The Impact of Cellular Orchestration Platforms on Cost of Goods

Cellular Orchestration Platforms (COPs), such as TrakCel, are designed to improve supply chain performance for cell and gene therapies (CGTs).

This is achieved by:

·        Providing full traceability of therapies from donor to recipient – this is especially important for autologous cell therapies, where following modification and expansion at a manufacturing site, starting material derived from a patient must be infused back into the same patient. As the number of therapies being received, processed and shipped by clinical sites, manufacturers and logistics providers grows this will become increasingly challenging.

·        Driving compliance with regulations, the trial protocol and Sponsor SOPs at clinical sites, through the implementation of prescriptive 21 CFR Part 11 compliant workflows. Again, as the number of parties involved in cell therapies grows in late stage clinical development and commercialisation, the need for consistency and control increases.

·        Capturing Data from multiple parties in the supply chain, giving Sponsors a single-system view of needle-to-needle supply chain performance allowing for analytics and performance optimisation.

·        Scheduling of activities in the supply chain to ensure upstream tasks occur only when there is downstream capacity available for subsequent process steps. For example, providing apheresis centres with visibility of manufacturing capacity so starting material is collected only on days when capacity is available for cell modification and expansion.

·        Simplifying QA release processes and supporting product quality by providing Quality Staff with all the information on a product’s chain of custody required to certify it is safe for infusion into a patient.

Through the above functionality, COPs can significantly reduce Costs of Goods during clinical development as illustrated below. Savings in this table are based on the following estimated costs for a clinical trial[i] (based on standard pharmaceuticals/biologics – for CGTs, we would expect the cost to be at the high end of this scale, if not higher):

·        Phase I $1.4M – $6.6M

·        Phase II $7.0M – $19.6M

·        Phase III $11.5M – $52.9M

‍Major cost drivers include clinical procedure costs (15-22%), study administration costs (11-29%) and clinical site monitoring (9-14%). For illustrative purposes, and based on the complexities of CGTs, we will use the higher figure in these ranges for CGTs.

‍Further supply chain challenges, and associated costs, need to be captured in each therapy’s Cost of Goods (COGs). While a COP may not directly impact on these processes per se, data captured by the system allows Sponsors/Developers to take a holistic view of their supply chain and identify opportunities for optimisation.

‍These include:

·        Logistics – COPs can provide logistics providers visibility to future needs, allowing for better forecasting and utilisation of courier services and improved management of specialised shipping system inventories, which in turn can reduce costs. Also, data captured can be used to analyse courier performance, route selection and potential points of failure.

·        Manufacturing/QC testing – In many cases, scheduling is performed manually across the supply chain. Automating this process can enhance utilisation of manufacturing assets, which has a significant impact on the cost of goods. Integration with manufacturing equipment allows for a more efficient review of manufacturing data at the time of release.‍

·        QA/QP release – This is a major cost and process bottleneck for even traditional pharmaceutical manufacturers. Capturing data and documentation across the entire supply chain, from multiple sources (as is often the case for CGTs) can be challenging and adds significantly to release timelines – particularly for initial batches. By capturing key data, COPs can help alleviate this – one QP we spoke to quoted up to 40 man hours at a cost of $10,000 to release a first batch of product when compiling data from multiple stakeholders, which can fall by around 85% if all information is available in a single system.

‍TrakCel’s experience to data has been focused on supporting our clients’ products through clinical development. We are well aware of the challenges ahead when products are commercialised. One client we spoke to when compiling this paper cited that, in order to justify their current market capitalisation, larger autologous CGT developers will need to sell 5-10,000 treatments per year. This in turn equates to 40-60 batches of product released every day. How is this going to be possible using manual traceability and supply chain orchestration? What will the labour cost of achieving this, let alone the risk of product failures in terms of lost material and damaged reputations, amount to? COPs were developed to enable cell therapies to reach their potential – this will not happen without traceability, consistency across all stakeholders, automation and holistic data-driven decision making across the supply chain provided by these systems.

[i] http://journals.sagepub.com/doi/pdf/10.1177/1740774515625964

Leveraging Cellular Orchestration Platforms to Support the Cell Therapy Supply Chain

Recently I had the opportunity to participate in the Hanson Wade Future Cell Therapy Commercialization Event in Boston, MA which was overall, a fantastic event. A big thanks to the organizers. With logistics being a cornerstone to the future success of cell therapy commercialization, a significant portion of the overall discussion was focused on supply chain challenges associated with the delivery of autologous therapies.

Due to TrakCel’s well established US and EU compliant, Cloud-based Cellular Orchestration Platform (COP) that pioneers the space and was first to market in 2012, Hanson Wade provided TrakCel and myself the opportunity to help assemble and moderate a panel titled, “Leveraging Cellular Orchestration Platforms and Other Systems to Support the Cell Therapy Supply Chain.”

For those that were not able to attend, this blog post is a summary of the three main takeaway messages of the presentation:

‍- What is a Cellular Orchestration Platform?

– Where does a Cellular Orchestration Platform fit amongst other IT systems?

