Challenges in Industrial Process Development of Exosome-Based Therapies: Characterizing and Managing Diversity
The traditional classification of extracellular vesicles (EVs) includes three types: exosomes, microvesicles, and apoptotic vesicles. Each type arises from a distinct origin and exhibits distinct characteristics. The problem is that their size ranges overlap and that the major surface proteins presented by exosomes also are present on the surfaces of microvesicles and apoptotic bodies. This makes it a challenge for process developers to identify the vesicle fraction that best serves a particular exosome therapy. Anion-exchange chromatography (AEC) can fractionate EVs into populations of different composition. This article highlights the complementarity of two analytical methods for characterizing distinctions among EV populations separated by AEC: imaging flow cytometry (IFCM) and size-exclusion chromatography.

Expression Systems: Innovative Techniques for Conventional Cell Lines
Although Chinese hamster ovary (CHO) and Escherichia coli cells have become the biopharmaceutical industry’s preferred platforms for producing recombinant proteins, perennial challenges have limited the capabilities of those expression systems. New CHO lines and improved upstream methods steadily are increasing expression titers, yet researchers continue to decry CHO’s relatively low growth rate. E. coli exhibits strong growth kinetics but cannot perform posttranslational modifications necessary for complex therapeutic proteins. Researchers need advanced technologies and analytical methods to overcome such limitations.

This eBook explores techniques that are assisting with scrupulous studies of CHO and E. coli. First, an interview with Ioanna Tzani of Ireland’s National Institute for Bioprocess Research and Training (NIBRT) describes next-generation sequencing (NGS) techniques and their implications for CHO-based cell culture. Tzani traverses current knowledge gaps regarding CHO genomics as well as technical requirements and template-preparation methods for successful NGS experiments. Next, Robert G. Brinson and Zvi Kelman, both of the US National Institute for Standards and Technology (NIST) describe their on the first platform for stable-isotopic labeling of monoclonal antibodies (MAbs) expressed in E. coli cells. Their discussion reveals the continuing relevance of E. coli in biopharmaceutical research and development, efforts to overcome E. coli‘s inability to glycosylate proteins, and the importance of isotopic labeling in protein characterization.

Cancer Vaccines: Innovation Fuels an Immunotherapy Renaissance
Despite early successes a decade ago, cancer vaccines designed to deliver peptides or proteins — or nucleic acids encoding those antigens — generally have fizzled out since then. As a result, cancer vaccine development and the field of immunotherapy lost some traction overall. But as freelance contributor Jim Kling describes in this eBook, new innovations in product design, testing, and manufacturing are fueling a renaissance in cancer vaccine development. From checkpoint inhibitors to neoantigens, immune regulators, and beyond, companies are exploring many modalities and technological strategies to make them work. What combinations of vaccines, immunotherapy, chemotherapy, and so on will provide cancer patients with the best results? Researchers remain optimistic as the detailed biology of tumors and our human immune system continue to be revealed.

Formulation, Fill, Finish: Biopharmaceutical Drug Products for a Modern Age
Biopharmaceutical drugs are increasing in sophistication, requiring technological advancements to solve related challenges. The contributors to this BPI eBook highlight drug-product formulation concerns and collaborative efforts toward solving the fill–finish conundrum.

First, the BioPhorum’s Scott Ewan describes a holistic approach to container–closure integrity and the organization’s work toward developing and expanding upon that approach. Ewan explores how advancing analytical technologies, risk management, and quality by design (QbD) are changing the strategies related to container–closure integrity, which remains a significant aspect of product safety and stability.

Then, authors from Neurelis highlight the difficulties faced by companies developing biopharmaceuticals for nasal delivery, featuring a promising solution for the key problem of absorption. They also point out difficulties with a familiar type of excipient: polysorbates, which have been common to drug-product formulation for many years. But recent studies show that they can degrade to cause aggregation and particle formation. In nasal delivery systems, polysorbates provide no assistance for solving the absorption problem, but alkylsaccharides can — without the aggregation side effects.

