better results. Here the BPI editors review some state-of-the-art alternatives in upstream and downstream MAb drug substance bioprocessing as well as drug-product manufacturing.
Emerging Tools for Exosome Purification and
This eBook introduces new analytical approaches that enable in-line chromatographic detection of exosomes. One approach can discriminate extracellular vesicles from nonvesicle contaminants, and one potentially can discriminate exosomes from other vesicles. Examples illustrate how they enable development of more effective and better documented purification methods. The special qualifications of monolithic chromatography media for exosome purification are discussed. New process tools designed to accommodate some of the special challenges of exosome purification are introduced.
Continuous Chromatography: Experts Weigh in on the Possibilities and the Reality
Discussions of continuous processing in the biopharmaceutical industry are an important part of current efforts toward intensifying bioproduction and bioprocessing. Biomanufacturers are looking at all components of their development and manufacturing processes for ways to reduce the size of their facilities, lower costs, and increase speed and flexibility of operations. Increasing options for and availability of single-use technologies have been major enablers of myriad attempts to improve efficiencies. Although the general consensus may still be that single-use components are more conducive to continuous upstream than to downstream processing, process intensification efforts to streamline manufacturing operations already have been challenging those assumptions in the past few years. Through new sensors, automation, and process control technologies, biomanufacturers can take advantage of greater connectivity of unit operations (1). Some are implementing hybrid processes (combining both continuous and batch unit operations throughout a manufacturing process), a few are attempting fully continuous unit operations, and many continue to use end-to-end processes based on staggered batch unit operations.
Biosimilars: Challenging the Justifications for Clinical Testing
The Biologics Price Competition and Innovation Act (BPIA) of 2009, describes the need for clinical trials as follows (1): “(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product.”
However, all the above studies are left to the discretion of the US Food and Drug Administration (FDA). Other requirements not left to the agency’s discretion include the same drug, the same dosage form, a US-licensed comparator, the same indication, the same mode of action (MoA), and current good manufacturing practice (CGMP) compliance.
Messenger RNA Drugs: Engaging the Machinery of Patients’ Cells to Therapeutic Effect
Although most of the bioprocess industry has focused on process development for large-molecule formulations (e.g., protein drugs), a growing segment of the industry has been concentrated on other types of biotherapeutics to leverage advances in understanding of immunology and genetic engineering. Such technologies may emerge both as tools for drug manufacturing and at some point, as biopharmaceuticals, biotherapeutics, vaccines, and cell and gene therapies, themselves. What brings mRNA research to BioProcess International’s attention is the increasing interest turned toward therapeutic applications, as explored in this review of current work toward that goal.
Part 1: Biological Assays — A Conference Report
In late October 2018, KNect365 brought together more than 250 analytical specialists to discuss characterization of well-characterized biologics in Rockville, MD. Speakers from the US Food and Drug Administration joined experts from leading biopharmaceutical companies, service providers, and consultancies, including BPI editorial advisor Nadine Ritter (president and analytical advisor of Global Biotech Experts). She began the final day moderating a special town-hall session where audience members could pose their regulatory questions to a panel of FDA reviewers, and she ended that day serving on a panel herself to address the topic of bioassays for cell and gene therapies.
Using Modern In Situ Analytics and PAT for Automated Feedback Control of Critical Process Parameters
The need for advanced control strategies for bioprocessing and biomanufacturing is growing, and several manufacturers already have leveraged new automation and software solutions for bioprocess monitoring and control. New bioprocess market dynamics and modalities are driving automation forward. A number of technologies and adaptations are now available for bioprocessing that are designed to help enable automation and enable online analytics for real-time monitoring. Measuring critical process parameters with highly specific and scalable technologies that are adaptable to all bioreactor formats creates a strong foundation for advanced automation in bioprocessing with process analytical technologies integration.
Partnerships in Immunotherapy: Working Together to Take Cancer Treatment to the Next Level
Biopharmaceuticals are a particularly complex expression of medicine — and immunotherapies perhaps even more so. As treatments, these products themselves often also need “partners” of a kind: e.g., radiation/radiotherapies, traditional MAbs, and chemotherapies. Just as this field of endeavor requires the input and expertise of many different disciplines — from medical researchers to process engineers, clinicians to business leaders, and market experts to policy makers — this discussion of the topic of partnerships in immunotherapy brings together different experts in the field. BPI’s senior technical editor introduces contributions by Angela Miklus of Datamonitor Healthcare (an Informa company), Stephen T. Isaacs of Aduro Biotech, Raymond Tesi of INmune Bio, Michael Har-Noy of Immunovative, and Patricia Reilly of Pharma Intelligence (an Informa business).
