Trends, challenges and priorities
The primary goal of the technology roadmap that was conceived 5-6 years ago was to set a strategy and build a consensus about technology of the future. This past year has seen significant changes in that vision in response to external factors. The goals of the group have broadened to encompass the challenges and innovations of the future.
BioPhorum Technology Roadmapping created a new vision that was published in September. This updated version was reflective of a holistic industry vision by consensus with an intended purpose to help the industry develop the technologies of the future and aid in the adoption strategies necessary to leverage those technologies and address future challenges.
This vision has resonated with both companies within and outside of BioPhorum, and the group is already seeing it implemented. For example, the vision included a recommendation for industry key performance indicators to assess performance against the strategy that is being mapped out. These key performance indicators will be critical not just for companies themselves but will also allow a measure of the internal progress within the BioPhorum community. The team is working closely with the phorums to ensure the indicators are describing a future that is relatable and necessary, and the members have recognized that they need to work with all stakeholders to make this vision successful.
The group has continued to develop and implement proofs-of-concept, which demonstrate in a tangible and practical way the possibilities and opportunities of technology. There are currently four proofs-of- concept, with an additional project expected next year.
The most mature is the Buffer Preparation Workstream proof-of-concept, which is being run in conjunction with the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL). The entire project was developed, implemented, and tested by member consensus. The team is about to launch a collaborative data package and intends to make it available as open-source data for the industry in collaboration with NIIMBL. This entire collaborative process is being referred to as democratization technology and is associated with numerous benefits, including achieving a development program that the whole industry has desired and doing so at relatively low cost and in less time based on the number of companies involved.
Additional proofs-of-concept are being developed by the In-line Monitoring/Real-time Release (ILM/RTR) and the Big Data to Smart Data Workstreams. The Plug and Play team is also developing a proof-of-concept based on a slightly different approach due to the pandemic. Their program will demonstrate the power of interoperability within the different technologies. After their initial work was impacted by the beginning of the pandemic, the group invested in BPN technology that they placed among key global sites that enabled them to orchestrate Plugfests to test different process orchestrational layers with different process equipment assemblies. Through this process, the team has been able to demonstrate how they can build true interoperability into our manufacturing suites. The group is currently on their sixth iteration of the Plugfests.
The digital technology roadmap will be the first roadmap based on the new vision 2.0 published in September. The team will be taking a holistic approach to describe the new opportunities in pharma 4.0 and inform what a digital strategy needs to address and how it can be implemented. The group will be looking at new topics and will focus on finding foundation in data, data flows through an end-to-end value chain, control mechanisms, validation mechanisms, and the data needs of our future processes. They will also continue to apply lessons from the initial roadmapping programs and will be addressing issues such as consensus business cases for digital implementation, barriers to adoption, and working with key decision makers in the industry to understand the challenges they face and the inputs they need to make smart decisions about a digital infrastructure. The group plans to publish the work in a few months.
Another team is beginning to assess how to reduce the risk of implementing and investing in technology. They are currently looking at best practices and building a suite of tools, information, and case studies for best practices for adoption of new technology. The group considers multiple facets, including stakeholder management, regulatory challenges, quality, and operational challenges, and determines how these factors need to align to lead to success and a meaningful impact. The group is working closely with other phorums, especially the Regulatory Governance group to ensure regulatory experts provide strong case studies and knowledge.
The Phorum realizes that to make an impact on the industry and be successful, the technology strategy groups must work closely with the operational partners and the customers the strategy is being developed for. The group has developed workshops to identify strategy gaps that need to be addressed next year and determine the key players who need to be involved to achieve success.
This harmonization is apparent across BioPhorum and is exemplified by the ILM/RTR program, which had its foundation in the ILM/RTR roadmap published in 2017. The group initially identified different challenges from both a technology and an operational perspective. The technology team has made significant inroads with the technology challenges, including business case consensus work, user prime specifications, and now proofs-of-concept. The cross phorum team is tasked with addressing the operational challenges associated with adopting these technologies and are guided by the vision of the roadmap. Harmonization is also important for regulatory challenges, and the technology groups are increasingly working with international standards bodies, research and academic hubs, and agencies and regulators themselves to talk about the strategies they are developing and inform what the standards of the future will look like. Several workstreams are actively working in this space, including the Continuous Bioprocessing, Plug and Play, and Data teams. This harmonization is a great example of multiple groups coming together as a community and demonstrates how powerful this type of collaboration can be.
Technology Roadmapping deliverables November 2021 to November 2022
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Aggregates RT-MALS Proof of Concept
Seventeen BioPhorum Technology Roadmapping member companies (eleven biomanufacturers, six supply partners) have voted to collaborate and provide cash funds to develop a proof of concept for aggregates monitoring at the cation exchange polishing step using multi-angle light-scattering technology. This two-year development will be hosted by Merck KGaA (Healthcare)’s Corsier sur Vevey site in Switzerland.
The amount of aggregates can vary significantly from batch to batch and the current measurement state is an off-line assay based on size exclusion chromatography. Pooling is controlled by UV threshold or fixed volume, which results in a significant safety margin being built into the process, resulting in the loss of good material and reduced yield. A move to in-line/on-line aggregate measurement will allow an optimal pooling strategy for every batch in real-time, thereby improving yield, purity and process consistency.