Biosimilars Pipeline and Market Trends
Most biopharmaceutical industry experts now consider biosimilars to be mainstream products, indicating that the field has progressed immensely over the past 10 years. Nevertheless, when comparing approvals and commercial offerings across the globe between 2013 and 2020, it becomes clear that some regions welcome these therapies more than others do. Western European biosimilars markets continue to be kind to these drugs’ production, distribution, and coverage; and companies headquartered in Asia and the Pacific Rim increasingly are getting involved in biosimilars and biogenerics production. But the United States, which boasts the world’s largest market for biopharmaceuticals, remains the largest potential and most underdeveloped biosimilars markets in the world.

In this eBook, a BioPlan Associates representative shares key results from his company’s 17th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production and explores why the States continue to lag behind other countries in distributing biosimilar products. Read on to learn how factors such as patent disputes and latent healthcare-system recalcitrance are holding back the development of biosimilars markets in the United States

Next-Generation Vaccines: COVID-19 Challenges, Opportunities, and Patent Questions
Resolving the COVID-19 pandemic depends on treatments, testing, and ultimately a widely disseminated vaccine against SARS-CoV-2. In recent decades, the biopharmaceutical industry has developed new approaches to vaccination using antigens, virus-like particles (VLPs), viral and bacterial vectors, and nucleic acids. Current events have placed those innovations at the front and center of public attention, offering many companies an opportunity to demonstrate their potential in an unprecedented way. Here, BPI’s senior technical editor describes the challenges that developers face in doing so, points to questions raised by hurried timelines and ethical concerns, and features some of the innovators leading the way. Patent attorneys from Knobbe Martens discuss the potential for governments to appropriate intellectual property related to products that emerge from all that development work. And a specialist from Sartorius Stedim Biotech highlights the importance of technology providers in achieving the goal of protecting everyone from COVID-19.

A Light-Chain Platform for Developing Bispecific Antibodies
Biopharmaceutical researchers are focusing on novel platforms to quickly develop bispecific antibody (BsAb) therapies for treating complex diseases such as cancer. BsAb therapies offer several advantages because they are designed to bind two unique epitopes. In this report, Bill Lundberg, president and chief executive officer at Merus, describes his company’s efficient approach to developing BsAbs using “common light chain” technology and other proprietary strategies. Lundberg also addresses the company’s approach to typical BsAb development and manufacturing challenges.

Development of Bioassays: A Report from the BEBPA’s First Virtual Meeting
Bioassay development is one of the most challenging aspects of biotherapeutic development. These tests are vital to providing an accurate picture of potency, stability, and biological activity. But bioassay development can be complex and expensive — and often test results can vary. Cell-based bioassays especially lack robustness. In March 2020, the Biopharmaceutical Emerging Best Practices Association (BEBPA) presented its annual bioassay conference in virtual format. Here, BPI’s senior technical editor reports on the conference’s discussions. Read on to learn more about statistical strategies, assay variation and validation, potency and precision, and the relationships between bioassayists and statisticians in the modern bioanalytical laboratory.

Microbial Expression: The Right Choice for Large Peptides and Small Proteins
Although animal cell culture has dominated the biopharmaceutical industry for some years now, microbial expression remains important for producing proteins that don’t require posttranslational modifications — or only those that prokaryotic microbes can perform. It also offers an affordable option for antibody fragments and gene therapies. Microbes may be less fragile than animal cells, and they do require simpler media, but they present other challenges related to temperature management and oxygen transfer in culture. Wherever practical, bacterial expression is preferred for a number of reasons, from relatively easy genetic engineering to cost-effective process development, high expression levels, and a wide range of versatile plasmid vectors and host strains.

