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Regulating Innovation, Quality, and Risk 2024

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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.

Pharmaceutical Technology/Pharmaceutical Technology Europe Regulating Innovation, Quality, and Risk eBook

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.

Pharmaceutical Technology/Pharmaceutical Technology Europe Regulating Innovation, Quality, and Risk

Quality/Regulations

Harmonization of global regulations fosters innovation and ensures quality medicines.

The Global Regulatory Village

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Hollywood has long presented artificial intelligence (AI) as a futuristic concept far from reality, but technology has now eliminated the gap between science fiction and science fact. AI is here and here to stay; 50% of global healthcare companies plan to implement AI strategies by 2025 (1). For pharmaceutical manufacturers, AI has the potential to revolutionize process design and control, and thus bring benefits to patients and challenges to regulators.

Owing to its fictionalized past, the term AI can mean wildly different things to different people. FDA’s Center for Drug Evaluation and Research (CDER) describes AI rather inclusively as “a branch of computer science, statistics, and engineering that uses algorithms or models that exhibit behaviors such as learning, making decisions, and making predictions” (2). The National Academies of Sciences, Engineering, and Medicine issued a report on innovations in pharmaceutical manufacturing that highlighted AI’s potential role in the measurement, modeling, and control used for pharmaceutical manufacturing (3).

Regulating Innovation, Quality, and Risk eBook January 2024

Adam Fisher, PhD is Director of Science Staff and Immediate Office within the Office of Pharmaceutical Quality at the Center for Drug Evaluation and Research at FDA.

FDA is anticipating how AI may advance manufacturing and improve supply chain security.

Artificial Intelligence in Pharmaceutical Manufacturing

Drug Master File (DMF) holders provide a hazard assessment for impurity classification to comply with International Council for Harmonisation (ICH) M7 (R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (1) that includes the use of (quantitative) structure-activity relationship ((Q)SAR) models. Impurities consist of starting materials, intermediates, by-products, and degradants and can total >15 for a single DMF. Currently, chemical structures for these impurities are submitted in the Electronic Common Technical Document (eCTD) (2) as unmanipulable portable data files (PDF files). Further review of the impurities using cheminformatics tools—by application of (Q)SAR models and registration in the FDA Global Substance Registration System (GSRS)—or for use in the Chemistry, Manufacturing, and Controls (CMC) review document, requires conversion of the structures to a computer-readable format. To resolve challenges with re-drawing chemical structures and to improve review efficiency, inclusion of structural information in the structure-data file (SD File) format can be very helpful in DMF reviews.

Regulating Innovation, Quality, and Risk eBook

Barbara Scott* is a Master Reviewer at FDA Center for Drug Evaluation and Research/Office of Pharmaceutical Quality/Office of New Drug Products/ Division of Lifecycle Active Pharmaceutical Ingredients, Barbara.Scott@fda.hhs.gov. David Green is a Senior Pharmaceutical Quality Assessor at FDA Center for Drug Evaluation and Research/Office of
Pharmaceutical Quality/Office of New Drug Products/ Division of Lifecycle Active Pharmaceutical Ingredients. Marlene Kim is a Chemist at FDA Office of the Commissioner/Office of Digital Transformation/Office of Data, Analytics, and Research/Health Informatics Staff. Naomi Kruhlak is Scientific Lead, Computational Toxicology Consultation Service at FDA Center for Drug Evaluation and Research/Office of Translational Sciences/Office of Clinical Pharmacology/ Division of Applied Regulatory Science. Tyler Peryea is a Chemist at FDA Office of the Commissioner/Office of Digital Transformation/Office of Data, Analytics, and Research/Health Informatics Staff. David Skanchy was the Division Director (retired) at FDA Center for Drug Evaluation and Research/Office of Pharmaceutical Quality/Office of New Drug Products/ Division of Lifecycle Active Pharmaceutical Ingredients.

*To whom all correspondence should be addressed.

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Regulating Innovation, Quality, and Risk 

When referring to this article, please cite it as Scott, B. et al. Master File Submission of Structures. 

The SD File format offers benefits for KASA and cheminformatics to support regulatory submissions.

Master File Submission of Structures

 This article was peer reviewed by a member of 

®’s Editorial Advisory Board and was previously published in the August 2023 issue.

A published paper, titled “Quality Quartets in Risk-Based Qualification” (1), provided a review of the International Society for Pharmaceutical Engineering’s (ISPE’s) Baseline Guide of 2019 on Commissioning & Qualification (C&Q) (2). That paper introduced a concept called “Quality Quartets” as a practical means of making use of four key concepts in the Baseline Guide: critical aspects (CAs) and critical design elements (CDEs), which were newly introduced in the 2019 Baseline Guide, and the already well-established critical quality attribute (CQA) and critical process parameters (CPP) concepts.

A Quality Quartet is essentially a documented expression of the knowledge that a company has about the relationship between CAs and CDEs and the associated CPPs and CQAs. It can be considered a knowledge management output, serving as a practical means of facilitating science and risk-based commissioning and qualification. In addition, the Quality Quartet concept represents a simple and concise means of capturing and communicating product and process knowledge and understanding.

 Pharmaceutical Technology/Pharmaceutical Technology Europe Regulating Innovation, Quality, and Risk

Kevin O’Donnell is Market Compliance Manager at Ireland’s Health Products Regulatory Authority. Cliff Campbell is senior consultant, retired.

Quality Quartets may be used to achieve knowledge-driven, risk-based approaches to commissioning and qualification that are consistent with ICH Q9(R1) principles.

