The Disposable Facility and Single-Use Technology – a Solution or a Revolution?
Over the last decade the application of disposables and single-use equipment has become increasingly popular. There is however a continuous discussion going on regarding the advantages and disadvantages versus a conventional stainless steel environment. Reviewing the vast literature available on this topic it becomes pretty clear that there is no single and simple argument pro or contra which could be taken as a decisive answer. It needs to be analysed in which environment, at what condition and for what purpose disposables and single-use equipment is being used. This presentation reviews and illustrates the very different arguments for the application of equipment as a consumable, including advantages and limitations of single-use technology, understanding improvement of process robustness, contribution to lean production as well as environmental impact of disposables, finally culminating in the question if this way of processing is a solution to improve biomanufacturing economy – or if it is even a revolution regarding process feasibility and elimination of constraints.
RecordedSep 18 201362 mins
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Recently, there has been a renewed interest in the field of continuous processing. Some key factors driving this interest are – availability of better cell retention devices, improved cell lines and culture medium capable of supporting high cell densities.
These factors have contributed mainly in reducing the batch duration for making the required quantity of product, thus reducing the medium requirement and chances of batch failures significantly. With the continuous processing being considered as ‘back-in-the-game’, the question remains: Can the current perfusion technology compete or replace the conventional and widely preferred fed-batch technology?
Two cases are discussed to compare the performance features of fed-batch and perfusion processes. In both the cases, the product output from perfusion process is significantly higher (2 to 5 folds) than that from fed-batch, due to combination of factors like higher cell density, higher cell specific productivity, lower accumulation of toxic metabolites etc. These cases demonstrate the potential of perfusion process in significantly increasing the product output. However, there are certain challenges and points to be considered before a company decides to switch to a perfusion platform. Some of these are highlighted in the article.
ADCs are complex compounds resulting from the coupling of cytotoxic small molecules to a monoclonal antibody. Their characterization as well as their bioanalysis (quantification in biological fluids) remains challenging. Mass spectrometry at different levels (intact, middle, peptide) can be a valuable tool, and can now be used in a regulated environment thanks to advances in both hardware and software.
Historically, quality of biological products has been ensured through testing representative samples. Shift in quality paradigm started with implementation of Good Manufacturing Practice (GMP) regulations with current focus on building quality during manufacture. Inherent variability and complexity of biological products pose challenges in implementing Quality by design (QbD) concept. This presentation discusses ways to build quality during manufacture of biological products.
The importance and value of continuous bioprocessing, both upstream and downstream has economic and sustainability advantages and due to the modular nature of continuous bioprocesses means that industry is able to adapt more rapidly to changing market demands. Continuous biopharmaceutical manufacturing in the context of other industries that have already successfully adopted continuous processing. Factor other than scientific ones, are the barriers to change from batch to continuous production. an excellent example of the manufacturing strategies of the steel industry in the 20th century, when this industrial sector incrementally switched from batch to continuous operations. biopharmaceutical industry has reached a stage that requires a change in the production paradigm. For a certain class of biopharmaceutical products upstream continuous manufacturing has always been applied: for example, unstable proteins that rapidly degrade in the culture broth. In order to obtain a high quality product, the residence time in the reactor must be minimized. This can only be achieved with continuous cultivation and preferably with perfusion reactors. a brief overview on the types of cell retention devices currently used in biopharmaceutical industry.
Furthermore, this is a universal production platform that can be extended to other classes of products, such as antibodies, which are relatively stable molecules. continuous manufacturing is as productive and with a much smaller footprint of the manufacturing plant, avoiding multiple non-value added unit operations. In essence, the investment for a continuous plant is much smaller compared to a batch-operated one.
The development and application of continuous manufacturing processes for vaccines presents both great opportunity as well as significant challenges, both technical and cultural, for the global industry. The key drivers are manufacturing capacity and flexibility, speed to market, and improved quality through the application of Quality-by-Design and Process Analytical Technology (QbD/PAT). Given the diversity of immunogens (toxoids, conjugate and subunit vaccines, live-attenuated and inactivated viruses, VLPs, etc.), and the variety of unique processes currently utilized to produce either single- or multi-component vaccines, it is unlikely that the transition to continuous processing will happen overnight. Additionally, cultural challenges are faced whenever a new mode of operation appears to some as “too different”, especially in a traditionally conservative sector like the developed-world vaccine industry. That said, market forces, global climate change, and Nature’s propensity to fill unoccupied niches with emerging infectious diseases will undoubtedly induce a first round of pioneers to explore this exciting new design space, ultimately leading to a more nimble industry and more and better opportunities for protection for the global population.
