🇺🇸 FDA - Fiscal Year 2024 Generic Drug Science and Research Initatives Public Workshop

Events / Workshops / Webinars
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@trust_user_a @trust_user_b @trust_user_c @trust_user_d

On May 20-21 FDA will host an in-person & hybrid workshop at the FDA Whtie Oak Campus. and Nitrosamines Exchange will be there…

The public workshop aims to provide an overview of the status of science and research initiatives for generic drugs and an opportunity for public input on these initiatives. FDA is seeking this input from the generic drug industry, academia, patient advocates, professional societies, and other interested parties as it fulfills its commitment under the Generic Drug User Fee Amendments of 2022 (GDUFA III) to develop an annual list of science and research initiatives specific to generic drugs. FDA will consider the information from the public workshop when developing its Fiscal Year (FY) 2025 Generic Drug User Fee Amendments (GDUFA) science and research priorities.

Topics discussed during the workshop will focus on research needed to address scientific knowledge gaps and associated challenges impacting generic product development and regulatory assessment, including complex generics. Sessions of the FY 2024 GDUFA Public Workshop will facilitate public input on research needs for generic products, including those related to:

  • Nitrosamine Drug Substance-Related Impurities
  • Drug-Device Combination Products
  • Predictive Tools to Improve the Efficiency of Generic Product Development
  • Other Research Needed to Address GDUFA III Science & Research Priority Initiatives

FDA is seeking ideas on research topics for FY2025 GDUFA Science and Research Priorities. submitting a comment on the public docket (FDA-2023-N-0119) on or before 11:59 p.m. Eastern Time at the end of June 21, 2024.

Event information: Fiscal Year 2024 Generic Drug Science and Research Initiatives Public Workshop - 05/20/2024 | FDA

What would you propose?

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In the pursuit of advancing generic drug development, it is imperative to emphasize predictive tools that harness the wealth of publicly available data while minimizing reliance on animal studies.

Additionally, I’d like to add a topic regarding analytical challenges, spanning from sample preparation to the analysis itself.

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Hi,
More emphasis should be given on the predictive tools for generic drug product development and also on the drug-device combination. I would like to recommend to add online mode also for the workshop for the maximum reach and benefits.

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Nitrites in excipients are one of the main contributors to the formation of NDSRI in drug formulations. The development of reliable methods for the determination of nitrites in excipients and its inclusion in the USP-NF monographs would encourage excipient manufacturers to focus on this problem.

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The event is hybrid, so you should be able to join via zoom as well. As always FDA will provide recordings of the event later

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Would love to see more on the potential role of scavengers within formulations.

There were several papers produced a while ago now, but I haven’t seen anything recently.

Those papers, including from the USP, suggested several potential different scavengers, and provided some data as to the effectiveness, but it was quite inconclusive. Some scavengers seemed to work better in solution than they did in actual products, and it appeared that scavengers that would work for one molecule was not as effective for a different molecule.

Several of the scavengers weren’t on the FDA list of approved excipients, and so while they showed promise in cases they can’t easily be used in a finished product.

There are many more potential scavenger molecules out there that could be used, and help develop a better understanding of the mechanisms (nitrite scavenging or anti-oxidant etc.) and guide people towards selecting the right scavenger for their molecule(s) and product format.

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Para el caso de la Nitrosaminas, como fabricantes de genéricos, revisar a fondo nuestros productos, desde el agua para la fabricación, hasta el sistema contenedor-cierre. Enfocar la investigación en el proceso integral y hacerlo multidisciplinario, involucrando a todas las áreas que participan en el proceso de fabricación, poner en tanto a todas estas áreas sobre la importancia de identificarlas y monitorearlas, así como de las condiciones en las que estás se presentan.

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Because the NDSRI list by the FDA includes both possible and impossible nitrosamines, I want to classify them as appropriate. If there are rules similar to CPCA, it would help us. The in-silico prediction is also good.

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Los “Do” y “Don´t” de los modelos In silico relacionado al tema de impurezas, tales como nitrosaminas

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It would be interesting to also evaluate other sources of nitrosating agents, for example NOx present in the air, which could mean a source with a cumulative effect from the fractionation stage to packaging.

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Will the topic of nitrosamines be discussed throughout both days of the workshop or only on the first half of Day 1? Where could I get this information? Couldn’t find it on the FDA’s page.

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Lucas, Sarvesh, Jaume, Mark, Luz, Yosuke, Martha, Angel, and Gregory, Thank you for your thoughts and reflections…

It is a humble opportunity and a significant step for our community! Workshop organizers have asked me to present USP Nitrosamines Exchange Experience and Challenges during the Nitrosamine discussion. This is a unique opportunity to raise the Nitrosamines Exchange’s voice as an essential aspect of our vibrant communities. I will be honored to present the challenges, ideas, and opportunities that emerge in our daily discussion with 4,500 community members!

Please keep sending your ideas and thoughts. You can always post it here annonimously or by direct messaging me.

image

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I would also like to know this information! Is there an official event schedule yet? :slight_smile:

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Hi to everybody.
My team is familiar with the clinicopathological correlation after intake of potentially contaminated drugs and the development of skin cancer.
About that topic w ehave published a lot…
Some nitrosamines seems to be also strong and potent photocarcinogens:
Mochizuki H, Nagazawa Y, Arimoto-Kobayashi S. Genotoxicity and the stability of N-nitrosomorpholine activity following UVA irradiation. Mutat Res Genet Toxicol Environ Mutagen. 2024 Jan;893:503721. doi: 10.1016/j.mrgentox.2023.503721. Epub 2023 Dec 2. PMID: 38272633.

and at the same time human carcinogens, especially the tobacco specific nitrosamines:
Stanfill SB, Hecht SS, Joerger AC, González PJ, Maia LB, Rivas MG, Moura JJG, Gupta AK, Le Brun NE, Crack JC, Hainaut P, Sparacino-Watkins C, Tyx RE, Pillai SD, Zaatari GS, Henley SJ, Blount BC, Watson CH, Kaina B, Mehrotra R. From cultivation to cancer: formation of N -nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications. Crit Rev Toxicol. 2023 Nov;53(10):658-701. doi: 10.1080/10408444.2023.2264327. Epub 2023 Dec 21. PMID: 38050998.

There is also an overlapping between the target genes of tobacco specific nitrosamines and the genes responsible for skin cancer / human skin cancer/ : p53 and RAS oncogenes!

What is and seems a little bit confusing is that on the drug packages there is no data of the nitrosamines por the NDSRIs which are also available…
My opinion is that this NDSRIS when listed must be checked for photo toxicity in order to clarify their photocarcinogenic effect? Nitroso- Photo carcinogenicity and Onco pharmacogenesis seems to sound strange , but could be not ignored anymore…

Another important opic of discussion is and might be the different lists of contaminated drugs which probably could clarify a lot…

Meanwhile the australian ministry of health has created ist own list where as it can be seen from the link above, one of the most dangerous contaminations is that of Terbinafine:
https://www.tga.gov.au/how-we-regulate/monitoring-safety-and-shortages/industry-information-about-specific-safety-alerts-recalls-and-shortages/nitrosamine-impurities-medicines/appendix-1-established-acceptable-intake-nitrosamines-medicines

What is ur opinion about the shared connections?
Should nitrosamines be listed on the drugs packages as avalability or should thay stay incognito?

Provocative thoughts and opinions are alwasy important in order to clarify some dilemmas…

greetings to everybody from Sofia

GT

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another issue is the problem with the simulatenously intake of polycontaminated polimedication in polimorbid patients.
Here we ahve till 16 skin cancers in one person or diffrenet types of cancer (simultaneously / subsequently) during the years…within this intake…

FDA and EMA havent regukate that problem till now…

The intake of different polycontaminated drugs simultaneously, which seems to be contaminated with different types of NDSRIS, is leading clinically to the development and progression of different types of skin cancer which we see daily…

Has anybody idea how this problem might be resolved…

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Some Nitrosamines seems to be photo carcinogentic:
Mochizuki H, Nagazawa Y, Arimoto-Kobayashi S. Genotoxicity and the stability of N-nitrosomorpholine activity following UVA irradiation. Mutat Res Genet Toxicol Environ Mutagen. 2024 Jan;893:503721. doi: 10.1016/j.mrgentox.2023.503721. Epub 2023 Dec 2. PMID: 38272633.

Do anybody has an idea if the Nitroamines in commonly prescribed drugs have been tested for photocarcinogenicity?

The photocarcinogenesis affecting all types of Skin cancer affects two major targets: p53 and Ras oncogenes!

Some Nitrosamines are also affecting te same genes…:
Stanfill SB, Hecht SS, Joerger AC, González PJ, Maia LB, Rivas MG, Moura JJG, Gupta AK, Le Brun NE, Crack JC, Hainaut P, Sparacino-Watkins C, Tyx RE, Pillai SD, Zaatari GS, Henley SJ, Blount BC, Watson CH, Kaina B, Mehrotra R. From cultivation to cancer: formation of N -nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications. Crit Rev Toxicol. 2023 Nov;53(10):658-701. doi: 10.1080/10408444.2023.2264327. Epub 2023 Dec 21. PMID: 38050998.

One of the most intruiging topics has to be:

Are the Nitrosamines in drugs also triggers of photocarcinogenicity …?

dont u think…

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Is nitrosamines related photocacrinogencity dose dependent?

N nitrosmorpholine related photocarcinogenicity?
??

Is photocarcinogenicity of nitrosamines in generally distributed drugs already been tested?

This is or would be a good explanation for the skin cancer model…after intake of nitrosamine contaminated drugs…?

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I’m 100% confident that you, @Naiffer_Host , will represent us very well!

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Dear @gregorjug.

Photocarcinogenicity risk assessment to nitrosamines is valid point to bring in for regulatory risk assessment. However, i understand, this could be more relevant to dermal perspective or nitrosamines that has good systemic circulation and accumulated in skin on repeated administration.

N-nitroso morpholine is one such instance we have encountered.

My suggestion is to have first screening to have for any nitrosamine before it goes for labelling:

  1. Does it have triggering point to absorb photons and trigger phototoxicity?
  2. Does it have potential systemic bioavailability and accumulate in skin to trigger skin cancer?

With the current drugs having nitrosamines at scant levels…I doubt they will be of huge concern for photomutagenicity driven cancer. But i do not mean this is completely negligible risk!

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