Inactivation of Enveloped Viruses: Seeking Alternatives to a Problematic Surfactant
Triton X-100 detergent makes an interesting case study in bioprocess sustainability strategy. Also known as octylphenol ethoxylate (OPE), this nonionic surfactant has many uses in biopharmaceutical research and development. It serves as a vaccine excipient and most notably a virus-inactivation agent in downstream processing. Despite a long history of industrial use and an established safety profile, OPE has been listed in Europe as a “substance of very high concern” because it recently has been shown to degrade in the environment to yield an endocrine disruptor. Consequently, many users are looking for alternatives — especially for high-volume uses such as viral inactivation of large-scale product streams. In this exclusive eBook, BPI’s senior technical editor reviews the problem and potential solutions in the works, including discussion with scientists at Bayer and Biogen.
BioProcess International Conference and Exhibition 2018 Postevent Report: Key Insights, Highlights, and Take-Away Messages
From the global shift in demographics to increased efficiencies in chromatography media, change is constant within the bioprocessing industry and a major reason delegates flock to the annual BPI Conference and Exhibition. As a place to get an overview of the hot topics affecting this industry, the meeting brings together key aspects of bioprocessing — therapeutic modalities, cells, expression systems, upstream production, downstream processing, development, and manufacturing — with digital integration and the increasing importance of analytics.
Cell Culture Media: An Active Pharmaceutical Ingredient or Ancillary Material?
A wide range of reagents and materials such as antibodies, growth factors, and enzymes are used in their manufacturing processes. Such necessary materials are administered through a cell culture medium. Active pharmaceutical ingredients (APIs) are the main ingredients that make products therapeutic. Ancillary materials (AMs) and raw materials (RMs) are essential components used during production but are not supposed to be present in final products. Some advances in cell-based therapies have revealed inconsistencies and lack of regulation in classifying materials that are used to produce these products as RMs, AMs, and APIs. Clear guidelines and regulations are needed regarding RMs and AMs in cell-based therapies.
Trends in Chemistry, Manufacturing, and Controls: Next-Generation Technologies and Product Modalities
New technologies bring new regulatory challenges. The biopharmaceutical industry must be cautious in its implementation of new scientific ideas and technology platforms — no matter how promising those might be. Regulators will look skeptically on any claim that isn’t backed up by good data, and with no solid history of successful use to build on, a company must have all the answers itself. How do compliance professionals anticipate what kinds of questions reviewers will ask when the time comes — and how can those in development laboratories and manufacturing suites best be prepared to respond to them? With all that in mind, this eBook addresses a number of new approaches to the regulation-defined areas of chemistry, manufacturing, and controls (CMC) for protein biologics.
Scalable Cell-Based Immunotherapy Manufacture: A Comparison of Single-Use Agitated and Static Expansion Technologies
Early clinical results indicate that personalized autologous immunotherapies could revolutionize cancer treatment. However, challenges lie in the realization of cost driven, scalable cell therapy (CT) manufacturing strategies for generating sufficient therapies. A strategical aim at The Cell and Gene Therapy Catapult (CGT) is collaborative development of next-generation autologous manufacture strategies. This study evaluates the expansion potential of stirred-tank bioreactors for immunotherapy manufacture and compares that to current state-of-the-art static and wave-agitated cultures.
Biopharmaceutical Training – Train Your Team to Meet Evolving Industry Needs
Welcome to this year’s focus on industry training programs. In the past three years we’ve brought this information to you in several forms: as a full supplement issue (2016), a featured report (2017) – and now this ebook. Each program that we’ve profiled offers its unique approach to training present and future biotechnologists. The best of the programs offer hands-on training with current equipment provided by supplier partners and with up-to-date approaches to documentation and regulatory requirements. Many university- and community-college–based programs, once lacking in practical, GMP training, now also benefit from a wealth of hands-on manufacturing experience toward resolving real-world issues.
Manufacturing CAR-T Cell Therapies — Insights and Challenges
The rapid evolution and clinical success of T-cell immunotherapies is an exciting advance in the war on cancer. Chimeric antigen receptor T-cell (CAR-T) therapy is emerging as the most studied treatment in T-cell immunotherapy and is the basis for many ongoing clinical trials. For better understanding of the manufacturing difficulties, the authors analyzed technical and economic challenges encountered by CAR-T contract manufacturers and innovators. The analysis reveals that further refinement and implementation of an automated closed system could facilitate expansion of CAR-T therapies into routine cancer treatment.
