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Emerging cellular therapies aim to manufacture cell populations for clinical indications, such as cancer, autoimmune and cardiovascular diseases. As hospitals and translational facilities explore implementation of this technology they concurrently evaluate whether or not to manufacture the therapies onsite. A manufacturing transition mandates compliance with Current Good Manufacturing Practice (cGMP) to ensure that the treatment is safe and meets quality standards.
“Compliance with governmental regulations is not something you choose to do. It is something you must do if you plan to produce cellular therapies. Although challenging, the process is not difficult. If a laboratory has even an inkling that manufacturing may occur they should start to plan and organize their body of work in a compliant manner. It is never too early to start as regulatory approval is needed before a product can be infused into a patient. All relevant requirements must be met and a safe-to-proceed letter received from the appropriate government authority,” explains Helen Huls, Ph.D., independent consultant.
Enforced by the FDA in the US, cGMP provides a general regulatory framework that ensures the quality of manufactured human drug and biologic products as well as the proper design, control and monitoring of manufacturing processes and facilities. The requirements are minimal and purposely flexible in order to allow manufacturers latitude on how to best implement the necessary controls as well as to provide for continual improvement. Similar regulations enforced by other countries and international organizations are typically referred to as GMP.
“The framework is not specific to any one type of biologic or pharmaceutical product; it is a way of doing manufacturing. Processes need to be under control and perform as expected. You need to say what you want to do before you do it, do exactly what you said you were going to do, be able to prove it and also be able to improve on the system. Manufacturing under cGMP should be very boring. When it is exciting it typically means something is wrong,” says Steven Keizer, senior manager quality assurance GMP program manager, CCRM.
As Dr. Huls emphasizes, it is never too early to start to document processes and gear data collection towards compliance. She suggests to start with a strong quality management system (QMS) that captures written procedures to ensure there is manufacturing oversight, that proper reviews and approval processes are in place, and that the testing criteria for meaningful measures of sterility, identity, purity and potency are reviewed and understood by the general group.
An experienced quality professional knows what is important, what information needs to be captured, and the minimal standards required to transition from a research bench. Although hospitals and translational facilities have quality assurance programs they may not be familiar with the regulations for cellular therapy. If timing is not right to hire a quality manager, consultants can advise on the steps and how to appropriately gather the data.
Quality must be built into the design and manufacturing process at every step to avoid unnecessary problems. It is true that quality systems are expensive, take time and resources, and are always a work in progress due to continual improvements, but, like insurance, they are invaluable when a problem occurs.
From a practical perspective it is all about the documentation that backs up the label claim. Consistency is imperative; procedures that meet the guidelines must be followed exactly the same every time.
Think of a QMS as the overall umbrella that covers quality, manufacturing, and marketing personnel to make sure they are all performing to the requirements that are in place for manufacturing and marketing drug products. Not to be confused with an IT system, a QMS is the entire set of documents, systems, and facilities that are involved in helping make the product.
A QMS needs the ability to evolve; the field is still learning about manufacturing cellular therapies. Starting out with too much complexity is not recommended. A program that allows continual improvement to guide the system’s future direction is a good strategy to consider.
An initial strictly-defined manufacturing process may be hard to reproduce simply because a new facility has no manufacturing data thus zero learnings. In addition, the number of batches needed for Phase I and II clinical trials of any one product is low, limiting learnings. Processes may not be ready to be locked down until the commercial level is reached, emphasizing the importance of a continual optimization mindset, and the need to begin as early as possible to document the procedures and changes.
At CCRM Keizer uses the recently issued European Commission GMP guideline for ATMPs (advanced therapy medicinal products) to develop the framework. The guideline is entirely risk based and takes a very broad understanding of the complexities and the real changes that need to take place in the traditional small molecule regulation to ensure that cellular therapies can get off the ground.
“The amount of documentation can be intimidating initially. A well-structured data and implementation plan will help to move the process forward smoothly. Expect new items to emerge that will need resolution. For example, the FDA requires assurances about access to cGMP-grade raw materials and reagents. With the appropriate validation procedures and prior discussions with the FDA, instances may be approved where RUO products can be used if cGMP-grade is not available. The decision is data driven; the FDA has the final say,” adds Dr. Huls.
As previously stated, cGMP incorporates how to design, control, and monitor processes. Testing on a small sample of a batch after manufacture does not ensure quality. Processes must be under control and always produce a useable product.
“If you want people to walk a certain path you have to provide ways for them to stay on that path. To change behavior is challenging and cGMP includes a lot of behavior management. You have to choose between new procedures, new training or new engineered solutions. Then you must monitor to ensure the change has the desired effect,” inserts Keizer.
“You want to make things easily manageable, do not want your system to be cumbersome so people just push paper around all day, and you want the system highly visible so you or an outsider immediately know when something is out of control. It is an art and a science.”
Another hurdle is onsite audits, a standard business practice required by relevant health authorities.
“You prepare all the time for the inspections. To make a facility auditable, the system must be transparent to easily reveal the level of compliance. Expect some human and minor documentation issues. But if an audit uncovers an issue with data integrity that is a signal that the implemented system is not strong enough to handle the manufacturing processes. Data must be readable, easily retrievable and permanent. Automated testing and manufacturing systems controls have to be properly in place to assure data integrity,” says Keizer.
Underestimating the scalability of the process is common. Research scientists may not have familiarity with bioprocessing equipment, or had to think about the logistics of biopreservation, product transportation, documentation, and chain of custody; items that are necessary to demonstrate that the product is controlled. Hiring experienced personnel can remedy this.
Autologous cellular therapy uses live cells, which require interactions, such as gas and media exchanges, to survive. To minimize contamination, the regulatory body will want to see plans for the development of a functionally-closed manufacturing process, for example, through the use of specialized filters for these exchanges.
To improve product quality upfront work on the input materials or automation should be considered. Older systems that are in place may be less than adequate by today’s standards, especially for novel cellular therapy products.
“Autologous cell therapy is a very tough product. Consider the variability of the starting material of each patient; one size does not fit all. You have to prove that operating procedures for manufacturing processes are reproducible, that you are able to detect and investigate product quality and deviations, and to maintain a reliable testing laboratory,” advises Dr. Huls.
“If you are considering an automated tool for cGMP it must help you get from point A to point B. The equipment must work around your process; you cannot work your process around the instrumentation and should not evaluate equipment based only on current requirements. Adaptability and flexibility are key. Processes are likely to change as better ways to optimize cell survival and quality are investigated and implemented.”
Automation eliminates the human variable that is always present with manual processes. Even if an instrument is slower than a human it will still perform better because it will always do the same thing.
“Scientists are invariably problem solvers, and, often, in manual processes will fix problems without documenting properly. That is great for R&D but for manufacturing you need continual improvement. An automated system lets you perform true root cause analysis,” points out Dr. Huls.
“Bringing equipment into a cGMP facility is a multistep process that includes developing a design qualification that describes the need, applying available specifications against that need, prioritizing what best fits then making the selection. At CCRM we focus on what is best for production and how it meets the needs of the product regardless of capital cost,” concludes Keizer.
cGMP certifications come from the regulatory bodies that govern the citizens the products will be marketed to and the specifics will depend on that marketing authority. Individual countries produce guidelines as well as the World Health Organization (WHO), the European Commission and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Other third-party certifications from organizations, such as ISO or FACT, which focuses on standardizing practices and procedures, are extremely valuable and add reputational weight to the manufacturing facility.