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.