Automating Cell Therapy Manufacturing For Increased GMP Compliance And Consistency

FDA’s current good manufacturing practice (cGMP) regulations are a critical factor in producing consistently safe and effective biopharmaceutical products. When a manufacturer is compliant with cGMP regulations, the process, facilities, equipment, and controls used to make the product will consistently produce a quality drug for human use. The regulations, 21 CFR Part 210 and 211, outline the minimum requirements for biopharmaceutical manufacturing. The regulations include controls over personnel, facilities, equipment, components, processes, testing, packaging, labeling, warehouse, and distribution. Traceability of these controls is a key aspect of ensuring compliance to all cGMP requirements.

As the landscape of the industry continues to grow and evolve, advanced therapies are now being produced in unique settings, including small-scale manufacturing facilities, hospitals, and translational facilities. They are also being developed using innovative processes, such as the genetic modification of a patient’s own cells. This creates significant challenges in cGMP compliance as these locations and processes may not be equipped to monitor and safeguard the manufacturing process. Even biomanufacturers with cGMP facilities outfitted for biologic production face obstacles when trying to ensure the stability, progression, and traceability of autologous cell therapies from the time cell material reaches their facility to when it leaves. Simplifying the day-to-day tasks of managing these cutting-edge, life-saving drugs and ensuring consistency in their production is vital to the future of the industry. Therefore, as automation continues to offer new possibilities in flexibility and optimized production in biomanufacturing, exploring its use in cell therapy and advanced therapeutic medicinal product manufacturing to improve safety, quality, and compliance becomes a key factor in advancing patient care.

Cell Therapy Manufacturing: Today And Tomorrow

Biomanufacturing has always presented unique challenges due to the use of living organisms to develop medicine, as their changing nature makes it much more difficult to guarantee consistency than when producing drugs synthesized through chemical reactions. These obstacles are magnified in cell therapy manufacturing, where sterility assurance is a key process attribute due to the inability for downstream sterilization of the cellular product. Human intervention, either through open manipulation steps or removing in-process samples, creates variability and risks sterility of the cell therapies, opening up the possibilities of contamination or inconsistent therapeutics.

In addition, autologous cell therapies require traceability during every step of the process to ensure the patient’s own cells are delivered back. A primary consideration for the future of cGMP-compliant manufacturing for autologous cell therapies is to combine automated, closed system manufacturing technology with electronic systems for records keeping, process controls, and audit trails. Closed system and automated processes provide a higher level of contamination control and manufacturing consistency, while electronic record systems provide the documentation for traceability and system performance.

Currently, many manual steps in cell therapy manufacturing are time dependent, such as waiting an average number of days for cell proliferation/population doubling based on previous development work, since collecting samples for analysis on every batch at multiple points could compromise sterility. Being able to monitor the entire manufacturing process within a closed system allows you to track operations, look at the health of the cells and the consistency of the process in real time, and identify and control any trends that could impact the final product. Better monitoring of these parameters facilitates replication of a high-quality manufacturing process. Ultimately, if an automated system can provide an aseptic barrier and the critical process parameters are maintained throughout the process, this could also lead to significant time and cost savings.

While manufacturing execution systems that offer these capabilities are used in bioprocessing today, they often come at a very high price tag, which is not always economically feasible when producing therapies at a small scale or during clinical trial development. They are also not specifically designed for cell therapy manufacturing, where tracking the chain of custody of a cell line is essential to proper handling of personalized medicines. As a supplier dedicated to providing advanced solutions for the biopharmaceutical industry coupled with application support, Cytiva recently announced the launch of Chronicle^TM automation software, the first cell therapy manufacturing solution developed by cell therapy platform engineers. It is designed to help optimize complex cell therapy processes while demonstrating regulatory compliance and creating a pathway for rapid adoption. Understanding the Chronicle system’s capabilities and the benefits it offers may be the key to implementing an automated system in your facility that simplifies your complex processes and ensures your process delivers consistent and compliant treatments for the patients you serve.

