USP-China is planning a Nitrosamine workshop on May 27th, 2022. As you know, the Chinese manufacturer was the epicenter of this incident and many DS/DP/excipient/packaging material manufacturers are impacted significantly in the past few years, there are still challenges and confusions on how to be compliant with guidance from various agencies. Our intention is to convene the experts on this subject to assist the local stakeholders get a better understanding of the regulator’s expectation and share the best practices.
Here we’d like to ask your advices of the topics and speakers, and if you are willing to share your thoughts in the event, please let us know, we will make the arrangement.
Below is a tentative agenda for your reference.
Session 1: Regulator’s perspective, US FDA, EMA/EDQM, JP, China NMPA/ChP/drug control institutes
Session 2: Risk assessment, control strategy, other mutagenic impurities
Session 3: Testing method and analytical challenges, nitrosamine impurities in excipients and packaging material
Session 4: Perspectives from local DS and DP manufacturers, and CRO
@trust_user_a@trust_user_b@trust_user_c We need your help & feedback / USP-China is planning a Nitrosamine workshop on May 27th, 2022. we’d like to ask your advices of the topics and speakers
Below is a tentative agenda for your reference.
Session 1: Regulator’s perspective, US FDA, EMA/EDQM, JP, China NMPA/ChP/drug control institutes
Session 2: Risk assessment, control strategy, other mutagenic impurities
Session 3: Testing method and analytical challenges, nitrosamine impurities in excipients and packaging material
Session 4: Perspectives from local DS and DP manufacturers, and CRO
Hi Naiffer,
Dr. BM Rao, VP & Head - CQC, ASAT & EM QA, Dr. Reddy’s Laboratories Limited, Hyderabad, India can be a good candidate to discuss on analytical challenges. He can also discus around Risk assessment if needed
Let me know if you want me to connect with someone in EMA/EDQM
That is interesting, can we add the reporting strategy, option 1 and 2 in EMA and if the flexi option 2 will be accepted bu other regularity bodies, how about less than life time calculation?
Could we have a module on the toxicity of this class of compounds, including allowable AI limits for N-nitrosamines? We are currently seeing somewhat of a disconnect, with FDA saying 26.5 ng/day (i.e. AI for NDEA) is an acceptable limit for new N-nitrosamines but putting in a default limit of 30 ppb irrespective of toxicity of N-nitrosamine or maximum daily dose (MDD) of drug. In addition for N-nitrosovarenicline they recently implemented an AI of 37.5 ng/day. In EU the default limit for new N-nitrosamines is 18ng/day which is significantly lower than the most potent member of the group, i.e. NDEA. We know that N-nitrosamines are a very heterogenous group with potency covering 4 -orders of magnitude - indeed about 20% of the class are Ames negative. The larger MW N-nitrosamine API derivatives, e.g. N-nitrosovarenicline are often weaker mutagens than the short-chain alkyl N-nitrosamines, e.g. NDEA - as such treating all N-nitosamines as equipotent with NDEA or even worse having a lower limit, i.e. 18ng/day is illogical and makes the analytical challenges even more severe - particularly where the MDD is high.
The other related challenge is that FDA is questioning the legitimacy of negative Ames tests for this class of compounds. So in the case of a high MW and/or sterically hindered N-nitrosamine (where a negative Ames might be predicted) they are refusing to accept that a negative Ames test discharges the risk and are looking for data from other mutagenic tests, e.g. COMET assay, etc., to fully discharge the risk
Hi Oliver, for somebody who was immersed in this problem during my PhD, Ames and nitrosamines have always had an issue. Take N-nitrosopropanolol as an example. A very well done Ames Test showed it to be Ames negative in 1986. However, at a later date, an in vitro as well as in vivo studies in rats showed it to be clastrogenic. So, now the ambiguity of the two studies, Agencies are not totally depending on negative Ames.
Thank you all for your valuable inputs and offering the help. I will talk to the local team and draft an agenda, will reach out to each of you later to discuss the topic.
We’ve covered some elements of this in the USP LATAM workshop back in November, I’d be more than happy to reprise and update my presentation from that. This would include the lessons that we could learn from SAR to suggest alternative limits for many complex nitrosamines.
Might also be worth including @conudel , who gave a really impactful presentation on limits and read-across?
