Because they occur after two highly engineering, and science-driven phases of biomanufacturing – expression and purification – biopharmaceutical fill and finish processes have not received the respect traditionally that they deserve. Yet of all competencies associated with bringing biopharmaceuticals to market, fill and finish arguably are the most specialized.
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.
Here is an excerpt:
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This report will discuss how to speed up the development and streamline up and downstream processing. You will see those opportunities at close reach to further increase speed to the clinic and accelerate biologicals purification processes. Besides, you will find answers to the following questions: Are scaled-up, and budget operations with the predominant downstream processing (DSP) operations fit for a challenging market? Does DSP with state-of-the-art purification methods warrant biotherapeutics regulatory clearance? Does shifting processes from batch to continuous manufacturing pose unnecessary financial risks? Production processes for biopharmaceuticals using protein A chromatography still suffer from platform limitations. How can we overcome those setbacks and the high operation expenses associated?
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This report will discuss how to streamline development and production of cell culture acceleration and optimization. You will see those opportunities at close reach to further increase speed of development and optimize processes. A curious glance at the novel technologies will let you discover proven models of yield maximization and economy of resources (controlling COGs). Besides, you will find answers to the following questions: What makes a bioprocess platform a winner setup? Do scaled-up and budget operations need to compromise in quality? Does a bioprocess with state-of-the-art organization warrant biotherapeutics clinical success? Does shifting processes from batch to continuous manufacturing pose unnecessary financial risks? Production processes for biopharmaceuticals using mammalian cells still suffer from cellular and platform limitations compared to bacterial or yeast-based expression systems. How can we overcome limited growth, low productivity, and stress resistance, and higher operation expenses?
A 2015 study shows that the biopharmaceutical industry provided 8,182 kg of monoclonal antibody products, representing nearly $100 billion in revenue in 2013 (US, Canada, Europe, and Australia). While the role of biologics in treating human diseases has evolved dramatically over the past decade, so has the technology to manufacture and the role of the manufacturing process on the structure and activity of the molecule. Eventually, current market drivers in the biotech industry require process innovation to increase manufacturing flexibility and decrease COGs. We are witnessing a proliferation of enabling tools, as analytical scientists have developed sophisticated techniques to decipher attributes critical to quality. In fact, N-linked glycosylation plays a crucial role in the efficacy of therapeutic proteins and is therefore considered as one of the major quality attributes. However, bioprocess conditions, media components, and scale-up issues can significantly influence the quality of a protein. System, bioprocess conditions, media supplements, as well as scale-dependent process characteristics, can have a decisive impact on process performance and product quality. Superior therapeutics with proven efficacy of various glycoengineered proteins has stimulated the development of novel optimized expression systems such as mammalian cells producing non-fucosylated antibodies. Controlling protein N-linked glycosylation tightly and other critical quality attributes (CQAs) during the manufacturing process thereby set new standards in bioanalytical throughput and precision. Besides, it is now becoming feasible to produce material rapidly for pharmacology, formulation, and toxicology studies without having to establish a stable cell line. At the same time, various production systems for glyco-optimized proteins, including yeast have already been engineered to produce the main steps of the human N-glycosylation pathway and enabled biobetter versions of therapeutic mAbs. While routine PTM optimization across the cell’s glycosylation machinery seems at far reach today, combining the expression from nonmammalian hosts with antibody glycosylation performed in vitro are promising. Continuous Bioprocessing can position the biotech industry to expand its commitment to serving even larger populations and unmet medical needs. Furthermore, an integrated continuous biomanufacturing (ICB) platform offers significant financial advantages due to multiple process intensification (such as smaller, fewer and more efficient unit operations, more flexible facilities, reduced turnaround time and increased automation) leading to hundreds of millions of dollars in savings.
A whitepaper from New England Controls
By necessity, pharmaceutical manufacturing must be highly controlled. When excursions, or any event that falls outside of normal operation, take place during the manufacturing process, a chain of evaluation must occur to ensure the proper response and control takes place. As such, an excursion can have a severe impact on the process, including delays in lot release, loss of batches, or receipts of non-compliance.
New England Controls has developed an automated excursion management solution that uses Emerson’s Logbooks software in conjunction with a manufacturing execution system (MES) and a distributed control system (DCS). By working together, Logbooks, the MES, and the DCS make the process of identifying, classifying, and correcting excursions much easier. The automated excursion management system monitors events that have been classified as excursions, and when these events occur, they are automatically passed to the automated excursion management system. Automated entry of these items prevents users from needing to interpret what is important at the time of the excursion and removes the possibility of transcription errors.
The automated excursion management system drives a resolution workflow involving several individuals or groups within the organization. The number of groups involved is based on the classified severity of the excursion which is introduced to prevent Quality from reviewing low impact items that don’t require Quality input. These groups include:
- Manufacturing Operator – An operator who witnessed the excursion occur is responsible for performing an initial review, where he or she provides additional information to the automatically collected Information.