Read this BPI eBook to explore challenges in addressing future needs and opportunities for microbial expression systems in biopharmaceutical manufacturing. You also will learn about what contract manufacturers are cultivating expertise in to make peptides, proteins, and plasmid DNA using microbial expression systems.

Sensor Technologies: Essential Tools for Bioprocessing 4.0
Sensors are essential devices that can be used for most, if not all, typical biopharmaceutical development and manufacturing processes to monitor fundamental process parameters such as flow, temperature, pH, and dissolved oxygen throughout all process stages. As the bioindustry progresses toward automation, digitalization, and other “Manufacturing 4.0” concepts, robust single-use and smart sensors for bioprocess monitoring will be needed. Read this BPI eBook to garner valuable perspectives on both of these types of sensors. Discussions herein focus on smart sensor capabilities, applications, and validation.

Peptide Therapies: Small Biomolecules Address Big Health Problems
This crash course in the development of peptide therapies brings together two articles: one on product research and the other on manufacturing and regulatory concerns. In “Fighting Alzheimer’s Disease from Within: A Breakthrough Peptide,” freelance journalist Marc Davis highlights current developments in Alzheimer’s disease treatment, focusing specifically on a peptide approach from Canadian company NervGen. In “Making Peptides Work,” BPI’s senior technical editor adds perspective on developing and manufacturing peptide therapies from the Informa Connect community, with commentary from experts in the industry. Look for remarks from George Perry (editor in chief of the Journal of Alzheimer’s Disease), Rodney Lax (PolyPeptide Group consultant), Michael Karney (CEM Corporation), Tom Barnes (Intellia Therapeutics), and Renata Varga (Teva Pharmaceutical). Market survey results highlight drug delivery and company collaboration, and conversations illuminate manufacturing technologies and quality by design.

Continuous Bioprocessing: Promises and Challenges
Biotechnological productions commonly are executed as batch processes, especially during downstream processing. Higher titers in fermentations, reductions in operating scale, and the quest for improving product quality all have led to an intensified effort for developing continuous processing. It is forecasted that within the next 10 years, about 50% of all drugs under development will be biopharmaceuticals, making it worthwhile to develop more efficient processes. In this BPI eBook, Babu Halan (project engineer) and Wolfgang Minas (global lead of the Competence Center for Biotechnology, both at Chemgineering Technology) highlight current trends, technologies, and challenges in continuous bioprocessing. Read on to learn more about the impact of single-use technologies on continuous bioprocessing and the downstream concerns that continue to hamper continuous operations.

Joining Forces: Industry Collaborations Toward Bioprocess Success
Companies in the biopharmaceutical industry increasingly are working together to solve the many challenges of product/process development and biomanufacturing. Suppliers seek end-user help in refining technologies; academics and small innovators attract the financing and business acumen of large companies; equal partners share in technological problem-solving; and sponsors engage the development expertise of contract research and manufacturing organizations. Other examples of biopharma industry collaborations abound, too. Citing critical examples from the September 2019 BioProcess International East Conference in Boston, MA, this eBook explores factors behind the upsurge in — and companies’ increased openness to — collaborations. Read on to explore representative examples of biopharma industry collaborations. You also will learn about the sense of “technological democracy” that is permeating the industry as well as emerging business models that seek to mitigate the risks of research and development (R&D) activities for end users and suppliers alike.

Viral Vectors for Vaccines: A Virtual Conversation on Production and Analysis
Although today’s vaccines are safer, more effective, and more accessible than they were even 20 years ago, the emergence of new, complex pathogens has exposed limitations in traditional vaccine strategies. Viral vector vaccines (VVVs) hold great promise for confronting those now-intractable pathogens. But drug companies and biomanufacturers still need to learn much about the modality to prepare VVV operations for commercial scales. This BPI eBook uses a “virtual roundtable” discussion among three industry experts — René Gantier (Pall Biotech, USA), Neal Gordon (BioProcess Technology Consultants, BDO USA), and Scott Wheelwright (Complya Asia) — to elaborate the challenges of manufacturing viral vector vaccines. Read on to learn more about the projected advantages of VVVs over more conventional approaches as well as key differences between vector production for vaccines and gene therapies, strategies for managing difficulties with quantifying and purifying virus particles, and ways that contract development and manufacturing organizations (CDMOs) can support drug sponsors during the transition from clinical trials to commercial-scale manufacture.