Single-Use Process Analytical Technologies (PAT) tools have a great potential to not only increase process understanding at the seed stage but also simplify cell culture operations. By utilizing PAT, the risk from bioburden or contamination can be significantly reduced and the overall operating efficiency increased. In fact, PAT also provides a data-driven platform to integrate Process Development and Manufacturing Operations that can mitigate risks associated with technology/process transfer.
New vaccine process designs – and all the kinks that go with them – are typically hammered out in a small scale capacity, for example, prior to manufacturing for early phase human clinical trials. They are then upsized and further defined for industrial scale to supply the vast market. Single-use technologies (SUTs) have been a hot topic for several years now and their advantages well-known: easy product changeover, processing in lower classification areas, reduced CAPEX, elimination of glass, sterility assurance, to name a few. In vaccine manufacturing, SUTs are used throughout the processing stages, from cell culture all the way to filling. SUTs are quickly and conveniently designed, purchased and implemented for short-term manufacturing of clinical trial phase materials. Here a large percentage of new vaccines in Research and Development do not even make it to market.
As the final production stages are critical as they are the last stages before patient injection, the scope of thisarticle covers SU applications involving drug substance formulations, adjuvant processing, final bulk formulation and filling. The actual process itself may include some or all of the following: filtration, pumping, ingredient addition, mixing, adsorption, filling, labelling, sampling and and storage.
In this presentation only liquid formulations (“presentations”) will be discussed.
Gloria Gadea-Lopez, John Maguire, Mark Maselli & Ken Clapp
The increased interest and adoption of single use systems (SUS) or disposables require that organizations rethink their operational business processes and the design and configuration of manufacturing execution systems (MES). Drawing from their previous experience implementing MES and SUS for biologics manufacturing, the authors discuss the key areas of impact of SUS on operational technology, outline new user requirements, and propose practical solutions for successful MES implementation.
Comparability exercises are commonly required at certain milestones during drug development as well as after product registration when changes are implemented into the manufacturing process. The goal is to evaluate if the product remains highly similar (not necessarily identical) before and after the change in terms of quality and stability and have no adverse impact on safety and efficacy predicted for the patients. This assessment requires product-specific knowledge gathered through drug development, taking a totality-of-evidence approach. The different levels of information are obtained from analytical studies for characterization of the molecule, animal studies for toxicity, pharmacokinetics and pharmacodynamics for pharmacological activities, and clinical studies for safety/tolerability, immunogenicity and efficacy. This Webinar discusses strategies and considerations for analytical characterization of protein structure and function which forms the foundation of the comparability demonstration.
Sponsored by Unchained Labs
Presentation Title: Limber up your lab with better tools for comparing biologics
There’s no magic bullet when it comes to characterizing a protein by structure or function. Specific tests may work for one molecule but not the next. Instrumentation that provides a high degree of flexibility, balanced with low sample consumption and faster time to result, is crucial to keep up with ever changing laboratory needs. Unchained Labs puts biologics characterization front and center for our instrumentation development. We will discuss how our instruments let researchers be more flexible and efficient, while also providing clear data to help make comparability assessments.
Observable foreign and particulate matter has for a long time been recognized as a critical quality attribute for production of injectable protein formulations. Recently, a focus shift towards these particles and even smaller particles (particulate matter or subvisible particles) has been seen from the pharmaceutical industry, academia and the different regulatory bodies. Two of the central documents in this context are:
1. The FDA Guidance for Industry on Immunogenicity Assessment for Therapeutic Protein Products1 and
Sourcing for the manufacture and control of Antibody-Drug Conjugates (ADCs) used in clinical trials requires strategic planning, establishment of a specialized support network, and execution of several interdependent tasks. ADCs are complex molecules, a fusion of a biological, the monoclonal antibody (mAb), and of small molecules, the linker and the toxic payload. Facilities of acceptable standards for the handling of high potency materials need to be engaged, and there is a limited supply currently. This is further complicated by the fact that there is not one contract facility that has fully integrated services, a “one-stop shop” capable of mAb production, linker and/or payload synthesis, conjugation of mAb to linker-payload to make the Drug Substance, and finally, formulation of the ADC to make the Drug Product. Strategizing the best outsourcing practices for producing and testing ADCs, and establishing guiding principles for externalization to ensure the selection of the right CMOs for ADC outsourcing and technology transfer, will be further discussed.
Continuous bioprocessing offers potential to enhance productivity and product quality uniformity while simultaneously decreasing facility footprint and associated operational overhead. Advances in technology and increasing commercial pressures are leading to an increased interest in continuous processing across the biopharmaceutical sector. A number of companies are exploring and advancing continuous bioprocessing and this presents a range of opportunity and challenges, including the use of Process Analytical Technology (PAT) for process characterization, process control, and process robustness, in support of a Rapid Product Release (RPR) strategy.
