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While allogeneic therapies can use existing regulatory and quality frameworks, autologous treatments will require pharma’s adoption of true just-in-time and right-first-time concepts, says consultant James Blackwell.
The past decade has seen cell and gene therapies move from research concept to reality, as treatments such as Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel) have become full-fledged commercial products covered by patient insurance. As development continues to progress for allogeneic and autologous treatments, there is an urgent need for predictable and consistent manufacturing methods, and the means to measure them.
In 2017, more than 600 clinical trials were in progress involving innovative therapies (1, 2), and, by 2018, FDA had received more than 700 investigational new drug (IND) applications for gene therapies (3). Growth in allogeneic treatments will require more efficient downstream separation and cell harvesting. Doses are expected to be in the billions-of-cells range, and batches made in quantities of up to 200 L (1).
Separation becomes a different problem for innovative therapies, as compared with conventional biopharmaceutical processes, because irrelevant adherent cells disaggregated (2). Companies such as Novartis and Kite Pharmaceuticals have already refined processes that allow cells to be manufactured in two to three weeks, while work on other new manufacturing platforms is progressing. Biopharmaceutical consultant James Blackwell shared some insights into the challenges that these therapies entail with Pharmaceutical Technology.
PharmTech: What are the biggest challenges with these therapies?
Blackwell: For commercialization, on the drug product delivery side, it’s much more challenging because the systems are much less well understood in terms of adsorption and potency, and you have related issues with scaling up. Their behavior in a clinical setting needs to be understood. Also, scale considerations will determine how you deliver product to the patient in those settings.
In order to achieve lower cost of goods sold (COGS) for autologous products, traditional batch area clearance concepts and the controls around them need to change. If you have a factory, a facility, or site that is manufacturing personalized medicines, you can’t be commercially viable if you have an individual processing suite for each patient.
Scaleup comes down to processing more single units, or doses, and the individual operations around the flows of a single product. These operations will occur in parallel. So, what’s really important is data integrity and the controls you have around the control space of that product lot on the production floor to prevent cross contamination or mix-ups and to provide validated documented evidence that none occurred.
You can use technology and advanced controls on the floor so you have an area around the lot that’s controlled, (e.g., by using barcode scanning and radio frequency identification [RFID]). Scaleup then becomes about operational excellence and achieving efficiencies on the operating floor and scaling those in parallel. The quality metric performance levels of the past won’t be acceptable any longer because failure won’t be an option for these types of operations. You will often be dealing with critical patients and materials will be needed for scheduled surgeries.
PharmTech: How will traditional definitions for established terms such as ‘batch’ and ‘lot’ change?
Blackwell: The definitions will be the same, but their interpretations and implementation in a manufacturing setting will be novel. Adjustments will be required, both on the part of manufacturers and regulators.
For example, we have a client that is developing a personalized therapy in a process that involves taking a sample from a patient, sending that sample to the lab for analysis, then, based on results, generating data to inform the manufacturing floor on various subunits, or lots, to be manufactured. These lots are combined to form a single batch that will be delivered to the patient.
PharmTech: How will the manufacturing plant floor need to be set up?
Blackwell: The floor must be set up in a way that is different from anything we’ve seen before because, with autologous therapies, personal patient data will be used to drive manufacturing and the necessary controls. We will also need to consider manufacturing in a hospital setting, in a situation where samples are taken right from patients, and the product is manufactured in equipment near that patient and delivered directly to his or her bedside. In this case, product could be considered as both a batch and a lot. Generally, anything that needs to be tracked individually would be viewed as a lot and would then go into a batch, which would be delivered to the patient.
PharmTech: How will any adverse events that are tied to manufacturing be handled in this type of setting?
Blackwell: The challenge stems from the fact that many of these therapies will need to be delivered just-in-time (JIT) to the patient. Existing technologies, manufacturing and supply chain practices, and testing methods haven’t caught up yet. Data and information need to be archived and accessible in a compliant manner in order to generate needed actions, and the reaction time will need to be instantaneous. Response rates will need to be in real time, so data access and integrity will be crucial.
PharmTech: How can companies improve data access?
Blackwell: Information technology (IT) and information sharing must be integrated holistically into a data sharing system. Controls will need to be rationalized and thought through so that there will be no cross-contamination or mix-ups. The quality system will then be able to release by exception and demonstrate that that all controls and procedures have been executed properly.
PharmTech: What tweaks will be needed for allogeneic therapies to work within the traditional cGMP regulatory framework?
Blackwell: The cells will be the product, so tighter controls will be needed (e.g., more care and control of materials that go into the process and more control over the process itself). If there is an upset to the process, manufacturers will need to prove that it will not result in a change within the cells that could affect their efficacy and potency. Proactive control is the best way to avoid having these types of questions come up.
PharmTech: Are you seeing innovations in the equipment and IT designed for innovative therapies?
Blackwell: For allogeneic therapies, the technologies are pretty much the same (i.e., single-use disposables). Most of the innovation is occurring in autologous product development, where we are seeing more self-contained units that prevent cells from being exposed to external environmental conditions.
PharmTech: Will traditional quality metrics work for these therapies?
Blackwell: When you think about it, these products, especially autologous therapies, will require use of right-first-time and JIT concepts, which pharma has lagged behind other industries in adopting. It won’t be business as usual. Lean thinking and concepts like it will be essential because, if the product doesn’t get to the patient on time, results can be catastrophic. With personalized medicine, surgeries will be scheduled based on dosing. In addition, many of the patients for whom these treatments are being developed are seriously ill.
These limitations will present significant challenges for the biopharmaceutical industry. In the end, success will come back to focusing on data integrity, bringing data onto the manufacturing floor, and managing them flawlessly in the manufacturing execution system.
PharmTech: To be able to develop personalized medical treatments, will manufacturers be forced to digitalize data management?
Blackwell: It will become a prerequisite. Many of the clinics that are conducting clinical trials today are drowning in paper, and overall systems are burdensome and highly inefficient. You won’t be able to scale these processes with paper-based systems. Data systems need to be integrated as part of ‘Manufacturing 4.0’ process and quality systems. Some companies are already starting to adopt this type of thinking. Biogen Idec’s new facility in Switzerland provides an example of what is coming. Data integration will become easier over time. Smaller companies will need to work closely with partners who have expertise in this area.
1. G. Pigeau et al., “Commercial-Scale Manufacturing of Allogeneic Cell Therapy,” Frontiers in Medicine 5 (8), 233 (2018).
2. W. Leong et al., “Critical Role of Automation in the Manufacture of Cell and Gene Therapies,” Cell and Gene Therapy Insights, January 2019.
3. A. Shanley, “Can Gene Therapy Deliver on Its Promise?”PharmTech.com, Nov. 14, 2018.
Vol. 43, No. 3
When referring to this article, please cite it as A. Shanley, “Reinterpreting Benchmarks for Innovative Therapies," Pharmaceutical Technology 43 (3) 2019.