Quality By Design for Monoclonal Antibodies — Establishing the Foundations for Process Development, Design Space, and Process Control Strategies
This article, combining parts 1 and 2 from BPI’s June and September 2016 issues, presents early steps in process development, including defining a target product profile (TPP), a quality target product profile (QTPP), and critical quality attributes (CQAs). It concludes by focusing on establishing a design space and optimizing process characterization through risk assessment and a well-defined control strategy. FDA’s 2002 initiative Pharmaceutical CGMP for the 21st Century: A Risk-Based Approach sought to improve interactions between pharmaceutical manufacturers and regulators by focusing on science- and risk-based approaches to development.
Raw Materials Quality, Processing, and Storage — A Manufacturing Case Study
Raw material storage, handling, and processing are essential to ensure high product quality and consistent process performance. Slight variabilities in raw materials (either inherent in the material or through processing) can compromise yield and even result in batch loss. Bunyada Vamnutjinda Kwong, senior engineer of manufacturing sciences, cell culture, at Genentech (Vacaville, CA) shares a manufacturing case study in raw material and storage conditions. It focuses on the current landscape of raw materials, cell culture process flow, the importance of raw materials for cell culture, internal requirements of raw-material handling, and an overview of a case study of how raw material had affected process performance and product quality.
SUStainability: Concerning Single-Use Systems and the Environment
Disposable materials have been used in many aspects of biomanufacturing since muromonab was first launched in 1986. Single-use stirred-tank bioreactors first became commercially available from HyClone in 2004 (1). Despite their demonstrated value to bioprocessing, disposable materials remain the subject of wide-ranging differences of opinion. Discussions of any
technology are healthy and important for identifying areas for improvement, but some hearsay and bold propositions made regarding single-use components and the environment are not always helpful. Sustainability is an important and much-publicized topic, and among both lay people and industrial decision-makers is a tendency to automatically equate “disposable” or “plastic” with an environmental liability. Because so many scientists and engineers are involved in biotechnology, we are hopeful that a true technical analysis of sustainability and single-use systems (SUS) for bioprocessing — thus, SUStainability — will get a fair hearing. This is important because the results of such analysis contradict popular opinion. SUS do provide an environmental advantage over traditional durable manufacturing facilities.
Bioprocess and Analytical Laboratories — Proving the Power of Data in Drug Development
Analytics pervade the entire biopharmaceutical development process — from protein characterization through biomanufacturing process optimization to final-product formulation and clinical testing. Every technical article in BPI requires data to back up the statements made, whether the topic is upstream/production, downstream processing, product development, or otherwise focused. And never mind publishing: Even more detailed documentation is required for regulatory submissions. If a company can’t back up the choices made and results obtained in development, manufacturing, and testing of its biopharmaceutical product, then that drug will never find its way to market or the patients who might have benefited from it.
The Future of Monoclonal Antibody Manufacturing — Incremental Improvement or Industrial Revolution?
Monoclonal antibody manufacturing is at a crossroads. Biomanufacturers could continue exploring new technologies and fine-tuning proven systems such as mammalian cell expression systems in stirred-tank bioreactor fed-batch cultures. But some experts say an opportunity is arising to turn the industry on its head by taking lessons from other branches of bioprocessing, such as the industrial enzyme sector.
Drug makers are criticized often these days for the high prices of their products. The lay media, governments, payers, and patients themselves all have voiced their share of grievances against “Big Biopharma’s” pricing strategies.
Development and Application of a Simple and One-Point Multiparameter Technique — Monitoring Commercial-Scale Chromatography Process Performance
In commercial-scale biopharmaceutical manufacturing, downstream chromatography steps are still a bottleneck and contribute to significant operational costs. Some of those costs are inherent (e.g., resins, large buffer quantities, and cleaning) whereas others are avoidable (e.g., product loss due to rejected lots or deviations that result in production downtime). Maintaining efficient and robust chromatography process performance is therefore critical for minimizing operating costs. In this eBook, the authors introduce a simple and one-point multiparameter technique (SOP-MPT) for monitoring chromatographic process performance.
The Commercial Expression Systems Market: What Has Changed in the Past Decade
A decade ago, BioPlan Associates prepared the findings of its 2008 directory of expression system technologies that were being promoted or considered likely to be suitable for commercial licensing for biopharmaceutical manufacturing. Due in part to the relatively slow advances in this critical area of bioprocessing, this study remains perhaps the only directory of biopharmaceutical-relevant expression systems available for licensing. In this eBook, author Ronald A. Rader discusses aspects of related bioprocessing technologies that have and have not changed in the past decade.
