Challenges and Successes in Externalization of the ADC Supply Chain
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.
RecordedFeb 14 201774 mins
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As a result of the increased adoption of single-use technologies (SUTs) in biotech manufacturing, companies need to develop and implement programmatic approaches for the management of these systems under regulatory compliance. This webinar discusses the key aspects of such programs, with emphasis on collaboration with suppliers, cost management, as well as practical insights about the use of SUTs.
The development of a suitable biologic formulation occurs often before analytical methods are validated. Certain chemical modifications are critical to monitor during the development process as they may cause protein instability and reduce biologic efficacy. Aspartic acid isomerization is one such modification, but is arguably the most difficult to detect. Analytical tools to track IsoAsp are discussed that can aid in making formulation decisions before the availability of qualified methods.
This Webinar will review the current progress in the risk management of extractables and leachables (E&L) impurities with focus on protein therapeutics. While toxicology assessments of E&L impurities are maturing toward best practices, their potential impact to product quality requires new approaches from the toxicologist toolbox. This webinar will discuss the in silico prediction of chemical fictional groups that pose high risk of covalent binding, potentially leading to structural modifications of proteins and impact to quality attributes.
The focus of this presentation is the application of Fourier Transform Infrared Spectroscopy (FTIR) and Differential Scanning Fluorimetry (DSF) methods to characterize vaccine components and their stability. Additionally, FTIR can be applied for the identification of final vaccine products, and DSF can be used to distinguish different formulations of vaccine candidates. These methods, when used in conjuction, provide valuable information regarding characterization and stability in the final stages of vaccine manufacturing.
The BPOG Leachables Working Group has recently published a Best Practice Guide for Leachables. The Best Practice Guide was developed to help Biopharmaceutical and Vaccines Manufacturers to develop science-based, robust, and efficient approaches to handling the risk of leachable compounds that is associated with increasing use of Single-Use Systems in manufacturing processes. The Best Practice Guide is composed of three parts: the risk assessment model, leachable study design, and analytical methods. This article provides insight into the application of the Best Practices for Leachables Study Design by end users and will include a case study to highlight the importance of the study design.
This presentation will analyse the benefits and limitations associated with the implementation of single-use technology at a large-scale, multi-product commercial manufacturing facility. By integrating single-use components into a stainless steel facility, a hybrid equipment approach enhances manufacturing flexibility while enabling an accelerated manufacturing cadence.
Continuous improvement, risk mitigation and adherence to compliance rely on the successful execution of key initiatives aligned with an organization’s strategic imperatives. This article summarizes the Project and Portfolio initiatives at Shire’s Biologics manufacturing facility at Shire, Lexington, MA site. In addition to practical advice, the authors discuss the need for sound business processes, alignment with Finance and budget cycles, and play special attention to the importance of resource allocation and management.
Ramila Peiris, Ph.D., Manager, Process Modelling and Process Analytical Technology, Sanofi Pasteur
The utilization of Multivariate Data Analysis (MVDA) techniques at Sanofi Pasteur, Toronto site has demonstrated innovative capabilities for improved process understanding, control and diagnostics. Examples from several successful and high impact applications will be presented. These examples cover the application of MVDA techniques in multivariate process control, root cause investigations and process analytical technology (PAT). The areas of application include fermentation, downstream purification and product formulation stages.
In commercial cell culture bioprocessing, consistent high quality protein is a fundamental goal that is typically accomplished during development through product and process engineering of bioreactor parameters. The FDA’s Center for Drug Evaluation and Research (CDER)’s Office of Biotechnology Products’ upstream bioprocessing laboratory, a part of the Office of Pharmaceutical Quality’s Center of Excellence (COE) in Manufacturing Science and Innovation, studies Process Analytical Technology (PAT) for upstream bioprocessing, focusing on the production of monoclonal antibodies. These capabilities are being leveraged to study continuous bioreactor cell culture production and compatible PAT tools. Case studies are presented that illustrate collaborative laboratory research being conducted on PAT tools for upstream bioprocessing to support regulatory decision making.
Technology transfer leading to a successful validation of a Monoclonal Antibody process at a CMO site is a complex task that would need seamless interaction between various functions of the sending and receiving organizations. The success of the process is very much dependent on the technical depth, personal trust and the strength of the relationships established between the team members across the various functions in both organizations. The interactions begin with the due diligence process and builds through laboratory scale technology transfer leading to engineering/GMP campaigns and ends with a successful validation. Depending on the stage in development of the molecule being technology transferred, the sending organizations could have personnel involved from both development and manufacturing making the process more complex. This write up will outline the role played by the various functions starting from Technical Services to Quality Assurance and will include functions like Shipping and Supply Chain.
