Much mystique and mystery surround the emerging industries of cell therapy and regenerative medicine. As companies progress toward commercial manufacture with potential game changers (e.g., cures for cancer and diabetes) the industry could be on the verge of significant breakthroughs. However, with no real successes to date, the question is raised: What core attributes are required to achieve commercial success? The tale of Dendreon’s struggles highlights how difficult it can be to commercialize even an approved cell therapy product.

Since early 2004, my company has worked with organizations dedicated to cell therapy and regenerative medicine to help them develop and implement commercial-scale manufacturing for a wide range of therapies. Our work has helped us identify elements that build a solid foundation for game-changing product development in these fields. We call these elements the “five pillars of success”:

• Manufacturability
• Cost of goods
• Efficacy
• Reimbursement
• Needle-to-needle logistics.

This article (the first of a two-part series) will cover each of the five pillars as a means of discussing requirements for planning the commercial-scale manufacture of products related to cell therapy and regenerative medicine. Topics include trade-offs and decisions that must be made to avoid the “valley of death” and enable successful progression to commercialization.

Manufacturability
How can a cell therapy company successfully transition to commercial‑scale manufacturing? Like all manufacturers seeking to create market-winning products, cell-therapy manufacturers must develop and refine their processes to be robust and error-proof, using manufacturing equipment that produces consistent and repeatable processes. The complex and multifactorial tasks of process work flow, work force, manufacturing equipment, disposables, facility, data flow, and traceability, quality testing, waste-handling and storage must be thoroughly considered before developing any technology. To assist you on the road to cell therapy commercialization, I’ve created a step-by-step guide to achieving manufacturability, based on our experience in guiding companies to marketing-winning product manufacturing.

First step, understand your process and the requirements to define your problem. Drill into the process to understand it. Start by asking the top-level questions, such as What does commercial scale look like to you? Continue with additional questions to flesh out specifics, such as

• If you aim to process a certain number of patients per year, how does that translate to doses processed per day?
• What is required (equipment, manufacturing, storage space, staff) to perform each process every day?
• If there are long incubation steps, how will the facility accommodate the number of batches that need to be in incubation in the facility at any one time?

What will be the effects of scaling up process flow?

• What is your desired facility utilization?
• What is your ideal manufacturing shift pattern?

In considering the above, if your company is processing 100 patients a day and the incubation time is seven days, even with 24/7 production, there will only be 700 batches in the incubators every moment of every day. However, with any interruption in processing, or ebb and flow of incoming material, significantly more product needs to be processed. The increased processing will drive down facility use and drive up required equipment capacity¬–e.g., capital cost—to process that peak load.

Second step, turn your operation into an industrial process. A great starting point for this step is to evaluate ways to remove operator error and process variability. For example, you could design disposable sets to be quickly and easily loaded onto equipment only one way. Additionally, you could build in mechanisms that detect errors in loading. These types of design tweaks eliminate or reduce the possibility for operator error, particularly those associated with batch records and data transcription.

The above step raises the question Can the current process be validated? A robust industrial process must be able to repeatedly perform complex actions and motions to achieve the same result as the manual process. For example, manual agitation of a flask to release and harvest adherent cells is an inherently variable process, not only among operators, but also with the same operator performing the function at different times. It is, however, a process well suited to automation because it enables the delivery of consistent and repeatable outcomes.

Third step, eliminate skill-based processing steps by minimizing human interaction in areas that affect product yield or quality. One ancillary goal of the second step is to identify and prioritize those steps that contain “art” or skill. Those steps often are the most variable in the process. Such steps can be made consistent and repeatable by selectively applying engineering design and innovation, e.g., manipulating the input sample (selecting cells of interest in an autologous process), manual pipetting, cell counting, or estimating confluence and knocking to release adherent cells. Finding a solution to these challenges may require you to repurpose existing technology — or perhaps invent a closed and automated solution to the problem — but a solution will be possible.

Fourth step, integrate data flows. Manufacturing execution systems (MES) and batch records should be automated, not processed manually. In my company’s experience, at least 50% of process errors are manual transcription and recording errors, rather than errors in process or incursion breaches. You can significantly reduce the need to manage variations and achieve a faster product release by mapping your process and transferring it to an integrated data management, batch record, and product tracking system. Automatic batch records can significantly reduce the number of operators required, thus reducing recruitment effort and minimizing the staff turnover (keys to managing scale-up of a manual open process to a closed, commercial-scale, manufacturing process).

