It seems that when we talked about Nitrosamines Impurities, for the most part, we refer to oral dosage forms. But how about inhalation drug products or other dosage forms?
A publication by Khan et al. “An Overview andDiscussion ofN‑nitrosamine Considerations forOrally Inhaled Drug Products andRelevance toOther Dosage Forms”
The presence of N-nitrosamines in drug products are currently an area of high regulatory and industry scrutiny, having been detected above acceptable regulatory levels in several solid oral drug products. For over 20years, there has been an expectation that N-nitrosamines be eliminated or controlled to acceptable levels in orally inhaled and nasal drug products (OINDP). As a result, the OINDP industry has developed and implemented risk management processes and considerations to address N-nitrosamines in final drug product, including management and understanding of upstream supply particu-larly for OINDP device and container closure systems. We provide an overview of N-nitrosamine formation, discuss key current regulatory expectations worldwide for N-nitrosamines in drug products, discuss risk management approaches relevant for drug device combination products, and share analytical “tips” with respect to handling N-nitrosamines chemi-cal assessments.
Dear Naiffer,
thank you very much for this infomation.
Is really a very interesting topic as the maximum daily doses are very low (usually levels of micrograms/day) and apparently the specification limits of these nitrosamines anticipated to be very high.
Is it possible to share this paper with us?
thank you in advance
Goodmorning also here,
I would like to flag the very high limits that we could have regarding the NDSRIs of APIs for inhaled drugs due to the very low maximum daily doses (MDD-class of micrograms).
Here is an example to make this more clear:
Symbicort (budesonide+formoterol) 160+4.5mcg: Regarding formoterol, the MDD is 12 inhalations/day or 12x4.5=54mcg or 0.054mg/day
The AI for the N-nitrosoformoterol (NNF) is 1500ng/day, so the spec.limit for this nitrosamine would be: 1500ng/day/0.054mg/day = 27777.8ppm or 2.8%!!!
(Actually this would be much more as the 12 inhalations/day is valid for few days, so the LTL approach could be applied)
So, in these cases, the limit for nitrosamines could be higher that the limit for the related substances, which in my eyes is not logical.
Does anyone have an experience on submission of so high levels of nitrosamines?
@chrischar - Please note the mode of calculation for limits does not mean, we are flexible to go up to that.
As per ICH tenet- The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process, and the limits should reflect contemporary manufacturing standards. Further, pharmaceutical quality, performance in downstream manufacturing process, and biopharmaceutical performance could be considered in setting the control limit.
Suggestion- So, please allow the N-nitrosoformoterol in Symbicort product only at levels reasonable!
dear Pradpharma,
thank you for your feedback.
May i ask you please, when you say ‘‘allow the limit of the N-nitrosoformoterol (NNF) only at levels reasonable’’ what do you exactly have in your mind?
The text from the ICH tenet you presented above i am afraid is more for the exactly opposite case, where the limits are very very very low and the analytical methods cannot work properly.
In the case of N-nitrosoformoterol, the limit of 2.8% is complies with all the above requirements (realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process)
What i mean is- if you feel confident enough with manufacturing standards with quality and efficacy of your product- You may choose as per calculated limit.
I doubt agency will allow any nitrosamine impurity at that level.
Coming to ICH- I agree, that for nitrosamines this might not look apt and that’s the irony, but i just thought to pass the sense.
thank you very much for your response.
I also doubt about the acceptance of so high level but the irony is that this level is comming out from the guidelines
Furthermore, the value AI/MDD is corresponds to 1/100000 risk which actually is more that conservative regarding the safety. In other words this very high level for NNF, which corresponds to a risk less than 1/100000, is theoretically very safe for the patient.
Anyway, thank you again for the knowledge you share with me.
Unfortunately this publication is not open-access so you will need to use your library to obtain a cope of it. Because copyright restrictions we can not just share a copy here.
In the past, I found a similar situation on some residual solvents of Formeterol, where the limit according to option 1 of ICH Q3D (intake of 10 g of API) does not have any sense and the limit according to option 2 (PDE and effective API intake) leads to limits greater than the MDD of Formeterol!
In that case, the limit was proposed according to GMP principle, considering the average value of the solvent and the maximum value found in the batches of API.
In this case, the EMA Q&A stated that:
It is considered that the presence of one or more N-nitrosamines at <10% of their respective AI constitutes a negligible toxicological risk, and as such, they do not need to be specified.
Of course:
If quantitative testing is performed to justify omission of specification, the LoQ of the analytical method employed should be ≤ 10% of the acceptable limit based on the AI
Therefore, in my opinion, if you meet both above requirement, you should not change the drug product specifications and therefore the problem of the “regulatory evaluation” of a variation submitted to the authority should not exist.
Hi Giovanni,
is exactly the way we are moving to in a similar case with an inhaled formoterol involved FP, to apply a method with an LoQ<10% of the spec which is correponds to its AI and to prove teh nitrosamine is below this and to ‘‘forget’’ about it.
Thank you very much for the time you spend dealing with my question!!
Have a great christmas time and some vocation witch are necessary for everyone.
regards
Christos
