Robert Gronke, Ph.D., Senior Principal Scientist, Technical Development, Biogen
Following on the commercial success of Spinraza® (the first successful treatment for patients with spinal muscular atrophy), antisense oligonucleotides (ASO) are now an important part of Biogen’s drug portfolio that enables us to better treat neuromuscular diseases. Development of the ASO process employs orthogonal chromatography to achieve industry high purities while maintaining good yield along with detritylation and UF/DF steps. This purification platform process is all aqueous based on green chemistry principals that easily fits into our existing biologics manufacturing facilities. To date, we now leverage this ASO platform process to purify 13+ ASO molecules that contain different sequences, chemistries, and most recently incorporating conjugation reactions.
Having completed process characterization for our lead ASO candidate, we have achieved a greater understanding of the process, its capabilities to clear process and product related impurities and understand the mechanisms that control the chromatography. On the manufacturing side, Biogen recently completed at scale PPQ validation batches of an ASO clinical candidate. Cases studies and learnings will be presented on results from characterization studies and PPQ batches.
Jurgen Mulberg Associate Director at Bristol Myers Squibb
Full Title: Application of Next Generation Sequencing (NGS) Based Methods for Detection of Viral Contaminants in Biomanufacturing
Contamination of a biological product with viruses, potentially harmful for humans, is of concern for therapeutics derived from human and animal sources, i.e. plasma, and for protein therapeutics and vaccines produced in mammalian cells. More recent “Advanced Therapeutic Medicinal Products (ATMPs)”, such as gene and cell therapies, share the same concern. Tests for viral contaminants are performed at several stages of manufacturing. Current tests for detection of viruses are lengthy; cell culture based assays and animal experiments are required. Alternative molecular tests, such as “next generation sequencing (NGS)”, provide faster results, and can eventually replace in vivo animal studies. It is noteworthy that identification of a viral contaminant that evaded detection in classical tests, by NGS, has been demonstrated. In addition, due to the fast turnaround time, application of targeted NGS for “in process” detection of viral contaminants can be envisioned. Current efforts for development of unbiased and targeted NGS based viral safety assays will be discussed
Flavien Susanne, Head of Chemical Development Engineering at Sanofi
In the past decade, there has been a growing interest in the application of continuous processing in the pharmaceutical industry with 100s millions of investments and several products delivered to the market using this technology.
Continuous processing demonstrates several value propositions for the Pharmaceutical industry. Amongst them we can name, access to better chemistry, product quality enhancement, reduction of CoGs but mostly speed to market where phase 3 to launch is drastically accelerated.
Sanofi R&D is building capacities to perform future GMP clinical batches using this technology. The first investment was completed last year, and we are in the process of expansion. It is a really changing time for science at Sanofi.
Sanofi is investing in modular concept with high capability of production of API and ability of infinite reconfiguration. We are not only thinking machine; to enhance our ability to always produce best quality drugs to our patient, we are also implementing digital twin system, tracking and controlling the quality of our product at any moment of time.
We are ready to meet the challenges of tomorrow and produce the new APIs to help patients.
Steve Hammond, Independent Consultant at Steve Hammond Consulting
It is well recognized that continuous processing requires continuous monitoring, at the “heart-beat” of the process to ensure product quality and patient safety. However, the use of PAT in the optimization of equipment and the development of processes from which a product will be manufactured is also of significant value, and justifies the investment in PAT for a continuous manufacturing. The data density and timeliness can deliver immediate feedback and exquisitely detailed information on the success of processing steps. The gathered information can aid in the establishment of an effective and robust processing regime for new or existing products.
This paper will discuss the use of information rich PAT technologies to understand equipment and process steps during development. Examples of equipment characteristics and the effect on the product will be examined.
An important area for PAT in continuous manufacturing is cleaning. The equipment trains to be effective must be capable of rapid change over. PAT’s designed for rapid assessment of surface cleanliness are important. Devices that allow rapid cleaning verification will be discussed.