– How to go about implementing a Cellular Orchestration Platform?

What is a Cellular Orchestration Platform?

Over the past several months it’s been evident that the cell therapy community has an acute awareness of Cellular Orchestration Platforms (referred to as COP here forward) but somewhat of an obtuse understanding around what exactly these systems do – hence the intention and main focus of the panel.

As the name suggests, these systems are designed to orchestrate, or manage processes and workflows across the entire supply chain, often driven by various third parties that lie outside the control of drug developers, including collection centers, couriers, manufacturers and infusion centers. To do so, these systems must have flexible configurations that yield prescriptive workflows as well as detailed rules and constraints that are specifically engineered to match the cell therapy company’s product portfolio.

The end result provides cell therapy developers a standardized, automated and controllable needle-to-needle supply chain with functionality including automated scheduling/resource alignment, notifications/alerts, capacity management and customizable dashboards for core users.

When complete, these systems become a drug developer’s “Control Tower” view and the thread that ties the overall process together.  By doing so, the COP system provides developers a complete and regulatory compliant electronic record for chain of identity and chain of custody from collection through to infusion.

Where does a Cellular Orchestration System Fit Amongst Other Systems?

Another major topic discussed by the panel was around where a COP fits within the universe of IT systems.

Primarily, a COP should not be compared against more traditional internal systems such as ERP, MES or LIMS which are of course intended to support more internal enterprise and manufacturing efforts.  This is something that’s often misunderstood by our industry and understandable considering the new and unique manufacturing requirements of autologous cell therapies.  Even though when one compares a COP against a more traditional manufacturing system and finds overlap in functional capabilities (such as barcoding, traceability, scheduling, etc.), the environments for which they are intended and the implementation efforts and expertise required are very different.

The second major message was that a COP does not, and should not, interfere with the implementation of customer relationship, enterprise, manufacturing and laboratory related management systems.  Too frequently companies feel that major internal systems should be implemented before considering a COP when the strategy should be the exact opposite!  Those that have managed mid to late-stage autologous trials understand firsthand how labor intensive and inefficient management of the autologous supply chain can be.

While the traditional systems mentioned above have their place in the commercial environment, COP becomes instrumental early in clinical development when patient numbers are in the 10s, not 1000s.  This leads to the last major topic of the presentation, implementation strategy.

 When and How to Implement a Cellular Orchestration Platform

 Stage 1 – Build the Foundation

So, what’s the first step to implementation? Like building a house, the first effort should be focused on building a solid foundation. In the world of COP implementation that means establishing clinical site workflows for both collection and infusion, generating both starting and final drug product labels, courier integrations and milestone reporting within manufacturing environments.

A successful COP foundation establishes the pathway and major processes conducted across the supply chain while also pinpointing each step in the process where custody of the product is exchanged and/or chain of identity verification if required.

To garner maximum value from the COP, implementation efforts should begin early in clinical development when the number of clinical sites are limited (during Phase I/II trials).  This early implementation allows for a validated system to be in place to support mid-stage trials, when clinical site numbers begin to expand and manual in-house systems begin to break down.  At this stage of implementation, the combined value of the COP along with the costs saved via introducing the system during early to mid-stage clinical onboarding efforts (instead of onboarding and then backtracking clinical efforts to introduce the COP) can immediately justify investment with a measurable return on investment.

Stage 2 – Incorporate Scheduling

Once the foundation is in place, the next stage of implementation should be focused on scheduling. The simple reason for this is based on the fact that tracking/traceability (established in the foundation) and scheduling are inherently interconnected and dependent on each other.

As patient numbers increase and manufacturing capacity utilization quickly reaches the upward limits of the cleanroom environment, the scheduling system must accurately assess and book capacity while also being able to cancel or reschedule without breaching the limitations of the third-party environments. To do so, implementation of scheduling requires careful analysis of all stakeholders and resources involved in the supply chain followed by applying detailed rules and constraints that subsequently ensures alignment of resources for collection, manufacturing, transportation and infusion.

As we all know too well, Murphy is alive and well in cell therapy – if something can go wrong…it will go wrong.  For this reason, the scheduling system must be adaptable to manage change. Lastly, implementation of a scheduling system often requires a detailed understanding of the treatment regime and the manufacturing process.

For this same reason, a COP provider must have a detailed understanding of the collection, logistics, manufacturing process and administration (including patient preparation) of each cell therapy it manages. Without this experience, rules could be built into the platform that would plague the utility of the system.

Stage 3 – Establish Commercial Integrations to Maximize Efficiencies

With the bulk of COP functionality now in place from the Stage 1 and Stage 2 implementations, developers are well positioned to provide an electronic audit file demonstrating chain of identity and chain of custody while also demonstrating capacity management for BLA application. This leads us to the final implementation stage (recommended to occur during Phase III trials) that is focused primarily on the integration of commercial systems to maximize efficiencies across the supply cycle. On the front end of the supply cycle, integrations may occur between the customer relations management software (CRM) – often the initial system used by patient case managers to gather preliminary patient enrollment related information and benefit verifications – with the COP.

