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Regulatory Focus™ > News Articles > 2021 > 5 > FDA sees different tactics were successful in established conditions pilot

FDA sees different tactics were successful in established conditions pilot

Posted 13 July 2021 | By Joanne S. Eglovitch 

FDA sees different tactics were successful in established conditions pilot

Manufacturers leveraged diverse approaches to defining established conditions (ECs), a core tenet of the International Council for Harmonization’s (ICH) Q12 guideline for managing post-approval changes, in its recently concluded EC pilot program, said US Food and Drug Administration (FDA) officials at a recent meeting.
Christopher Downey, review chief in FDA’s Office of Biotechnology Products in the drug center’s Office of Pharmaceutical Quality, spoke of some of the lessons learned from the pilot at the virtual CMC Strategy Forum on Thursday sponsored by the California Separation Science Society (CASSS).
The ICH Q12 guideline aims to facilitate the management of post-approval chemistry, manufacturing and controls (CMC) changes for new and marketed pharmaceutical drug products and drug substances. In the guideline, regulators will allow manufacturers to identify and submit ECs for new drug applications and prior approval supplements. ECs are defined as “legally binding information considered necessary to assure product quality.” After manufacturers identify ECs, they can propose reporting categories for post-approval changes.
FDA published a draft document outlining its plans to implement ICH Q12 in the US in May;the guidance clarifies how the ICH Q12 tools and enablers can be implemented within the US regulatory system (RELATED: ICH Q12: FDA guidance explains US implementation, Regulatory Focus, 21 May 2021).
Different approaches used to define ECs
Downey said that FDA accepted 10 requests for the EC pilot. Submission types included new drug applications, generic drug applications, biologics license applications and prior approval supplements. Out of the ten, six were approved, two applications are pending and two have not yet been submitted.
FDA announced the EC pilot program in 2019 to gain practical experience in assessing proposed ECs and engaging with applicants during the review cycle to refine the proposed ECs, and to ensure that assessment decisions are made without negatively impacting the agency’s ability to meet user fee timeframes and identify agreed upon ECs at the time of approval. (RELATED: CDER Plots Established Conditions Pilot, Regulatory Focus, 14 February 2019).
Downey said that one of the lessons learned from the pilot is that applicants take different approaches to defining their ECs. “We saw cases where for existing products that had a prior approval [supplement], the company would propose explicit designation of already approved process parameters and map these onto their criticality assessments.”
Others would conduct a parameter-by-parameter assessment and criticality assessment and propose different reporting categories for ECs and non-ECs. Some applicants would propose ECs but not the reporting categories, while others had proposals that were “more complex” than the examples in the ICH Q12 guideline.
Another lesson learned is that the criticality assessment for determining the ECs should reflect the severity of harm, said Downey. Deeming a parameter critical does not necessarily mean it should go in the prior approval reporting category. ECs “need to be sufficiently detailed,” he said, and “should not supersede scientific understanding and importance of understanding risk.”
Downey said that use of ECs should translate into more transparent regulatory submissions. “I have been at FDA almost ten years and I have seen over the years the level of details put in submissions have decreased. I think that is because companies were afraid to put in something that may then be burdensome to change later.”
Need for ICH Q12
One large company’s pilot experience was shared by Frank Montgomery, AstraZeneca’s global head of regulatory CMC. His firm had three rounds of questions and one teleconference, he said. “There was a lot of focus on the PQS [pharmaceutical quality system] and how it would operate.” Montgomery called it a “very productive discussion.”
Montgomery, a proponent of ECs, noted that they allow “rapid improvements” to be made to products, enabling a process that keeps pace with speedier drug development.
“We now find ourselves in a different scenario where the clinical development is hugely accelerated, and we have development that can often be completed within five years,” said Montgomery, pointing out that COVID-19 therapies were developed within one year. This accelerated pace, he said, is “great for the patient but terrifying for CMC.”
Grappling with implementation
Montgomery also observed that regulators are in different phases of implementing ICH Q12.
While FDA published ICH Q12 and is accepting all examples of ICH Q12 tools, the European Medicines Agency (EMA) is still reviewing their variations regulations to allow for the implementation of ECs. Japan is in the process of reviewing their regulations to determine how a notification reporting category can be introduced for low-risk changes, while Health Canada is developing an ICH training program and is also considering an ICH Q12 pilot program.
CMC Strategy Forum


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Tags: FDA, ICH, Q12

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