Biologics Stability: Lifecycle Management of Drug Products
The biomanufacturing industry’s increasing attention to risk mitigation through quality by design (QbD) and the emergence of complex therapeutic modalities have driven the need for a lifetime-management approach to assuring drug product stability. To that end, industry guidelines have been (or are being) developed to guide the industry toward a “holistic approach” to conducting stability assessments. However, not all methods are stability indicating, and many more industry concerns need to be addressed. This BPI eBook offers perspectives on ICH Q12 guidelines and the upcoming USP <1049.1> general chapter. It also surveys advancements in analytical technologies that could provide better drug product stability testing.

Speed to IND: Balancing Risk and Reward
With so many biopharmaceuticals obtaining breakthrough or fast-track designations, companies that use accelerated strategies to be first in human studies can be left with significant quality and manufacturing challenges that must be solved later on. Despite regulatory encouragement to create solid design spaces and define parameters according to quality by design (QbD), those may go by the wayside given the pressures of speed. The reward is the investigational new drug (IND) application itself — but if companies lock in subpar processes at that stage while trying to speed to IND, they could get stuck with them. In this eBook, BPI’s editor in chief discusses the pros and cons of timeline acceleration in early development with Susan Dana Jones, senior vice president of product development at Harpoon Therapeutics. Speed at all stages can bring earlier achievement of development milestones (and ultimately return on investment sooner), but going too fast can leave gaps in process understanding and scalability that must be addressed.

Addressing Production Complexities: Strategies for Working with Difficult and Susceptible Proteins
All proteins are complex — but some are more complex than others, particularly when it comes to recombinant protein expression and production in commercial quantities. What works in a research laboratory to make a milligram of pure protein for study won’t necessarily work on a manufacturing floor to make kilogram batches for drug-product formulation. An increasing number of technological options are available, however, from a simple switch in expression host or adding folding steps in downstream processing to special genetic modifications and tagging to cell-free synthesis. High-throughput screening, design-of-experiments, and other analytical advancements are offering developers the means to discover and test possible solutions to the problem of complex protein production. In this eBook, BPI’s senior technical editor highlights several upstream strategies and technologies available to companies dealing with problem proteins. Specific innovations include engineering solutions from Thermo Fisher Scientific, MaxCyte, Cell Culture Company, LifeSensors, Lucigen, Arbor Biosciences, New England Biolabs, and more.

Bioassays for Biopharmaceuticals: Finding Best Practices in a Quality Systems World
Bioassays are complex and challenging experiments to run reliably with accurate and dependable results. Consistent performance requires a controlled environment and qualified reagents; skilled analysts who understand cell physiology, regulatory requirements, and the latest techniques; and assay protocols that are intelligently developed, characterized, and validated. Here, BPI’s senior technical editor discusses bioassay best practices with representatives of the Biopharmaceutical Emerging Best Practices Association (BEBPA) organization. Topics span quality by design, assay validation, cell banking, potency testing and host-cell protein monitoring, and special considerations for biosimilars and regenerative medicine.

Automation: The Value of Plug-and-Play Automation in Single-Use Technology
The biopharmaceutical industry’s movement away from large-scale, fixed-tank facilities to flexible facilities featuring single-use technologies (SUTs) has demonstrated the value of modular equipment and agile process design. SUTs have proven to be clear advantages to end users because those technologies enable quick facility build and changeover times. But linking SUT equipment with equally flexible automative technology has been difficult. Herein a group of automation experts from the BioPhorum Operations Group (BPOG) elaborate “plug-and-play” principles and introduce a supervisory control system that can standardize bioprocess communication protocols and reduce equipment startup or process changeover validation time (GMPs).

