How to best invest in automation and the ideal time to make those decisions
Cell and advanced therapy manufacturers need to instill confidence in clinicians, patients, and regulatory bodies that the manufacturing process will guarantee a high-quality product is produced for each and every batch. Early clinical stage manufacturing processes are generally manual and open and the path to commercial success requires resolving many complex challenges simultaneously. Automation is one of the key elements in enabling a cost-effective therapy to be manufactured; however, with limited funds, cell and advanced therapy companies need to determine how to best invest in automation and the ideal time to make those decisions.
A key driver for the move towards automated, single-use disposable systems is cost savings. Automation generally is looked at as an effective way to reduce your cell therapy manufacturing costs, and certainly where applied appropriately, it can help to significantly reduce the labor component of a cell therapy manufacturing process. We have seen companies achieve a 40 to 90 percent reduction in direct labor costs by implementing automation; however, that’s not the sole rationale. Companies also need to ensure that they can manage and maintain the quality of their product. By automating steps in the cell therapy manufacturing process, you can provide the assurance that the process is the same every time it’s run.
Prioritizing unit processes for cell therapy manufacturing automation
When it comes to identifying which unit processes in a cell therapy manufacturing workflow should be prioritized for automation, you should begin by reviewing each step in the manufacturing process and identifying the unit processes that are most complex and/or variable. Once those are identified, you need to start thinking through questions such as: How we can make those processes consistent? How can we adapt them to a closed manufacturing system? Are there solutions available in the market to automate those processes? Can those off-the-shelf solutions be integrated and will that integration be appropriate at commercial scale?
One example is how we assisted a company scale-up and validate an allogeneic process. The process was a 2D adherent culture that when the disposable system was filled with cell suspension, it weighed close to 15kg. If you think about the practicality of carrying out manipulation steps such as cell harvest and trypsinization at that scale in a manual fashion, it’s clear that there were many challenges, not only physically, but also in ensuring steps are performed in a consistent way each time. By translating that process into an automated one, we ensured our client could replicate those manipulation steps at scale, consistently. A relatively simple level of automation was the solution, and yet it transformed the process into one that could be validated.
You may be able to delay decisions on automation in cases where manual processes do not negatively impact quality, risks or costs. For example, one of the more common and straightforward steps that we work with clients on is the washing of cells. In the research setting, this is a simple process often with conventional centrifugation steps that occur throughout the workflow.
At the other end of the complexity spectrum is the automation of intricate, skilled processes, like the 2D adherent culture example given above. It’s these unique and complex steps in the manufacturing process that a company needs to look to automate for commercial production. These are typically the steps undertaken by a skilled operator, and are often an open process. You want to avoid taking these steps into commercial-scale manufacturing, particularly if you are scaling up an autologous cell therapy with a large number of patient products to manage per year.
At Invetech, we walk through this selective identification process with our clients to create a stepwise automation plan and timeline that prioritizes the automation of their specific unit processes. This plan is focused around reducing variability, increasing efficiencies, minimizing risk, and maximizing ROI. This typically includes identifying existing technologies that can be leveraged for immediate value and determining the best way to integrate those technologies into the manufacturing workflow as they scale-up.
When to invest in cell therapy manufacturing automation
Therapeutic development is a game of resource allocation and risk management. Balancing the combined risks of a non-linear therapy development pathway, funding limitations, clinical trial progress and scarcity of skilled personnel means giving the “right” amount of attention to commercial manufacturing considerations at the right time. Too little attention, paid too late in the development process, risks embedding schedule or cost burdens. So, when is the right time to invest in automation
I recommend that the manufacturer take the following steps:
Do not install anti-virus software. Dramatic as this may sound, the likelihood of a malicious executable targeting the CPU architecture and operating system of this instrument is extremely low. But if clients do request anti-virus software (perhaps for marketing reasons), engage security experts to develop it, as commercial products for this architecture are not readily available.
Install a software firewall for the TCP/IP stacks provided by the Wi-Fi and Ethernet access points. Only the TCP and UDP ports necessary for communication with the manufacturer’s cloud-based information system will be open.
Only connect the instrument to Wi-Fi networks that are securely encrypted. We strongly recommend that end-users use the Ethernet connection during installation wizard.
Remove all non-essential Linux tools and programs (for example, bash shell and telnet) from the deployed root file system.
Run the application software in user mode limiting access to system functions.
Give each instrument a unique root user password, which is automatically generated during manufacturing and recorded only on the manufacturer’s internal network.
The only encryption keys to be stored on the instrument are public keys that are part of a public–private pair (such as RSA). In the unlikely event of a security breach, the attacker gains no valuable information.
The actions listed here are general in nature and can simply be considered good security practice. In reality, you would implement significantly more mitigations, including activities specifically designed to protect the manufacturer’s intellectual property.
Pre-clinical to Phase I
During this development stage, you should be exploring ideas and developing your commercialization plan. This includes building a clearer picture of your indication, determining the predicted number of patients you will treat per year, and deciding whether to adopt a centralized or decentralized manufacturing model. Then you need to start thinking about the impact each of those elements will have on selecting and implementing the appropriate level of automation. You also need to determine which of your unit processes are not going to be practical or cost-effective at commercial scale.
This is the ideal time to identify which technologies and unit processes can be appropriately automated, and if necessary integrated into your manufacturing workflow. It is at this point in development where the ROI of investment in automation solutions is greatest. The therapy is sufficiently mature, development timescales are sufficient to introduce automation for Phase III, and by doing so you ensure commercial availability as soon as Marketing Authorization is received.
Phase III to commercial
Until we have more absolute product characterization, ‘the product is the process’ from the regulatory standpoint. Changing any part of your process after Phase III could result in having to carry out a comparability study to prove those process changes haven’t altered the product. It is important to be using the technologies that you are going to utilize at commercial scale for manufacturing your product in Phase III clinical trials. Stepwise automation during Phase III can be an effective ‘bridge’ to a fully integrated commercial manufacturing solution.
Having your automation processes in place by Phase III will ensure a much clearer path for regulators to see that, while the process becomes more automated at commercial scale, it’s not fundamentally being altered and the product output is the same.
Brian Hanrahan has more than 15 years of product development experience across the biomedical and cell therapy industries. In his current role, Brian is the manager of Invetech’s cell therapy group in San Diego, CA, USA, helping cell and advanced therapy companies across the globe realize clinical and commercial-scale cGMP manufacturing solutions. Brian has been a key contributor in building Invetech’s cell and advanced therapy capabilities and continues to have a deep involvement in projects ranging from the development of cell separation instruments to single-use, automated cell therapy production systems. Brian has a bachelor’s degree in applied science from RMIT University in Australia.