It would be interesting to understand the reasoning (and procedural impact) of COFEPRIS in adopting principles like CPCA, EAT, in vivo mutagenicity testing indirectly via Appendix 2 but not really in the key guidance. Can they evaluate AIs with no international publication precedent (linked to the NDSRI structure and/or value proposed) or do they only endorse already published AIs? (And if this has a link with defaulting to 18 ng/day.)
Would also like to hear the perspective on international recognition from other panelists like ISP Chile having no nitrosamine guidance/regulation beyond ranitidine and sartans and more broadly how these non-NITWG members look at NITWG.
Thank you for sharing a summary of the panel output later this month.
Hi Naiffer, thanks for bringing up this with the Community - unique opportunity indeed
For Mexico: how is the Authority planning to implement, considering key factors as the listed by @Diego_HM and @ccdw some days ago in this “conversation line”, from which I see as critical the requirement for local personnel/lab to perform activities, unknown nitrosamines “falling by default” into 18 ng/day and the acceptability of EAT and in-vivo mutagenicity data
For other NRAs would be good to “explore” if there is any potential upcoming update/guidance already planned or “in the table as idea” to be issued by their side
Will be of very much interest any output you could share after the Conference.
Estimados colegas:
Citando lo indicado en la guía Cofepris: “La evaluación de riesgos debe ser elaborada por personal calificado y con experiencia requerida en el tema, el cual debe ser revisado y autorizado por el TRS y FIF en México", alguien me podrían indicar ¿qué tipo de calificaciones y experiencias en el tema han sido consideradas por sus instituciones y/o empresas para tratar este tipo de temas?. ¡Muchas gracias!
This presentation summarizes COFEPRIS’s (Mexico’s health regulatory agency) guidelines for the management of risks posed by nitrosamines in pharmaceuticals in Mexico.
The presentation highlights the serious health risks associated with nitrosamines. Nitrosamines can cause damage to DNA, leading to uncontrolled cell duplication and potentially the development of tumors or cancer.
While scientific knowledge of nitrosamines in food dates back to the 1950s, their presence in pharmaceuticals didn’t come to light until 2018. This discovery led health authorities worldwide, including EMA, Health Canada, and ANVISA, to issue guidelines for controlling and mitigating the risks associated with these impurities.
COFEPRIS, in line with these international efforts, initiated the development of its own guideline in June 2023, which was finalized in December 2023 and made public in July 2024.
The guideline is expected to undergo constant modifications and updates, reflecting the dynamic nature of this field.
The guideline’s creation involved extensive collaboration between COFEPRIS and other entities, including: The National Academy of Pharmaceutical Sciences, The National Autonomous University of Mexico, The United States Mexican Pharmacopoeia, Representatives from the industrial sector
The COFEPRIS guideline for managing nitrosamine risks is divided into three stages:
Risk Assessment:
This stage, with a proposed timeframe of eight months (until March 2025), involves a thorough evaluation to determine the potential for nitrosamine formation or introduction into pharmaceuticals. If a risk is identified, a report is submitted to COFEPRIS, detailing the quantification, testing methods, and relevant findings.
Confirmatory Testing:
This stage involves rigorous testing to confirm the presence and levels of nitrosamines in pharmaceuticals deemed to be at high risk.
Risk Management:
This stage outlines the necessary actions to be taken upon confirmation of nitrosamine presence.
This includes: Reporting the findings to COFEPRIS. Facilitating on-site inspections by health authorities to monitor the situation. Implementing measures to reduce or eliminate nitrosamines. In extreme cases, withdrawing the affected product from the market.
The guideline emphasizes that the primary responsibility for addressing nitrosamine risks lies with the pharmaceutical companies, specifically the marketing authorization holders and manufacturers.
The presentation also clarifies that the current COFEPRIS guideline is “merely orientative” and does not carry a mandatory or legally binding status for the industry. COFEPRIS views the guideline as a recommendation to assist pharmaceutical companies in effectively managing nitrosamine risks.
COFEPRIS has also implemented several other initiatives related to nitrosamines, including: A dedicated email address for inquiries (nitrosamines.mexico@cofepris.gov.mx). An internal working group consisting of experts from various COFEPRIS units.
The presentation concludes with a Q&A session addressing common queries regarding the guideline. These clarifications provide further insights into COFEPRIS’s approach to handling nitrosamines in pharmaceutical products:
Q: Are confirmatory tests for nitrosamine impurities in drugs and medications to be performed in third-party laboratories authorized by COFEPRIS?