Bioreactor Scale-Up: From Pilot to Commercial Scale in the Modern Era
Upstream bioproduction always has begun with laboratory systems producing limited amounts of product for test purposes, then those bioprocesses are scaled up to make more product more efficiently for larger clinical trials — and ultimately commercial distribution. With the advent of single-use technology and continuous processing, how have scale-up approaches changed in recent years, specifically at the pilot-to-production level? In this online exclusive, BPI editors review the science and technology affecting decisions made at this stage of process development, with a focus on bioreactors and flow geometry, based on conversations with industry experts as well as a review of recent conference talks and literature.

Autologous Cell Therapies: Commercialization Strategies
Autologous cell therapies are derived from a patient’s own stem cells, typically collected from bone marrow. Those cells are then cultured, expanded, and reinfused back into the patient. Unlike allogeneic cell therapies, this process is repeated for each dose and for one patient. The one-to-one process carries several challenges to commercialization, including high development costs, the need to control the risks of manual processing, and compliance with strict timelines.

This eBook presents two perspectives on addressing these challenges. The first article is an interview with George Goldberger from Cell One Partners, a company experienced in consulting biomanufacturers in the development and manufacture of cell and gene therapies. He discusses process challenges, costs, logistics, technologies, and need for innovation for autologous cell therapies.  In the second article, Lynn O’Donnell, clinical associate professor of hematology and director of the Cell Therapy Laboratory at The Ohio State University’s James Cancer Hospital and Solove Research Institute, provides her perspective on the clinical side of autologous therapies. She discusses the importance of coordinating therapy development and administration, controlling ancillary material costs, and easing patient burdens.

Industrializing Advanced Therapies
Phacilitate Leaders World and BioProcess International joined forces to create a special four-part eBook series dedicated to Industrializing Advanced Therapies.

This educational platform has been designed to provide you with insight, information, and perspective necessary to stay ahead of the cell and gene therapy development and process curve.


Allogeneic Cell Therapies Commercialization Strategies
Manufacturers of allogeneic cell therapies face development and commercialization challenges unlike those of traditional cell therapies. In a discussion with Phil Vanek of GE Healthcare, we outline several of the key challenges of processing these products and bringing them to market. Approaches for reducing development costs and lowering pricing are highlighted, and a separate analysis presents three pricing models specific for allogeneic “off the shelf” cell products.


Biopharmaceutical Characterization, Part 2: Applications and Strategies for Diverse Products — A Conference Report
Last fall, KNect365 brought together more than 250 analytical specialists to discuss biological assays and 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 for case studies, regulatory interactions, sharing perspectives, and learning about emerging technologies. Part 1 of this report in January 2019 focused on the bioassay section of the meeting. Here in Part 2 sponsored by Sartorius, BPI’s senior technical editor reports on the “Well-Characterized Biologics” tracks. As you make plans for attending conferences this fall, consider the next installment of this series in Reston, VA, on 11–13 November 2019 — and contribute to the ongoing discussions.

Efficient Production of Adherent Cells – The Bolt-On Bioreactor Project, Next Phase
In this exclusive eBook, the authors update developments in The Bolt-on Bioreactor (BoB) project. The BoB project was launched with an objective of bringing to the market an efficient bioreactor for culturing adherent cells. In 2015, BioProcess International published a four-part series of articles about their work, in which they identified four challenges that needed be addressed to succeed: volumetric productivity, process automation, containment and sterility, and process economics. These updates include the entrepreneurial venture the team has embarked upon, system design updates, and future plans.

