Continuous manufacturing applicants saw quicker approvals, higher revenue than batch applicants

Regulatory NewsRegulatory News
| 06 July 2022 | By Jeff Craven 

Applicants that used continuous manufacturing (CM) technology to bring their products to market waited less time before approval after submission compared to batch manufacturing products, according to results from a US Food and Drug Administration (FDA) audit published in the International Journal of Pharmaceuticals.
 
Authors from the FDA Center for Drug Evaluation and Research (CDER) said these manufacturers had a potential estimated increase in revenue due to the CM products having more time in the market because of quicker approval. Use of CM technology also did not appear to affect whether these products underwent manufacturing process changes or pre-approval inspections on FDA’s end, the agency said.
 
“[O]verall, 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,” Commander Mahesh R. Ramanadham, Pharm.D, MBA, RP, associate director for scientific operations in the Office of Pharmaceutical Manufacturing Assessment, Office of Pharmaceutical Quality at the FDA, said in a podcast interview accompanying the CDER Small Business and Industry Assistance Chronicles newsletter.
 
Ramanadham and colleagues noted in their study that FDA has “long championed the development and implementation of advanced manufacturing technologies like CM for drug substances and finished drug products,” citing potential benefits like increased product quality, lower manufacturing costs, reduced waste, lower inventory, and greater flexibility in manufacturing based on demand. FDA’s CDER issued draft guidance on CM in 2019 and launched an Emerging Technology Program to promote CM to pharmaceutical industry stakeholders.
 
“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,” Ramanadham said in the podcast interview.
 
However, adoption of in pharmaceutical manufacturing has been slow, the agency pointed out, and may be the reason why six sigma manufacturing capability has not been regularly reached by the pharmaceutical industry compared with other industries.
 
In their audit, FDA examined six solid oral drug products with approved applications and used CM, comparing them to 134 approved new drug applications (NDA) for batch processing products between 2015 and 2020. The agency analyzed time to approval and market entry, potential revenue, and manufacturing process changes across both types of products.
 
Compared with the batch processing product applications, Ramanadham and colleagues found CM applications were approved in the first review cycle with no Complete Response letters. Additionally, CM applications had a mean approval time that was 9 months quicker than batch applications (6 months vs. 15 months) and was ahead of the user fee goal date. The mean time to marketing from approval was 0.40 months for CM applications and 3.49 months for batch applications. The agency noted that four of the six CM applications were also granted Breakthrough Therapy designations, which further accelerated their review.
 
There was also a benefit in terms of increased revenue for products with CM applications, with the authors estimating a $171 million to $573 million increase due to these products spending more time on the market. “[W]e saw a clear economic advantage for sponsors and manufacturers translated through the time to approval, time to market, and early revenue benefit,” Ramanadham said in the podcast interview.
 
Of 114 batch applications where annual reports were available between 2016 and 2020, there were 33 mentions of manufacturing process changes, while there were no mentions for 5 CM applications where annual reports were available over the same time period. Pre-approval inspections occurred for nearly all CM applications, and Ramanadham noted this was “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,” he explained in the podcast interview. “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.”
 
Ramanadham said in the podcast interview that manufacturing process scale-up flexibility and improved manufacturing agility are among the regulatory advantages to using CM. “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,” he said.
 
Int J Pharm Fisher et al.

 

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