Renu: Welcome to the CDER Small Business and Industry Assistance (SBIA) Chronicles Podcast Series.
Today’s Topic: An FDA Self-Audit of Continuous Manufacturing for Drug Products
Continuous manufacturing technology has the potential to improve product quality and reliability, lower manufacturing costs, reduce waste, decrease inventory, and increase manufacturing flexibility and agility in response to product demand. But is it possible that continuous manufacturing could also increase time to regulatory approval and market entry, hinder submission of post-approval changes, and raise inspectional scrutiny? FDA’s Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, or OPQ, set out to find answers by conducting a self-audit of approved U.S. regulatory submissions that employ continuous manufacturing versus traditional batch processes and analyzing regulatory outcomes during the product lifecycle and at approval.
My name is LCDR Renu Lal, and today I’ll be speaking to Commander Mahesh Ramanadham, Deputy Director of OPQ’s Office of Policy for Pharmaceutical Quality, to discuss findings from this self-audit, which was recently published in the International Journal of Pharmaceutics.
Mahesh: Thank you Renu, I’m happy to be here. So, to set the stage on what continuous manufacturing or CM is, it’s an advanced manufacturing technology that sends materials produced during each process step directly and continuously to the next step for further processing, eliminating hold times between these steps. Input materials are continuously fed into production and transformed, and processed output materials are continuously removed. This technology offers an opportunity for increased product quality assurance (for example, fewer deviations) given the ability for enhanced process capability and control.
Renu: Can you start by talking a bit about how FDA conducted the self-audit of continuous manufacturing?
Mahesh: Sure, so in this self-audit, OPQ analyzed outcomes in key regulatory areas between application products manufactured by CM versus batch manufacturing technologies; specifically time to approval and market entry, manufacturing process changes reported in Annual Reports, manufacturing-related post-approval application supplements, and pre-approval inspections. So at the start of 2022, there were six approved applications that utilized CM, and in this study we focused on finished solid oral drug products. One application’s product was approved to be manufactured by either a batch or continuous manufacturing process, by the same company. OPQ used a set of 134 approved comparator products manufactured using batch operations, meeting certain selection criteria, and we made comparisons on additional subsets of this dataset. We analyzed the effects of continuous manufacturing versus batch operations on time to approval, market entry, as well as manufacturing process changes reported in annual reports, and a number of post-approval inspections and application supplements, and finally with pre-approval inspections.
Renu: I know many people are interested in these results, so let’s start with time to approval and market entry.
Mahesh: Of course, so based on this self-audit, the applications that used continuous manufacturing were approved in a shorter time than the comparator batch applications. CM applications were approved in the first cycle of review with no Complete Response letters issued. Furthermore, they were approved ahead of the User Fee goal date, on average nine months faster than the batch applications that we compared against. Note that for four of the six approved CM applications, they were granted Breakthrough Therapy designation which expedited their review timeline. But overall, what we saw was the use of CM did not impact FDA’s ability to review and act on applications using continuous manufacturing even when there are expedited review timelines.
Now regarding market entry, the products using continuous manufacturing entered the market twelve months faster on average after regulatory submission, and three months faster after approval when compared to the batch applications
Though there are many factors in determining the time between approval and marketing, batch manufacturers typically need to utilize new equipment, update processes, complete process performance qualification, making supply chain considerations and manufacturing scale-up common roadblocks. In contrast, continuous manufacturing operations have fewer process and equipment considerations in reaching commercial-scale operations, for example this could be done simply by increasing the length of time, or speed, at which the CM process is run.
In addition to resulting in patients receiving earlier access to products, CM applications saw a positive economic impact for the sponsors relative to batch applications. We estimated the dollar value of the time advantage for CM compared to the batch products to be between 171 and 537 million dollars. This is based on the mean and median time to marketing from submission.
So all continuous manufacturing applicants in this audit engaged with CDER’s Emerging Technology Program, which may have supported first-cycle approvals. The Emerging Technology Program seeks to promote the adoption of innovative approaches to pharmaceutical product design and manufacturing, such as CM, and through direct engagement with industry representatives, FDA staff and participants discuss, identify, resolve potential technical and regulatory issues regarding development and implementation of a novel technology prior to filing of a regulatory submission.