Vaccines – Industry Collaborations to Increase Uptake
In this exclusive eBook, BioProcess International’s managing editor, Maribel Rios talks to Rahul Singhvi, chief operating officer at Takeda about how vaccine developers and manufacturers are partnering with private and government agencies to increase global vaccine uptake. The areas of focus in their discussion include challenges with production capacity, distribution, safety, and accessibility. Singhvi also shares how the implementation of new technologies such as virus-like particles and cell/DNA-based vaccines are helping biomanufacturers take on vaccines for emerging diseases.

BioProcess International Europe 2019 Event Report
BioProcess International Europe has distinguished itself as a must-attend event for industry decision makers around the world. While complementing and connecting to content delivered at all BPI events, this conference delivers unique and applicable information not presented anywhere else.

In this exclusive event report, BioProcess International’s publisher and senior technical editor offer their perspectives on this year’s meeting in Vienna, Austria, with a program overview and exploration of themes that arose from the sessions and talks: from accelerated cell-line engineering to continuous bioprocessing, new separation/purification platforms and product modalities, and “industry 4.0.”

The editor of BioProcess Insider reports on process intensification and associated challenges. And a group of speakers gets together for an exclusive roundtable discussion of vaccine and gene therapy topics from their dedicated track at BPI Europe.

Expression Systems — Increasing Productivity and Reducing Costs
Biopharmaceutical manufacturers are facing increasing pressures to improve productivity and reduce time to clinic and market. Increasing productivity begins with selecting the appropriate expression system for each protein. Current efforts to boost expression titers also are focused on implementing selection/screening technologies, engineering Chinese hamster ovary (CHO) expression systems, and accelerating timelines for the development of complex next-generation therapies. BioProcess International asked three representatives of the industry’s leading companies to comment on current expression system technologies and strategies.

2019 BioProcess International West Event Report
At the BPI West conference in Santa Clara, CA, common themes wove throughout multiple tracks specific to process stages and levels of regulatory scrutiny. The BPI West program brings upstream and downstream experts together into the same sessions based on whether they share early or late-stage concerns. Even though special tracks addressed viral safety and technological advancements this past March, and preconference symposia focused on specific topics, a significant amount of session overlap throughout the week ensured that attendees could mix and mingle while getting exposed to one another’s work. Commonalities emerged from these discussions as vaccine makers rubbed elbows with monoclonal antibody (MAb) developers and gene/cell therapy pioneers — and cell culture biologists with downstream process engineers and formulators.

In this eBook, editors of BioProcess International and BioProcess Insider examine the common themes of process intensification and continuous processing, automation and process control, analytics and characterization, and the importance of data management to all these.

Making Filtration Work
Steady improvements in batch-fed cell culture have led to bottlenecks in downstream processing. Filter suppliers are working to improve available tools for purifying therapeutic proteins, to wring every possible efficiency out of those tools, and to make them operate together harmoniously. The combination of high titers and high-value products places a premium on preventing yield loss. Bioprocessors want to optimize filtration primarily for cost reasons.

In this eBook, author Angelo DePalma discusses financial aspects, clarification/harvest and virus filtration options, and innovations in filtration for downstream bioprocessing is covered with experts from the biopharmaceutical industry. They highlight how each stakeholder can work toward solving the case of upstream–downstream capacity mismatch.

Antibody Derivatives: Deconstructing MAbs for the Next Wave of Biotherapies
Although they make up the largest and most successful category of biopharmaceuticals so far, monoclonal antibodies (MAbs) suffer from certain disadvantages. Some companies are addressing those limitations by deconstructing MAb molecules to create new emergent therapeutics. These antibody derivatives include: antibody fusions and fragments, bispecifics, trifunctional antibodies, and more.

This eBook combines market analysis from consultant David Orchard-Webb with technical discussion from BPI cofounder and senior technical editor Cheryl Scott. It also includes commentary from editorial advisor Michiel Ultee and BioProcess Insider editor Dan Stanton, to present a current picture of where these “next-generation” therapeutic proteins stand.

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
In-Process Monitoring

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.

Biopharmaceutical Characterization,
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.