The FDA’s Office of Pharmaceutical Quality (OPQ) is working to encourage the development and adoption of emerging technologies in the pharmaceutical industry that have potential to enhance drug product quality. To achieve this goal, OPQ established the emerging technology team (ETT) program and focuses on advancing regulatory science for emerging technologies. OPQ has identified Continuous Manufacturing as one such emerging technology which has the potential to increase the efficiency, flexibility, agility, and robustness of pharmaceutical manufacturing. The ETT provides industry early engagement opportunities with FDA to receive feedback on potential technical and regulatory issues and FDA’s recommendations for regulatory submission content related to continuous manufacturing and other emerging technologies. In addition, OPQ has started a regulatory science and research program on continuous manufacturing to address remaining gaps in our knowledge and experience. Our research program is currently focused on the following areas in (1) integrated process modeling, (2) understanding of the impact of material properties, and (3) implementation of advanced process control strategies and real time release testing. The results and knowledge developed in this program can be utilized to support the implementation of continuous manufacturing and to ensure that FDA regulatory policies reflect state-of-the-art manufacturing science.
Monoclonal antibodies (mAbs) represent a big portion of therapeutic proteins. Mass spectrometry (MS) coupled with modern separation technologies has become an essential tool in characterization of mAbs within the Quality by Design (QbD) paradigm during development. In this article, we use case studies to discuss the application of MS analysis in clone selection, optimization of fermentation conditions, development of purification and formulation. Specifically, simultaneously detect and monitor variants due to incomplete leader sequence processing, accurately determine afucosylation level of N-glycosylation, characterize host cell proteins (HCPs), identify degradation pathways and critical quality attributes (CQAs) will be discussed.
During the past decade, continuous processing has steadily gained traction within pharmaceutical industry. The smaller footprint, the reduction or minimization of technology transfer and overall flexibility of these systems generate the economic drivers for change. The advancement of technology, such as integration of process equipment and process analytical technology (PAT) enables concentrated process understanding and effective process control for these systems. There are an increasing number of joint efforts from industries, academia and regulatory agencies in this area. Continuous manufacturing implementations for commercial products are beginning to emerge as companies begin to turned this vision into reality.
Among all the process analyzers, NIR is still one of the most widely used platform PAT tools in continuous processes. Some critical aspects should be considered for NIR (or other common PAT tools) implementation in continuous processes.
Because of worldwide demographic changes a dramatic increase of the geriatric population is expected in the next decades. While pediatric drug delivery principles are becoming integrated into the development of new medicines, drug developers are less prepared to appropriately address the specific needs of this booming patient population. This webinar tries to give an overview about the possible drug delivery strategies addressing old age dependent differences. There will be specifically focused on how patient convenience and compliance can be improved, how disease specific drug delivery strategies can help geriatric patients, and how learnings from pediatric drug development can be used as a platform towards geriatric drug delivery.
Peter will share experiences and observations how the scientific high-tech community, can benefit from adopting paperless processes in the laboratory. Is it because paper doesn’t require any significant investment budget, or is it the low barrier to access, since paper even works without power or the need to have access to an information infrastructure, or is it just simply that the “what’s in it for me” question hasn’t been answered satisfactorily for the scientists?
Cross-functional collaboration between research, development, quality assurance and manufacturing is all about optimising and integrating multi-discipline distributed processes from start-to- finish. A paperless electronic record keeping system will add significant value to support these goals. LIMS, SDMS, LES and ELN products all reduce variability, transcription errors. Do we believe that traditional paper based systems could ever support these complex processes?
Though single-use technology and the general use of disposables are widely accepted and applied both in process development, pilot plant and selected production processes, they are not in general a reasonable choice at any scale or application. Notably process chromatography is considered a critical unit operation regarding feasibility to single-use application with the chromatographic matrix assumed to be the typical cost driver. But is this really true? The answer to this quite ambivalent: it depends! Numerous young and innovative companies have developed new and/or alternative products which can help to significantly reduce the costs of goods, thus providing an interesting basis for single-use applications. After all, taking into account reasonable scales and suitable manufacturing targets, the doors have been opened widely due to the supply of appropriate low-cost matrices and feasible hardware.
The spread of counterfeit and substandard medicines is a global threat to public health. The sources of most counterfeit medicines found globally were traced to Asia. Although many of these products were found outside the region, many Asian countries are at high risk of exposure to them. There is a need for easy and affordable tools for screening medicines. Handheld Raman devices have gained increasing interest as such tools. Many of the devices available share some advantages in the detection of counterfeit medicines but there are challenges in the detection of substandard products. Fixed-dose combination medicines present even greater challenges.
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