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Phacilitate Automation SIG: 2019 Report 2

ForewordNicola AmblerEditorPhacilitate:Exchange

After a string of approved advanced therapies over the past few years, we are moving well beyond a proof of concept and we’re now looking at a sea change in the standard of healthcare worldwide.

It’s no secret that therapies both on the market and in development are blighted by spiralling COGs and manufacturing inefficiencies and technical challenges.

Automation is the most efficient solution for reducing cost and process complexity and increasing productivity when it comes to advanced therapies. However, the decision on how, when, and what to automate is far from easy. A common yet flawed approach is waiting to get a therapy approved before considering automation, but with the aforementioned approvals, that ‘later’ has suddenly become ‘now’.

This is really why the Automation SIG was created; it’s an annual gathering of senior decision-makers, tool developers and engineers. The core aim is to provide a collaborative environment where experience and knowledge can be easily shared, and solutions worked on throughout the year.

This report is written by the rapporteurs that lead each themed working group, communicating the findings and outcomes of the live discussions and polls. The report’s 14 chapters are divided into four parts for easy navigation:

• Making business sense of automation• Strategic data, analytics and technology

management• Innovation in process technology• Speeding up commercialisation

Here is a foundation for your automation strategy and integrating it into your process development. Enjoy!Nicola

Ps. If you’d like to be considered for a place in the 2020 SIG, please let us know on [email protected]


MAKING BUSINESS SENSE OF 5 AUTOMATION

1.1 What can industry 4.0 offer 6 advanced therapies?

1.2 Navigating the cost and time of 10 automation: full, partial or anywhere in between

1.3 Cross industry communication: 13 exploring opportunities for consortia, working groups and co-development projects

1.4 The cell and gene therapy industry’s 16 chicken and egg question: which comes first, manufacturing processes or automation?

STRATEGIC DATA, ANALYTICS AND 20 TECHNOLOGY MANAGEMENT

2.1 Automating quality analytics 21

2.2 Automating the convergence of viral 23 and non-viral technology to future-proof advanced therapy manufacturing

2.3 Controlling manufacturing variability 27 through a move towards Quality by Design principles

2.4 Cell production monitoring and 30 analytics: a look towards artificial intelligence

INNOVATION IN PROCESSING 34 TECHNOLOGY

3.1 Are the concepts of flexibility, 35 modular technology and plug and play applicable to our manufacturing platforms?

3.2 Automating downstream: harvesting, 40 washing, cell concentration, formulation, fill/finish and preservation

3.3 Automating upstream: new 43 technology in sensors, robotic handling equipment, bioreactors

3.4 Next steps for physical and digital 46 machine to machine connectivity

SPEEDING UP COMMERCIALISATION 50

4.1 Automating Chain of Identity and 51 Chain of Custody to simplify logistics and get treatments to patients faster

4.2 Designing a rapid manufacturing 53 process with distributed production moving towards points of care

4.3 Decentralised cell therapy 57 manufacturing from the Point of Care perspective

4.4 For a decentralised model there is a 60 need for clinicians and the healthcare systems to be on board. How challenging is this?

PART 1 PART 3

PART 2PART 4

Contents


PART 1

MAKING BUSINESS SENSE OF AUTOMATION

Over the years, the world has experienced and benefitted from several industrial revolutions. The first being the use of steam and water to mechanise manufacturing equipment, the second introducing assembly lines to manufacturing processes and the third being the use of programmable logic controllers to automate manufacturing operations. The fourth industrial revolution, known as ‘Industry 4.0’ uses the Internet of Things (IoT), smart technologies and sensors to create fully integrated and visible manufacturing, the considerable impact of which can be seen in the automotive and consumer goods industries.

If these technologies can be implemented within cell and gene therapy the benefits could be game changing for an industry that is currently driven by patient specific therapies that require separate batches to be manufactured for every patient. Having complete visibility allows for products to

be made safer and repeatedly, at a lower cost and within shorter periods of time.

The discussion at the SIG focused on these roadblocks, and what we needed to do, collectively as an industry to overcome them.

We addressed this in three questions:

1) How flexible will stakeholders need to be to accomplish this goal?

2) How important is standardisation and security and how is it accomplished throughout the industry?

3) How do we incentivise therapeutic developers, technology developers and medical sites to prioritise this initiative?


1.1 What can industry 4.0 offer advanced therapies?

Matthew Marsh joined the Innovation and Engineering department to apply his previously obtained knowledge of cell biology and biomaterials to help drive the cell therapy industry to new heights. During his time at HCATS he has evaluated and helped develop several pieces of technology used to manufacture quality cell therapy products. He has also participated in developing business strategies based on industry trends and research in this area. His overall goal is to create a lean and efficient cell therapy manufacturing process that will help companies develop a cost effective, rapidly available, and safe product.

Matthew MarshBiomedical EngineerHCATS

Jim Furey is the Founder and General Manager at PendoTECH and he holds a BS Degree in Chemical Engineering from Drexel University in Philadelphia and an MBA from Rutgers University in New Jersey and over 20 years experience in the biotechnology/bioprocess industry in both upstream and downstream processing technology. This includes defining of user requirements, defining functional specifications, design, testing, validation, evaluation, cost of goods estimation, and product management of single use manufacturing technology. He has been closely involved with micro-controller based system engineering, project management and validation. He has several technology patents and patents pending in the area of bioprocess technology.

Jim FureyPresidentPendoTECH


to be disclosed to others. To mitigate the need for extensive multi-party confidentiality agreements, the company who develops the technology that collects and distributes the data should be responsible for maintaining confidentiality, storage and organisation of any data collected throughout the process. Having all data centralised in a standardised format would allow for expedited and simplified regulatory reviews.

The conclusion of the group was that there would need to be a significant amount of flexibility among all stakeholders, but that collection sites and hospitals may have the least amount of flexibility given the impracticalities of converting such a large volume of facilities around the world to a brand-new technology system. It would therefore make sense to use the data collection and security systems used at these facilities as the foundation for the Industry 4.0 initiative, leveraging their experience in dealing with large quantities of patient data that can already be sent from facility to facility.

How flexible will stakeholders need to be to accomplish this goal?

For the goal of visibility and smart manufacturing to be reached, all stakeholders will need to collaborate. A single company cannot reasonably provide all the aspects (patient material collection, cell engineering, and infusion) that make up this process. The best possible model would be to gain buy-in from key service providers, i.e. apheresis collection sites, shipping companies, cell therapy manufacturers and hospitals. However, this would require all stakeholders to:

i) provide access to their computer systems and data banksii) adjust their technology to collect and store their data in a way that is compatible with other stakeholders and which can communicate with an overarching cloud-based system

It’s likely that this will be met with great hesitation by many involved, as some of what makes their products or services unique and novel will need

Fig 1. Integrated OT/IT ecosystem


criteria. Similarly, logistics providers would need to standardise shipping conditions and data recording capabilities such as temperature, pH and location.

Security, one of the most important considerations in the process, also needs to be standardised. For example, patient identification numbers (PINs), along with tracking chain of custody (CoC) and chain of identity (CoI) will be key in maintaining patient privacy, along with ensuring that the correct product is manufactured for and administered to the correct patient every time.

Security of data storage will also need to be standardised to comply with regulations, such as HIPAA. Although certain aspects and qualities of this system will more than likely be determined by hospital requirements, there will need to be a consensus as to which data can be shared with which stakeholders. This will be key to ensuring all parties receive enough information to properly execute their responsibilities but not so much that safety and privacy may be compromised. So, who will be responsible for determining these standards? Two possible answers were discussed. The first being the cell therapy sector of the Standards Coordinating Body and the second being the initial group of stakeholders piloting this process, along with input from regulatory bodies. In either case it’s critical that standards are created with the rest of the industry in mind.

How important is standardisation and security and how is it accomplished throughout the industry?

Automotive and consumer goods are both large industries, which have benefitted immensely from the fourth industrial revolution but the key difference is that our industry’s primary raw material source and end customers are patients. This combined with the fact that cell and gene therapies are currently driven by autologous products makes the need for this system even clearer, but it also adds roadblocks that will need to be overcome to achieve implementation. To decrease the level of complexity in each of the stages of the process certain standards need to be developed and implemented.

