Theresa Mullin, PhD serves as CDER’s Associate Director for Strategic Initiatives and leads CDER’s International Program in FDA.

Theresa Mullin

When a pharmaceutical manufacturer wants to launch a product, they submit applications to dozens of international regulators for that product’s review and approval. The manufacturer faces the risk that different regulators will have different expectations for the content and framework of their application. But when it comes to quality, does this have to be the case? Patients’ quality expectations around the globe are consistent: safe and effective medicines free of contamination and defects.

FDA Principal Deputy Commissioner, Janet Woodcock, made headlines when she foretold “a single dossier for quality in the cloud” and “a single regulatory position worldwide” as part of a global approach to quality (1). Though the world is still far from this single regulatory position on quality, some regulators are chipping away at the international status quo.

While the United States has the largest single pharmaceutical market in the world, over recent decades pharmaceutical manufacturing has globalized, and many manufacturers now strive for product launches that are global events. While a regulator may deal with one application for a new drug product, one manufacturer may deal with multiple international regulators for that single product’s review and approval. A public health worst-case scenario is one in which a pharmaceutical manufacturer has a promising new technology that could benefit patients—and perhaps even confidence that FDA will approve it—but decides not to pursue it due to the uncertainties associated with navigating a web of global regulators. Fortunately, global regulators work together to keep international expectations from becoming disjointed to the point that manufacturers are unwilling to develop and implement innovations that might benefit patients.

An important example of global regulators working together to promote innovation occurred with the November 2022 adoption of the International Council for Harmonisation (ICH) guideline, 

Q13 Continuous Manufacturing of Drug Substances and Drug Products

. Continuous manufacturing is the continuous feed of input materials, transformation of in-process materials, and concomitant removal of output materials from a process. This new guideline describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing across regulatory regions. Still less widespread in pharma than in other industries, continuous manufacturing has the potential to improve process quality, reduce waste, lower costs, and increase manufacturing agility. Though FDA has had success in approving applications with continuous manufacturing faster than applications with traditional batch manufacturing (2), ICH Q13 will give manufacturers around the world more confidence in the international regulatory expectations for continuous manufacturing, and by extension increase their appetite to adopt it as a strategy.

FDA is a founding regulatory member of ICH, still a relatively young organization (considering that FDA is nearly 120 years old), birthed in Brussels in 1990, nearly 4000 miles from FDA headquarters. ICH’s consensus-driven process brings together technical experts from regulatory authorities and industry to develop science-based guidelines on critical topics. The overall purpose is to achieve harmonized technical requirements by regulators to ensure that safe, effective, and high-quality medicines are developed, registered, and maintained in a resource-efficient manner. International harmonization is a five-step process starting when a group of experts develops a consensus draft of a new guideline. The ICH Assembly then approves the draft guideline and regulatory members endorse it. At this point, FDA publishes the document as a draft FDA guidance in the Federal Register to initiate a public comment period in the US. ICH members then use the public comments from all of their regions to develop a final guideline to be approved by the ICH Assembly. The process ends in the US when FDA adopts and issues ICH guidelines as final FDA guidance to industry. A particularly prominent example of the value of ICH is the electronic common technical document (eCTD), which provides a common interface that standardizes marketing applications across ICH regulators (3). Continuous manufacturing is only one of several quality topics currently being developed into international guidelines by ICH. For example, other guidelines are currently being developed to address analytical procedure development and validation (ICH Q2(R2)/Q14), viral safety evaluation of biotechnology products (ICH Q5A(R2)), extractables and leachables (ICH Q3E), and the quality portion of the common technical document (ICH M4Q(R2)). Together these guidelines will provide clearer international expectations for manufacturers on these critical quality topics.

The alignment of regulatory practices lies a step beyond harmonizing guidelines. Even with harmonized guidelines in place, the consistent implementation of those guidelines can be a challenge. Consider that ICH Q8–Q11 guidelines describe a harmonized control strategy based on science and risk. Yet, when industry measured the acceptance rate of the core chemistry, manufacturing, and control (CMC) documents of more than 100 applications across the US, Japan, Canada, and the European Union, the probability of a document’s acceptance across all four countries was typically less than 10% (4). This regulatory inconsistency can lead to control strategies for a single product that vary globally. Imagine instead a future ‘regulatory cloud’ where applicants could provide one application for all global regulators to assess simultaneously. Imagine a single ‘collaborative hybrid facility inspection’ that meets the needs of all global regulators. A regulatory future could include harmonized regulatory expectations for data elements and standards, assessments, and inspections, and a virtual repository for lifecycle management of submissions. The future could hold open information flow between regulators enabling the most pragmatic and efficient regulatory oversight possible. This is not as speculative as it sounds; in fact, in some ways it’s not even unprecedented.

Mutual Recognition Agreements (MRAs) between FDA and foreign regulatory authorities allow drug inspectors to rely on information from drug inspections conducted within each other’s borders. Under MRAs in place, FDA collaborates with inspectorates of 28 different countries and reviews their inspection reports to determine a manufacturer’s suitability for the US market, in lieu of conducting an FDA site inspection. The 2012 Food and Drug Administration Safety and Innovation Act gave FDA the authority to enter into these agreements if FDA determines that a foreign authority is capable of conducting inspections that meet US requirements. Under MRAs, FDA now collaborates with European inspectorates, including those of the United Kingdom and Switzerland, to avoid conducting duplicate inspections and focus resources on inspecting drug manufacturing facilities with higher US public health risks. The power of MRAs was on full display at the height of the global COVID-19 public health emergency; critical data from MRA partner inspections enabled facility assessments and product approvals despite the travel restrictions imposed by various governments.

FDA is also part of the International Coalition of Medicines Regulatory Authorities (ICMRA), a group of 39 regulatory authorities that provides strategic direction to jointly address common challenges, such as those posed by the COVID-19 pandemic. ICMRA is working to establish a new capability for Pharmaceutical Quality Knowledge Management that ensures participating regulators have timely and complete information related to an applicant’s quality and risk management. ICMRA’s knowledge management strategy could enable the simultaneous submission of harmonized pharmaceutical manufacturing information from sponsors and the simultaneous access to that information by multiple regulators. International convergence of this scope requires the collaboration of many, and ICMRA is calling on the international community of regulators, legislators, and manufacturers to advance this strategy for the benefit of patients.

International regulatory divergence can not only keep manufacturers from pursuing new treatments and technologies, but it can also complicate executing a manufacturing change after FDA approves a drug. One manufacturing facility may supply drug product to many different countries, and it can be difficult to move a manufacturing process to a new facility unless all of those countries agree to it. Consider the impact of COVID-19 on supply chains and the need for manufacturing agility. Many manufacturers needed to quickly move or modify their manufacturing processes to respond to challenges posed by COVID-19. In the years prior to 2020, FDA would assess around 7000 application supplements for human drugs. In 2020 alone, FDA approved more than 10,000 application supplements for quality-related changes for human drugs.

To improve international manufacturing agility, FDA is part of two ongoing pilot programs with ICMRA on collaborative international assessments of postapproval changes and collaborative hybrid inspections to inform assessments. The objective of the pilot program on postapproval changes is for multiple regulatory authorities to engage in a single interactive, collaborative assessment of proposed postapproval changes. The collaborative hybrid inspection pilot of a manufacturing facility will use a combination of on-site inspection and remote assessment for regulators to collaboratively assess a facility. This pilot will provide information on how to prepare, execute, and report the inspection and how stakeholders can engage surrounding the inspection. Ideally, the pilots will identify potential areas for alignment or harmonization across participating regulatory regions in the context of manufacturing lifecycle management and find potential conditions (e.g., products/cases) for future collaborative assessments.

To be clear, the world is still very far from a single regulatory position on quality, and barriers undoubtedly exist between the unoptimized present and the desired future. Yet, the technical barriers may be less significant than the ‘people’ barriers. Consider that technology advancements enable many organizations to use international cloud-based data systems to collaborate globally. The hardest challenge may well be the ‘people’ challenge: getting people from different countries with different regulations to agree to change the way they do things. Current international efforts suggest that this change may have begun.

Cox, B. Woodcock: The US FDA Sets the Stage for Global Quality Dossiers. 

Fisher, Adam C., et al. An Audit of Pharmaceutical Continuous Manufacturing Regulatory Submissions and Outcomes in the US. 

ICH. M4: The Common Technical Document. www.ich.org/page/ctd (accessed Jan. 20, 2023).

Beierle, J.; Cauchon, N.S.; Graul, T., et al. Toward a Single Global Control Strategy: Industry Study.

Ashley Boam, MSBE, is the Director of the Office of Policy for Pharmaceutical Quality in FDA’s Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER). Theresa Mullin, PhD serves as CDER’s Associate Director for Strategic Initiatives and leads CDER’s International Program.


Vol. 47, No. 2
February 2023
Pages: 30-31, 33

When referring to this article, please cite it as Boam, A. and Mullin, T. Convergence in the Global Regulatory Village. 

Articles

Harmonization of global regulations fosters innovation and ensures quality medicines.