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PharmTech.com Regulating Innovation, Quality, and Risk eBook January 2024 Pharmaceutical Technology ® 17 Regul ations Regul ations ICH and global regulators An important example of global regulators working together to promote innovation occurred with the November 2022 adoption of the International Coun- cil for Harmonisation (ICH) guideline, Q13 Continu- ous Manufacturing of Drug Substances and Drug Prod- ucts. Continuous manufacturing is the continuous feed of input materials, transformation of in-pro- cess materials, and concomitant removal of output materia ls f rom a process. T his new g uideline de- scribes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing across regulator y regions. Still less widespread in pharma than in other industries, continuous man- ufact ur i ng has t he potent ia l to i mprove process qua l it y, reduce wa ste, lower cost s, a nd i ncrea se manufacturing agility. Though FDA has had success in approving applications with continuous manu- facturing faster than applications with traditional batch manufacturing (2), ICH Q13 will give manu- facturers around the world more confidence in the international regulator y expectations for continu- ous 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 mi les f rom FDA headquar ters. ICH's con sen sus-d r iven process br i ngs toget her technical experts from regulator y authorities and industr y to develop science-based g uidelines on critica l topics. T he overa l l pur pose is to ach ieve harmonized technical requirements by regulators to ensure that safe, effective, and high-quality med- icines are developed, registered, and maintained in a resource-efficient manner. International har- monization is a five-step process star ting 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 de- velop a final guideline to be approved by the ICH As- sembly. 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 doc- ument (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 val- idation (ICH Q2(R2)/Q14), viral safety evaluation of biotechnology products (ICH Q 5A(R2)), extractables and leachables (ICH Q 3E), and the quality portion of the common technical document (ICH M4Q(R2)). Together these guidelines will provide clearer inter- national expectations for manufacturers on these critical quality topics. Alignment of regulatory practices The a lignment of reg ulator y practices lies a step beyond harmonizing guidelines. Even with harmo- nized guidelines in place, the consistent implementa- tion 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 industr y measured the acceptance rate of the core chemistr y, manufacturing, and control (CMC) doc- uments of more than 100 applications across the US, Japan, Canada, and the European Union, the prob- abilit y of a document's acceptance across all four countries was typically less than 10% (4). This regu- latory inconsistency can lead to control strategies for a single product that vary globally. Imagine instead a future 'regulatory cloud' where applicants could pro- vide one application for all global regulators to assess simultaneously. Imagine a single 'collaborative hy- brid facility inspection' that meets the needs of all global regulators. A regulatory future could include harmonized regulator y expectations for data ele- ments and standards, assessments, and inspections, and a virtual repositor y for lifecycle management of submissions. The f uture could hold open infor- mation f low 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 in- spectors 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 deter- mine a manufacturer's suitability for the US market, in The alignment of regulatory practices lies a step beyond harmonizing guidelines.