In the SIG discussion, we devoted time to determining which aspects of the cell therapy process needed to become standardised for success in this endeavour. For most, the top priority seemed to be to standardise how these pieces of technology communicate to the Cell Orchestration Platform (COP). It does not matter if the technology uses Ethernet, WiFi, Bluetooth etc to communicate with the cloud system, so long as it has the capability.

Raw material collection sites (hospitals, apheresis sites) need to standardise the material data that they collect, including cell count and possibly flow cytometry to meet initial raw material release

Fig 2. Potential benefits to cell therapy manufacturing when all systems are integrated.

Fig 2. Caption to be confirmed


Automotive and consumer goods are both large industries which have benefitted immensely from the fourth industrial revolution but the key difference between those industries and ours is that ill patients are our primary raw material source and end customer. This combined with the fact that cell and gene therapies are currently driven by autologous products makes the need for this system even clearer, but it also adds roadblocks that we will need to be overcome to achieve implementation. To decrease the level of complexity in each of the stages of the process, certain standards need to be developed and implemented. In the SIG discussion, we devoted time to determining which aspects of the cell therapy process needed to become standardised for success in this endeavour. For most, the top priority seemed to be to standardise how these pieces of technology communicate to the Cell Orchestration Platform (COP). It does not matter if the technology uses Ethernet, WiFi, Bluetooth etc to communicate with the cloud system, so long as it has the capability.

Raw material collection sites (hospitals, apheresis collections sites) need to standardise the material data that they collect, including cell count and possibly flow cytometry to meet initial raw material release criteria. Similarly, logistics providers would need to standardise shipping conditions and data recording capabilities such as temperature, pH and location.

Security, which is one of the most important considerations in the process, will also need to have several aspects standardised. Standardising patient identification numbers (PINs), along with tracking chain of custody (CoC), and chain of identity (CoI) will be key in maintaining patient’s

Fig 2. Caption to be confirmed


Automotive and consumer goods are both large industries which have benefitted immensely from the fourth industrial revolution but the key difference between those industries and ours is that ill patients are our primary raw material source and end customer. This combined with the fact that cell and gene therapies are currently driven by autologous products makes the need for this system even clearer, but it also adds roadblocks that we will need to be overcome to achieve implementation. To decrease the level of complexity in each of the stages of the process, certain standards need to be developed and implemented. In the SIG discussion, we devoted time to determining which aspects of the cell therapy process needed to become standardised for success in this endeavour. For most, the top priority seemed to be to standardise how these pieces of technology communicate to the Cell Orchestration Platform (COP). It does not matter if the technology uses Ethernet, WiFi, Bluetooth etc to communicate with the cloud system, so long as it has the capability.

Raw material collection sites (hospitals, apheresis collections sites) need to standardise the material data that they collect, including cell count and possibly flow cytometry to meet initial raw material release criteria. Similarly, logistics providers would need to standardise shipping conditions and data recording capabilities such as temperature, pH and location.

Security, which is one of the most important considerations in the process, will also need to have several aspects standardised. Standardising patient identification numbers (PINs), along with tracking chain of custody (CoC), and chain of identity (CoI) will be key in maintaining patient’s


Whenever a new product or service offering is brought to an audience, they always want some reassurance that it will work as advertised. Although Industry 4.0 has proven to be valuable in other industries, it does not necessarily mean it will translate to cell and gene therapy. Most participants concluded that a pilot of this system would instil more confidence as to the efficacy of this program. There are many providers in each of the necessary areas but selecting those with the technology that most closely fits the needs of this system will be key to saving both time and resource. This will not be a simple process to develop or implement, and that is why ensuring that stakeholders receive long-term return on their investment will be key to the success of this initiative.

In summary… Through intense discussion and collaborative problem solving, this diverse group was able to not only unearth potential roadblocks, but to also devise strategies to overcome them efficiently. Participants continued to see how this could benefit their business more and more as the session progressed, which was observed in both direct feedback and enthusiasm of discussion.

If utilised correctly, the integrated and fully visible qualities of an Industry 4.0 system could provide patients safer, cheaper and faster therapies that they desperately need. The session was somewhat split as to how long until Industry 4.0 could be fully implemented; responses ranged from two years all the way to 23 years, with some participants believing that we haven’t even implemented Industry 3.0 yet. Although we were not able to reach a conclusion on this question, most of the group agreed that not only would the industry get there eventually, but it needs to.

If you only take away one thing from this chapter, it’s that although there are multiple hurdles that will need to be overcome, the one common theme needed to overcome them is cooperation. All parties must foster an atmosphere of “coopetition” in which competing companies combine efforts for mutual benefit.

How do we incentivise therapeutic developers, technology developers and medical sites to prioritise this initiative?

When presented with the concept of Industry 4.0, all members of the discussion at the SIG were able to visualise how this system could benefit their business and the patients involved. However, most of the group also concluded that this initiative is not at the top of their list of needs.

Cell therapy developers regard speed to market with higher importance than implementation of Industry 4.0. Due to this, technology developers have not seen a need from their customers to develop technology that can communicate with other systems. In order to overcome this problem, we must either incentivise or convince stakeholders that this should become a priority. For example, a scale from Mettler-Toledo (with scales often being required in cell therapy manufacturing) is used by a plethora of industries and most likely produced in the 100,000s with all models. These scales are available with range of communication ‘language’ options (called the application layer such as PROFIBUS) that travel over a hardware layer such as Ethernet to all control and data exchange between process devices. However, many devices used in CGT manufacturing devices don’t have this ability because many evolved from a laboratory piece of equipment. Instrument and device suppliers need to put on their product road map hardware and software options to enable the connectivity and integration capability to enable CGT automation.

Cell therapy developers and manufacturers are especially hesitant to invest in this initiative since those whose products are not yet commercially available are working with limited funds. To overcome this obstacle, the piecemeal model was proposed and received positive feedback from the group. This involves a step by step implementation of certain technology investments that will eventually culminate in a fully integrated system. This could begin with adopting a MES system, followed by electronic batch records when appropriate, so that the initial investment is not as large and intimidating.


Background This hypothesis was supported during the 2018 SIG2 with one group considering the competing objectives of retaining process flexibility during process development and the requirement to progressively ‘lock down’ the process prior to clinical trials.

They found that the industry is in urgent need of a range of unit modules for performing unit operations that have stable and proven performance and can be adopted in early testing, and carried through to commercial production.

At present there are very few examples of modules that provide robust unit operations, particularly when trials transfer from healthy donors to patient material. Furthermore, standards of interconnectivity are required between these modules for fluidics, data transfer and control supervision. Recognising that the needs for automation are likely to be different for products in clinical phases when compared with products in the early commercial stages, we approached the session in two groups to account for these differences.

This session began with the premise that process automation can deliver benefits such as reduced risk of contamination, improved consistency and reduced cost of production. These benefits are typically delivered by closing the process and reducing the direct operator/QC technician manipulations.

The business strategy for consideration was that some of these benefits may be realised by partial automation1. The introduction of partial automation is both less expensive and presents a lower business and financial risk during clinical phases. Unfortunately, the main barrier to implementation of this strategy is not motivation or conviction, rather the availability of commercially attainable, proven, reliable, configurable devices.

The focus of the session was, therefore to identify the highest priority device and technology developments that would yield the greatest benefit to product developers.

Geoff is a manager in the Cell Therapy Group at Invetech, working with clients to develop industrialised process solutions that dramatically reduce the cost, and increase the safety of manufacturing both autologous and allogeneic therapies.

Geoff BallManager, Cell TherapiesInvetech

Nadège is manager in the industrialisation team of Celyad in charge of evaluating the added value of the automation at all stage of the process to support the development of a sustainable commercial product.

Nadége GrabowskiIndustrialisation ManagerCelyad

1.2 Navigating the cost and time of automation: full, partial or anywhere in between


Automation of sampling, IPC and QCThe elimination of the need to manually take in-process samples for lab-based analysis would also have a substantial impact on reducing operator interactions, closed process and reduced waiting time in the process (e.g. waiting for a cell count to make a formulation decision).

