The challenge of Screening vs Risk assessment was discussed this morning by @AndyTeasdale during ‘Risk Assessment Workhop’. We are seeing manufacturers by passing the risk assessment exercise and simply trying to comply with FDA/EMA list of nitrosamines cited on the guidance. It’s well argumented that:
Test alone is not sufficient. Testing does not determine the nitrosamine source or type of nitrosamine to be at risk
If no risk is determined per the risk evaluation, it’s not necessary to test
Detection requires method development and validation for each type of nitrosamine. It’s impossible to create a general test for the presence of ALL nitrosamines.
I totally agree and it’s also important to remember that while we do not need to test for that list of nitrosamines if there is no risk for them, we do need to evaluate the possibility of other nitrosamines as well, when other amines can be nitrosated.
That is the correct approach and is also being recommended by Regulatory Agencies.
Testing without a predetermined understanding of potential sources of Nitrosamines will not help in eliminating Risks associated with presence of Nitrosamines.
It would be difficult to generalise methods especially when considering drug products where matrix interferences, container closure interactions, drug excipient interactions will play a significant role.
Enclosed is a weblink to some of the Published methods by Regulators: https://www.edqm.eu/en/ad-hoc-projects-omcl-network
I totally agree with you. The challenge is to develop and validate a suitable and sensitive method for those nitrosamines expected (sometimes API’s or impurities derivatives) according the risk assessment.
Hi @Ana_Castro, you and the colleagues from Azierta bring a unique perspective to the community. Please feel free to share your experiences dealing with Nitrosamine in multiples fronts. Is there any particular area of concern for your?
Need to understand the perspective of controlling the carriers like water / solvents that are used in the API / DP process which can also carry nitrosating agent which can interact with amine to form Nitrosamine impurity at a particular step.
Hence would like to know what control factors industry is at present practicing to limit such external source which can risk the product.
What are limits of Nitrite & Nitrate adopted in water / solvents specs ? to de-risk the API / DP.
@Nitesh interesting you flagging the control of Nitrosamine in carriers like water. My team knows anecdotally that there is a lot of nitrosamine testing going among India’s manufacturers is in water. Although we have not been pointed out to specific cases where water is the main source of Nitrosamines, it raises my curiosity as to why so many manufacturers testing their water. Regarding solvents, I am aware of control strategies been deployed at API manufacturers.
@MichaelBurns@David do you think we coordinate a presentation to discuss the work that Lhasa is leading on Nitrates excipient content database.
This thread on excipients shines some light on this topic. In there @Yosukemino shared an example presented by Dr. Urquhart, where the “worst case” scenario was calculated for a formulation assuming 100% conversion on Nitrosamines.
Good question @Nitesh and @Naiffer_Host
Back in 2020 it was a recommendation from the EMA in review nitrosamine in water as part of the risk assessment. No limits were specified.
And yes, we have Customers analyzing water with LC-MS in different points during the manufacturing process.
Since we were discussing water as part of the risk in Nitrosamine forming. it would be good to backbit on time (2011) and share this article supported by the Canadian Water Network, and Ontario Research Fund.
This study proves the possible connection between the transformation of PPCPs and the formation of nitrosamines during chloramination process. Further research would be needed to determine the possible impact from different water matrices. Kinetic studies are also required to investigate the possible reaction mechanisms involved. Moreover, metabolites and transformation products of some PPCPs may also pose the potential to form nitrosamines, thus the overall nitrosamine formation potential of PPCPs should consider the parent compounds, their metabolites, as well as the possible transformation products