ALIGNMENT BETWEEN GLOBAL REGULATORS? Reality or Wishful Thinking?

FDA continues to participate in and support international collaboration to bring global health authorities together to manage risk in the global supply chain for medical devices and critical drug therapies.? This has been the intent of the harmonization efforts between US 21CFR Part 820 and ISO 13485:2016 since 2018.? The Final Rule for the Harmonization of Medical Devices Regulations was issued on February 7, 2024.? There is a need for deep analysis to understand what this really means for the global medical device industry.? I will leave that for now to another article or blog post.?

In the world of drug therapies, one of the key programs FDA has been actively supporting is the Internal Coalition of Medicines Regulatory Authorities (ICMRA).

There are two focused areas that have been identified to inform and enable collaboration across global health authorities.? The two focused areas include:

·?????? CMC Post-Approval Changes

·?????? Hybrid Inspections

These two areas are important across the pharmaceutical and biopharmaceutical industry.? In my humble opinion they are the right issues to address by the ICMRA.? They address concerns raised in every major conference I have attended for over 25 years.? They are discussed at the Executive and Senior Leadership Levels in all major pharmaceutical and biopharmaceutical companies.

CMC Post-Approval Changes

There is an intensive burden placed upon the developers and manufacturers of pharmaceutical and biopharmaceutical products due to the differences in regulatory requirements for approving a post-approval CMC change globally.? A change that requires 30-day approval in one country can require one (1) to three (3) years for approval in another country.? Managing inventory and launch of products approved in multiple countries around the globe with CMC changes is a nightmare, at best.? It is like managing a giant jigsaw puzzle.?

Managing post approval CMC changes for global pharmaceutical and biopharmaceutical products adds significant cost and complexity across the industry the supply chain globally.

Many companies avoid making CMC-related changes which would improve product quality, reduce production cycle time, reduce cost, and/or improve the reliability of the supply chain due to the complexity and total cost to manage the implementation CMC-related changes impacting their products.

There has been a recent success emerging from these focused efforts by the ICMRA.? The FDA and the European Medicines Agency (EMA) have completed the first collaborative assessment of a proposed post-approval CMC change for an oncology biologic.? The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) participated as observers.

The outcome of this initial pilot for a post approval CMC change is summarized by Theresa Mullin, Ph.D., CDER’s Associate Center Director for Strategic Initiatives, and Michael Kopcha, Ph.D., R.Ph., director of CDER’s Office of Pharmaceutical Quality in their recent post on the FDA Website:

“For the first application reviewed under the pilot program, the FDA/EMA collaborative assessment teams had a positive and productive experience, which produced a common set of highly aligned information requests and comments to the applicant. Not only did this assessment result in an FDA approval, but there was no delay in the standard assessment timeline. In fact, it was completed under the four-month goal window for a standard manufacturing supplement assessment. The EU also approved the submission on the same day as FDA, marking a significant accomplishment in aligning FDA and EMA on the assessment process and timeline. This assessment experience also received positive feedback from industry on the coordination of efforts between the FDA and EMA.”

This is a tremendous accomplishment and the company benefitted significantly from this pilot.?

Hybrid Inspections

Mullin, Ph.D., CDER’s Associate Center Director for Strategic Initiatives, and Michael Kopcha, Ph.D., R.Ph., director of CDER’s Office of Pharmaceutical Quality stated in their recent post on the FDA Website:

“The hybrid inspection pilot has accepted two proposals that cover: 1) a pre-license inspection to support the drug substance manufacturing and quality control site transfer for a biologic, 2) and a preapproval inspection to support the addition of a drug manufacturing site.”

This is good news and will help align the health authority inspection process globally.? If the pilot is successful, we may indeed see many more hybrid inspections in the future which will reduce the overall health authority inspection burden in the pharmaceutical and biopharmaceutical industry.

It is not easy to understand the burden of multiple global health authority inspections on a pharmaceutical or biopharmaceutical production plant in a given year unless you have “lived it”.? In one (1) to two (2) years a single plant can receive multiple inspections from several different global health authorities.

?There is significant work involved in preparing, managing, and responding to any health authority inspection.?? Weeks of effort by a very large number of production site staff and the supporting organizations is spent on each inspection.? During my tenure as a Sr. Director at a large sterile, injectable product production plant I hosted two (2) to four (4) inspections from FDA and other global health authorities in any given year.? I calculated that, in some years, I spent over 50% of my time preparing for, leading, and responding to the observations presented at the conclusion of the inspection.? Note: These were general, routine inspections which resulted in findings that were not critical and did not pose a risk to product quality or safety.? This was 50% of my time lost in the end-to-end health authority inspection process.? Time I should and could have spent driving improvements in the plant Quality Management System.?

This could have been much more efficient if there was collaboration across the global health authorities.? Harmonization of regulations AND mutual recognition of health authority inspection results has been a request from the global pharmaceutical and biopharmaceutical industry for decades.? This initiative to conduct hybrid inspections has tremendous value.

I am anxious to see outcomes of the harmonized pre-license inspection to support the drug substance manufacturing and quality control site transfer for a biologic, and the preapproval inspection to support the addition of a drug manufacturing site.? I look forward to hearing the benefits obtained from these two pilots from FDA in the near future.?

For both of these pilot programs, I am hopeful that our global health authorities and industry can collaborate and enable these efforts to move beyond the pilot phase into a standardized approach we will all benefit from.

So in conclusion…? ALIGNMENT BETWEEN GLOBAL REGULATORS?? Reality or Wishful Thinking??

I would answer these questions by saying this…?

This update from FDA on the progress made by the Internal Coalition of Medicines Regulatory Authorities (ICMRA) has me hopeful!

Acknowledgements:? Theresa Mullin, Ph.D., CDER’s Associate Center Director for Strategic Initiatives, and Michael Kopcha, Ph.D., R.Ph., director of CDER’s Office of Pharmaceutical Quality for their insightful update on this topic posted on the FDA Website.?? Their informative update from FDA served as the source of information for my post.? I have summarized the information presented in their post and added my personal perspective on these important initiatives.