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Applying new technology and approaches to the analytical challenge of assessing the empty full ratio for adeno associated virus
Get PDFAbstract: Assessing the empty full ratio for Adeno associated virus (AAV) is a key critical quality attribute. It needs to be done both in-process and at the Drug Substance/Drug Product release phase of manufacturing. Measuring the ratio at different phases of the processes offers up different challenges. I will be focusing on in my talk how we have been using new technology to gain more empty full ratio information from less in-process material and using automation to increase throughput. I will also focus on how we have been using new software with older technology in the use of Analytical ultra-centrifugation as the release test for the empty full ratio measurement with Ultrascan software. This solution is 21CFR part 11 compliant and allows for a multi wavelength scan which gives unrivalled information on AAV DNA load packaging
Driving innovation in sustainability through product Life Cycle Assessments
Get PDFWatson-Marlow Fluid Technology Group is committed to improving the sustainability of our products. Customer expectations are growing in relation to the sustainability performance of our products and services and many are looking to us to help them meet their sustainability targets. Therefore delivering products and services that improve the sustainability of our customers’ operations is central to our Company Purpose. One of the pillars of our Sustainability strategy is a commitment to carrying out life cycle assessments (LCA) for our products. LCAs are critical to understanding the environmental impact of a product, from raw material extraction through to product disposal and beyond considering end of life solutions. In collaboration with the University of Exeter, an approach to conducting robust LCAs has been established focusing on Cradle to Grave and End Of Life impacts. To date, products integral to the use of Watson-Marlow’s puresu® and aspecticsuTM single-use technologies have been assessed including the BioClamp® and Aflex Hose products as well as the Qdos 30 pump for industrial applications. The outputs of the LCAs are enabling Watson-Marlow to develop and deploy innovation in sustainability throughout their supply chain and in their product development pipeline
Addressing the pain-points of single-use intensified multi-product downstream and liquid processing in a dancefloor production room layout
Get PDFThe sales of biologics will reach over $300 billion in 2020 and the market continues to have accelerated double-digit growth under the COVID-19 burden, thus biopharmaceutical companies continue to pipeline biologics for a mounting global patient base. Nevertheless, biologics are changing and the needs of their manufacturing are changing with them. Emerging biologics (e.g., antibody–drug conjugates, viral vectors, mRNA, bi/multi-specifics) are coming with complex or lean manufacturing requirements. Additionally, the global market is searching for more affordable & sustainable biologics and biosimilars, creating an increasingly competitive space within the emerging countries who seek to manufacture locally.
The BioPhorum Operations Group (BPOG), a cross-industry organization of biopharmaceutical end users and suppliers collected biopharmaceutical industry drivers stating;
- 90% reduction in capital expenditure (CAPEX) and manufacturing costs in the next decade.
- reduce product changeover times by 90% to improve responses to variability in demand
- drive down new facility build times by 70%
The question is, how does this translate to actionable and prioritized points of improvement for a biological implementer & supplier to work on?
With this general need in mind, combining Design Thinking methodology and insights from single-use biological manufacturing users were gathered through an extended survey with key biopharma industry companies and institutes representing the various user groups. All interviewee responses were populated, to enable the categorization and sorting of distinct user perceptions of likes, pain-points, and benefits. The outcome of the survey was thestarting point to define what are the critical components for a sustainable technology roadmap to address the needs for the rapidly intensifying biologics manufacturing market.
In the presented work will be an overview of these validated pain-points, an explanation of the corresponding technology characteristic which address the underlying user need and a journey along the downstream purification steps. The format will be interactive with feedback questions and presentation of anonymous answers from the audience. The presentation will finish with concluding remarks on how sustainable single use processing could benefit the manufacturing of biologics
Developing a flexible automated continuous downstream processing system for research to clinical supply
Get PDFContinuous manufacturing has gained a lot of attention over the last 10-15 years for numerous reasons such as the potential for higher efficiencies, reduced cost of goods, and improved product quality. However, the adoption of these technologies has been slow due to concerns over operating these processes in a GMP manufacturing environment. Some of these concerns relate to the operation of multiple continuous unit operations in an integrated process sequence. This presentation will highlight these concerns and show how these issues were addressed by developing an overarching automated and modular platform which can be easily reconfigured for processing most products.