Production of Cell-Line Development and Control of Product Consistency During Cultivation:
Myths, Risks, and Best Practices
Health authorities are requesting substantial details from sponsors regarding practices used to generate production cell lines for recombinant DNA–(rDNA) derived biopharmaceuticals.
Authorities also are asking for information about the clonality of master cell banks (MCBs) and control strategies to minimize genetic heterogeneity. Such requests are prompted by recent reports indicating “nonclonality” for certain production cell lines. To address these and related issues, the CASSS CMC Strategy Forum on “Production Cell Line Development and Control of Product Consistency During Cell Cultivation: Myths, Risks and Best Practices,” was held 23 January 2017 in Washington, DC.
Innovations in CRISPR Technology: A Perspective on Research and Bioprocess Applications
One of the fastest growing areas in genome engineering is research using the powerful editing tool of clustered regularly interspaced short palindromic repeats (CRISPR). When paired with the Cas9 (CRISPR-associated protein 9), an RNA-guided DNA endonuclease enzyme from Streptococcus pyogenes, the site-specific prokaryotic immune system can be used to cut and manipulate DNA strands in cells of patients with genetic diseases to treat, or in some cases, prevent such diseases. Within the past couple of years, CRISPR has been shown to improve signficantly the engineering of chimeric antigen receptor T cells (CAR-T cells) and to deliver CAR to specific sites within T cells. To gain a perspective on how the use of CRISPR is affecting research in genetic disease and may reduce costs in bioproduction, Maribel Rios, managing editor of BioProcess International, spoke with Anthony Davies, PhD, chief executive officer and founder of Dark Horse Consulting.
Viral Vaccine Production: Cultivation of Vero Cells in Packed-Bed Bioreactors
Using mammalian cell culture for viral vaccine production has advantages over production in embryonated chicke eggs, including: a shorter lead time, a production process that can be more tightly controlled, and reduced risk of microbial contamination. Vero cells are anchorage-dependent cells, and commonly grown in roller bottles or T-flasks. Stirred-tank bioreactors provide advantages in process development and industry-scale production. In stirred-tank bioreactors, Vero cells are typically grown on microcarriers. Fibra-Cel disks are an alternative attachment matrix because they provide a three-dimensional environment that protects cells from damaging shear forces. However, such disks have not been tested for the cultivation of Vero cells. The authors of this eBook tested cultivation of Vero cells in a benchtop single-use and glass bioreactors with a packed bed made of Fibra-Cel disks.
Alternative Delivery of Biologics — Underdogs Pursue Roads Less Traveled
A number of failures in development of noninjectable delivery methods for therapeutic proteins have caused numerous development programs to crash and burn along with investors’ hopes, dreams, and cash. Most everyone reading BioProcess International is familiar with the issues and challenges: Needles hurt and involve risks to both caregivers and patients. Injections often require administration by trained personnel in specialized settings. But alternative forms of delivery are fraught with greater challenges related to dosing, bioavailability (particularly for oral dosing), and inherent difficulties in formulating fragile protein drugs. Alongside human and ergonomic factors, these issues put the industry into (as Oliver Hardy might have said) “a fine mess” that has defied the efforts of the best engineers in the business. This eBook includes discussion of the various forms of alternative delivery methods currently under consideration for biologics: inhalation, edible, sublingual, microneedle, and implants.
Development of a Representative Scale-Down UF/DF Model: Overcoming Equipment Limitations and Associated Process Challenges
Scale-down models (SDM) are physical, small-scale models of commercial-scale unit operations or processes that are used throughout the biopharmaceutical industry for validation studies, commercial deviation investigations, and postapproval process improvements. To support these studies, regulatory guidelines state that SDMs should be representative of the commercial process. For some downstream unit operations such as column chromatography, developing a representative SDM is straightforward because a linear scale-down approach can be used. However, developing a representative SDM for other downstream unit operations such as ultrafiltration/diafiltration (UF/DF) is more difficult because of scale-down equipment limitations and associated process challenges. The authors present a systematic (stepwise), science-based approach used to overcome these limitations during the development of a UF/DF SDM.
Addressing Quality in Cell-Line Development — Direct Analysis of Bioreactor Harvest for Clone Selection and Process Optimization
Therapeutic monoclonal antibodies mostly are manufactured using mammalian cells cultured in a bioreactor for two to three weeks. Often the bioreactor harvest is considered too “dirty” to be tested with any analytical method. The authors of this eBook explored direct analysis of bioreactor harvest using capillary sodium-dodecyl sulfate (cSDS) electrophoresis, size-exclusion high-performance liquid chromatography (SE-HPLC), and surface plasmon resonance (SPR) assays. The results provided valuable information and guidance on immunoglobulin G (IgG) integrity and quality during clone-selection and bioreactor scale-up.
