Long-awaited ICH continuous manufacturing guideline coming soon

Regulatory NewsRegulatory News | 15 July 2021 |  By 

The International Council for Harmonization (ICH) Q13 guideline on continuous manufacturing is expected to be released for public comment soon, as the US pharmaceutical industry continues slow but steady adoption of this mode of manufacturing.
Cyrus Agarabi, a reviewer in FDA’s Office of Biotechnology Products in the Office of Pharmaceutical Quality, updated attendees on the status of the ICH Q13 guideline at the 14 July CMC Strategy Forum sponsored by the California Separation Science Society (CASSS). Agarabi is on the agency’s Continuous Manufacturing Team.
A draft ICH Q13 guideline has been finalized and has moved to Step 1 sign-off; the document is awaiting publication on the ICH website. There are plans for the ICH Expert Working Group (EWG) to have a face-to-face meeting in November 2021 to discuss the comments received on the draft. Plans are to issue a step 3 sign off in November 2022 with adoption of the guidance to follow, said Agarabi.
While not divulging the particulars of the draft, he said that it consists of a main guideline and five annexes, with one addressing therapeutic proteins.
Slow but steady progress
Although in the US the number of approved continuous manufacturing applications is small, Agarabi said that progress towards implementing this mode of manufacturing has been steady. He said that “many more [applications] are under discussion.”
In response to an email, an FDA official told Focus that there are 10 approved continuous manufacturing applications, including original applications and supplements. The first approval was for Vertex’s cystic fibrosis drug Orkambi (lumacaftor/ivacaftor) in 2015. (RELATED:  FDA Allows First Switch From Batch to Continuous Manufacturing, Regulatory Focus, 12 April 2016).
“We are seeing an increase in continuous manufacturing being used by all modalities, drug substances and small molecule manufacturing. We are seeing continuous manufacturing facilities all over the world, in Asia and Europe and the Americas. The technology and the knowledge base have expanded considerably over the past ten years; regulators now have staff with continuous manufacturing expertise. We have gained a lot of experience with both small molecule and biotech over the past ten years,” said Agarabi.
In the US, continuous manufacturing has been under discussion for at least ten years, said Agarabi. FDA has been encouraging its adoption to improve product quality, minimize product defects, and reduce drug shortages, saying it is a more efficient process than the more antiquated batch production process.
Last year, FDA officials promoted advanced manufacturing techniques, saying these technologies would be employed to help address some of the manufacturing and supply chain problems the US has seen during the COVID-10 pandemic. (RELATED: FDA touts advanced manufacturing to address COVID-19 shortfalls, Regulatory Focus 4 August 2020).
Developing a guideline that is acceptable to all members of the EWG is a challenge, said Agarabi. Currently, 11 regulatory authorities and industry organizations sit on the working group, including representatives from the Pharmaceutical Inspection Cooperation Scheme (PIC/S).
In addition to regional considerations, “Even just terminology can be different… so there are a lot of challenges that we have to work together to overcome,” he said, also calling for “flexible approaches” to assess continuous manufacturing technologies for drug substances and drug products.
Q13 versus FDA’s guidance
How the ICH guideline will work with FDA’s published guidance on continuous manufacturing, and which document will take precedence, remains to be seen, said Agarabi. FDA in February 2019 published a draft guidance on continuous manufacturing, before ICH accepted the topic as a work item. The draft FDA guidance is narrower than the ICH guidance, only addressing small molecule products, while the ICH guidance is broader in scope and addresses large molecule and small molecule products. (RELATED: Continuous Manufacturing: FDA Drafts Quality Guidance, Regulatory Focus 26 February 2019)
“The question of what to do with our draft guidance will be determined once ICH Q13 is finalized and then we will make a decision on what to do with the more narrower FDA guidance,” said Agarabi.
FDA received 24 comments on the guidance, with many wanting clarification on what kind of information should be in the review dossier versus what will be inspected at the site, added Agarabi. There were also questions on diversion strategies, extension of run times, data handling, data integrity and continuous process verification.
One impending issue brought up by drug maker GlaxoSmithKline (GSK), the Active Pharmaceutical Ingredients Committee (APIC) and the International Pharmaceutical Excipients Council of America (IEC-Americas) was how FDA’s guidance will relate to the upcoming Q3 guideline. (RELATED: Continuous Manufacturing: Industry Calls for Changes to FDA’s Draft Guidance, Regulatory Focus, 31 May 2019)
CASSS CMC Summer Strategy Forum


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