Oliver Steinhof, PAT Scientist at Biogen and Nicolas Langenegger, Senior Associate Scientist at Biogen
Full Title: Development of automated chemometric platform for accelerated Raman-based model optimization in biologics
The increasing use of multivariate models both as part of the control strategy in commercial (bio)pharmaceutical production as well as for process monitoring calls for an efficient strategy for model development and model life cycle management. The traditional approach to develop multivariate models based on spectroscopy involves manual data management such as selection and transfer of spectroscopic data, import into modeling software and selection/exclusion of data. That is followed by addition of reference data, alignment of time stamps and import into the modeling software. 90% of the time required to construct a multivariate model is spent on data preparation. It was decided to develop a solution to automate these steps to prepare (stage) the data required for model development, reducing the time required to prepare a typical set of batch data to about five minutes. A second tool was developed to automatically optimize data pretreatment parameters and spectral range for PLS models. Both tools allow our scientists to invest their time into more value-added activities.
Dr. S.K. Jana at Serum Institute of India Pvt. Ltd. and Vikas Revankar at Merck
Full Title: Vaccine Development & its Manufacturing using Integrated High Throughput Technology
The billions of doses of vaccines manufactured worldwide each year are used to vaccinate the healthy people. This is the fact which drives vaccine manufacturing to be among rigorously designed, manufactured, monitored & compliant health products. In order to produce this huge number of doses, there is a need to have a manufacturing process which strongly influence the cost effectiveness, volume, application of technologies involving ease of scale-up, flexible in nature, automated integration with different manufacturing unit operations, minimal manual intervention or hybrid for complex biologics like vaccines manufacturing. The use of integrated way of automation with different online sensors like IOTs, AI at different measurement points of processes to make manufacturing process continuous, seamless, robust with high throughput yield, higher process capability with less time or no failure is the cornerstone of a modern, advanced & powerful manufacturing system. The concept of High Throughput Manufacturing is related to time required for a product to pass through a manufacturing process converting raw materials in to finished goods involving automation, integration of several unit operations with minimal manual intervention during the manufacturing. The ability to manufacture vaccines safely and consistently must be built on the theme with consistent quality, compliance, easier regulatory authorization in order to reach the market fast as manufacturing complexity is compounded by the need for different producing strains, type of vaccines & their processes. The present talk on “Vaccine Development and its manufacturing using integrated high through put Technology” is going to address some challenges & opportunities and its full scale application to future biologics manufacturing.
Sarah Nielsen, Director of Process Science at Janssen
The Janssen real time release strategy will be presented. Multivariate statistical process modeling is used as a way to guide batch release (either via RTR or conventional testing). The RTR strategy uses spectroscopic release tests, skip lot testing and a surrogate model for dissolution. The surrogate dissolution model was developed with a dedicated pilot scale DOE and validated with commercially manufactured product. Multivariate raw material and process “health check” models ensure that the surrogate dissolution model is used appropriately. RTRT provides greater manufacturing efficiency, process monitoring and allows for additional sampling when compared to a traditional release strategy. The presentation will illustrate the commercial use of this technology for a batch manufactured product within Janssen
Full Title: Implementing a Quality by Design (QBD) Approach In Integrated DSP In-Line PAT Advanced Analytical Technologies to Monitor Critical Quality Attributes
Continuous processing technologies and connected downstream unit operations may require advanced analytical technologies for process monitoring and control Evaluation of:
Different advanced analytical technologies with the potential to accelerate process development and facilitate continuous manufacturing control strategies. The suitability of the selected techniques at scale
The combination of outputs from different sensors in a combined manner to increase process understanding during downstream process development and reduce offline analytics and enable prediction of future platform processes
Results of these endeavors will be presented including a critical review of the and challenges of inline analytics and processing of large data sets to increase process understanding and enable process control.
