Suppose a particular regulatory starting material (API RSM) is used in multiple Active Ingredient/ Drug Substance then what should be the approach to determine the limit for common or small nitrosamine impurities and develop analytical method accordingly.
Should the RSM manufacturer determine the limit based on the MDD for all the applicable Drug Substance/ Drug Products and apply the stringent limit determined on a worst-case scenario approach? This may be the best approach considering the detection of particular nitrosamine limit but would not be feasible for the RSM manufacturer since this is not a mandate requirement for a RSM manufacturer and may be challenging for the RSM manufacturer. Further, RSM manufacturer may not have the details of all applicable Drug Substance.
Would it be appropriate for the RSM manufacturer to develop analytical method considering the ICH Q3A limit? In this case the method may not be sensitive enough to determine particular nitrosamine impurities.
Should the RSM manufacturer coordinate with the respective customer for establishing appropriate limit? In this case, there will be repetition of same activity for the RSM manufacturer for different customers.
Would it be appropriate approach to develop analytical method at the LOQ of 0.03 ppm irrespective of any MDD? In this case there may be concern on the method sensitivity if in case the acceptable limit is found to be tighter later.
Please suggest better approach among the approach mentioned above or any other approach which may be feasible for RSM manufacturer and acceptable by API/ Drug Substance Manufacturer.
The methodology may be unified, while the limits should be established based on the clearance capability of the specific product’s synthetic process. A reasonable general limit can be formulated with reference to the synthetic process and detection level of the starting materials, and it is not imperative to implement the limits in strict accordance with the Acceptable Intake (AI) values for impurities with specific toxicity.
Thank you so much for the response Andrew . Is there any reference guidance in support of your response or any practical experience (case study)? It would be really helpful. Further, can we apply general limit of 0.03 ppm in API Starting material for balanced approach since it is not mandatory for an API Starting material to achieve control at the Acceptable intake level applicable for API (Drug Substance) and Drug Product.
The publication in the reference discussion is not accessible.
Further, I am looking for a help regarding the limits of common and small nitrosamine impurities in API RSM irrespective of any maximum daily dose. As explained in my query, suppose if any particular RSM is used in multiple APIs/ Drug Substance then what should be the approach to establish limit. I have also included some approach in my query.
I am aware of the same that limit is calculated based on AI and MDD of respective Drug Product. But, in case any particular RSM is used in multiple APIs/ Drug Substance then what should be the approach by RSM manufacturer. I have discussed few approaches in my query and looking for better or any other recommendations.
I feel, Even though the same RSM for different APIs, the limit is based on the respective DS or DP; it’s not generic like residual solvents. Otherwise, we would follow the lowest limit, like general Nitrosamines at 26.5 ng AI with 880mg/day, or the CPCA approach.
Thank you very much for the response once again DrNagaraju!!!
To set the limit of any nitrosamine impurities, we must know the Acceptable intake of that particular nitrosamine impurity and MDD of respective DS/ DP.
Acceptable Intake (AI) of general nitrosamines are not an issue since they are already published in various guidances.
The concern is about the MDD. As I have mentioned what should be the strategy by RSM manufacturer in the case of limited knowledge about APIs in which it may be getting used. If the list of APIs in which it is to be used is known then limit can be calculated based on the respective nitrosamine AI and MDD of the API/ DP (highest MDD can be considered on worst case scenario). But if in case, there is limited knowledge about the APIs in which it is to be used then how will the RSM manufacturer set the limit. I have already discussed different approach in my original query. Looking forward for better and acceptable approach from the same and/ or any other option.
. Is there any reference guidance in support of your response or any practical experience (case study)? It would be really helpful. Further, can we apply general limit of 0.03 ppm in API Starting material for balanced approach since it is not mandatory for an API Starting material to achieve control at the Acceptable intake level applicable for API (Drug Substance) and Drug Product.