Quality Quartets in Risk-Based Qualification: 

Manufacturing performance determines quality of outputs. When a company experiences significant manufacturing performance issues, improvements to production design are typically needed.Many industries have demonstrated the value gained from improving manufacturing capabilities, from both quality and business perspectives. However, in the pharmaceutical industry, the business costs and benefits that distinguish manufacturing choices are not always sufficiently understood and described when design options are weighed. When unreliable operations are used to produce medicines, the consequent lower assurance of quality can impact multiple stakeholders, including but not limited to manufacturers, the healthcare system, patients, and governments.To support selection of appropriate manufacturing technologies in accord with the principles of ICH Q9(R1) 

, the pharmaceutical industry would benefit from wide adoption of comprehensive models that better quantify the business benefits of investing in quality. 

This paper provides key insights from an extensive literature analysis and discusses the clear business case established by non-pharmaceutical industries for avoiding unreliable operations due to the risks they pose to both quality and business outcomes.

Rick L. Friedman, MS, is Deputy Director for Manufacturing Quality, FDA Center for Drug Evaluation & Research. David Lebo, PhD is Professor of Pharmaceutics, Temple University School of Pharmacy. Lawrence Liberti, PhD, BPharm, RAC, is Director, The University of Southern California (USC) DK Kim International Center for Regulatory Science, and GK Raju, PhD is Light Pharma CEO, and Research Affiliate, Massachusetts Institute of Technology.

When referring to this article, please cite it as Friedman, R.L.; Lebo, D.; Liberti, L.; Raju, GK. ICH Q9: Attaining a Quality-Business Synergy through Quality Risk Management, ROI Analysis, and Highly Capable Facilities. 

Pharmaceutical Technology/Pharmaceutical Technology Europe Regulating Innovation, Quality, and Risk eBook January 2024.

This paper explores the relationship between investing in pharmaceutical manufacturing risk reduction and meeting business objectives.

ICH Q9: Attaining a Quality-Business Synergy through Quality Risk Management, ROI Analysis, and Highly Capable Facilities

®’s Editorial Advisory Board and was previously published in the September 2023 issue.

The current International Council for Harmonisation (ICH) Q9(R1) Quality Risk Management (QRM) guideline is a targeted revision of the initial guidance issued in 2005, intended to address subjectivity, formality, risk-based decision-making, and other specific areas for improvement. While not a formally defined area for improvement, the revised guidance invokes many new references to “knowledge” and “knowledge management (KM)” in supporting improvement in QRM practice and, by extension, to the goals of an effective pharmaceutical quality system.

Recognizing that QRM and risk-based decision-making (RBDM) both depend on knowledge to be effective, it could be suggested that knowledge is the currency of managing risk. This paper presents research and perspectives on the opportunity to better connect risk and knowledge through improved integration of QRM and KM, including presenting several potential benefits of such integration. A framework is proposed, the Risk-Knowledge Infinity Cycle (RKI Cycle), which could be used to improve the connectivity of risk and knowledge along with preliminary and practical recommendations to operationalize the RKI Cycle. In addition, the paper invokes concepts of systems thinking in connecting QRM and KM as well as the opportunity to consider the role of knowledge and KM more holistically across the pharmaceutical business through application of a process classification framework.

Martin J. Lipa*, PhD, martin.lipa@prst.ie, is senior research fellow, Pharmaceutical Regulatory Science Team. Anne Greene, PhD, is professor, Technological University Dublin, and director, Pharmaceutical Regulatory Science Team.


*To whom all correspondences should be addressed.

Recent research and perspectives shed light on an opportunity to better connect risk and knowledge through improved integration of systems.

Knowledge as the Currency of Managing Risk

While his focus was on balancing personal freedom versus state power, 18th century political theorist John Locke’s following thought could arguably be applied to current pharmaceutical regulators’ attitudes when he famously declared, “the end of law is not to abolish or restrain, but to preserve and enlarge freedom” (1). While those currently reading sundry observations listed on an FDA Form 483 will feel significantly “retrained”, the intent of regulations is to allow a fair and equal access to a playing field that encourages participation by as many novel and creative solutions, as applied to disease states, as humanly possible.

Anshul Mangal, president and general counsel of Project Farma, stated, “The FDA aims to streamline the approval process for platform technologies, leveraging the Omnibus Appropriations Act of 2023 to facilitate referencing prior manufacturing data during the review process. Encouraging more gene therapies to seek accelerated approval and improving harmonization with global regulators, especially for rare diseases will be of critical importance. Additionally, the FDA is launching the START pilot to support small companies developing gene therapies for rare pediatric diseases, drawing lessons from the COVID-era Project Warp Speed. If the pilot is successful, it could become a permanent program dedicated to supporting the mission. The agency’s continued support will be paramount in propelling the therapeutic pipeline forward and teeing up the sector for another year of groundbreaking achievements” (2).

As innovation accelerates, pharmaceutical regulators continue their path of maintaining proportion, balance, and restraint. Please enjoy the following articles which, in many ways, fully embody that ethos.

Locke, J. Second Treatise of Civil Government 1690.

Mangal, A. JP Morgan Healthcare Conference Summary. LinkedIn (accessed Jan. 18, 2023).

When referring to this article, please cite it as Spivey, C. Moderating Innovation to Equipoise Risk. 

, Regulating Innovation, Quality, and Risk eBook January 2024.

From The Editor

As innovation accelerates, pharmaceutical regulators continue their path of maintaining proportion, balance, and restraint. 

PharmTech Sponsored eBooks-01-31-2024