Qvents Templates

Nitrosamines Risk Assessment of APIs – Supplier Questionnaire Evaluation

API Name

API Manufacturer Details

Preliminary Evaluation

S. No.	Questions	Answers	(Risk Evaluation Matrix)
Questionnaire 1
1.	Is Sodium Nitrate or any other Nitrosating agents involved in the Route of Synthesis (ROS) for the API?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
2.	Is Sodium Nitrate or any other Nitrosating agents involved in the Route of Synthesis (ROS) for the Key Starting Material (KSM)?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
3.	Are Secondary or Tertiary Amines used in API ROS	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2.
4.	Are Secondary or Tertiary Amines used in API KSM ROS	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
5.	Are amide-based solvents (e.g., N,N-DMF, NMP), which can produce secondary amines, used in the API’s ROS?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
6.	Are amide-based solvents (e.g., N,N-DMF, NMP), which can produce secondary amines, used in the KSM’s ROS?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
7.	Are azides (e.g., NaN3) used in the API’s ROS?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
8.	Are azides (e.g., NaN3) used in the KSM’s ROS?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
9.	Are recovered solvents used during the API manufacturing process?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
10.	Are recovered solvents used during the KSM manufacturing process?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
11.	Is there a possibility that solvents used in the process contain traces of triethylamine or other secondary/tertiary amines alongside sodium nitrite or other nitrites?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
12.	Are third-party facilities involved in recovering solvents used in the API’s manufacturing process?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
13.	Are third-party facilities involved in recovering solvents used in the KSM’s manufacturing process?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
14.	Are nitrosating agents used in any other product or process at the API site?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
15.	Are nitrosating agents used in any other product or process at the KSM site?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
16.	Are secondary or tertiary amines used in any other process at the API manufacturing site?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
17.	Are secondary or tertiary amines used in any other process at the KSM manufacturing site?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
18.	Are amide-based solvents (e.g., N,N-DMF, NMP) used in any other process at the API manufacturing site?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
19.	Are amide-based solvents (e.g., N,N-DMF, NMP) used in any other process at the KSM manufacturing site?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
20.	Is water used in the manufacturing process?	Yes ¨ / No ¨ / NA ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
21.	Are there any other risks of nitrosamine contamination, generation, or presence in the API manufacturing process?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
22.	Risk of NDSRI in API: Does the API have secondary or tertiary amine functional group and nitrites are involved in manufacturing process?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
23.	Risk of NDSRI in API : Can the degradation of starting materials, intermediates, or the finished API produce secondary or tertiary amine functional groups, with nitrites present in the manufacturing process leading to NDSRI risk?	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
24.	Risk of NDSRI in API: Is there a possibility for any of the NDSRI impurities as per USFDA Guidance Control of Nitrosamines in Human Drugs and / or EMA/CMDh: Appendix 1 for Nitrosamines list to be formed in the API or KSM process.	Yes ¨ / No ¨ / Not sure ¨	· If NO, Nil Risk. · If Yes / Not Sure go to Questionnaire 2
· If response to all questions are No proceed to Overall Risk Categorization as Nil Risk. Questionnaire 2 is not required to be evaluated. If for any question answer is Yes or Not sure proceed for extended assessment as per Questionnaire 2 · Carryover risk of Nitrites: Yes if Sodium Nitrate or any other Nitrosating agents involved in the Route of Synthesis (ROS) for the API (Question 1) · Carryover risk of Amines: Yes if Secondary or Tertiary Amines used in API ROS (Questions 3) · Nitrosating agents: Nitrites (e.g., sodium nitrite, NaNO2) and nitrous acid (HNO2), nitric oxide (NO), nitric oxide due to nitric acid, nitrosyl halides (e.g., ClNO, BrNO), dinitrogen trioxide (N2O3), dinitrogen tetroxide (N2O4) and organic nitrites (e.g., t-BuONO), Ozone with amines leading to nitrites, Chloramine Other sources of secondary amines: Amide based solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-methyl pyrrolidinone (NMP), quaternary ammonium salts such as tetrabutylammonium bromide (TBAB), tertiary amine bases, primary amines such as methylamine, azides. · Note: Nil risk against answer No for each question is only applicable to the specific question. Consider each question as independent of each other for performing the complete evaluation

Detailed Evaluation

Questionnaire 2:			(Nitrosamine Risk Evaluation Matrix)
S. No.	Query	Yes/No/I Not sure	Risk Category
1.	Are nitrosating agents and secondary/tertiary amines present in the same manufacturing step of the API process?	Yes ¨ / No ¨ / Not sure ¨
2.	Are nitrosating agents and secondary/tertiary amines present in the same manufacturing step of the API KSM process?	Yes ¨ / No ¨ / Not sure ¨	As per Overall Risk Categorisation Matrix
3.	Are nitrosating agents and secondary/tertiary amines present in different manufacturing steps of the API process?	Yes ¨ / No ¨ / Not sure ¨
4.	Are nitrosating agents and secondary/tertiary amines present in different manufacturing steps of the KSM process?	Yes ¨ / No ¨ / Not sure ¨
5.	Are nitrosating agents and amide-based solvents (e.g., DMF, NMP) that can produce secondary amines present in the same manufacturing step of the API or KSM process?	Yes ¨ / No ¨ / Not sure ¨
6.	Are nitrosating agents and amide-based solvents (e.g., DMF, NMP) that can produce secondary amines present in different manufacturing steps of the API or KSM process?	Yes ¨ / No ¨ / Not sure ¨
7.	Is there a possibility that solvents used in the process contain traces of triethylamine or other secondary/tertiary amines while nitrosating agents are present in the same step?	Yes ¨ / No ¨ / Not sure ¨
8.	Is there a possibility that solvents used in the process contain traces of triethylamine or other secondary/tertiary amines while nitrosating agents are present in different steps?	Yes ¨ / No ¨ / Not sure ¨
9.	Are there shared equipment between this API and another product/intermediate with a Nitrosamine impurity risk? (Risk due to nitrosating agents and secondary / tertiary amines or amide based solvents in same or different steps)	Yes ¨ / No ¨ / Not sure ¨
10.	Is recovered solvent used in API or KSM coming from a third party facility i. Is the third party facility evaluated for nitrosamines carry over risk? ii. Is there nitrosamine impurity carry over risk in recovered solvents from third party facility?	Yes ¨ / No ¨ / Not sure ¨ i. Third party risk evaluation: Yes ¨ / No ¨ / NA ¨ ii. Nitrosamine risk: Yes ¨ / No ¨ / Not sure ¨
11.	Potential for nitrosamine impurities to be carried into API from recovered solvents recovered at same facility. i. Does the site recover and reuse solvents from API or API KSM process where Nitrites and secondary / tertiary amine or amide based solvents are used in same or different steps ii. Does the site recover and reuse solvents in the same facility from a different API or API KSM process where Nitrites and secondary / tertiary amine or amide based solvents are used in same or different steps	i. Same API / KSM: Yes ¨ / No ¨ / NA ¨ ii. Different API / KSM: Yes ¨ / No ¨ / NA ¨
12.	Nitrosamines due to Process Water: i. Does the API / KSM process use potable water and secondary / tertiary amine or amide based solvents are used in same or different steps ii. Does the API / KSM process involve sodium nitrite or other nitrites and use water from ion exchange process in same or different steps iii. Does the Process water treatment involve Chloramine	i. