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On Jan. 12, 2024, the European Medicines Agency (EMA) announced that its Pharmacovigilance Risk Assessment Committee (PRAC) is recommending that precautionary measures be taken in the use of valproate medicines in male patients. According to PRAC, there is a potential increased risk of neurodevelopmental disorders in children born to men who used valproate medicines during the three months before conception. Male patients receiving valproate treatments should be supervised by a specialist in the management of epilepsy, bipolar disorder, or migraine, PRAC says.

The recommendation comes after the committee reviewed data from a retrospective observational study conducted by companies that market the drugs after a previous review of valproate used during pregnancy using registry databases in Denmark, Norway, and Sweden. The study focused on birth outcomes in children born to men that took valproate, lamotrigine, or levetiracetam around the time of conception. Data was also considered from non-clinical studies, scientific literature, and consultations with patients and clinical experts.

According to the data, approximately five out of 100 children whose fathers were treated with valproate had a neurodevelopmental disorder compared with around three out of 100 children born to fathers treated with lamotrigine or levetiracetam. The risk to children born whose fathers stopped using valproate more than three months before conception was not studied.

“The possible risk in children born to men treated with valproate in the [three] months before conception is lower than the previously confirmed risk in children born to women treated with valproate during pregnancy. It is estimated that up to 30 to 40 out of 100 preschool children whose mothers took valproate during pregnancy may have problems with early childhood development, such as being slow to walk and talk, being intellectually less able than other children, and having difficulty with language and memory,” EMA stated in a press release.

“The study data on male patients had limitations, including differences between the groups in the conditions for which the medicines were used and in follow-up times. The PRAC could therefore not establish whether the increased occurrence of these disorders suggested by the study was due to valproate use. In addition, the study was not large enough to identify which types of neurodevelopmental disorders children could be at increased risk of developing. Nonetheless, the Committee considered precautionary measures were warranted to inform patients and healthcare professionals,” EMA clarified in the release.

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The European Medicines Agency safety committee says there is a potential risk of neurodevelopment disorders in children born to men treated with valproate. 

Precautionary Measures Recommended in Use of Valproate Medicines

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. 

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

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 This article was previously published in 

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.

Regulating Innovation, Quality, and Risk eBook January 2024

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

Harmonization of global regulations fosters innovation and ensures quality medicines.

The Global Regulatory Village

Feliza Mirasol is the science editor for 

On Jan. 11, 2024, Boehringer Ingelheim announced that it is investing €120 million (US$131 million) to further expand and upgrade its production facility in Koropi, Greece. With the investment, the company plans to increase manufacturing capacity of new and existing medications, some of which are in late-stage development in the company’s pipeline. The company is investigating several main disease areas, including cardio-renal-metabolic diseases, mental health, and pulmonary fibrosis.

According to a company press release, the expansion will boost medicine exports from Greece, in particular Jardiance (empagliflozin) for treating type 2 diabetes, chronic (long-term) heart failure, and chronic kidney disease, to the US market. The expansion will also create 110 additional jobs. The company had originally announced multi-year investments in 2020 to expand the Koropi site and its production capacity.

The expansion falls in line with the company’s goal of implementing innovative production technologies to support its R&D activities, the company stated in its press release. In 2022, the company spent €4.6 billion (US$5 billion) for its Human Pharma R&D unit, with 25% of Human Pharma net sales being reinvested to advance science and cutting-edge research for innovative therapeutics.

“This expansion investment will bring some of our most innovative therapies to an increasing number of patients globally,” said Hubertus von Baumbach, chairman of the board of managing directors at Boehringer Ingelheim, in the press release.

Boehringer Ingelheim is investing €120 million (US$131 million) into its Koropi, Greece site to expand production for new therapeutics.

Boehringer Ingelheim Expands Facility in Greece for Production of New Therapeutics

Adam C. Fisher, Phd, is Director of Science Staff, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA.

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This article was previously published in 

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.

The Future is the Present: Artificial Intelligence in Pharmaceutical Manufacturing

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).

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

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.

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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.

Pharmaceutical Technology/Pharmaceutical Technology Europe

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

Kevin O’Donnell is Market Compliance Manager at Ireland’s Health Products Regulatory Authority.

Cliff Campbell is senior consultant at KPC.

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 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.

Quality Quartets in Risk-Based Qualification: ICH Q9(R1) Considerations

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: 

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

GK Raju, PhD is Light Pharma CEO, and Research Affiliate, Massachusetts Institute of Technology.

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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. 

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

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.

Martin J. Lipa, PhD, martin.lipa@prst.ie, is a senior research fellow at Pharmaceutical Regulatory Science Team.

Anne Greene, PhD, is director PRST, Technological University Dublin.

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®’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.

Knowledge as the Currency of Managing Risk: A Smart Investment for Patients

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

Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

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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.

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

Moderating Innovation to Equipoise Risk

On Jan. 8, 2024, Pluri, an Israel-based biotech company, announced it launched a new business division named PluriCDMO that will offer cell therapy manufacturing services as a contract development and manufacturing organization (CDMO). The new division includes a 47,000-ft2 good manufacturing practice (GMP) cell therapy production facility.

Through this new division, Pluri will offer services relating to early preclinical development through late-stage clinical trials and commercialization. The company has expanded its experience over the past two decades to include process and analytical development, process scale-up, validation, logistics, automation, and regulatory approved comparability studies, according to a company press release.

The company operates a proprietary, patented bioreactor system that enables 3D cell expansion, allowing it to produce high-quality cells in mass quantities via an automated, fully controlled, and validated process. In addition, the company’s PluriMatrix technology enables industrial-scale production of cell-based products.

Pluri’s technology supports large-scale growth of cells and provides batch-to-batch consistency. It is also scalable, cost-effective, GMP-compliant, and has been used to support late-stage clinical trials in key jurisdictions, including FDA, the European Medicines Agency, Israeli’s Ministry of Health, Japan’s Pharmaceuticals and Medical Devices Agency, and the Ministry of Food and Drug Safety of the Republic of Korea, the company stated in its press release.

“Opening the CDMO division is a strategic move that we expect will boost revenues and cash flow utilizing our … technology and manufacturing facility,” said Yaky Yanay, Pluri’s CEO and president, in the press release. “PluriCDMO’s vision is to provide our clients with … access to valuable knowledge in cell therapy development that has been generated over the [past] two decades. PluriCDMO … can accelerate the development efforts of our partners and provide better control of the risks.”

“Pluri has an established track record of development and manufacturing in this arena and has solved many of the challenges that confront innovative companies in the cell therapy market,” said Andy Lewin, who was appointed as chief commercial officer at Pluri to lead the CDMO division, in the press release. “The [c]ompany has developed innovative production technologies, which allow it to offer large scale (and further scalable) production of cell-based products in GMP grade. Pluri’s technology, long-standing collaborations, and extensive experience enable the manufacturing of a wide range of products, including [m]esenchymal

[s]tem [c]ells (MSCs), [i]nduced [p]luripotent [s]tem Cells (iPSCs), [e]xtracellular [v]esicles (EVs) and gene-modified cells, including CAR-T [chimeric antigen receptor T] cells.”

Pluri has launched PluriCDMO, a new contract development and manufacturing organization business that will offer cell therapy manufacturing services.

Featured Content

Behind the Headlines Episode 27

Ask the Expert

Drug Digest September 2025

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

Top Trends Reshaping Pharma R&D