Renu: That’s really encouraging! And a great tip about the Emerging Technology Program! For those that aren’t aware, FDA has a dedicated webpage for the Emerging Technology Program, which you can find by visiting fda.gov/cdersbia, clicking on ‘Regulatory References’ and then searching for ‘Emerging Technology.’ It also contains information on how apply to participate in the program. So now let’s move on to the second topic OPQ analyzed: manufacturing process changes reported in annual reports.
Mahesh: Yea, so to assess manufacturing changes reported in annual reports, OPQ analyzed annual reports using a text mining approach for the term “manufacturing process change.” There were no mentions of this term in annual reports for the five applications where the product was only manufactured using CM. We did find five mentions of the term in the one application product that’s made by both CM and batch manufacturing processes, but only one of these terms, or these hits, was related to the CM manufacturing process. We did find, by contrast, 33 mentions of the term in the annual reports for eligible comparator batch applications (which equated to about 114 batch applications where at least one annual report was filed within the study window). Within those 33 mentions, we found that the drug product process was changed in 21 times in these annual reports. For the batch processes, mentions of the term decreased over time from the date of approval, as you might expect as a batch process matures.
Renu: Interesting. And how about the effects of continuous manufacturing on the number of post-approval application supplements?
Mahesh: So, OPQ manually audited post-approval application supplements for the CM products, given that we had a much smaller volume compared to the annual reports. Approximately 30% of those post-approval supplements for all applications (so that’s inclusive of batch and CM) were related to the manufacturing process. So there was not a substantial difference in the number of process changes reported in the application supplements between batch and CM. However, when we looked deeper into the types of changes related to the manufacturing process, we noted that there were no changes in equipment, processing conditions, or batch size in supplements for those CM applications whereas they were present for the batch applications supplements. One hypothesis for this finding is the inherent flexibility of CM processes, in that certain process changes can be made without the need for a supplement to the application.
Renu: This is all really good news for the use of continuous manufacturing. Can you also describe findings related to pre-approval inspections?
Mahesh: Of course. So OPQ also manually audited pre-approval inspection documents to assess the frequency of inspections and the findings on those inspections. We found that nearly 100% of the CM products for CM applications had a pre-approval inspection, and the majority of batch products also had a pre-approval inspection. CM applications though had more process-related issues observed during inspection than batch applications. These observations were primarily related to the oversight of manufacturing process and their controls, and may indicate a difference in the inspection focus between batch and CM processes. In contrast to facilities manufacturing the batch products, many CM facilities and processes are new, and FDA has relatively limited knowledge on the manufacturing capabilities of those facilities. This difference may contribute to an increased focus on manufacturing processes and controls during these pre-approval inspections. The need for the pre-approval inspections and the number of process-related issues observed during inspections at facilities using CM should lessen though as FDA gains more confidence in manufacturers’ abilities and capability to manufacture using CM technologies.
Renu: So it sounds like FDA would encourage the utilization of continuous manufacturing for the development and manufacturing of drug substances and finished drug products?
Mahesh: Definitely. Overall, the findings of this self-audit do not indicate higher regulatory risks to submissions or outcomes for CM applications when compared to batch applications. In fact, there are potential regulatory advantages for applications using CM, such as manufacturing process scale-up flexibility, improved manufacturing agility, you name it. In addition, we saw a clear economic advantage for sponsors and manufacturers translated through the time to approval, time to market, and early revenue benefit. The implementation of CM is also advantageous for patients, not only because of early access to medicines, but also due to the potential to reduce or mitigate drug shortages and increase product availability.
Renu: CDR Ramanadham, thank you so much for taking the time to talk with SBIA today and to share OPQ’s findings!
For a complete description of the methods and results described in this podcast, please refer to the 2022 publication in the International Journal of Pharmaceutics titled “An audit of pharmaceutical continuous manufacturing regulatory submissions and outcomes in the US.”
A link to the full SBIA Chronicles article and more information about CDER’s SBIA Program can be found at: fda.gov/cdersbialearn and fda.gov/cdersbiachronicles. And be sure to stay connected with upcoming events by visiting fda.gov/cdersbia to sign up for SBIA email updates, and to follow SBIA on LinkedIn. Thanks for tuning in!