The developed automation platform is the result of a project funded by Innovate UK that brings together a number of biopharmaceutical companies including Allergan, AstraZeneca, Fujifilm Diosynth Biotechnologies and GSK to identify and address these issues. One objective of the project is to develop a flexible automated biologics downstream process consisting of multiple unit operations that can be rapidly reconfigured for manufacturing different products. To that end the process has been design with modularity in mind with each module having common inputs and outputs. The automation software has also been developed in a way that most typical downstream processes can be implemented in the system with little to no software updates. The ability to rapidly reconfigure the process has been demonstrated by using the system to produce three products with different process sequences.
Another issue that inhibits the adoption of continuous technologies is the concern over simultaneously operating multiple unit operations. This presentation will detail how the automation software was developed to control both the key unit operations such as chromatography and filtration steps but also intermediate operations such as feed conditioning and viral inactivation steps. The automated system reduces the complexity of downstream processes, which can have in excess of eleven unit operations, to a single user-friendly interface. Implementing this control platform enables a single operator to control the entire process.
This presentation will also detail how the automation strategy has been developed to enable a single operator to deal with start-up/shutdown, perturbations in the process and mid-process equipment turnover. It will highlight the challenges that have been faced when developing this system and how these have been overcome.
The aim of this project was to improve efficiency by reducing processing time when compared to the current batch process and this was demonstrated by testing the system with three different products (a MAb and a MAb fusion protein). Furthermore, this presentation with show data from the production of three products that demonstrates comparability between the continuous process and the original batch processes. It will then detail how this was used to demonstrate the production of a large-scale clinical batch run
Microarray patch delivery of un-adjuvanted influenza vaccine induces potent and broad-spectrum immune responses in a phase I clinical trial
Get PDFMicroarray patches (MAPs) offer the possibility of improved vaccine thermostability and dose-sparing potential as well as the potential to be safer, more acceptable, easier to use and more cost-effective for the administration of vaccines than injection by needle and syringe. Here, we report a phase I trial (ACTRN12618000112268/ U1111-1207-3550) using the Vaxxas high-density MAP (HD-MAP) to deliver a monovalent influenza vaccine to evaluate the safety, tolerability, and immunogenicity of lower doses of influenza vaccine delivered by MAPs. To the best of our knowledge, this is the first study determining dose reduction potential using MAPs in humans. Monovalent, split inactivated influenza virus vaccine containing A/Singapore/GP1908/ 2015 [H1N1] haemagglutinin (HA) was delivered by MAP into the volar forearm or upper arm, or given intramuscularly (IM) once. Participants (20 per group) received HD-MAPs delivering doses of 15, 10, 5, 2.5 or 0 µg of HA or an IM injection of quadrivalent influenza vaccine (QIV). In two subgroups, skin biopsies were taken on days 1 (pre-vaccination) and 4 for analysis of the cellular composition from the HD-MAP application sites. All laboratory investigators were blind to treatment and participant allocation. The primary objectives of the study were safety and tolerability. Secondary objectives included immunogenicity and dose de-escalation assessments of the influenza vaccine delivered by HD-MAP. Both objectives were assessed for up to 60 days post-vaccination.
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Development of analytical characterization tools for process monitoring of adenovirus-based vaccines (ChAdOx and Ad5)
Get PDFProduct quality understanding is a critical part of viral vector vaccine manufacturing and regulation. Mass spectrometry is a technique that has widely been applied to protein-based therapeutics and could be used as a characterisation tool to monitor viral vector vaccine product quality. The ultimate objective of this Bill and Melinda Gates Foundation funded project is to enable vaccine manufacturing in Low and Middle-income countries (LMIC) through increased scientific understanding of viral vector vaccine manufacturing bottlenecks and therefore de-risking of vaccine development and manufacturing.