- Manufacturing Supervisor – A manufacturing supervisor ensures that the proper information was recorded and/or can resolve excursions classified as being owned by manufacturing. This prevents a Quality representative from having to review low impact excursions.
- Manufacturing Sciences – A manufacturing sciences representative can optionally be involved in the review process for specifically evaluating the science behind the change in the process caused by the excursion.
- Quality Representative – The quality representative will review the most severe excursions and take necessary action, which might include attaching justification documents or acknowledging that the issue requires further investigation, which he or she does by creating a CAPA. Quality only is involved in excursions classified as requiring quality or for unassigned excursions that are too generic to classify.
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Recent clinical trials in the field of cell and gene therapy demonstrate remarkable therapeutic benefits with excellent safety. Despite demonstrated therapeutic effects, the commercialization of cell and gene therapies and their patient outreach remain scarce. Much of the research and development on cell and gene therapies is performed either on an academic level or by small and medium enterprises, largely excluding large pharmaceutical companies. Regulatory approval for cell and gene therapeutic products is performed on an individual product basis and is classified based on the degree of manipulation and intended end use. The primary deterrents to the lackluster commercialization of cell and gene therapies include the inherent complexities of the cells, issues with scalability for manufacturing and logistics and the complex regulatory requirements and time-consuming clinical trials. Cell and gene therapy products also have to navigate through the disparities in the regulatory requirements across regions. Furthermore, the complexity of product classification, extra requirements for combination of cell and gene therapies with a medical device, extensive paperwork surrounding the often ambiguous certification procedures and most importantly, the lack of harmonization of regulations across regions deter new investments and innovation in the field.
Limited understanding of the complex interactions of cell and gene therapeutics, absence of established standards and relatively scarce research data on the mechanism of action of these therapeutics make it difficult for stakeholders to navigate the complex and stringent regulatory requirements.
We elaborate the fundamental regulatory concerns associated with the development of cell and gene therapy products, and the need for international harmonization of regulatory requirement for approval of cell and gene therapies. The paper also addresses specific regulatory aspects in the EU and Japan as well as the roll-out of fast track mechanisms for market authorization in the EU and Japan. Finally, the paper addresses the urgent unmet need to provide regulatory certainty in the field of cell and gene therapeutics in the fast evolving global regulatory landscape.
There is an investment gap between research funding programs and venture capital investors where early-stage biotechnology companies struggle to obtain funding. As such, companies have to be creative on where they raise funds and how they allocate it. They must also use different strategies to shorten the regulatory process, enabling them to maximize their patent portfolio life. The article examines how companies are using new business models, reducing costs, accelerating development as well as obtaining alternative capital.
Some of the business models we will be looking into are the virtual company model (a model where the company hires a minimal amount of permanent staff), as well as discussing new partnering arrangements with CROs (such as the one with CatoBioventures). Also examined are some of the ways companies can use to reduce costs such as Microdosing (also called Human Phase 0 studies) and Outsourcing Abroad (mostly for CMO and CRO services).
Then follows a brief overview of the different FDA programs available to increase the speed of an early biotech regulatory process: the four main programs examined in this article are Fast Track Designation, Breakthrough Therapy, Priority Review, and Accelerated Approval Designation. Finally, we complete our overview with a short presentation on two innovative funding opportunities, Philanthropy foundations Venture Capital (which are VC arms of traditional philanthropies) and Equity Crowdfunding (raising funds through a large number of individuals in exchange for equity).
The object of this article is to generate thoughts and ideas for early biotechnology companies, and should be a useful thought starter for many starting their journey in fundraising.
Author: Jean-François Denault is a consultant specialized in Market Research for Life Sciences companies. With 15 years of experience, he has worked with many clients, from start-ups to global pharmaceuticals. He can be reached at firstname.lastname@example.org
Currently there are 672 cell and gene therapy companies worldwide and 20 products approved by the food and drug administration (FDA). Dendreon’s Provenge autologous cell therapy although approved by the FDA ultimately failed commercially due to a manufacturing and distribution model that was not efficient. Cost of Goods (CoGs), manufacturing process and logistics are critical to the success of cell therapy commercialisation and these need to be considered from the inception of a cell therapy company in addition to the clinical science. Three key enablers for success are manufacturing automation/ single use technologies, a diverse pipeline in modularised facilities, and sophisticated data acquisition/ logistics.
Quality by Design (QbD) is a scientific, risk-assessment framework for process design based on relating product and process attributes to product quality. A risk assessment is conducted to prioritize the study of the most influential critical process parameters and material attributes. In addition to reducing risk QbD also increases efficiency as critical experiments are front loaded (Figure 1). This is particularly important in identifying required changes to the manufacturing protocol early reducing comparability risks.
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