Fifth step: manage cost of goods. Achieving the lowest cost for a consistently producible product that meets identified critical quality attributes (CQAs) depends on the following:

• process development (defining CQAs and refining the process for cost, yield, and reproducibility)
• manufacturing system development (optimizing use of equipment, disposables, and facilities)
• timing facility and equipment development (determining the lowest cost path to market).

Sixth step: think in terms of scaling up. A strategy for scaling up your process from bench-scale laboratory to industrialized commercial manufacturing is absolutely critical. You will have no product — worse, no company — if that cannot be done. You must understand the technology, develop your process, and apply innovation to develop manufacturing solutions that deliver an optimal scale‑up solution and final manufacturing process. To this end, the critical factors are

• product characterization (What are our CQAs
• process robustness and stability (Can you make the same product every time?)
• process integrity (How can you error-proof your process?)
• labor and variability (How can you eliminate human-introduced variability?)
• cost (When do you invest in development and purchasing of current good manufacturing (CGMP) process equipment?)

Your process development team must work closely with your engineering development team to refine the manufacturability of your process. The combined team should be thinking in terms of characterization, CQAs, manufacturing process transformation, equipment use and manual labor, and development time, considering the following inputs:

Characterize the Product and Identify CQAs: This is the basis of everything. Characterizing the product and determining CQAs will identify the impact of process changes (big and small) on your cells. Move away from the “product is the process” paradigm to the true intent of GMP, which is to have a characterized process that is open to continuous improvement. CQAs are not only release parameters, but also process control measures that determine whether you have a manufacturing process or you’re just flailing around in the dark.

Transform the Manufacturing Process: Your process should be scalable and consist of closed-unit process operations in the lowest class clean space possible. Leveraging single-use technologies so that your process is functionally closed allows manufacturing to be performed in a lower-class cleanroom (e.g., Class C instead of Class B). Doing this can significantly affect both your facility costs and on-going operating costs.

Translate the Manual Process: Select the appropriate technologies, processes, and equipment for manufacturing. For example,

• move from a manual, open Ficoll (GE Healthcare) selection step or a range of traditional centrifuge wash and media exchange steps to performing a counterflow centrifugation process. This is performed in a closed, disposable system that can be aseptically connected to both upstream and downstream unit operations which is more suited to commercial manufacturing.
• transition from a manual formulation step to one performed as an automated, closed formulation process. This minimizes operator interaction reducing it to connection of closed processing vessels (both empty and those containing fluid and product) and initiation of the process (pushing the start button).

Maximize Equipment Use: Optimize the use of capital tied up in your manufacturing equipment by ensuring high throughput and minimal residence time of products on the most expensive equipment. Transfer long-duration process steps such as incubation either for transfection or expansion to low-cost equipment or low-cost spaces (e.g., shared incubators).

Manage Development Time: Development of a manufacturing system is at least an 18–24 month project for even the simplest therapies; however, upon completion, an immediate benefit is that process validation can occur at your manufacturing site. As such, the decision to time your expenditure and the resources to support it must be planned in advance to match the deadlines of the clinical program and funding availability. We suggest performing an early assessment of manufacturing feasibility and develop a plan that envisions what the manufacturing operation will look like. This step is a key input for corporate decision-making, paints a vision for the future of your company, and provides a useful tool for communication to boards and investors.

Finally, plan for success. Successful commercialization of cell therapies and regenerative medicines depends on resolving many complex challenges simultaneously. Failure to resolve just one element can put your entire enterprise at risk. Crucial to success is developing a plan early to understand how and when to address these elements so that a viable business can be established when the therapy is approved after phase 3 trials.

Part 2 will conclude this article in BPI’s October 2015 cell therapy supplement. It will address the remaining pillars of success: reimbursement, clinical efficacy, and needle-to-needle logistics. •

Richard Grant is global vice president of cell therapy at Invetech, 495 Blackburn Road, Mt Waverley, Melbourne, VIC 3149, Australia; Richard.Grant@invetech.com.au.