The group identified an urgent need for regulatory standardisation in what should be measured and how.

In particular:• clear and precise definition of cell parameters (phenotyping, potency)• improved clarity in terminology and tests used in cell therapy (cell viability, system yield, proliferative capacity)

This gap in regulatory standardisation is one of a number of perceived barriers or hurdles to developing and implementing tools for inline sampling and real-time monitoring.

Other issues that need to be addressed include the need to select what should be monitored the lack of data integration, which is due to variability in methods of assessment and the lack of technology and access to tools due to the field being small and digitisation of patient material traceability

The highest priority areas for automation of sampling, IPC and QC in the clinical phases are:

• automation of analytics (having better tools to measure non-invasively in real time) with sensors integrated in bioreactor to support costs and labour reduction, decreasing contamination risk• identifying what to measure, less is more• implementation of electronic tracking tools to interconnect product, materials used, test results and decrease tracing errors

Group I: priority device and technology developments for the pre-clinical and clinical phase of the product lifecycle

All product developers will have encountered the dramatic increase in cost and complexity in the lab as a product transitions from pre-clinical to clinical production. Aside from the cost of GcP compliance (procedures, sterility, QC, documentation etc.) the operators are also faced with a major jump in scale from batches of E6 to E9 cells. The impact on manual manipulations and volume of materials is very substantial at the same time as sterile practice becomes essential. Thus, making all of these manipulations a little more challenging.

We identified two of the main cost drivers in clinical phase as:• skilled resources• cost of obtaining classified space

In the next tier: • cost of critical reagents (vector or growth factors)• QC testing • starting material (logistics, cost and consistency of apheresis donations or bone marrow)

Automation of process operationsClearly, automation of the highly manual and dexterous steps (such as Ficoll separation) would be very beneficial in reducing operator effort and has the potential to improve batch to batch consistency.

The group felt encouraged that the industry was producing a number of devices in the primary process operations of separation, transfection and transduction, expansion and formulation/bag filling. It is understood that optimisation of these devices is ongoing and that outcomes are still often quite variable and unpredictable.

The highest priority area for process operation automation is the optimisation of each process step to minimise cell loss.


In addition, the connectivity of production equipment to data historian/MES is emerging as increasingly important and device developers should be aware of this need and plan to accommodate it.

Naturally, devices and systems that can work in development, clinical and large-scale commercial will be essential to ensure smooth process development and regulatory transition between stages.

Automation of sampling, IPC and QC The theme of connectivity also featured heavily in this discussion. The group considered the development of inline analytics to be critical for future commercial production.

If it is possible to perform process and product analytics inline then several current problems are addressed such as:

• timing and delays associated with turnaround of QC samples • sterile sampling, ensuring no adverse impact on the bulk• volume impact of samples

Furthermore, the concept of an electronic QP that reports only by exception, with reports analysed and actioned by a traditional human QP is highly anticipated. It is particularly important for autologous products where the full burden of QC cost is carried per dose. At the same time the number of batches, and therefore release events, is a very significant driver.

In summary…The attention of cell therapy drug product developers and producers is shifting from automated production modules increasingly to inline analytics, IPC and QC and digital connectivity for electronic batch records.

It must be emphasised that this does not infer satisfaction with production devices and modules that are currently available. More likely, an assumption that development is already underway on process modules, whereas development of suitable inline sensors and analytics is still very experimental.

Group II: priority device and technology developments for the early commercialisation phase of the product lifecycle

As a product is transferred from clinic to GMP production there is a sharpened focus on costs and stable, predictable production. The loss of a batch may have a very severe impact on a patient, but at the same time the impact on the cost of production must not be ignored.

We identified many cost drivers during this early commercial phase, including: • variation (patient to patient) of starting material• skilled labour (including training) • QC and IPC (in-process control)• sampling/analysis/decision making/reporting• QC release deviations; kitting, materials, single source• environmental monitoring and factory scheduling (plant, equipment, operator utilisation)

Two significant opportunities for cost reduction are closed processes and supervisory computer systems (MES/eBR). Closed processing drives cost improvements in room classification reduction, leading to reduced environmental monitoring costs, reduced gowning costs, densification and OPEX. MES/eBR systems facilitate release by exception and reduced ‘non-process’ deviations, such as transcription errors, dates, missing signatures and other handwriting errors.

Similar to the analysis of gaps in the clinical phase, analysis of the technology and device gaps for the early commercial phase mainly concern either process operation automation, or alternatively sampling/IPC/QC.

Automation of process operations The group observed that the need for automation of operations has been recognised and understood for several years. Despite progress by device suppliers and custom engineering, the non-universal approach to interconnectivity between unit modules (both data and fluidic) is keeping process open in certain areas.

Notes: 1. We understand “partial automation” to include fairly basic mechanisation (operator aids), as well as automation of modules to perform unit operations2. Phacilitate Automation SIG: 2018 Report CHAPTER EIGHT “Ensuring Bioprocess Flexibility: How to Choose Between Module or Sub-Module Solutions.”


Though it is still possible for individual developers and technology providers to invent ever better solutions, we all agree that by working with others more can be achieved and the rate of change will also be much faster. However, there are a variety of issues to consider when thinking about collaborative projects and partnerships.

• How do we find appropriate collaborators? • How can we ensure that collaborative projects are successful?• What are the barriers and risks to carrying out collaborative projects? • What can we learn from more mature industries?

The cell and gene therapy industry has evolved rapidly in the last decade or so, with enormous leaps being achieved in a relatively short space of time. Using a biological analogy, it can be said that it has followed human evolution; the big breakthroughs in cell transplantation (walking upright), the acquisition of technology (humans making tools), which moved cell therapy from a scientific dream to a clinical and industrial reality. The next big leap allowed sapiens to surpass their biological capabilities, i.e. working cooperatively with other humans.

Dr. Hernandez is a stem cell biologist with more than 20 years’ experience in medical research and at least 12 years in the cell therapy field both in academia and industry. After several years in basic academic research at Imperial College and UCL, she has led several collaborative projects between academia and biotech first from the academic side and then from the commercial side all in the area of cell therapy. She currently leads a research group at Anthony Nolan, a charity established in 1974 as the first bone marrow register in the UK. Today, Anthony Nolan administers the aligned UK bone marrow register, carries out research into stem cell transplant, has a series of programmes to support patients needing and undergoing stem cell transplantation and supports the cell and gene therapy industry in the UK by providing materials and services to therapy developers.

Dr Diana HernandezHead of ImmunotherapyAnthony Nolan Research Institute and Senior Lecturer, Cancer Institute University College London

Dr. Baila received his PhD in 2007 based upon translational research and development of gene therapies for hemophilia at the Children’s Hospital of Philadelphia. Since that time he has been actively involved in the process development and manufacturing of advanced therapeutic medicinal products through business development and strategic marketing roles at Areta International, a CDMO, and by leading field implementation and commercialisation activities for the cell processing unit of Terumo BCT. Stefano also worked as Industrialisation Manager at Celyad where he led process development and automation efforts for CAR-T therapeutics. Now he serves as Director of Operation for Anemocyte.

Dr Stefano BailaDirector of Operations and Business DevelopmentAnemocyte

1.3 Cross industry communication: exploring opportunities for consortia, working groups and co-development projects


2. Financial constraints The second issue was around financial constraints and how expensive it was for product developers to test new technology even when good terms were offered by the technology providers.

3. Timeline misalignmentThe third barrier (this was more specific to academic collaborations) was around timeline misalignment. While most commercial biotech run on tight deadlines due, principally, to financial constraints, academics tend to think on much longer timescales.

Though no hard and fast solutions exist for any of these issues, they are not insurmountable and can be avoided by defining the rules under which all aspects of the project will be carried out and as early as possible in the establishment of the collaboration. Again, good communication between parties is essential to ensure alignment in all aspects of the work and regular meetings to ensure this continues should take place through the whole project.