Gloria Gadea-Lopez, Ph.D., John Maguire and Megan Rabideau
The success of manufacturing relies on the availability of all the resources –personnel, materials, equipment, work instructions - , orchestrated in such a way that the operations proceed in an efficient and predictable manner. This article describes the implementation of a finite scheduling system for biologics production, the foundational work required prior to project launch, lessons learned, and benefits achieved from this deployment.
Since the introduction of disposables and gaining popularity of Single-use Technology (SUT) for biopharmaceutical manufacturing there is nevertheless an ongoing controversial discussion on the advantages and disadvantages versus a conventional stainless steel environment.
In a “classical” facility design any validation cost effort can easily be distributed to a considerable number of production runs thus contributing only to a non-decisive amount to the overall production costs. The scale for such plant is nearly unlimited as is the scale of operation. The “flexible” approach using disposables and single-use equipment offers significant advantages regarding changeover work and time thus a high throughput of different processes will definitely take profit as any cleaning and related validation and costly analytics doesn’t apply to a larger extent.
Despite the potential benefits loudly advertised by the respective industry, these potential advantages derived from single-use equipment and disposables can be significantly diminished by lack of detailed process cost analysis, missing economic analysis and cost comparison between conventional and SU technologies as well as underestimating the cost of long term dependency on consumables. Due to missing appropriate standards, there is a widely non-compatibility between the equipment and consumables of the various suppliers, resulting in a strong dependence on the consumables of a single supplier once a single-use equipment has been purchased, curiously leaving some customers with surprise that they hardly have any room for price negotiations on the required consumables.
This paper’s focus is on the very different arguments for the application of SU equipment and consumables, including advantages and limitations of SUT, understanding improvement of process robustness, contribution to lean production as well as environmental impact of disposables.
Single Use technology is being used more each year in the biotechnology industry. However, extractables and their potential impact on product and patients continue to be one of the biggest challenges. The challenge is augmented by the lack of standardized methodology for suppliers to execute extractable studies that meets end user requirements. The end users are responsible and required by law to assess the impact of extractables and leachables on overall Product Quality and Safety. Due to lack of a standard, customized data had to be generated for/by each end users. This resulted in long lead times, higher costs and inefficient utilization of resources. Typically, the data generation and qualification of single use component can take up to a year, which can impact implementation of single use. BioPhorum Operations Group (BPOG) developed a standardized protocol9 for generating extractable data that would meet user requirements and simplify/reduce implementation time within industry. A standardized protocol gives confidence to suppliers that testing performed by them would meet end user requirements and enable faster implementation. Some suppliers shared the BPOG vision and proactively tested their single use components using BPOG protocol, which has helped expedite the use of their products.
Technical teams rely on the availability of meaningful data and effective tools to perform process monitoring, to conduct root cause analysis and investigations and, most of all, to obtain new insights into their operations. In this article, the authors discuss the implementation and management of a comprehensive system for data analytics at Shire –Lexington, MA site, the lessons learned, and practical advice towards the successful deployment of these key applications.
Near-infrared has a long tradition as analytical technology in pharmaceutical industry. In this article/webinar new applications, technology and improvements in regulatory guidances will be presented which will support further growth of nearinfrared in the pharmaceutical and biopharmaceutical industry.
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.
Dr Trevor Deeks, Principal and Consultant of Deeks Pharmaceutical Consulting Services, LLC
Single-use (SU) systems are now in common use in pharmaceutical bioprocessing, as well as in other related technologies such as the manufacture of diagnostics and other biological products, and their popularity is increasing. Some types of SU systems have been in use for many decades now. The earliest SU systems being disposable filter cartridges that do not require a stainless steel (SS) filter housing. This present article seeks to focus in particular on SU bioreactors for cell culture and bacterial fermentation for the purpose of producing therapeutic proteins, monoclonal antibodies and vaccines. SU bioreactors are of particular value in early phase (Clinical Phases 1 and 2) GMP manufacturing. In some cases their use has now stretched through into commercial processing, albeit that the scale of operation is currently limited and in general the largest commercially available SU bioreactors are around 2000L working volume (WV). However, the small footprint that they require, and the reduction in investment needed for support services and utilities, means that the scale limitations can be overcome to a significant degree by having multiple SU bioreactors operating in parallel within a facility. The harvest from multiple bioreactors can be pooled for downstream processing, or each harvest can be processed as a separate batch, based upon considerations of the risks versus the economies of pooling.
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