Genotoxic and Elemental Impurities Network

While focussing on the N-nitrosamines, examining the complexities related to a wide range of GTIs and NMI, our mission extends far beyond this, and brings together regulatory, toxicological, analytical, pharmaceutical experts who continue to exchange their advanced strategies at this premier cross-functional platform   #VLgenotoxic 🔹 9th Impurities: Genotoxic, Nitrosamine & Beyond 🔹 📆 9-10 April 2025 📍 Munich, Germany & Online 🔗 Register 👉https://lnkd.in/dnAeEm3x Attend in-person or online two-days conference and exhibition with the leading professionals, explore novel tech, tools, instruments, extend partnerships, dive into valuable insights. #analytical #api #carcinogens #chemistry #drugsafety #ichm7 #GTIs #extractables #elementalimpurities #leachables #ames #amestest #gmp #genotoxicity #gtis #ich #ICHM7 #impurities #laboratory #mutagenic #mutagenicimpurities #mutagenicity #nitrosamine #regulatory #safety #toxicology #regulatory #NMIs #mutagenic

In recent years, nitrosamine impurities in pharmaceuticals have raised concerns and brought the focus on requirements of robust methods to evaluate their carcinogenic potential. Transgenic Rodent (TGR) in vivo assays have emerged as a crucial method for understanding the mutagenic effect of such impurities. TGR assays can detect DNA mutations across multiple tissues, which is essential in estimating carcinogenicity risk. Despite the fact that regulatory agencies are still cautious about deriving acceptable intake (AI) limits from TGR assays alone, their significance in predicting mutagenicity cannot be denied. Is Next-Generation Sequencing (NGS) a better option? This blog explores the current use of TGR assays and examines promising advancements in carcinogenicity testing. #nitrosamines #nitrosamineimpurities #TGRAssays ##Carcinogenicity #mutagenesis #mutation #toxicology #NextGenerationSequencing #FDA #EMA

📢 A recent article by Bercu et al. proposes refining the Carcinogenicity Potency Categorization Approach (CPCA) for N-nitrosamine Drug Substance-Related Impurities (NDSRIs) with a molecular weight exceeding 200 Da. Through their review and analysis of TD50 values for approximately 15 N-nitrosamines (with MW >200 Da), sourced from the Lhasa Carcinogenicity Database (LCDB), they recommend a default acceptable intake (AI) limit of 150 ng/day for CPCA Category 1/2 NDSRIs with MW >200 Da. This proposed limit is 10 times lower than the ICH M7 threshold of toxicological concern (TTC) value of 1500 ng/day and would still conservatively result in a theoretical cancer risk of less than 1 in 100,000. This pragmatic proposal, if adopted by regulators, could significantly further streamline nitrosamine risk assessments and help prevent drug shortages. Read more: https://lnkd.in/g5WtdCkF #Nitrosamines #NSDRIs #CPCA #LCDB #TD50 #Acceptableintake #carcinogenicity #ICHM7 #Pharma #drugsafety #riskassessment #safetyassessment

A new paper relating to "Qualification of impurities using metabolite data" published online 1 Sept 2024 in Journal of Pharmaceutical Sciences: Early clinical drug product shelf-life setting using accelerated predictive stability and metabolite data for impurity qualification: A case study Author links open overlay panel Jenny Ottosson, Angela Ku, Magnus Fransson, Carina Leandersson, Lars Weidolf, Jufang Wu Ludvigsson, Magnus Klarqvist https://lnkd.in/gxUneWdX https://lnkd.in/gAF4dQzd

The U.S FDA released its guidance document on “𝗖𝗼𝗻𝘁𝗿𝗼𝗹 𝗼𝗳 𝗡𝗶𝘁𝗿𝗼𝘀𝗮𝗺𝗶𝗻𝗲 𝗜𝗺𝗽𝘂𝗿𝗶𝘁𝗶𝗲𝘀 𝗶𝗻 𝗛𝘂𝗺𝗮𝗻 𝗗𝗿𝘂𝗴𝘀” yesterday. The guidance now includes recommendations for both small molecule nitrosamines and NDSRIs. 𝗧𝗼 𝘀𝘂𝗺𝗺𝗮𝗿𝗶𝘇𝗲 𝗳𝗲𝘄 𝗿𝗲𝗰𝗼𝗺𝗺𝗲𝗻𝗱𝗮𝘁𝗶𝗼𝗻𝘀: 𝗦𝘂𝗽𝗽𝗹𝗶𝗲𝗿 𝗤𝘂𝗮𝗹𝗶𝗳𝗶𝗰𝗮𝘁𝗶𝗼𝗻 • 𝗡𝗶𝘁𝗿𝗶𝘁𝗲 𝗩𝗮𝗿𝗶𝗮𝗯𝗶𝗹𝗶𝘁𝘆: Consider nitrite impurities across excipient lots and suppliers. • 𝗪𝗮𝘁𝗲𝗿 𝗖𝗼𝗻𝘁𝗮𝗺𝗶𝗻𝗮𝘁𝗶𝗼𝗻: Be aware of nitrite and nitrosamine impurities in potable water. 𝗠𝗶𝘁𝗶𝗴𝗮𝘁𝗶𝗼𝗻 𝗦𝘁𝗿𝗮𝘁𝗲𝗴𝗶𝗲𝘀 𝗳𝗼𝗿 𝗡𝗗𝗦𝗥𝗜𝘀 • 𝗦𝗰𝗿𝗲𝗲𝗻 𝗘𝘅𝗰𝗶𝗽𝗶𝗲𝗻𝘁𝘀: Use a supplier qualification program to account for nitrite impurities or reformulate with excipients having lower nitrite levels. • 𝗜𝗻𝗰𝗼𝗿𝗽𝗼𝗿𝗮𝘁𝗲 𝗔𝗻𝘁𝗶𝗼𝘅𝗶𝗱𝗮𝗻𝘁𝘀: Add antioxidants (e.g., ascorbic acid, alpha-tocopherol) to inhibit NDSRI formation. • 𝗠𝗼𝗱𝗶𝗳𝘆 𝗽𝗛: Design formulations with neutral or basic pH to reduce NDSRI formation. 𝗧𝗲𝘀𝘁𝗶𝗻𝗴 𝗮𝗻𝗱 𝗥𝗶𝘀𝗸 𝗔𝘀𝘀𝗲𝘀𝘀𝗺𝗲𝗻𝘁 • 𝗗𝗲𝗺𝗼𝗻𝘀𝘁𝗿𝗮𝘁𝗲 𝗡𝗼𝗻-𝗙𝗼𝗿𝗺𝗮𝘁𝗶𝗼𝗻: Test drug products to show nitrosamines won't form under nitrosating conditions. Omit confirmatory testing if justified by risk assessment. 𝗖𝗼𝗻𝗳𝗶𝗿𝗺𝗮𝘁𝗼𝗿𝘆 𝗧𝗲𝘀𝘁𝗶𝗻𝗴 • 𝗦𝗽𝗲𝗰𝗶𝗳𝗶𝗰𝗮𝘁𝗶𝗼𝗻 𝗖𝗿𝗶𝘁𝗲𝗿𝗶𝗮: If nitrosamine levels are ≤10% of the AI limit, no specification is needed if the root cause is understood and controls are validated. Reevaluate during process validation and lifecycle changes. • 𝗔𝗻𝗻𝘂𝗮𝗹 𝗥𝗲𝗽𝗼𝗿𝘁𝗶𝗻𝗴: Include confirmatory test results in the annual report if within 10% of the AI limit. 𝗧𝗶𝗺𝗲𝗹𝗶𝗻𝗲 • 𝗗𝗲𝗮𝗱𝗹𝗶𝗻𝗲: Complete NDSRI confirmatory testing and submit changes by August 1, 2025. 𝗔𝗜 𝗟𝗶𝗺𝗶𝘁 𝗝𝘂𝘀𝘁𝗶𝗳𝗶𝗰𝗮𝘁𝗶𝗼𝗻 • 𝗛𝗶𝗴𝗵𝗲𝗿 𝗔𝗜 𝗟𝗶𝗺𝗶𝘁𝘀: Manufacturers can submit a rationale for AI limits higher than FDA's recommendations using safety data or read-across assessments. FDA may request additional information. • 𝗚𝗹𝗼𝗯𝗮𝗹 𝗩𝗮𝗿𝗶𝗮𝘁𝗶𝗼𝗻𝘀: AI limits may differ across regulatory agencies. U.S. manufacturers should follow FDA's recommendations. 𝗦𝗮𝗳𝗲𝘁𝘆 𝗧𝗲𝘀𝘁𝗶𝗻𝗴 • 𝗘𝗻𝗵𝗮𝗻𝗰𝗲𝗱 𝗔𝗺𝗲𝘀 𝗔𝘀𝘀𝗮𝘆: Recommended for assessing mutagenic risk of nitrosamines. A negative result can support higher AI limits, but additional safety data may be required. • 𝗔𝗱𝗱𝗶𝘁𝗶𝗼𝗻𝗮𝗹 𝗧𝗲𝘀𝘁𝘀: FDA requests a second in vitro mammalian cell mutation assay and in vitro metabolism data to support an AI limit of 1500 ng/day. In vivo mutagenicity data may be needed for limits above 1500 ng/day. A negative result in an in vivo mutagenicity study may not be supportive of an AI limit equal to the qualification thresholds stated in ICH Q3A(R2) and Q3B(R2). FDA acknowledges that these recommendations may differ from those of other drug regulatory agencies. #nitrosamines #toxicology #USFDA #impurities