Finding partners for collaborative projects was a challenge for many and complementary to this was finding appropriate mechanisms that can support collaborative projects across industries and across borders. Nationally, some specific mechanisms were identified (such as Innovate UK collaboration grants in the UK) but working with partners further afield was more complex. Working groups of several international organisations were mentioned as good initial platforms for identifying common challenges and bringing together potential collaboration partners. Further work is welcome in this space both in terms of providing an initial ‘directory’ of organisations working in different spaces within the sector and providing further forums for connections to be made. In this respect, Phacilitate workshop style meetings provide an excellent forum for meeting potential collaborators.

A final point raised was that of looking for collaborators and advisors beyond the obvious, especially when faced with challenges that may have already been overcome by other, more mature sectors such as the food industry. Learning from others’ mistakes and seeking more universal solutions to the challenges we face will allow more rapid progress and hopefully a less expensive delivery of the promise of cell therapy as the new era of healthcare.

In summary…

Collaborate to innovate

An excellent definition of collaboration shared within the discussion group was “collaboration starts either where internal expertise ends or when there is a mutual interest”. There was general consensus that successful collaborations and partnerships emerged when there was a good alignment of aims and expectations.

This seems obvious but in practice is not always the case as misinterpretations of expectations can arise. Good communication is therefore essential both in avoiding conflict and maximising output. Successful collaborations are built on good understanding between partner’s identification of needs and competencies and true alignment of goals.

Once established, the partnerships that exhibit a very hands-on approach and communicate well with one another are the most successful. It was felt that when relationships between partners were too transactional rather than truly cooperative, the chances of success were diminished. In contrast, when a partner (e.g. a technology provider) became truly embedded in the process of a developer, there was a much higher probability of goals being achieved. There are, however, barriers to consortia being created and also risks associated with collaborative projects which in turn become further barriers to future collaborations. We identified three main areas that were perceived as the most difficult barriers or risks to overcome.

1. Intellectual propertyThe first one relates to intellectual property (IP), specifically around ownership of IP developed during the project and the impact it had on the downstream pipeline of both partners. From the point of view of technology providers, it was important to be able to use any improvements or new developments in their products, even those which would be sold to potential competitors of the product developer partner. Time invested in the project would not pay off if any new improvements could only be used in in the project partner’s subsequent products.

Conversely, from the point of view of the product developer, it was equally difficult to justify time invested in an improvement if this was not going to provide a competitive edge or guarantee some kind of exclusivity. The issue of confidentiality can also make corporate lawyers nervous which usually results in long and complex negotiations.


The cell and gene therapy industry has evolved rapidly in the last decade and to reach the maturity of other sectors it needs to foster collaboration between different players within the sector but also to look at other sectors which may provide alternative solutions which are ‘outside the box’.

Collaborative projects with varied organisations are an excellent means of progressing projects quickly, provided that a good alignment of aims can be identified and there is communication between partners from the outset and throughout the project.

In summary…

The cell and gene therapy industry has evolved rapidly in the last decade and to reach the maturity of other sectors it needs to foster collaboration between different players within the sector but also to look at other sectors which may provide alternative solutions which are “outside the box”.

Collaborative projects with varied organisations are an excellent means of progressing projects fast, provided good alignment of aims can be identified and there is communication between partners from the outset and throughout the project.

LAUNCHING IN JANUARY 2020, ADVANCED THERAPIES WEEK WILL

BE FIVE DAYS OF EVENTS AND COMMUNITY ACTIVITIES TO RAISE

PUBLIC AWARENESS AND TO SUPPORT INNOVATION IN THE ADVANCED

THERAPIES INDUSTRY. IT’S AN INITIATIVE PROUDLY LED BY PHACILITATE AND SUPPORTED BY GLOBAL PARTNERS

AND ORGANISATIONS.

MIAMI



https://www.advancedtherapiesweek.org/

At the SIG, we explored the major elements influencing the decision of if, and at which stage, automation should be implemented in CGT manufacturing processes. We asked the following questions:

• What are the major pain points preventing automation at early (R&D) stages of the manufacturing process? • Are there manufacturing processes that will not benefit from automation, e.g. because labour costs represent only a minor share of the total product prize?• How can we mitigate concerns of early automation, e.g. skyrocketing costs, reduced flexibility, etc?

Silvio is the Head of the Industrial Process Development Team at Miltenyi Biotec being responsible for providing automated cell and gene therapy procedures on the CliniMACS Prodigy for industrial customers. Silvio has more than 10 years of R&D experience in various fields of cell biology, including immunology, regenerative medicine and pharmacology. After joining Miltenyi, Silvio has been coordinating custom-tailored development of automated processes for T-cell mediated immunotherapy, stem cell engineering and other innovative cell and gene therapy approaches using the Miltenyi Biotec CliniMACS Prodigy platform. Silvio holds a diploma degree in Biochemistry from the University of Bielefeld and a doctoral degree in Biochemistry from the University of Kiel.

Silvio WeberHead of the Industrial Process Development Team Miltenyi Biotec

1.4 The cell and gene therapy industry’s chicken and egg question: which comes first, manufacturing processes or automation?

In an ideal world, process development would take place with automation considerations accounted for at the earliest phases of cell and gene therapy manufacturing processes. With this approach, the challenges that come with complex up-scaling procedures and regulatory approvals at the later stages of product development may be avoidable. However, based on lack of understanding of the current automation technology at hand, many companies and research institutes still decide to start their manufacturing process without considering automation.

Daniel Paull is Vice President of Stem Cell Technology Platforms at the NYSCF Research Institute. He leads the NYSCF Global Stem Cell Array, an automated platform for large scale derivation, genome editing and differentiation of human induced pluripotent stem cells®. Combining biology, software and hardware engineering, this platform has generated thousands of stem cell lines both within collaborations and as a community resource through the NYSCF Cell Line Repository. Prior to joining this platform, while based in the lab of Professor Dieter Egli, he led the development of a novel technique to prevent the inheritance of mitochondria disease using IVF-type approaches. Daniel was also heavily involved in developing techniques to derive human cell lines using somatic cell nuclear transfer and developing models of diabetes using iPSCs. Daniel obtained his PhD from University College London.

Daniel PaullVice President Automation Systems and Stem Cell Biology, The New York Stem Cell Foundation Research Institute


• Most companies (especially R&D start-ups), will not have sufficiently deep pockets and knowhow to develop their own automation platforms. As such, they will have to rely on vendor solutions which might have shortcomings in terms of customisation, or which may be unexpectedly taken away from the market

• Speed vs quality is a paradox for all companies, however, smaller yet innovative companies might shy away from the rather high investment costs at the beginning while favouring fast visibility of their product to stay alive in the bustling CGT market

• In case intensive development work needs to be done on the automation system there is a good chance of being too late with the market entry of the CGT product

Similar to the widely accepted Diffusion of Innovation Curve (Rogers, 1962), we propose the existence of an ‘Adoption of Automation Curve’ for manufacturing procedures in cell and gene therapy (Figure 1). Every phase of automation technology adoption comes with its own pros and cons and the group sought to flesh out the most significant arguments by debating along the forementioned questions while representing either an early stage or a late stage adopter view.

Late adopter’s view

Pain points: • Early adoption of automation may restrict flexibility in process development and reduce the chance of on-the-run integration of novel technology and product feature developments

Attendees were asked to start a parliamentary style debate by taking one of the following positions:

1. Late adopter - adapting existing processes to automation in later stages. Challenge: issues with regulatory approval, ‘product is the process’.

2. Early adopter - developing manufacturing processes in early stages with automation in mind. Challenge: the cost skyrockets

Figure 1: The Adoption of Automation Curve (modified from Rogers, 1962 – Diffusion of Innovation Curve)

Figure 1: The Adoption of Automation Curve (modified from Rogers, 1962 – Diffusion of Innovation Curve)

Similar to the widely accepted Diffusion of Innovation Curve (Rogers, 1962) we propose the existence of an ‘Adoption of Automation Curve’ for manufacturing procedures in cell and gene therapy (Figure 1). Every phase of automation technology adoption comes with its own pros and cons and the group sought to flesh out the most significant arguments by debating along the abovementioned questions while representing either an early stage or a late stage adopter view.