Chronicle^TM Automation Software For Cell Therapy

Developing and manufacturing cell therapies is a vital task that requires profound care and efficiency. If something should happen to patients’ cell material during the course of manufacturing, the responsibility falls on the team responsible for the safe handling of these potentially life-saving therapies. Implementing a system to safeguard these processes could lead to lower costs, increased throughput, expert resources who feel supported in their roles, and an overall greater possibility of meeting the patient dose requirements.

Mitigate risk through alarms, monitoring, and SOPs

Chronicle users can benefit from one unified digital space by monitoring various elements in manufacturing and across their supply chain with real-time data acquisition and alarms supported by standard operating procedures (SOPs). Because Chronicle is a software-based web application optimized for smartphones and tablets, you can, for example, receive an alert via text or email notifying you something is wrong and respond immediately through the system to address the issue. Implementing SOPs into a digital format enables you to use digital tools to track your manufacturing operations across batches.

Collect and store true automated batch records

The system also offers efficiency through automated batch records. A batch record for a therapy can run hundreds of pages long, which can be a daunting task as it has to be manually drafted, reviewed, and matched to achieve traceability. Instead, Chronicle captures various elements in manufacturing, such as executed process steps and process deviations, as well as product information, including lot ID and expiration dates. The software automatically scans QR codes on consumables, samples, and instruments (including detailed data from connected Cytiva and third-party equipment) and storing them in a secure cloud with unlimited storage limits. These electronic batch records can be collected, saved, and archived for later access, ensuring traceability for years to meet regulatory requirements.

Get up and running quickly

Chronicle is a GAMP 5 Category 3 software, which means it was developed to meet the specific needs of the regulated company.¹ It requires only days or even hours to install, rather than months, can connect to and integrate with third-party equipment, and can be accessed across multiple roles in a manufacturing setting. For example, a quality team can look at how many deviations have occurred and whether training requirements for the people using the equipment have been met; supply chain experts can monitor the number of consumables used in a period of time, their expiration date, and how they are being disposed; and a logistics team can check the number of shipments in the queue and how many have already occurred.

In addition, it is delivered as a Software as a Service and pay-per-use model that is based on how many batches you plan to process, whether it is at a commercial scale or just one batch in a small-scale setting. For example, Vanderbilt-Ingram Cancer Center recently partnered with Cytiva to use automation and digitized workflows to improve productivity in its cell processing operations, including using Chronicle software. A system that can grow with you and your needs offers flexibility that is critical for a market expanding as quickly as cell therapy.

Scale As You And The Industry Grow

Chronicle works for both non-cGMP and cGMP environments. This offers the possibility to start small with an accessible, flexible solution for investigational or development work and, when the time is right, scale-up and lockdown processes to manage efficient, consistent production with the potential for thousands of connected units across multiple continents. The ability to maintain consistency in your operations at multiple scales is important to not just a drug manufacturer but also to the industry. This is because the technology we use to advance our manufacturing processes to meet cGMP guidelines must be able to evolve and advance with the science used to create life-saving medications. For instance, new vaccine manufacturing evolved from using egg-based manufacturing to much more consistent and efficient cell culture production. Cell therapy manufacturing is also evolving as new manufacturing systems and techniques are developed. Using a patient’s cells to prevent, diagnose, and treat disease has led to exciting new opportunities in treating cancer and a wide variety of other rare diseases. Without advancing manufacturing technology to ensure the safe and consistent production of new therapies, we risk stalling the advances in science that are already bringing new hope to so many patients in need.

1. AmpleLogic i-QMS. (July 2018). Brief on GAMP 5 Categories, V Model and 21 CFR Part 11, EU Annex 11. Retrieved from https://www.amplelogic.com/blogroll/brief-on-gamp-5-categories-v-model-and-21-cfr-part-11-eu-annex-11/