Harmonizing global regulations encourages innovation and ensures the quality of medicines.
When a pharmaceutical manufacturer wishes to launch a product, it submits an application to a number of international regulatory authorities for review and approval of that product. Manufacturers face the risk that different regulators have different expectations of the content and framework of their applications. But does it have to be when it comes to quality? Patients worldwide have consistent quality expectations: safe and effective medicines free of contamination and defects.
Janet Woodcock, FDA’s Chief Deputy Commissioner, has announced that as part of her global approach to quality, she will establish a “single dossier for quality in the cloud” and a “single regulatory status worldwide.” ” and headlined (1). The world is still far from this single regulatory position on quality, but some regulators are nudging the international status quo.
Although the United States has the world’s largest single drug market, drug manufacturing has globalized in recent decades and many manufacturers are now striving to launch their products, a global event. Even if a regulatory agency responds to her single application for a new drug, a single manufacturer may respond to multiple international regulatory agencies for review and approval of her single product. The public health worst-case scenario is a drug manufacturer developing a promising new technology that could benefit patients, and perhaps even though the FDA is confident that it will be approved, a complex It’s a scenario that you decide not to pursue because of the uncertainty involved in navigating the network. global regulator. Fortunately, regulators around the world are working together to prevent fragmented international expectations in terms of manufacturers’ unwillingness to develop and implement innovations that could benefit patients. Preventing.
ICH and global regulators
An important example of global regulators working together to foster innovation is the November 2022 adoption of the International Council for Harmonization (ICH) guidelines. Q13 Continuous manufacturing of drug substances and drug productsContinuous manufacturing is the continuous supply of input materials, the transformation of materials during the process, and the concomitant removal of output materials from the process. This new guideline addresses scientific and regulatory considerations for continuous manufacturing development, implementation, operations, and lifecycle management across regulated jurisdictions. Although not as prevalent in the pharmaceutical industry as in other industries, continuous manufacturing can lead to improved process quality, reduced waste, lower costs, and increased manufacturing agility. While the FDA has been successful in approving continuous manufacturing submissions more quickly than traditional batch manufacturing submissions (2), ICH Q13 provides manufacturers around the world with international regulatory guidance for continuous manufacturing. It increases trust in expectations and, in turn, the willingness to adopt them. as a strategy.
The FDA, a founding regulatory member of the ICH, is still a relatively young organization (given that FDA is nearly 120 years old), born in Brussels in 1990, nearly 4000 miles from FDA headquarters. ICH’s consensus-driven process brings together regulatory authorities and industry technical experts to develop science-based guidelines on important topics. The overall objective is to achieve harmonized technical requirements by regulatory authorities so that safe, effective and high quality medicines are developed, registered and maintained in a resource efficient manner. International harmonization is a five-step process that begins with a group of experts developing a consensus draft of new guidelines. The ICH General Assembly then approves the draft guideline and the regulatory authorities approve it. At that time, FDA will publish this document in the Federal Register as a Draft FDA Guidance and begin a public comment period in the United States. ICH members will then use public comments from all regions to develop the final guidelines to be approved by the ICH General Assembly. The process ends when FDA adopts and publishes his ICH guidelines as the final FDA guidance to industry. A particularly prominent example of ICH’s value is the Electronic Common Technical Document (eCTD), which provides a common interface for standardizing marketing applications across ICH regulators (3). Continuous manufacturing is just one of several quality topics currently being developed as international guidelines by the ICH. For example, development and validation of analytical procedures (ICH Q2(R2)/Q14), viral safety assessment of biotechnology products (ICH Q5A(R2)), extractables and leachables (ICH Q3E), and quality of common technical documentation. Part (ICH M4Q(R2)). Together, these guidelines provide manufacturers with clearer international expectations on these important quality topics.
Adjusting regulatory practices
Coordinating regulatory practices is a step beyond harmonizing guidelines. Even with uniform guidelines in place, it can be difficult to consistently enforce those guidelines. Consider that the ICH Q8–Q11 guidelines describe harmonized control strategies based on science and risk. However, when the industry measured acceptance rates for key chemistry, manufacturing and controls (CMC) documents for over 100 applications across the United States, Japan, Canada, and the European Union, all four countries had documents accepted. The probability is usually less than 10% (4). This regulatory discrepancy can lead to different control strategies for a single product globally. Instead, imagine a futuristic “regulatory cloud” where an applicant can provide her single application to be evaluated simultaneously by all global regulators. Imagine a single “joint hybrid facility inspection” that meets the needs of all global regulators. Future regulations may include harmonization of regulatory expectations for data elements and criteria, assessments and inspections, and virtual repositories for application lifecycle management. In the future, open information flow between regulators is likely to be maintained, allowing for the most practical and efficient regulatory oversight possible. This is not as speculative as it sounds. In fact, it’s not even unheard of in some ways.