Late adopter’s view

Pain points:

• Early adoption of automation may restrict flexibility in process development and reduce the chance of on-the-run integration of novel technology and product feature developments.

• Most companies (especially R&D start-ups), will not have sufficiently deep pockets and knowhow to develop their own automation platforms. As such, they will have to rely on vendor solutions which might have shortcomings in terms of customisation, or which may be unexpectedly taken away from the market. Speed Vs quality is a paradox for all companies, however, smaller yet innovative companies might shy away from the rather high investments costs at the beginning while favouring fast visibility of their product to stay alive in the bustling CGT market

• In case intensive development work needs to be done on the automation system there is a good chance of being too late with the market entry of the CGT product. It is often unclear from the beginning if an automated procedure would really lead to a significant advantage


starting too late with automation can likely lead to a lake of comparability between the two manufacturing processes. As the process is still the product, this could require the development of two independent manufacturing processes to achieve scalability and cost-efficient manufacturing at later phases (phase III, commercialisation) of manufacturing. The consequence would be much higher costs but also prolonged CMC times for IND submission when taking the seemingly less risky route and waiting for too long with automation

• Inefficient training and recruitment of skilled manufacturing personnel is another, often neglected, factor. The latter is important to maintain product quality by avoiding deviations or even out-of-spec products during the complex CGT manufacturing processes. When changing the manufacturing process from manual to automatic at a late stage of development this could really become a quality issue. In addition, it is anticipated that successful automation can lead to significantly reduced amounts of hand-on work and thus labor costs per product

No benefit:• As always, when novel technology is implemented the starting costs for development, equipment and reagents are high. However, history has shown that the prices will drop as soon as the needed products will be produced for a mass market. Inter-company collaborations and big funding networks can help to overcome this valley of death

• The mantra of R&D scientists that creativity and flexibility are the highest values of development are appreciated by the early adopter of automation. The early-adopter group suggest integrating automation e.g. for the analysis of in- process controls and drug substances (quality control), which won’t have an influence on process performance and the product identity. The same could be done to plan the entire supply chain from an early time point to better understand if the manual or an automated process thereof could indeed be used to yield an economically viable product or if development of alternative manufacturing steps are needed

• It is often unclear from the beginning if an automated procedure would really lead to a significant advantage when it comes to efficacy and quality of the product which may justify replacement of already existing equivalent CGT products on the market

No benefit: • At this point, automation of really complex manufacturing processes, e.g. neuronal differentiation and engineering, would need extraordinarily high investment costs right from the beginning as automation at a later time point will lead to a considerably different process. As the efficacy of, say, IPSC or HSC-based regenerative therapy still needs much more clinical evidence, implementation of automation is risky

• In general, early R&D CGT work might be too constrained when it is carried out with automation equipment, even in the case of platform approaches. Collecting as much data as possible during different conditions is often key at this stage. However usage of ‘light’ robotics like low-priced liquid handling stations might serve as a starting point for later automation

Mitigation: • As a late adopter you will always hope for the second technology wave, which can be surfed with less risk and better sight from the shore. ‘Wait-and-see’ is a reasonable strategy and may prevent hasty actions which will come back to you as a costly boomerang sooner and later

Early adopter’s answer:

Pain points:• The flexibility and the adaptability of automated cell and gene therapy processes have changed considerably during the last years. Platform-based approaches allow for customisation of a variety of different CGT manufacturing processes without losing too much time when compared to setting up of manual manufacturing processes. It’s therefore key to pick the right technology at the right time

• The late adopter argument of significant investment at the very beginning of the process without a guarantee for efficacy seems to be intriguing. However,


Or shall we take the riskier option and automate early? As such, we could potentially scale up early, ignore comparability issues and save money on the long-term perspective but might miss the chance to integrate parallel process improvements to keep a superior product position in the market. This seems to be especially true when solutions exist which can be adopted, in particular when the IP resides more in owning a specific asset rather than a special manufacturing process.

Currently, the best solution is to rely on highly adaptable, flexible and maybe also modular platform solutions that can integrate novel manufacturing procedures on the hardware as well as on the software level without taking too much development time and costs. Finally, having a constant eye on the ‘automation curve’ in the CGT business while taking prompt and smart decisions also demands for highly agile and lean management structures that have to be closely intertwined with industry’s internal (scientific) experts.

Ultimately, flexible platforms and fixed product requirements are the major prerequisites to automate CGT manufacturing processes from the earliest possible time point and will thus improve scalability and cost by resulting in highly proportional automation.

Mitigation: • The best way of mitigating the risk is to know and understand the manufacturing process in every detail. Automation will definitely help you on this way, as you cannot automate something that you do not entirely understand

In summary…

There is no doubt that early automation is desirable when thinking of economically viable CGT products with built-in Quality by Design. However, the extraordinary speed of biological developments and unforeseeable challenges when it comes to regulatory approval, building up of sustainable supply chains and innovative reimbursement models puts the industry in a continuous dilemma situation; shall we take the seemingly safer route and automate late? Thus, we could maintain maximal flexibility, use available supply chain structure, start off with smaller financial investments and keep full understanding of the manufacturing procedures? However, the question that should immediately follow is: will the manufacturing process I chose be the right one for commercial scale and success?

WHAT’S GOING ON AT ATW?

HERE’S

Head over to www.advancedtherapiesweek.org to find out how you can get involved

20th January 2020 The Future of Medicine Day

21st – 24th January 2020 World Stem Cell Summit 22nd – 23rd January 2020

Advanced Therapies 101: For the Nursing Professional

21st – 24th January 2020 Phacilitate Leaders World

HERE’S A SNAPSHOT OF SOME OF THE EVENTS THAT WILL BE TAKING PLACE…


https://www.advancedtherapiesweek.org/

PART 2

STRATEGIC DATA, ANALYTICS AND TECHNOLOGYMANAGEMENT

Automation can be introduced into quality control early, starting from clinical development. The discussion between participants identified the key analytics that would be most useful to be automated with a view to reduce release timing. The possibility to automate analytical methods is also linked to the technology applied. For cell and gene therapy, the most relevant potency assays could be automated because they are performed by a flow cytometer or cell counter. The automation of these tests would both reduce assay variability and allow more samples to be analysed simultaneously. For automation to be fruitful it has to cover sample preparation, sample testing and data analysis. These aspects are extremely important considering that potency assays are also an indication of product stability and have to be developed in a reliable way, starting from the first clinical stages.

Cell and gene therapy can be considered as the frontier of new medicine. However, to realise the high potential of these types of products, advancements must be made to optimise manufacturing equipment, processes and controls. This last point is particularly critical because often it is the bottleneck for drug product readiness. For analytics the following aspects are very critical:

• timing• throughput• reproducibility starting from first in man and for potency assays• conformity to different state legislation

The session was mainly focused on these aspects and when and how automation of analytical methods could help to solve or to reduce risks linked to the product release.

2.1 Automating quality analytics

Giuliana Vallanti is Development and Quality Control Director and Qualified Person in MolMed. She joined MolMed in 2005 and worked with growing responsibilities in Development and Quality Control units, contributing to the development of processes and assays in cell and gene therapy field. She has main experiences in the development and industrialisation of T- and haematopietic cells transduction processes with lentiviral and retroviral vectors. She worked on the development of GMP processes for large scale vectors production and purification. She holds a degree in Biology from Università degli Studi - Urbino and a Ph.D. in biochemical and pharmacological methods with a study on Lentiviral Vector for gene therapy anti HIV-1.

Giuliana VallantiDevelopment & Quality Control Director Molmed

Currently I am a Director of Smiro Qualitas Ltd, a consultancy company, providing quality consulting services to the pharmaceutical industry, as well as acting as a contract Qualified Person for several companies. Robert set this company up after leaving his role as Global Head of Quality for the Clinical Pharmacy Research Services group at Genzyme, in June 2012. He is a qualified pharmacist, Qualified Person and Vice-Chair Royal Pharmaceutical Society QP Eligibility Panel of Assessors. He has spent over 25 years working in the pharmaceutical industry. During his career, he has worked in both clinical trial supplies and the commercial sector of the pharmaceutical industry. Robert’s current interest is in biological products including vaccines and Advanced Therapeutic Medicinal Products.

Robert SmithDirectorSmiro Qualitas Ltd


and batch records review. If this assessment is positive, the product can be administered to the patient. The final certification step is performed by a QP when all test results are available. The working groups discussed the importance of a risk assessment to identify the minimum analytical panel of tests to be included in the first certification step.

Another topic of discussion was the different regulation requests for final vector and product release in EU and US, which centred on the possibility for a mutual recognition between EU and US. What is really needed is not only the harmonisation of the testing strategy for raw materials, vectors and DP but also harmonisation of the level of requests in terms of qualification and validation of facilities, analytical methods, processes, reagents and materials. It seems that EU requests are higher for first in man studies, while the US requests are very challenging for market approval.

In summary…

Automation in analytics is growing year after year demonstrating that ATMP manufacturing can benefit from this implementation in terms of sampling, time, throughput and, not least, costs. It is needed to identify new methods and technologies that can be automated in order to favour real-time release and as a direct consequence permit the faster availability of products to patients. A continuous interaction with regulatory bodies facilitates progress and the harmonisation of activities needed for authorisation in EU and US.

Different companies are working on automation methods to detect impurities and enhance product safety, which is possible because it is based on qPCR and ELISA. Also, for these assays, automation consists of the integration of automatic sample handling by the instruments in conjunction with the final results read out. The throughput that can be achieved is very high and the reduction of timing, costs and samples used is considerable. However, manufacturers are concerned about the time to release because this could have an impact on patient safety. Automation can help to design ‘real-time release’ that permits reduced testing on the final drug product. In order to have a real-time release, it is necessary to build up datasets with online and offline data that permit a strong correlation with the final quality attributes of the product. Emerging technologies such as Raman spectrometry can help to do this. Real-time release is also applicable when the process is completely standardised and the reproducibility is high, therefore, it is unlikely that this can be applied for first in man or phase II clinical trials.

In order to provide the drug to the patient in a timely reduced way, some companies decided to apply what is suggested by Eudralex Vol4 “Guidelines on Good Manufacturing Practise specific to Advanced Therapy Medicinal Product”; the two-step certification release. If there is a strong justification for medical needs and/or short product shelf life, some products can be released before completion of all quality control assays. The first step of Qualified Person (QP) release is based on a risk assessment that has to evaluate the available QC results, environmental monitoring


2.2 Automating the convergence of viral and non-viral technology to future-proof advanced therapy manufacturing

Ruth is Platform Marketing Manager at Sartorius, with strategic marketing responsibilities which include positioning Sartorius as a solution provider for cell and gene therapy applications. Before joining Sartorius, Ruth has held business development management roles at Agilent Technologies, GE Healthcare, Life Technologies and Novozymes Biopharma, following 10 years in biotechnology technology and IP commercialisation. Ruth’s technical knowledge has been built on a background of research in cell bioprocessing, stem cells and gene therapy. Ruth holds a PhD in Cell Biology and an MBA.

Ruth McDermottPlatform Manager, Regenerative MedicineSartorius Stedim

Fernanda is a Chemical Engineer with a Masters and PhD in Biochemical Engineering. Her main interests over her various positions have covered process development and next generation solutions for CGTs. At Sartorius, she provides technical expertise to customers and internally to help streamline processes and accelerate development of these therapies.

Fernanda MasriTechnology Expert, Regenerative MedicineSartorius Stedim

Dr Maguire is President and CEO of Avectas, which he has led since its inception in 2012. He has 20 years of experience in the life sciences industry, serving as a founder, investor, director and business leader. Dr. Maguire graduated from Trinity College, Dublin, as a biomedical engineer and completed his PhD on local delivery to the lung. Dr. Maguire is focused on creating value by addressing challenges in delivery of advanced therapeutics.

Michael MaguireCEOAvectas

Genetic modification is increasingly used in cell and gene therapy manufacturing processes. Among the common types of modification are gene transfer and gene edit. In either case, the material is delivered to a cell population, at scale and in a manner that is good manufacturing practice (GMP) aligned. Viral vector delivery is the most embedded technology today for GMP aligned gene transfer. However, there are limitations in the carrying capacity of viral vectors and challenges in cost and supply chain. This has caused developers to evaluate non-viral delivery methods.

Currently, non-viral delivery methods are inferior to viral vectors for gene transfer. In gene editing applications, for knock-in strategies, a transgene is introduced at the edit cut-site and can be in the form of a non-integrating viral vector. Non-viral technology, for example, electroporation, is the most embedded technology today for GMP aligned gene editing. However, there are limitations in the viability of some cell types, and some functional changes to cells after electroporation. Non-viral technology is favoured for delivering gene-editing cargos to knock out genes as the editing tool modifies the cellular genome and then leaves the cell, preventing additional off-target edits.


Table 1: Summary of different approaches and achievements of each technology

Part I: gene editing versus gene transferThe SIG group discussed the differences between gene editing and gene transfer. In the context of gene transfer, the discussion addressed the different formats of delivery material including DNA and mRNA where the objective is to have the cell population express protein that is missing or damaged in the patient’s cells or where it is desired to alter the phenotype of a cell therapy product. Common clinical application examples were discussed and included the synthesising of CAR-T, CAR-NK and iPSC cells for autologous or allogeneic indications. The distinctions between in vivo gene therapy and ex vivo gene-modified cell therapy were highlighted.

In contrast to gene transfer, genome editing aims to manipulate the cell genome, correcting mutations precisely. Delivery materials include nuclease systems that can find, cut and repair specific sequences at sites of mutations. Editing systems include transcription activator-like effector nucleases (TALENs), zinc finger nucleases (ZFNs) and the Clustered Regularly Interspaced Short Palindrome Repeats and their associated Cas proteins (CRISPR/Cas9) system. These systems generate cuts at specific DNA sites that are corrected by the cells’ DNA repair machinery. The SIG discussion group aimed to classify some of these methods based on what each technology achieves. For instance, a gene transfer technology can elicit permanent effects or long or short-lasting effects, whereas gene editing is generally a one-off, permanent modification. Table 1 summarises examples of different technology approaches and what each technology achieves.

As the cell and gene therapy field evolves, therapeutic developers are aiming for higher levels of complexity in their cell engineered products. A diverse range of cargos (mRNA, proteins, DNA) and cells (T cells, NK cells, HSCs and IPS cells) require increasing levels of sophistication in the choice of gene editing and gene transfer delivery technology. Strongly linked to this technology choice is the level of automation that may be available to support the manufacture of the therapeutic through the trial phases. It is evident that for many of these therapies, one method of genetic modification is not enough to achieve all the desired modifications. Based on the group discussion session at the SIG, this chapter explores if and how these viral and non-viral engineering methods might be complementary and how their manufacture will be automated. Three questions were discussed in the SIG session:

• Gene editing versus gene transfer. What does each technology achieve? Why use one or the other or multiple? Also, when is the persistence of expression desirable and when is it not?

• Are viral and non-viral delivery methods suitable or amenable to automation?

• Will next-generation therapies be a combination therapy of virally transduced plus non-virally edited cells?

• Viral transduction

• Carrier mediated o Cationic lipids e.g. LPN o Cationic polymers

• Direct membrane disruption o Peptides o Nanoparticles

• Permeabilised membrane mediated o Electroporation o Cell squeeze o Permeabilisation reagents

PERMANENT EFFECT

• Synthetic gene carriers o Sleeping Beauty o Piggy Bac

SHORT TERM EFFECT

• Nucleases o Zinc Fingers o TALENS o CRISPR

• Ribonucleoprotein (RNP)

ONE-OFF MODIFICATION

GENE TRANSFER GENE EDITING


The SIG group debated at which point would the viral and non-viral steps take place? If they take place earlier in the manufacturing process, these steps are likely to be at a small scale compared to later ones, which will also impact which gene engineering approach would be most suitable. Emerging microfluidic platforms were also discussed and are attractive for automation in genetic engineering. They offer controllable, predictable, single-use environments but scale-up tends to be an issue, as most rely on parallelism (or scale-out) approaches which are less suitable for scale-up, regardless of whether the manipulation is taking place early or late in the manufacturing process.

The SIG group discussed the significant opportunity for automation in screening. For example, what is the efficiency of the delivery system, viability of the cells (and how to adequately define and measure viability), functionality (up/down regulation of transcriptome, metabolic behaviours) and proliferation? The number of variables and parameters to assess is large and the SIG group agreed that a current bottleneck lies on how to effectively screen, at small scale, a large number of different parameters for any of these gene editing or transfer technologies. Going forward, a technology’s suitability to high-throughput small scale screening may make a difference to its adoption in the field.

The SIG group also discussed process analytical technology (PAT) becoming available for cell and gene therapy processes but observed that the industry needs to pause and to address standardisation and harmonisation of the measurements used to qualify the effectiveness of gene modification systems. Critical quality attributes of cells such as efficiency, functionality and viability at different time-points lack agreed standards. The multiplicity of infection (MOI) can vary from 1 to 8 in a three-hour window; viability is still a very loose term that encompasses many types of measurements and is mostly left to each therapy provider to define in detail. Cell quality can also change drastically in a few hours. Without standard methods, protocols or practices to quantify and qualify the effectiveness of the various genetic engineering techniques, it will be extremely complex to implement automation with confidence and in a robust manner.

Why use one or the other or multiple?Viral vector transduction is currently the most commonly used for cell immunotherapy (e.g. chimeric antigen receptors) and in vivo gene therapy approaches, whereas non-viral technologies are used for knock-out gene editing. Knocking-in a gene with an editing tool may enable better site-specific integration, which could be beneficial in terms of safety but, as yet, there is not enough clinical data to support this. The efficiency of each delivery technology is cell type-dependent, but the consensus was that most delivery methods remain inefficient. Notwithstanding the effectiveness of viral vector delivery systems, the manufacturing process efficiencies and throughput, cost of production and standardisation are currently not optimal. The SIG group summarised the position as viral vectors were ideal for gene transfer, non-viral for KO gene editing. Where both objectives are needed in a therapy design, these are effected in sequence, generally starting with viral transduction and then non-viral transfection.

When is the persistence of expression desirable and when is it not?The group debated the need for transient or persistent expression and discussed single dose ‘one-and-done’ therapies in contrast to re-dosing regimens where immunogenicity may be a factor or where dose escalation is required. The group referenced the work in developing an mRNA CD-19 CAR as an example of a transient therapeutic approach. Generally, the group believed persistence is an essential quality in gene transfer, whereas persistence of expression of the gene-editing tool is not required as the gene edit is inherently permanent. The desired therapeutic mechanism of action will impact the choice of gene editing and transfer technology.

Part 2: are viral and non-viral delivery methods suitable or amenable to automation?Amenability to automation depends on considerations such as throughput, quality of the cells post-genetic modification, linear scalability, intended therapeutic indication and its place within the manufacturing process. The SIG group discussed several commercial systems for automating unit processes including Prodigy, Maxcyte, Lovo, Solupore and Nucleofector. Some of these systems address viral and non-viral unit process; however ‘tying-up’ a valuable resource for long periods during cell expansion phases was seen as a challenge to adoption.


Part 3: will next-generation therapies be a combination therapy of virally transduced plus non-virally edited cells?The SIG group observed that viral and non-viral modalities are already used in publicly disclosed manufacturing processes from immuno-oncology companies such as Cellectis and Allogene. The group agreed that in the short term, viral transduction would dominate and that ultimately, non-viral approaches will play an increasingly significant role. However, there remain biological, technical and regulatory hurdles to overcome.

In summary…

Viral delivery is the most embedded technology in the industry today for genetic modification. There may be a shift in the longer-term to non-viral delivery methods if the economic and technical performance of non-viral platforms out-compete viral delivery platforms. Therapeutic developers working on next-generation products seek to engineer cells in more sophisticated ways leading to a market need for viral and non-viral delivery within one manufacturing process. Currently, the measurement of process parameters including delivery efficiency, viability, functionality and process yield are not standardised. Such standardisation will be an essential next step for the industry to future-proof advanced therapy manufacturing.

1Increasing the safety and efficacy of chimeric antigen receptor T cell therapy. Hua Li, Yangbing Zhao. Protein & Cell. August 2017, Volume 8, Issue 8, pp 573–589

PART 3: WILL NEXT-GENERATION THERAPIES BE A COMBINATION THERAPY OF VIRALLY TRANSDUCED PLUS NON-VIRALLY EDITED CELLS?The SIG group observed that viral and non-viral modalities are already used in publicly disclosed manufacturing processes from Immuno-oncology companies such as Cellectis and Allogene. The group agreed that in the short term, viral transduction would dominate and that ultimately, non-viral approaches will play an increasingly significant role; however, there remain biological, technical and regulatory hurdles to overcome.

In summary…

Viral delivery is the most embedded technology in the industry today for genetic modification. There may be a shift, longer-term, to non-viral delivery methods if the economic and technical performance of non-viral platforms out-compete viral delivery platforms. Therapeutic developers working on next-generation products seek to engineer cells in more sophisticated ways leading to a market need for viral and non-viral delivery within one manufacturing process. Currently, the measurement of process parameters including delivery efficiency, viability, functionality and process yield are not standardised. Such standardisation will be an essential next step for the industry to future-proof Advanced Therapy Manufacturing.

1Increasing the safety and efficacy of chimeric antigen receptor T cell therapy. Hua Li, Yangbing Zhao. Protein & Cell. August 2017, Volume 8, Issue 8, pp 573–589

TECHNOLOGY REVIEW:GENE EDITING

Brought to you in partnership with

Phacilitate Automation SIG: 2019 Report 26Phacilitate Automation SIG: 2019 Report 26

https://www.phacilitate.co.uk/article/technology-review-gene-editing

2.3 Controlling manufacturing variability through a move towards Quality by Design principles

Marco Fadda, Biomed. Eng., began as researcher in a biomechanics laboratory, investigating bone cutting quality using robot held tools, followed by development of medical robotics, together with customer training and OR support. Successively, served as executive for top brands in the Medical Device Industry, with focus on understanding medical needs and transforming them into successful and remunerative global surgical solutions. Since 2014 he is dedicated to the development of principles and solutions for managing cell manipulation, expansion and transformation in aseptic environments. Main goal is the application of principles of Isolation Technology to ATMP development and production, with integration of all the necessary process tools and devices into a Grade A environment. The final aim is to perform GMP research and production of ATMPs, under full Isolation Technology, to simplify the production processes and to automate them as much as possible, aiming at a final reduction of the COGS, for a wider acceptance and a larger possibility of use of these products.

Marco FaddaATMP Solutions Manager Comecer

Dr Sullivan earned his PhD at the Roslin Institute (Edinburgh) under Professor Ian Wilmut and Dr Jim McWhir, becoming one of the first researchers in Europe to culture human embryonic stem cells. Thereafter, Dr Sullivan worked as a Research Fellow at the University of Cambridge, Harvard University, and UCSD and has worked at Novartis and the Irish Stem Cell Foundation. In June 2017, Dr Sullivan joined GAiT (www.gait.global), an initiative supporting implementation and clinical application of therapies derived from pluripotent stem cells for the benefit of patients globally. GAiT is supported by an international consortium of organisations including the Cell and Gene Therapy Catapult (London, UK), the Centre for Commercialisation of Regenerative Medicine (Toronto, Canada), the Korea HLA-Typed iPSC Banking Initiative (Seoul, Korea) and the New York Stem Cell Foundation (New York, USA), Hong Kong University (Hong Kong, Hong Kong) and INSERM (Paris, France).

Stephen SullivanInternational Liaison Officer and Programme ManagerGlobal Alliance for iPSC Therapies

These include, but are not limited to, bespoke manufacturing technologies, automation, in process controls, in quality checks, improved modular and flexible environments and, finally, integration of suitable solutions for addressing the viral or non-viral transfection challenges for gene editing.

Some of the above considerations are often collected under the umbrella of the Quality by Design (QbD) approach and it was the intention of this session to deploy and go deeper into these topics.

