Continuous manufacturing (CM) 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. Alternatively, is it possible that CM can also increase time to regulatory approval and market entry, hinder submission of post-approval changes, and raise inspectional scrutiny? CDER’s Office of Pharmaceutical Quality (OPQ) set out to find answers by conducting a self-audit of approved U.S. regulatory submissions that employ CM vs. traditional batch processes, and analyzing regulatory outcomes during the product lifecycle and at approval.
CM is an advanced manufacturing technology that sends materials produced during each process step directly and continuously to the next step for further processing, whereby input materials are continuously fed into production and transformed, and processed output materials are continuously removed.
In this self-audit, OPQ analyzed time to approval and market entry, manufacturing process changes reported in Annual Reports, manufacturing-related post-approval application supplements, and pre-approval inspections. At the start of 2022, there were six approved applications that utilized CM for their finished solid oral drug products. One application’s product is approved to be made by either a batch or CM process, by the same firm. OPQ used a set of 134 approved comparator products manufactured using batch operations and meeting certain criteria, and made comparisons based on additional subsets of this dataset.
Time to approval and market entry
Based on this self-audit, utilization of CM resulted in faster approvals and market entry. The applications that used CM were approved in the first review cycle with no Complete Response letters issued. Furthermore, they were approved ahead of the User Fee goal date, on average nine months faster than batch applications. Note that four of the six approved CM applications were granted Breakthrough Therapy designation which expedited their review timeline.
Regarding market entry, the products using CM entered the market twelve months faster after regulatory submission and three months faster after approval when compared to batch applications. Though there may be many factors determining the time between approval and marketing, batch manufacturers typically need to utilize new equipment, update processes, and complete process performance qualification, making supply chain considerations and manufacturing scale-up common roadblocks.
CM operations have fewer process and equipment considerations in reaching commercial-scale operations. In addition to resulting in patients receiving earlier access to products, CM also led to a positive economic impact for the sponsors.
All CM applicants in this audit engaged with CDER’s Emerging Technology Program (ETT), which may have supported first-cycle approvals. The ETT Program seeks to promote the adoption of innovative approaches to pharmaceutical product design and manufacturing, such as CM, through direct engagement with industry representatives. Under this program, FDA staff and participants discuss, identify, and resolve potential technical and regulatory issues regarding the development and implementation of a novel technology prior to the filing of a regulatory submission.
Manufacturing Process changes reported in annual reports
To assess manufacturing changes reported in annual reports, OPQ analyzed annual reports via text mining for the term “manufacturing process change.” There were no mentions of this term in the annual reports for the five applications for products made only through CM. There were five mentions of the term in the one application product made by both batch and CM, but only one was related to the CM process. There were 33 mentions of the term in the annual reports for the 114 batch applications, and that the drug product process was changed in 21 of these annual reports. For batch processes, mentions of the term decreased over time from the date of approval as one might expect as a batch process matures.
Number of post-approval application supplements
OPQ manually audited post-approval application supplements for CM products. Approximately 30% of post-approval supplements for all applications (batch and CM) were related to the manufacturing process. Thus, there was not a substantial difference in the number of process changes reported in application supplements between batch and CM applicants. However, there were no changes in equipment, processing conditions, or batch size in supplements for CM applications whereas they were present for batch applications supplements , perhaps indicating the inherent flexibility of CM processes.
OPQ also manually audited pre-approval inspection documents for nearly 100% of the CM products and for the majority of batch products. CM applications had more process-related issues observed during inspection than batch applications. These observations were primarily related to oversight of manufacturing process and controls and may indicate a difference in inspection focus between batch and CM processes. In contrast to facilities manufacturing batch products, many CM facilities and processes are new, and FDA has relatively limited knowledge of the manufacturing capabilities of CM facilities. This difference may contribute to an increased focus on manufacturing process and controls during inspections of CM facilities. The need for pre-approval inspections and the number of process-related issues observed during inspections at facilities using CM should lessen as FDA gains more confidence in manufacturers’ capability to implement CM.
FDA encourages the utilization of CM for the development and manufacturing of drug substances and finished drug products. Overall, the findings of this self-audit do not indicate higher risks to regulatory submissions or outcomes for CM applications as compared to batch applications. In fact, there are potential regulatory advantages for applications using CM, such as manufacturing process scale-up flexibility and improved manufacturing agility. In addition, there is a clear economic advantage for sponsors and manufacturers translated through time to approval, time to market, and early revenue benefit. Implementation of CM is also advantageous for patients, not only because of the earlier access to medicines, but also due to the potential to reduce or mitigate drug shortages and increase product availability.
For a complete description of the methods and results, 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.”
- Fisher AC et al., An audit of pharmaceutical continuous manufacturing regulatory submissions and outcomes in the US. Int J Pharm. 2022; 622:121778
- Emerging Technology Program
- Draft Guidance for Industry: Quality Considerations for Continuous Manufacturing
- Draft Guidance for Industry: Q13 Continuous Manufacturing of Drug Substances and Drug Products
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