Extractables & Leachables (E&L) If you make a medical device from a polymer, it is likely that the polymer either originally or via subsequent processing, contains relatively small molecules that can be extracted or which will leach out over time. Those selling the devices have to prove that the E&L components will not cause patient harm when the device comes into contact with fluids added to the component or when the device is in contact with the human body. One necessary step in E&L analysis is to think about diffusion coefficients of the various molecules through the polymers involved. Because it is unreasonable and unrealistic to expect every supplier to measure the diffusion coefficient of every relevant molecule/polymer combination, users need reliable estimates of the coefficients and then need to calculate how much of any molecule might diffuse out over a given timescale. A wonderful set of publications allowed experts from the FDA to produce an impressive model, but one that's not especially user-friendly. So I've appified their work (which I've cited) at: https://lnkd.in/ejiqGSMv. In addition I've added a way to estimate, via HSP, the effect on diffusion coefficient of the extracting fluid. If the fluid is compatible with the polymer, the polymer will swell and diffusion coefficients can increase by orders of magnitude. Because the app is based on the excellent FDA study, even if you choose not to rely on it, it is at least a user-friendly way for those in the E&L world to explore these complex issues. At the bottom of the app I acknowledge the 3 industry experts who helped and encouraged me. As it says, responsibility for errors is all mine. As a bonus, I was encouraged to write a multi-layer diffusion app which you can find at: https://lnkd.in/e2S7PdMq

The latest analysis of toxicology data supporting durational qualification limits for non-mutagenic impurities #genotoxic #mutagenic #toxicology

#genotoxic #impurities

As the curtains draw on the #VLgenotoxic 2024, we extend deepest gratitude 💎 to each and every one of you, incl our partners from Resolian, Brightlabs BV, Intertek, Lhasa Limited, MultiCASE, Inc., for valuable contributions, enthusiasm, and engagement. GRATITUDE for REMARKABLE CONTRIBUTIONS 🏆Acomplished Moderators🏆 Kausik K Nanda Merck / MSD Aloka Srinivasan RAAHA LLC 🌟Esteemed Speakers🌟 Mark Harrison AstraZeneca Raphael Nudelman Teva Pharmaceuticals Susanne Glowienke Novartis Alexander Amberg Sanofi Rok Grahek Sandoz Lutz Mueller Roche Jacky Van Gompel MoonWave Consulting Carla Landolfi, ERT ToxHub Srl George Johnson Swansea University Markus Obkircher Merck Life Science Paulo Eliandro Silva Integra Consultancy Marko Trampuž Sandoz Roustem Saiakhov MultiCASE, Inc.  Gabriela Silveira Lhasa Limited  Nathanael Page Resolian Yuriy Svartsov Intertek (Schweiz) AG ✨Dedicated Attendees✨ ✨Partners and Sponsors✨ 🧪Resolian (formerly Alliance Pharma Inc and Drug Development Solutions Ltd) 🧪is a global contract research organisation (CRO) supporting pharmaceutical and biotech companies with specialised bioanalytical and analytical sciences solutions. 🔗resolian.com 🌡Brightlabs 🌡is the analytical laboratory for all your analytical questions. We offer a complete service ranging from physical, chemical, and microbiological quality control testing of pharmaceutical products, from raw materials to finished dosage forms.🔗brightlabs.nl/en/pharma-en 🧬Intertek🧬provides custom, flexible, regulatory-driven, phase-appropriate laboratory services in support of CMC programs for both small molecules and biologics from our GLP/GCP/GMP laboratory network. 🔗https://lnkd.in/ek-ze4rJ 💉Lhasa Limited 💉is a not-for-profit organisation. At Lhasa, we are driven by our purpose: To enable informed decision making on chemical safety. In line with this purpose, we create cutting-edge software technology that streamlines compound development and minimises animal testing. 🔗lhasalimited.org 💊MultiCASE 💊has been developing state-of-the-art in silico tools for chemical toxicity evaluation since 1996. The MultiCASE software platform is licensed globally by regulatory agencies, pharmaceutical, chemical, and cosmetic companies to fulfil information requirements outlined in guidances such as ICH M7, Nitrosamine Evaluation, and REACH. 🔗multicase.com ☑️ Request RECORDING & PRESENTATION materials: 🔹8th #Impurities: #Genotoxic, #Nitrosamine & Beyond🔹 📆 April 10-11, 2024 📍 Vienna, Austria & Online 🔗Access link: https://lnkd.in/dQCidaFy Best regards,  Vonlanthen Group of Companies❤️ vonlanthenevents.com #analytical #api #carcinogens #chemistry #drugsafety #ichm7 #GTIs #extractables #elementalimpurities #leachables #ames #amestest #gmp #genotoxicity #gtis #ich #ICHM7 #impurities #laboratory #mutagenic #mutagenicimpurities #mutagenicity #nitrosamine #regulatory #safety #toxicology #regulatory

At the #VLgenotoxic Vienna 2024 by Vonlanthen Group of Companies in partnership with MultiCASE, Inc., Lhasa Limited, Intertek, Brightlabs BV, Resolian, we gather industry experts to chart a path toward advances and future considerations re- myriad types of #impurities in #pharmaceuticals: Kausik K Nanda Merck / MSD Mark Harrison AstraZeneca Raphael Nudelman Teva Pharmaceuticals Susanne Glowienke Novartis Alexander Amberg Sanofi Rok Grahek Sandoz Lutz Mueller Roche Jacky Van Gompel MoonWave Consulting  Carla Landolfi, ERT ToxHub Srl George Johnson Swansea University Markus Obkircher Merck Life Science Paulo Eliandro Silva Integra Consultancy  Marko Trampuž Sandoz Roustem Saiakhov MultiCASE, Inc.  Aloka Srinivasan RAAHA LLC  Gabriela Silveira Lhasa Limited  Nathanael Page Resolian  Yuriy Svartsov Intertek (Schweiz) AG    💊MultiCASE 💊has been developing state-of-the-art in silico tools for chemical toxicity evaluation since 1996. The MultiCASE software platform is licensed globally by regulatory agencies, pharmaceutical, chemical, and cosmetic companies to fulfil information requirements outlined in guidances such as ICH M7, Nitrosamine Evaluation, and REACH. 🔗multicase.com   💉Lhasa Limited 💉 is a not-for-profit organisation. At Lhasa, we are driven by our purpose: To enable informed decision making on chemical safety. In line with this purpose, we create cutting-edge software technology that streamlines compound development and minimises animal testing. Our technology is designed by scientists, for scientists, in collaboration with industry stakeholders and regulators. 🔗lhasalimited.org   🧬Intertek🧬 provides custom, flexible, regulatory-driven, phase-appropriate laboratory services in support of CMC programs for both small molecules and biologics from our GLP/GCP/GMP laboratory network. 🔗https://lnkd.in/ek-ze4rJ 🌡Brightlabs 🌡 is the analytical laboratory for all your analytical questions. We offer a complete service ranging from physical, chemical, and microbiological quality control testing of pharmaceutical products, from raw materials to finished dosage forms.🔗brightlabs.nl/en/pharma-en   🧪Resolian (formerly Alliance Pharma Inc and Drug Development Solutions Ltd) 🧪is a global contract research organisation (CRO) supporting pharmaceutical and biotech companies with specialised bioanalytical and analytical sciences solutions. 🔗resolian.com   🔹8th Impurities: Genotoxic, Nitrosamine & Beyond🔹 📆 April 10-11, 2024 📍 Vienna, Austria & Online 🔗Registration link: https://lnkd.in/e4tHAhdj #analytical #api #carcinogens #chemistry #drugsafety #ichm7 #GTIs #extractables #elementalimpurities #leachables #ames #amestest #gmp #genotoxicity #gtis #ich #ICHM7 #impurities #laboratory #mutagenic #mutagenicimpurities #mutagenicity #nitrosamine #regulatory #safety #toxicology #regulatory