Scalable accurate, safe, high quality manufacture is a must if we want to make sure advanced therapies will be available in the correct timing, with the required quantities, for all the patients with the right indications and at affordable costs for our healthcare providers.

To hit that target, we must identify the key manufacturing technology gaps which need to be covered, ensure control over the variability of the processes (understanding individual, environmental, functional factors) and integrate all the information under a global quality strategy.


Knowing our targets better, in terms of throughputs, expected treatment and needed volumes can help. Maybe this is the only way to select the most suitable technology – to get this, characterisation of the starting material is a key point.

Quality by Design In contrast to traditional drug development, when it comes to cell and gene therapies some of the more challenging questions relate to product manufacturing and quality and safety.

The QbD approach should not only be applied to process development but also to analytical methods for cell therapies as analytical methods are mini processes in their own right.

Often cell therapies have a short shelf life, which makes the analytical technologies for QC ever more complex. Combined with the exceptional growth seen in the industry this increases the need for cutting-edge analytical QC provision which is rapid, low-footprint and cost-efficient.

Cell and gene issues For the SIG session, the first round of analysis focused on gene-modified cell therapy, as for in-vivo gene therapy the considerations would be different depending on the quantities needed.

For gene modified cell therapies. The capacity of the CMO is a challenge, and it is now clear that we should work with an approach similar to that of doing an industrial process. We can say that the cost of vectors could also be reasonable but we need to secure the supply chain, as the main risk today is a lack of raw materials. The alternative is in-house production but the process is very expensive and complicated in the early phase.

A second round of analysis was dedicated to non-viral vectors, where the need to go over the supply chain problem and the desire to get away from biological methods were identified as drivers for non-viral vectors. However, as it would not be doubled for the same type of editing, the payload would be excessive. Non-viral techniques were also interesting, particularly in cases where transient expression is needed (it doesn’t require long term patient follow-up and could be an opportunity for fitting reimbursement issues) and it could also be useful for patients for whom viral therapies will not work.

The focus within the SIG session was then set on three main issues:

1) identify and address the technology gaps2) understand process variability and bio-analytics3) specific issues concerned with cell and gene therapy

The technology gap It was the opinion of the participants that the technology gap has different aspects, for instance, technology is generally available but we know its adoption is slow. This is common in the pharma and biopharma industries and cell therapy is no exception. There is also a general attempt to stop using class B rooms and move to functional closed systems but there are still a lot of manual steps to be addressed. Even some instruments need to be adapted to the size of cell and gene therapy because they were designed for different applications. One typical example is the bioreactor, where even the size of the smaller units still seems too big.

Cells are very delicate and need particular setups, which sometimes prevent scalable approaches. There is still space for a clear understanding of different tools and a lack of an industrial approach of the fundamentals of things to do. As an example, we can compare to biotech, where automation is commonplace. We do not have a good automation platform because it is hard to do full characterisation. For this reason, it is also hard to figure a common platform. However, there could be some good news, as manufacturing of viral vectors is similar to manufacturing of monoclonal antibodies.

Process variabilityPatient to patient variability is another issue. Decreasing of manual operations is unclear as many processes still depend on the number of cells you have available. It is difficult to have adaptive manufacturing mainly because algorithms are based on tests which are done on different starting materials, in particular on healthy patients.

Could an option be to get doses when the patient is diagnosed? When there is evidence could it be used to treat a patient earlier, before too many other treatments have been applied? There is a need to perform basic research to know which markers allow for better control of our processes. We should run a second level of comparison among autologous and allogeneic procedures, being easier for allogeneic to copy and paste existing processes in biotech.


Manufacturing technology can be mediated from other successful experiences, like the biotech industry, and this provides a chance to revise some of the existing tools for adapting dimensions in the cell and gene therapy industry. As a consequence of the approach, QbD needs to be applied to post process measuring tools and for this reason, analytical methods need to be considered processes in their own right.

Finally, as the vectors still represent a key point in the manufacturing of gene-edited therapies, securing the supply chain is essential. Alternatively, working in parallel on non-viral vectors is an option for the future, for both back-up and special needs purposes.

Variability can be successfully addressed with adaptive automated manufacturing procedures, providing that the feedback we have from the process is well-managed and interpreted, the components of the process (e.g. vectors) produced and added under strong quality controls and the feedback itself provided accurately and in time.

In the third round of analysis, the group looked at problems connected to gene-editing platforms (CRISPR/ Cas9/ TALEN). Here some of the limiting issues are concerned with patents and clinical evidence. Actions are recommended for addressing these two fields.

The take-home messages were identified as:

1) gene editing is still more of a challenge than therapy delivery2) stable producer lines are the real game changer to drive down cost of goods

In summary…

The choice of which platform and which approach is concerned with understanding the required throughputs, volumes and expected treatments. Tools for better forecasting, planning and testing processes can be game-changing. This reflects on the need to develop more accurate methods for material characterisation, as adaptive manufacturing and automation are definitely concerned with a definition of an accurate starting point.


in 2018) and a wide range of application areas including the detection of disease, management of chronic conditions, clinical trial design and drug discovery. However, the applications of AI for monitoring and controlling cell and gene therapy bioprocesses is a largely under developed area. This is despite the obvious advantages that AI could bring to these often long and complex manufacturing processes.

2.4 Cell production monitoring and analytics: a look towards artificial intelligence

Damian Marshall is the Director of New Technologies at the Cell and Gene Therapy Catapult and has almost 20 years of industrial experience gained working for SME’s and large companies. He is responsible for providing vision, expertise and leadership to a team of ~70 scientists working with a wide range of cell and gene therapy developers. Together they are addressing some of the fundamental barriers to growth within the industry, developing improved cell and gene therapy manufacturing processes and integrating technologies for advanced product characterisation and process control.

Damian MarshallDirector, New Technologies Cell and Gene Therapy Catapult

Shashi Murthy is a Professor of Chemical Engineering and the Founding Director of the Michael J. and Ann Sherman Center for Engineering Entrepreneurship Education at Northeastern University. He is an expert in the areas of cell separation and automated cell culture and current projects in his lab focus on patient-specific dendritic cell generation and dendritic cell-mediated T cell expansion for therapeutic use. Prof. Murthy earned his Ph.D. in Materials Science & Engineering at the Massachusetts Institute of Technology (MIT) in 2003 and his B.S. in Chemical Engineering at Johns Hopkins University in 1999. He joined Northeastern in 2005 following a postdoctoral fellowship at the Harvard Medical School and Massachusetts General Hospital. Prof. Murthy holds visiting appointments at the Massachusetts General Hospital, Shriners Hospital for Children, and the Broad Institute of Harvard & MIT. He is the recipient of the National Science Foundation’s Faculty Early Career Development (CAREER) Award and the Søren Buus Award for Outstanding Research in Engineering at Northeastern University and was elected Fellow of the American Institute for Medical and Biological Engineering (AIMBE) in 2015. Prof. Murthy has co-authored over 70 publications and is an inventor on 7 issued or pending patents. He co-founded Quad Technologies which commercialised hydrogels as releasable magnetic beads for cell separation and reagents for cell activation. More recently, he founded Flaskworks, which is commercialising automated systems for the manufacturing of patient-specific dendritic cells and dendritic cell-stimulated therapeutic T cells.

Shashi MurthyProfessor, Chemical Engineering,Northeastern University, College of Engineering

Despite being around for over 60 years it has only been in the last 15 that artificial intelligence (AI) has really taken off. This has been fuelled by exponential gains in computer processing power and storage ability that allow companies to process, analyse and mine vast quantities of data. The healthcare sector is a key market for AI technologies, driven by huge investment ($2.3bn


storage that ensure security traceable to national or international standards already exist and have been applied in other industries.

Despite concerns over data volumes, we have started to see the first high profile collaboration

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REPORT 2019 - Phacilitate · REPORT 2019. HOST PARTNER FOUNDING PARTNERS TECHNOLOGY SHOWCASE PARTNERS TECHNOLOGY PARTNERS ... future-proof advanced therapy manufacturing ... He has