Automated Bioreactor Proof of Concept
The team is continuing the scoping of a proof of concept for a fully automated alternating tangential flow filtration (ATF) perfusion, single-use bioreactor with automated control of selected attributes, automation of seed train inoculation and harvest, and MVDA (multi-variant data analysis) orthogonal verification. Costed proposals to host the proof of concept have been received from innovation hubs and BioPhorum member companies and the team has shortlisted candidates.
Single-use bioreactors and advanced perfusion systems are now available and already well developed as off-the-shelf solutions in the market. However, the use of process analytical technology (PAT) tools for dynamic and autonomous control is still lagging, especially in terms of widespread implementation. Industry guidance on how to implement and validate these tools in a more holistic way is needed. The combination of PAT tools and automating an array of control actions would be innovative as most publications have shown only single control actions, e.g. glucose control.
Rapid Methods for Adventitious Agents
A BioPhorum survey completed by biopharmaceutical end-users revealed that the biggest hurdles to adopting new and rapid alternative adventitious agent detection methods are the regulatory acceptance of these alternative methods, filing a regulatory change control and the time taken to validate a non-compendial method. Further, there was consensus that detection technologies were continuing to evolve but the provision of a guidance document that enabled sharing of best validation practices within the industry (including multi-site and multi-company) and including regulatory involvement, would have the greatest impact on widespread industry adoption of new methods.
To meet this need, the Rapid Methods team has developed technology-agnostic URSs for rapid mycoplasma and viral tests, which have been rubber stamped by related Phorum workstreams. A best practice approach for adventitious agent ARMM evaluation, validation and implementation based on an existing Fill Finish document has been drafted, and the team is now authoring a best practice approach for Mycoplasma NAT-based detection methods which will incorporate member company case studies.
These deliverables will help speed up product release from 35 to less than two days for mycoplasma and virus testing. They will enable the faster adoption of new rapid methods suitable for lot-release testing and provide regulatory agencies with the view of a single, consolidated validation package.
Best Practice in Adoption of New Technologies
The biopharmaceutical industry is risk averse when considering the adoption of new technologies onto production lines. A cross-industry team of end-users and suppliers has started writing a set of best practice resources for new technology adoption. The resources include the
following key elements:
- Defined key strategic drivers for senior leaders to adopt
- A process for technology adoption
- Elements to support best practice adoption, such as case studies, templates and guidelines
- Benchmarking via a technology adoption maturity assessment is being considered.
Digital Technologies Roadmapping
The team is collaborating on a digital technologies roadmap for the biomanufacturing industry, looking to 2030 and beyond. They have developed a longterm strategic vision building on the digital plant maturity model (DPMM) level 5 adaptive plant with autonomous facilities that are self-configuring and self-healing, utilizing and enabling advanced technologies (ref. Industry 4.0) such as AI, machine learning, the Cloud and simulation for predictive maintenance and with exception management handled by remote experts using AR/VR and robotics. The team envisions processes with predictable outcomes, fewer exceptions and higher quality, with lower costs that ultimately benefit our customers, i.e. the patients.
There are barriers to adopting some of these gamechanging technologies and industry-wide hurdles. These include the need for a step change or transformation of QMS and regulatory acceptance of the emerging technologies, data governance, integration, organizational readiness and risk management.
The team is now moving into the authoring phase and has agreed a mission to produce a roadmap which offers strategic decision makers an understanding of the technologies and capabilities needed to develop a business case for any scenario. The foundation stones described in the document represent pre-requisites agreed by consensus from this collaboration of biomanufacturers and suppliers; and building blocks which not only define the working solutions offered by Industry 4.0 technologies but the capabilities without which many digital transformations fail to deliver expected value.
This collaboration has completed the design, build and test of a full-scale cGMP buffer stock blending (BSB) system in collaboration with the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL).
Testing demonstrated that the skid performs well against the expectations laid out in the white paper (November 2019). The team has expressed their excitement at the virtual collaboration across three different time zones for debugging of the automation hook up during chromatography testing and highlight a noticeable increase in the level of discussion of buffer management across the industry. BSB system’s speed is described as a gamechanger.
Data analysis has enabled the team’s data scientists to produce data visualizations which provide evidence of the skid’s performance and support evaluations of skid’s components to be described in publications later in the year. Member companies are scheduled in for their own 30 days with the skid to test for themselves with several currently evaluating the NIIMBL BioPhorum technology against others for multi-facility implementation. The skid was displayed at the InterPhex conference in October 2021 and the team are looking forwards to launching the design and performance data as open source information.
Plug and Play
The Plug and Play team are collaborating on interoperability standards for key pieces of biomanufacturing process equipment and operational steps. The team have completed a series of PlugFest events, the most recent of which took place in October 2021.
These proof of concept test events have been used to successfully demonstrate MTP interoperability between process orchestration layers (POLs) and process equipment assemblies (PEAs) in increasing layers of complexity. The output from these events has not just been the data and technical observations, but also recommendations that the team has been able to leverage to prepare industry specifications for interoperability, several of which have been published with more to come.
The team hopes to work with standards partners to move these documents from consensus specifications to industry standards, and an awareness and adoption sub-team is working to create proposals on how to align industry on this proposal.
Big Data to Smart Data
The Big Data to Smart Data team are collaborating on data ontology challenges, using continuous process control of a bioreactor as their use case. They are working with BTEC at the University of North Carolina to create and analyze large data sets from bioreactor runs, with the objectives of creating recommendations on how to describe a simple and effective data ontology that adds value to monitoring a bioprocess.