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On-Line influenza virus quantification for viral production processes thanks to affinity-based surface plasmon resonance biosensor
Get PDFInfluenza virus seasonal epidemics, associated with the constant threat of new pandemic outbreak, challenge vaccine manufacturers to develop responsive processes that can outreach the limitations of traditional egg-based technology. Recent progress made regarding cell culture bioprocesses allowed for numerous alternative strategies to developed future vaccine candidates, as for example the recombinant HA or Virus—like Particles (VLP) vaccines. However, while cell culture allows for more versatility than ovoculture, regarding process development and monitoring, these alternatives still require optimization to seriously concurrence the traditional process. To drive these developments, WHO and regulatory agencies underlined the need for developing better influenza vaccine potency assays1,2. Actual influenza vaccine formulation and lot release rely on single-radial immunodiffusion (SRID) assay, which requires strain-specific reference sera and antigen reagents. However, the annual preparation of these reagents takes between 2 to 6 months and constitutes a critical bottleneck for the release of vaccine lots3. Additionally, SRID is not implementable for process development as such technique cannot handle in-process low concentrated and non-purified material. We developed an assay for rapid and label-free quantification of influenza hemagglutinin (HA) antigen and influenza virus based on surface plasmon resonance (SPR). The method is based on affinity capture of hemagglutinin antigen by sialic-acid terminated glycans present at the surface of the fetuin-functionalized sensor. Conditions were optimized for the regeneration of the surface, in order to run multiple sequential analyses on a unique sensor. Two types of purified standard were used during the development of the assay. Commercial trivalent inactivated vaccine (“TIV”) has been used for the determination of optimal analytical conditions, while a stock of split inactivated H1N1 virus has been produced and calibrated in our laboratory to study the specific response obtained toward this HA subtype. This assay offers a quantification of influenza hemagglutinin within minutes with a wide dynamic range (30 ng/mL-20 µg/mL). Also, the technique provides a limit of detection (LOD) 100 times lower than SRID, and a better reproducibility than SRID and its potential alternatives recently proposed (1,4,5. Additionally, the applicability of this assay for an on-line vaccine production monitoring has been validated by off-line measurement of influenza H1N1 virus particles derived from cell culture supernatant. Such a test allowed to achieve a LOD of 106 Infectious Viral Particles/mL Thus, our assay provides an innovative tool to evaluate influenza new vaccine bioprocesses, from viral production kinetics in mammalian cell culture to vaccine potency evaluation
Development of an oral protein subunit COVID-19 vaccine to induce mucosal and systemic immune response
Get PDFIt is widely recognized that mucosal immunization is the most efficient route of delivery to offer protective immunity. Oral administration can boost the economic value of vaccines, make needle-free delivery possible, and allow for safe and convenient self-administration. Despite these critical advantages, there are very few oral or nasal COVID-19 vaccine in development, and none on the market. The main challenge for an efficacious vaccine administered orally is the need for an efficient antigen delivery system into the mucosa. VaxForm has developed a technology that consists of co-adsorbing antigen(s) and a C-type lectin (CTL) receptor agonist to an aluminum delivery particle and encapsulating the vaccine with an enteric polymer to protect it from the stomach acidic environment and enhance stability. Once in the intestines, the protective polymer dissolves, and the CTL agonist targets the microfold (M) cells in the gut associated lymphoid tissues (GALT), allowing efficient delivery of the antigens adsorbed to aluminum particle
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Multimodal chromatography combining steric exclusion and cation exchange as an intermediate downstream step to purify yellow fever virus-like particles
Get PDFYellow fever (YF) is an hemorrhagic viral disease transmitted by infected mosquitoes, which is endemic in many African and Central/South American countries. The severe symptoms and the high mortality rate of the disease can have devastating effects in case an outbreak occurs in an area where the population is non-vaccinated. Before the current YF vaccine became available, outbreaks in cities like Barcelona (Spain) and Philadelphia (USA) led to the death of approximately 10% of the population. Recent outbreaks have shown that YF continues to be a major public health threat due to production capability issues and shortage of vaccine stockpiles, which even led to the use of an emergency fractional (1/5) dose in Africa in 2016 and in Brazil in 2018. Yellow fever virus-like particles (VLPs) represent an interesting alternative to develop a new YF vaccine.
With the aim of developing an efficient and affordable process to purifiy yellow fever VLPs, in this work we developed a multimodal strategy combining cation exchange (CEX) and steric exclusion chromatography (SXC) under conditions where the product of interest does not bind to the CEX adsorber, whereas many contaminants do. In this way, the product of interest is retained just due to steric exclusion by the polyethylene glycol (PEG) added to the mobile phase. Product desorption can be achieved by decreasing PEG concentration, while contaminants remain bound to the adsorber and are eluted in the regeneration step. To the best of our knowledge, the application of such a multimodal strategy has not been published before.
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