The Resulting concept of using a process analytical technology (PAT) approach can ensure continuous processing with tight controls at all times and thus has the potential of integration into a new DSP continuous manufacturing platform
Terryl Kibodeaux, Director, IT-Business Relationship Management (BRM) Regeneron Pharmaceuticals, Inc.
Full title: Laboratory 4.0 Digitalization and IoLT (Internet of Laboratory Things) Strategies to Enrich Industry 4.0
The joining of online process automation devices and data (Operational Technology or OT level) and offline laboratory management systems and data (Enterprise Information Technology or IT level) is becoming an indispensable modernization and digital maturity aspect that needs to be realized to make the Industry 4.0 paradigm an industrial reality. This presentation describes options for the building of a sound Lab 4.0 digital laboratory environment, which consists of laboratory informatics, automation and robotics, interconnectivity, big data, analytics and machine learning to create a more holistic and better-connected, self-monitoring smart digital manufacturing ecosystem. The digitization of laboratories, along with the IT – OT interconnectivity, makes the availability of near real-time offline laboratory methods and results an actuality in the exercise to achieve the Industry 4.0 benchmark.
In contrast to other impurities the control of extractable and leachables is not well defined yet. Currently guidance is provided e.g. by USP and PQRI, but there is room for interpretation. New guidance (ICHQ3E) is being developed. In general, comprehensive screening is applied, using gas- and liquid chromatography techniques hyphenated with mass spectrometry, to aim for complete coverage on E&L. Although considered to be the state-of-the -art approach, in practice this approach is not as straightforward as it may seem. Many assumptions are made and for effective approach an E&L database is deemed necessary. Moreover, the strategy is completely opposite compared to the strategy applied for potential mutagenic impurities which is highly relying on a theoretical assessment (Risk based approach). The presentation will focus on the analytical technique selection, challenges of coverage of E&L in the current strategy and finally a perspective on E&L analysis.
Kenneth Tai at Kite Pharma, Lori Daane at BioMerieux and Alexander Bartes at Roche Pharma
For nearly 30 years, mycoplasma testing for biologics have been performed using cell culture-based methods. The compendial mycoplasma detection method has been the gold standard in the biopharma industry. Its high sensitivity (0.1 CFU/mL detection) is achieved through multiple subcultures and observations of culture media and agar plates over the course of 28 days. While awaiting for the results of testing, CHO-derived antibody drug substances are stored in freezers; however, long storage times have contributed to an inefficient supply chain network resulting in huge costs.
Pressure to reduce long turnaround times (TAT) has spurred innovation through the use of nucleic acid technologies (NAT), such as real-time PCR. With guidance from the European pharmacopeia chapter (2.6.7), multiple biopharmaceutical companies have successfully validated real time PCR methods for testing. In addition to the benefit of reducing TAT from 28 days to a single day, cost to the patients are reduced from lowering FTE, reducing storage costs, and creating a more agile supply chain network.
TAT reduction becomes even more critical in the new cell and gene therapy landscape, where some of these medicinal products are customized from the patients themselves. Furthermore, integration of testing built into the production line can improve efficiency and further expedite live saving medicines. As innovate therapies emerge, quality control tests must also become creative to adapt to these new modalities. That includes mycoplasma testing.
Presented by Dr Clemens Günther, Senior Expert Nonclinical Safety, Director at Bayer AG, R&D Pharmaceuticals
Full title: Risk Assessment of Extractables and Leachables in Different Phases of Development.
As the knowledge on the manufacturing process evolves during the development of a drug product or medical device, it is advised to include learning cycles into the development program to avoid existence of critical E&Ls. These learning cycles offer the opportunity to increase the knowledge on E&L associated with the product over its development time. Initially, chemical information should be collected on the materials used. First extraction studies will guide concerns, followed by simulation studies which are designed to mimic reality. At the end, the leachable study has to meet regulatory requirements and must cover real use conditions until end of product shelf-life, and these leachables need to be covered by a thorough toxicological risk assessment.
Trishna Ray-Chaudhuri, at Roche Group, Donald Young at Thermo Fisher and Marcus Bayer at Hamilton Company
Single use system (SUS) quality needs are similar to requirements used for their stainless steels analogs. As an example, a user implementing a stainless-steel system must oversee the design completely and is responsible for process validation. Similarly, when a user retrofits a stainless-steel system, the user and SUS supplier partner to demonstrate equivalent levels of quality and process control. The supplier is responsible for manufacture, cleanliness and sterilization while the end-user remains accountable to the regulatory agency for the quality of the process and final drug product.
This webinar will review the current best practices for implementation of single use systems with regard to quality, specifications, and user requirements. The content was created in partnership with companies and suppliers across the industry and represents the current perspectives for best practices.
Yuyi Shen at Bolt Therapeutics and Nick Whitelock at GoSilico GmbH
Full Title: Mechanistic Modelling in Early Stage Chromatography Process Development for Improving Process Efficiency and Productivity
This webinar provides an overview of current process innovation challenges and needs. The presenter identified that computational mechanistic modelling can be used to simulate chromatographic process performance and process optimization. Various case studies, applications and lesson learned from modeling will be shared by the presenter. The webinar concludes a comparative analysis between empirical and mechanistic modeling and provide the insights of balance needs for both approaches.
Jason Creasey, Managing Director at Maven E&L Ltd and Dries Cardoen at Nelson Laboratories, LLC
Presented by Jason Creasey, Managing Director at Maven E&L Ltd
Jason Creasey is a graduate Analytical Chemist. He has recently setup as an independent consultant providing advice in the area of extractables and leachables, after working for GSK in the area of extractables and leachables since the mid 1990’s.
Over that time, he has seen demand in this area grow exponentially and Jason has held roles of increasing seniority relating to the support that GSK has given to extractables and leachables (E&L). Before setting up Maven E&L Ltd, he was the director of a team of analytical chemists who are responsible for GSK’s global R&D support for E&L activities across a wide range of product types and modalities. This included; biopharmaceutical and small molecules including Inhalation, Parenteral and Cell & Gene Therapy use. He has had the pleasure of commenting on PQRI guidelines on E&L for GSK, the E&L section in EMEA guidelines on inhalation and nasal products and co-authoring a chapter within a book entitled “Leachables and Extractables Handbook: Safety Evaluation, Qualification, and Best Practices Applied to Inhalation Drug Products”.
Jason has been a member of several external groups concerned with the development of best practice guides for extractable and leachables issues these include; the IPAC-RS material working group, BPOG and continues as a scientific advisor to Extractable and Leachable Safety Information Exchange otherwise known as ELSIE. Currently he is working and commenting on risk- based approaches to E&L requirements, which he hopes will form part of an ICH guidance in the not too distant future.
Christian Airiau,Global Head Data Sciences at Sanofi and Chris McCready, Lead Data Scientist at Sartorius
Full Title: Hybrid Models: The Best of Both (Mechanistic & Empirical) Worlds to Accelerate and De-Risk Process Development
Presented by Christian Airiau, PhD, Global Head Data Sciences, Biologics Development at Sanofi and Chris McCready, Lead Data Scientist at Sartorius Stedim Biotech
Process optimization through the use of modeling is a key objective to accelerate and de-risk process development. A critical step to improve our process development, process monitoring and process control is to understand the strength and limitations of each types of modeling approaches. Using the most relevant empirical approaches - from DoE to Multivariate Analysis - and the mechanistic understanding we have about our processes – Kinetics, thermodynamics – we are rethinking the way we conduct process development.
The Journal for Asia's Pharmaceutical and Biopharmaceutical Industry
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Exosome Manufacture Based on the iCELLis® Bioreactor PlatformDavid Haylock, CEO VivaZome Therapuetics and Roberto Ciboldi, Scientific & Laboratories Services Pall Corporation[[ webcastStartDate * 1000 | amDateFormat: 'MMM D YYYY h:mm a' ]]120 mins