Of Microbrews and Medicines: Understanding Their Similarities and Differences in Bioprocessing Can Help Improve Yields and Quality While Reducing Cost
Whatever attracts a scientist or engineer to making medicines and/or craft brews, a surprising number of principles hold true for both bioprocesses despite the significant differences between biopharmaceutical and brewing practices. Author Lisa J. Graham examines how different software and hardware applications can provide the scientific insight required for success with either type of bioprocessing. Techniques for developing both process analytical technology (PAT) and novel data analytics approaches could cross over between these biotechnology industries.
Bioinks for Bioprinting: Three-Dimensional Printing in Research and Medicine
Three-dimensional (3D) printing is on the precipice of becoming a useful technology in biomanufacturing, research, and clinical medicine. 3D cell culture provides a biomimetic model of cell systems for many applications including cell/tissue models and constructs for basic/medical research, product testing, and regenerative medicine. 3D bioprinting (3DBP) uses printing techniques to create 3D structures such as living tissue. 3DBP technologies have been used to generate organ-on-a-chip systems for modeling tissue units of function through incorporating both 3D cell systems and fluid flow on a microscale.
In this exclusive eBook, authors from Advanced Solutions Life Sciences and GE Healthcare describe the state-of-the-art in 3DBP. The authors discuss some challenges facing the wider adoption of bioprinting, as well as the promise of this emerging technology.
Postapproval CMC Changes: Increasingly a Fact of Biopharmaceutical Life
Postapproval changes (PACs) to chemistry, manufacturing, and controls (CMC) were initiated reluctantly and carefully in the era of “the process is the product.” Today, CMC PACs are a normal part of the biopharmaceutical industry business. In this exclusive eBook, BPI covers the reasons for filing CMC postapproval changes, the global regulatory processes, safety signals in pharmacovigilance, raw materials changes and the degree of testing needed, some common assumptions that need to be more thoroughly considered, and unofficial changes.
Challenges Facing Biosimilar Entries into US Markets
Since 2009, the European regulatory agency (EMEA) has approved 31 biosimilar products. In the same timeframe, the U.S. Food and Drug Administration has licensed only six products (under PHS 351k), and approved one product under FD&C 505(b). Why the discrepancy? What are the critical challenges and obstacles impeding biosimilar approvals in the US? Sarfaraz Niazi, PhD, SI, FRSB, FPAMS, FACB, founder of Karyo Biologics, and adjunct professor at the University of Illinois provides insight into these questions and many other factors.
Emerging Markets: Current Insights into the State of Global Biopharmaceutical Manufacturing
Opportunities for establishing strong biopharmaceutical capabilities are expanding across the globe. This e-book seeks to encapsulate the current state of emerging markets/countries, tracing key elements above and offering examples to show where (in the world) the biopharmaceutical industry is expanding and securing its footholds.
Regulation, Analytical, and Process Issues with Leachables: Toward Harmonization for Latin America with Europe and North America
In this exclusive editorial eBook, authors from Mexico describe some issues related to plastic leachables in the context of ongoing efforts to harmonize regulations between the United States, European Union, and Latin America. They offer solutions in accordance to the “state in the art techniques” to fulfill this important gap in pharmaceutical industry.
BPI Lab: Essential Technologies for Development, Characterization, and QA/QC
There’s a secret hiding in plain sight: many analytical methods and technologies initially designed for pre-clinical development have equally important applications in commercial development. BioProcess International and BioTechniques, partnered to create this special eBook, highlighting and detailing fourteen analytical technologies that provide laboratory technicians and scientists with vital information to help project managers and engineers make educated decisions that ultimately affect every company’s bottom line.
Extractables and Leachables: Standardizing Approaches to Manage the Risk
The implementation, maturation, and benefits of single-use technologies in biopharmaceutical development and manufacturing are well documented and understood. As analytical methods and testing services also rapidly improve, it is clear that management of risk associated with extractables and leachables also must evolve. Standardization is universally accepted as a goal; how to define, implement, and educate the industry is where debate resides.This BPI eBook reviews the industry’s approach to leachables and extractables to address an underlying question: How close are we to making standardization a reality?
Biopharmaceutical Fill and Finish: Technical and Operating Challenges for the Latest Formulations and Devices
This eBook reports on the technical and operating challenges impacting the latest formulations and devices including: outsourcing, contamination, standardization (pre-filled syringes), lyophilization, and serialization. Get informed on the current state-of-the-art technologies in fill and finish to ensure your product development efforts take full advantage of the innovation in this area of biomanufacturing.