A: While the current version of the guideline stipulates this, COFEPRIS acknowledges the need for flexibility and plans to revise this requirement in the upcoming version 2.0. The updated guideline will allow pharmaceutical companies to conduct tests in their own laboratories or utilize laboratories abroad if their manufacturing is overseas.
Q: Who is responsible for conducting the risk assessment and what qualifies an individual as “qualified personnel” to perform this task?
A: Pharmaceutical companies are responsible for selecting qualified personnel to conduct the risk assessment. Although no specific certification body exists in Mexico for this purpose, COFEPRIS recommends that the selected individual possess significant experience and expertise in risk assessment procedures.
Q: What happens if my drug is not listed in Appendix 2 of the guideline?
A: Appendix 2 currently focuses on pharmaceuticals marketed in Mexico. However, COFEPRIS recognizes the need for a more comprehensive list and intends to expand the appendix in the next version to include all products currently marketed in Mexico, as well as those that may be introduced in the future.
Q: Is the guideline mandatory?
A: Currently, the guideline serves as a recommendation rather than a mandatory requirement. COFEPRIS, in conjunction with the Scientific Council and the Health Authorization Commission, is evaluating the possibility of binding the guideline in the future.
Q: In what language should the report be submitted?
A: While the formal letter submitted to COFEPRIS must be written in Spanish, the supporting information and conclusions can be provided in English. This flexibility allows for easier submission of pre-existing risk assessments, often prepared in English.
Buenos días Naiffer. Esta información tan concisa y concreta nos permitirá establecer mejores estrategias para hacer más seguros nuestros productos y resuelve las dudas sobre la guía que todos teníamos en México. Gracias
@romnaiffer muchas gracias por compartir las diapositivas y el resumen tan preciso que nos das, me ha aclarado mi duda sobre el personal calificado. Estoy muy ansiosa por escucharlo en la reunión de la AMELAF, mil gracias!
Hi, in fact I wonder if they really apply CPCA principle in Appendix 2 as I see some discrepancies in AI values between EMA Appendix I and COFEPRIS Appendix 2 for same nitrosamines with the same quoted CPCA category.
This is what I called indirect adoption, not only using principles in the Appendix that are not in the guidance but also using these principles by copying other assessments instead of applying individual assessments (copy/paste with territory filter). COFEPRIS seemingly took the EMA list as it stood at a certain point in time and copied AIs if the sources were relevant for the territory, instead of adopting their own assessment (which also explains the mismatch between Appendix 1 and 2 of COFEPRIS). See also in COFEPRIS Appendix 2 footnotes the confirmation that this document was built based on the February 2024 edition of the EMA limit list. As the EMA list keeps evolving, this makes the COFEPRIS list indeed not aligned anymore (but the COFEPRIS list is “illustrative”). One of the topics the EMA has been working on, is more consistently applying CPCA instead of readacross for smaller nitrosamines and the COFEPRIS list now runs behind in that. I don’t have the impression COFEPRIS was scanning the FDA limit list for matches with medicines on their territory per se and the footnotes in Appendix 2 confirm that.
I brought it up in the discussion CPCA. Although it is not mentioned in the guide, they utilizing it (based on the AI limits reported). The representative mentioned an upcoming revision to address many of the questions that industry has submitted to them.
I encourage to submit questions to Cofepris via their email address: nitrosaminas.mexico@cofepris.gov.mx
Feel free to submit your questions here. We will soon participate in a roundtable discussion with Cofepris. I plan to bring ‘the voice of the community.’
Well you are the voice of the nitrosamine community Naiffer
I think there will be quite a lot of questions, we have certainly had some in-depth discussions internally around what exactly has been meant by certain clauses, without always reaching agreement.
Cofepris being so open to discussion is great news, they were also equally open a good few years ago when they published their guidance of method validation. They look to have picked a moment in time to base certain limits on, when in reality we know that it is an ever changing landscape.
This would be really helpful. Personal experience here, we have send our questions to the HA by several means, and still not had any answer. Therefore, good to know that by Seminars means some answers are received.
Also, something we are really wondering internally, if which industry group participated in developing the guideline. I have asked other industry forums and they are clueless.
During the presentation, few were mentioned… no details on what capacity their participation was. UNAM (Academy), FEUM (Pharmacopeia), AMELAF, ANAFAN, AMIIF, other I could not remember
