CDER Input on CMC Changes Experience
CDER Office of Policy for Pharmaceutical Quality director Ashley Boam is urging pharmaceutical manufacturers to use recommendations contained in the 5/2021 draft guidance “ICH Q12: Implementation Considerations for FDA-Regulated Products” for evaluating chemistry, manufacturing and control (CMC) change reporting requirements. Boam offered this advice during a presentation at the 46th International GMP Conference in Athens, GA 3/9 where she detailed the Center’s new experience with the ICH Q12 final guidance, which offers tools to help drug makers reduce the number of CMC changes that require a postapproval submission. She noted that reduced reporting requirements should increase with “stronger scientific development, risk management, and quality systems through the product lifecycle,” which are core components of quality management maturity (see earlier story).
“We've been receiving both original applications and supplements proposing established conditions, which is one of those Q12 tools,” she told the conference. “I'll note that our implementation guidance provides important advice and for any of you that might be preparing a submission to propose ‘established conditions,’ I strongly recommend that you consult that draft guidance. For example, it recommends flagging the submission as proposing established conditions that would happen both in the cover letter and in Section 3.2R of the CTD [common technical document], and specify the facility or facilities where those established conditions will be implemented.”
Boam recommended that FDA terminology be used in the submissions when discussing reporting categories for changes to established conditions. “We note that the ICH Q12 guideline includes terms like ‘notification moderate’ and ‘notification low’ when the FDA notification level could be either a [changes-being-effected] CBE-O or an annual report,” she said. “And then please take advantage of pre-submission meetings where those are available to you to get feedback on your planned approach to established conditions.”
CDER’s assessment of the established conditions (ECs) and the associated reporting categories will focus on the company’s scientific justification, according to Boam. “Justifications for ECs should focus on explaining your approach to criticality assessment, risk assessment, etc., but it doesn't mean you have to change your approach,” she said. “We just need to understand how you determined which parameters or elements are proposed as ECs and which are not, and how you determined what the appropriate reporting category should be. Those justifications should be current and accessible, and their location specified, so that we can find them easily and then understand how you put together your proposal…”
Boam said the second prong of FDA’s assessment is to look at available information about the pharmaceutical quality system (PQS) at facilities where the ECs will be implemented. “So we'll be looking at information like inspection history, any assessments we've done using alternate tools, like those records requests or remote evaluations, as well as quality management maturity information once that becomes available in the future. The depth of our PQS assessment will be commensurate with the level of flexibility proposed.”
Moving to CDER’s Emerging Technology Program (ETP), which allows industry to meet with FDA experts to discuss and resolve potential technical and regulatory issues related to new technologies prior to filing a submission, Boam said CDER had its milestone 100th FDA/sponsor ETP meeting in 2021. She also said the program “graduated” its first technology — continuous direct compression — which means the technology can move through the application assessment process without input from ETP experts. CDER is now working on the next generation ETP 2.0 “to meet the expanding workload challenges as we continue to receive more ETP proposals to help enhance communication with those applicants who are looking to adopt new technologies,” she said.
Regarding advanced manufacturing technologies, Boam said CDER believes these technologies can produce better quality medicine because they facilitate operation above the Six Sigma level. “They are more robust processes that can help reduce quality related manufacturing issues, which today cause over 60% of drug shortages, and they can help us with improvement in emergency preparedness.”
Additionally, Boam said FDA has engaged with the National Academies of Science, Engineering and Medicine to help it identify innovative technologies that could be coming down the pike in the next five to 10 years. The effort led to a report entitled “Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations.” She said CDER is now “identifying areas that require additional consideration and policy focus, with a goal of developing a regulatory framework that we're calling FRAME that will support use of these technologies and reduce regulatory uncertainty for those wanting to pursue them.”