Mutual Recognition Agreements (MRA) between the FDA and foreign regulatory authorities allow drug inspectors to rely on information from drug testing conducted within each other’s borders. With the MRA in place, FDA will work with inspectors from 28 countries to review inspection reports to determine a manufacturer’s suitability for the U.S. market instead of conducting FDA on-site inspections. increase. The Food and Drug Administration’s Safety and Innovation Act of 2012 gave the FDA authority to enter into these agreements when the agency determines that foreign authorities can conduct inspections that meet U.S. requirements. Under the MRA, the FDA is now working with European inspectors, including those from the United Kingdom and Switzerland, to avoid duplicating inspections and focus resources on inspecting drug manufacturing facilities that pose a high public health risk in the United States. . The power of MRA was maximized during the height of the global COVID-19 public health emergency. Significant data from MRA partner testing has enabled facility evaluation and product approval despite various government travel restrictions.
FDA is also part of the International Coalition of Pharmaceutical Regulatory Authorities (ICMRA), a group of 39 regulators that provide strategic direction to collectively address common challenges such as those posed by the COVID-19 pandemic. . ICMRA is working to establish a new Pharmaceutical Quality Knowledge Management capability that will ensure that participating regulatory authorities have timely and complete information relevant to applicant quality and risk management. ICMRA’s knowledge management strategy may enable simultaneous submission of harmonized drug manufacturing information from sponsors and simultaneous access to that information by multiple regulatory authorities. International convergence in this area will require much collaboration, and ICMRA calls on the international community of regulators, legislators and manufacturers to advance this strategy for the benefit of patients.
International regulatory differences not only prevent manufacturers from pursuing new treatments and technologies, but can also complicate implementing manufacturing changes after the drug has been approved by the FDA. A facility may supply medicines to many different countries, and moving the manufacturing process to a new facility can be difficult unless all those countries agree. Consider the impact of COVID-19 on your supply chain and the need for manufacturing agility. Many manufacturers have had to rapidly migrate or change their manufacturing processes to meet the challenges posed by COVID-19. In the years prior to 2020, the FDA evaluated approximately 7,000 application supplements for human medicines. In 2020 alone, the FDA approved more than 10,000 additional submissions for quality-related changes in human medicines.
To improve global manufacturing agility, FDA is part of two ongoing pilot programs with ICMRA, a joint international review of post-approval changes and a joint review to inform evaluations. I am doing a hybrid test. The purpose of the pilot program for post-approval changes is to engage multiple regulatory authorities in a single, collaborative, interactive evaluation of proposed post-approval changes. The Manufacturing Facility Joint Hybrid Inspection Pilot uses a combination of onsite inspections and remote regulatory assessments to jointly assess facilities. This pilot will provide information on how to prepare, conduct, and report on inspections and how stakeholders can be involved in inspections. Ideally, the pilot will identify potential areas of coordination or harmonization across participating regulatory jurisdictions, in the context of manufacturing lifecycle management, and identify potential conditions (product/case, etc.) for future joint evaluation. ).
To be clear, the world is still far from a single regulatory position on quality, and there will undoubtedly be barriers between our unoptimized present and our desired future. , technical barriers may not be as important as “people” barriers. Consider that technological advances have enabled many organizations to collaborate globally using international cloud-based data systems. The most difficult challenges can be those of the “people”. Getting people from different countries with different regulations to agree to change the way things are done. Current international efforts suggest that this change may have begun.
References
- Cox, B. Woodcock: The US FDA is preparing a global quality dossier. pink sheet. January 10, 2020.
- Fisher, Adam C., et al. Auditing regulatory submissions and results for continuous manufacturing of pharmaceutical products in the United States. International Journal of Pharmaceutics 2022 622: 121778.
- ICH. M4: Common Technical Document. www.ich.org/page/ctd (accessed 20 January 2023).
- Bayer, J.; Caution, NS; Graul, T., et al. Towards a Single Global Control Strategy: Industry Research. Pharmaceutical engineering January February 2022.
About the author
Ashley Boam (MSBE) is Director of the Office of Drug Quality Policy in the Office of Drug Quality at the FDA’s Center for Drug Evaluation and Research (CDER). Dr. Theresa Mullin serves as Associate Director of CDER’s Strategic Initiatives and leads CDER’s international programs.
Article details
pharmaceutical technology
Flight. 47 2
February 2023
Pages: 30-31, 33
Quote
If you refer to this article, please cite it as Boam, A. and Mullin, T. Convergence of Global Regulatory Village. pharmaceutical technology 2023 47 (2) pp. 30-31, 33.