To further information automation in the ultimate effort to streamline visibility into the needle-to-needle supply, integrations during Stage 3 may also occur between ERP, MES, QMS and LIMS systems as each system may have independent yet important data to contribute to the COP.  The COP then becomes the tool that weaves several standalone systems together to provide the detailed view of the patient and the drug product journey.  It can also become an interface for the patient and the physician to provide visibility into the progress of the life-saving therapy. Beyond infusion, drug developers are also considering the lifecycle of the COP to go beyond the delivery of the drug and become a vital tool for the long-term tracking of the patient for reimbursement, therefore requiring integrations with potential downstream payor-related systems. In the end, COP can become the overarching platform that tracks and manages the overall patient journey from identification to final reimbursement for the therapy.

The bottom line message is that Cellular Orchestration Platforms play an instrumental role in cell therapy – especially for autologous therapies.  While the functionality they deliver is undoubtedly needed in the commercial setting, I hope this blog emphasizes the incredible value these systems provide in early clinical development and why it makes sense to begin implementation efforts as early as possible. As a final point, Steven Buckanavage one of the panelists, who led commercial efforts at AstraZeneca, GSK and most recently Celyad and now President at Mentoris Advisors, emphasized several times that we as an industry must have flawless execution every time to be commercially successful.

We at TrakCel see COP systems as a vital tool in the effort to bring Six Sigma level of quality to cell and gene therapy.

‍If you have any further questions or would like to learn more about TrakCel’s Cellular Orchestration Platform please email me at rob.margolin@trakcel.com.

Potential Introduction of ATMP-Specific GMP Standards in the EU

During June of 2016 the European Commission opened a three-month consultation on proposed Good Manufacturing Practice (GMP) guidance for Advanced Therapy Medicinal Products (ATMP). The purpose of the consultation was to allow academic groups, CMOs and commercial developers of ATMPs to provide feedback on the proposed ATMP-specific manufacturing rules. Perhaps, surprisingly for the European Commission, the draft guidance document received a lukewarm reception from the industry. The commission’s aim was to develop ATMP-specific manufacturing standards which would expedite the access to these products by clarifying the guidelines associated with manufacturing them. However, notable responses from the Alliance for Regenerative Medicine and PIC/S (Pharmaceutical Inspection Co-operation Scheme) have questioned some of the details contained in the guidance document.

One of the starkest rebuttals of the guidance document came from PIC/S in an open letter, PIC/S is not alone with its concerns regarding the possibility of having separate GMP standards for ATMPs and non-ATMP products.  Several QPs have questioned the logic associated with this potential scenario.  Furthermore, there is discontent regarding the potential for lowering GMP standards for first into man manufacturing of ATMP products. Another key observation was the missed opportunity to develop a pan-European approach to interpretation of the EU’s directives associated with the collection and handling of blood, tissues and cells. Currently, European Union member states are allowed some discretion when interpreting and enforcing the details of the European Union directives. For example, the German interpretation of the Blood Directive requires QP certification of blood products whereas other European countries do not necessary require this as part of product release. This may seem like a minor detail, but with the current preference for centralised manufacturing strategies for autologous therapies, a single European approach to the way in which patient-specific starting materials are managed would have been welcomed by the Cell Therapy Industry.

The guidance document also addresses traceability, which is a key attribute to a successful autologous supply cycle.  Indeed, the requirements must not be overlooked for allogeneic therapies; for both autologous and allogeneic products records associated with the collection of starting materials and manufacture must be maintained for thirty years (which agrees with current EU directives), this contrasts with the FDA’s requirement for ten years’ record retention. Interestingly, the proposed new guidance allows for traceability records to be kept outside of manufacturing batch records providing that these are auditable and inextricably linked to the manufacturing records. Furthermore, and in contrast to some practices for autologous supply outside of the EU, the draft guidance details that traceability must be recorded up to delivery of the therapy to the patient; some autologous treatments in North America have only been traced to delivery at the hospital/treatment centre. TrakCel’s software platform has been used to provide full traceability throughout supply cycles of ATMP products, demonstrating both chain of identity and chain of custody from collection of starting material to the treatment of patients and facilitates long-term, compliant, data storage and controlled access to records.

The uncertainty regarding borderline ATMP products could be very challenging, if two separate GMP strategies exist, manufacturers must be sure of their product classification, in order to apply the correct GMP standards during manufacture. However, the Committee for Advanced Therapies (CAT) will be able to determine if the investigational product meets the scientific criteria which qualifies it for ATMP status.

The complexity associated with the regulatory environment could become exacerbated following the UK’s exit of the European Union, although it is unlikely that the UK would turn its back on the existing legislation framework, there are no certainties regarding QP certification by a UK-based QP being accepted by mainland-Europe QPs once the UK has waved goodbye to its membership status. Whatever the case, detailed scrutiny will be given to the outcomes of the guidance document and the protracted UK-EU Brexit negotiations.

Consultation Document Good Manufacturing Practice for Advanced Therapy Medicinal Products

Reflection paper on classification of advanced therapy medicinal products

Standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components

Standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells