Co-hosts: FDA and the Center for Research on Complex Generics (CRCG)
In person (at The Universities at Shady Grove; Rockville, MD) and virtual workshop.
The purpose of this workshop is to review the current research and recommendations on methods for confirmatory testing of NDSRI formation, safety testing methods for NDSRIs and recommended acceptable intake limits for NDSRIs based on predicted carcinogenic potency and compound-specific data or read-across analysis. The workshop will also discuss strategies to mitigate the risk of NDSRIs formation. Another key focus of the workshop is to provide an update on FDA policy and guidance in assessing formulation stability, and recommendations for bioequivalence approaches when drug developers are considering reformulation.
Registration has opened for the ’ Updates on Approaches to Acceptable Intakes of Nitrosamine Drug Substance Related Impurities (NDSRIs) and Bioequivalence Assessment for Reformulated Drug Products
Date and Time: November 6 & 7
Co-hosts: FDA and the Center for Research on Complex Generics (CRCG)
Several of the Nitrosamines Exchange community will be in-person presenting at this event.
The workshop’s focus is to review the current research and recommendations on confirmatory NDSRI formation, safety testing methods for NDSRIs and recommended acceptable intake limits for NDSRIs based on predicted carcinogenic potency and compound-specific data or read-across analysis. The workshop will also discuss strategies to mitigate the risk of NDSRI formation. Another key focus of the workshop is to provide updates on the guidance in assessing formulation stability and recommendations for bioequivalence approaches when drug developers are considering reformulation. The speakers and panelists will also discuss the regulatory approaches for navigating the implemented changes and share their regulatory experiences in pre- and post-approval changes in ANDA/NDA submissions and supplements illustrated with relevant case studies.
Hi @Naiffer_Host ,
Thank you for sharing the registration link.
The event starts @ 6 pm IST and runs late night. Can we get the event recordings if we miss any of the presentations.
Is there a possibility to get the slides from this event. I am attending a different Conference at the same time and therefore can not join this event, which is a pity.
@trust_user_a@trust_user_b@trust_user_c@trust_user_d
Community members
The November 6,7, FDA—CRCG Workshop agenda is available! Have you registered yet? You do not want to miss this event, which will provide many updates and critical information! I see you there in person or virtually!!
Excitement is in the air as I join some of the brightest minds in the nitrosamines space for the next two days. It’s inspiring to see so many nitrosamine rockstars in one room, each bringing unique expertise and insights to advance our understanding and management of these impurities.
I’m eager to discuss the challenges, solutions, and latest findings in nitrosamines testing—topics that are essential for protecting patient safety and enhancing our shared knowledge. It’s always incredible to witness the power of collaboration and the impact we can make as a connected scientific community.
Hi Naiffer,
definitely will be a great workshop.
Do you know if it will be recording? For us who are living in the other side of the planet (), full on-line participating is not very easy so it will be great if we could watch this even recorded.
thanks in advance
Christos
Development and Regulatory Application of the Carcinogenic Potency Categorization Approach (CPCA)
by: Dr. Naomi Kruhlak (FDA)
Main Themes:
Nitrosamine impurities pose a significant risk to human health. These compounds, often found in pharmaceuticals, are potent carcinogens and necessitate stringent control measures.
Regulatory bodies, including the FDA, have issued guidance for controlling nitrosamine impurities. This guidance outlines steps for detection, prevention, and establishing acceptable intake limits.
The Carcinogenic Potency Categorization Approach (CPCA) is a novel tool for assessing nitrosamine risk. This structure-activity relationship model categorizes nitrosamines based on their predicted potency and assigns acceptable intake limits accordingly.
Important Ideas & Facts:
Widespread Presence: Nitrosamines have been detected in a wide range of pharmaceuticals, with estimates suggesting 25-81% of APIs carry some risk of contamination.
Regulatory Response: The FDA’s 2020 guidance on nitrosamine impurities has been updated multiple times, reflecting the evolving understanding and increasing focus on this issue.
CPCA as a Solution: The CPCA provides a standardized, less subjective method for assessing nitrosamine risk compared to traditional read-across analysis, particularly valuable for complex structures (e.g., NDSRIs).
CPCA Foundation: The model leverages the understanding of the alpha-hydroxylation metabolic pathway, which plays a key role in the carcinogenic activity of nitrosamines. Structural features influencing this pathway are incorporated into the model.
CPCA Model Development: The CPCA is based on a training set of 81 nitrosamines, utilizing rodent carcinogenicity data and mechanistic information. Expert visual inspection and pattern identification were used to develop the model.
Implementation: The CPCA is implemented through a flow chart, designed for accessibility and transparency. Automated calculators are also available for streamlined application.
Model Limitations: The CPCA is limited to monocyclic and alicyclic nitrosamines. Other types, such as nitrosamides or those with double bonds to heteroatoms, are excluded due to differing activation mechanisms.
Ongoing Research: Further research is ongoing to refine and expand the CPCA, including the investigation of specific structural features and the use of advanced modeling techniques (e.g., quantum mechanics, metabolism modeling).
Key Quotes:
“They’re [nitrosamines] radiated more tightly than typical mutagenic impurities because they’re potential for high carcinogenic effects.” This quote underscores the significant concern surrounding nitrosamines due to their potent carcinogenicity.
“It has been estimated that between 25% and 81% of people who have pharmaceutical ingredients have some risk in their personal information due to the presence of sedatives or depredating incentives in the CPL technology.” This highlights the widespread presence of nitrosamine contamination in pharmaceuticals.
“The CDCA was designed to be implemented very sequentially in data-backed, non-local type calculation, by looking at the chemical structure and identifying the future.” This emphasizes the structured, systematic approach of the CPCA in assessing nitrosamine risk.
“The model is not perfect, but the expectation is that it’s going to face an age gap where we have some sort of limitation in our model rather than underpredict with the expectation that…” This acknowledges the limitations of the CPCA while highlighting its conservative approach, prioritizing safety by erring on the side of over-prediction.
Conclusion:
Nitrosamine impurities represent a significant challenge for the pharmaceutical industry. The CPCA offers a valuable tool for assessing and mitigating risk, providing a standardized and relatively accessible approach. However, the model has limitations, and ongoing research is crucial for its refinement and expansion to address the evolving landscape of nitrosamine contamination.
Bridging QM methods and the CPCA to Enhance In Silico Hazard Assessment of Nitrosamines
by: Dr. Jakub Kostal
Main Themes:
Quantum Mechanics (QM) in Chemical Risk Assessment: The speaker highlights the potential of QM to move beyond traditional atomistic approaches in chemical risk assessment. QM offers a higher resolution understanding of electronic behavior, crucial for predicting chemical reactivity and toxicity.
The Multifaceted Nature of QM: QM encompasses a diverse set of approaches with varying levels of theory and complexity. The speaker emphasizes the importance of selecting appropriate methods based on the specific problem and desired level of resolution.
Synergy of QM with Existing Approaches: The speaker advocates for integrating QM with existing risk assessment frameworks like the CPCA (presumably, a structure-activity relationship based approach). QM can help validate, refine, and expand the scope of such methods.
Practical Applications of QM: The speaker presents several examples of QM applications, particularly in understanding the toxicity of nitrosamines. These examples showcase how QM can:
Elucidate the impact of molecular structure on reactivity and toxicity.
Identify key steps in metabolic pathways that determine toxicity.
Develop quantitative structure-activity relationships (QSARs) for predicting toxicity.
Most Important Ideas/Facts:
Beyond Atomistic View: “Chemistry is just a flux of electron density in a particular environment.” This statement underscores the importance of understanding electronic behavior for accurate chemical assessments.
Trade-offs in QM: QM involves trade-offs between accuracy, computational cost, and system complexity. “So it’s a very diverse field. in terms of the diversity, the way I’d like to start is to think about the system side.”
QM for Refining Risk Assessment: QM can strengthen existing risk assessment rules and potentially expand their applicability. “The main objective of those goals is to help validate and strengthen the CPCA rules and to ensure the ability to expand it or prevent the CPCA.”
QM for Direct Toxicity Prediction: QM can be used directly to predict toxicity, as demonstrated by various studies. “You can also use QM for direct protection. In some ways, you can look at this as even the lower end.”
Key Quotes:
“Quantum mechanics is not a bomb. It’s a field of approaches to different trade-offs, taking different levels of theory to address different problems.”
“So you can regard that while the atomistic approach is fast and useful, the electronic approach can give you a higher resolution or a possible high in chemistry that is underlying the metaphoric process.”
“So we have these tiers of assessment that can be combined together to give you a much better understanding of the behavior of the compound.”
Overall Impression:
The speaker presents a compelling case for the integration of QM into chemical risk assessment. They highlight the potential of QM to enhance existing methodologies and provide a more accurate and nuanced understanding of chemical toxicity. However, they also acknowledge the need to carefully consider the complexities and limitations of different QM approaches when applying them to specific problems.
In Vitro Ames (i.e., Ring Trial) and In Vivo Transgenic Rodent Mutation Studies
by: Dr. Joel Bercu
Main Themes:
Evaluation of the Ames assay (specifically the enhanced Ames test) for predicting the carcinogenicity of nitrosamines. This includes assessing its sensitivity and specificity in relation to in vivo carcinogenicity data and exploring its applicability to both small molecule nitrosamines and larger, more complex structures like NDSRIs.
Correlation between in vivo mutagenicity data (from transgenic rodent mutation assays) and carcinogenicity data for nitrosamines. This involves establishing a relationship between mutagenic potency and carcinogenic potency, potentially leading to more informed AI (acceptable intake) estimations.
Proposal for a framework to utilize biological data from mutagenicity studies to set more accurate and biologically relevant acceptable intake (AI) limits for nitrosamines. This aims to move beyond the limitations of solely relying on the TTC (threshold of toxicological concern) and the categorical approach of the CPCA (compound-specific acceptable intake) system.
Most Important Ideas/Facts:
The enhanced Ames test demonstrated high sensitivity for detecting the mutagenicity of nitrosamines, particularly when using both rat and hamster S9. This is crucial, as nitrosamines typically require metabolic activation for their mutagenic effects.
“The Ames assay was actually pretty, was really sensitive for detection of carcinogenicity. What we did find, is that the hamster X9 was more sensitive than rat X9. And increasing the percentage actually increased the sensitivity.”
While the enhanced Ames test showed high sensitivity, it also exhibited lower specificity, leading to a higher rate of false positives. However, removing compounds positive without metabolic activation significantly improved specificity.
A strong correlation was observed between the TD50 (tumorigenic dose) from carcinogenicity studies and the BUDL (benchmark dose lower confidence limit) from transgenic rodent mutation assays for several small molecule nitrosamines. This suggests that mutagenic potency can be a reliable predictor of carcinogenic potency.
“Bottom line, if you look at just pairing the TD50 to the BUDL-10 for a transient road mutation assay, there’s an extremely strong correlation.”
Data from NDSRIs (nitrosamine drug substance related impurities) indicated lower mutagenic potency in the transgenic rodent mutation assay compared to small molecule nitrosamines. This aligns with their structural complexity and potentially lower carcinogenic potential.
“And so, you know, in my mind, if you’re using this data, you can then get to a better estimation of carcinogenic diseases.”
A preliminary framework was proposed that utilizes the correlation between BUDL and TD50 to establish ranges for AI based on the observed mutagenic potency. This approach aims to incorporate biological data for a more nuanced risk assessment, particularly in cases where the CPCA system might not be sufficient.
“So if you were to use this in practice, I would say if you had a BDL 50 greater than 3, your molecule would be within the TTC range.”
Quotes:
“The enhancement test didn’t really, reduce specificity compared to the standard aims, but we did feel like its sensitivity was much higher than the traditional standard aims.”
“If you look at the ICHM-7 guidelines, there’s different categories of what you can do for a positive AIDS assay to basically understand the vivo relevance.”
“And we believe that the mutagenic potency is really important to understanding its carcinogenic potency as well.”
Overall Conclusions:
The presentation emphasizes the importance of incorporating both in vitro and in vivo mutagenicity data for a comprehensive risk assessment of nitrosamines. The proposed framework, while preliminary, offers a promising approach to move beyond categorical limits and leverage biological data for establishing more relevant and accurate AIs. Further research and validation of this framework are crucial for its potential implementation in regulatory guidelines.
), full on-line participating is not very easy so it will be great if we could watch this even recorded.
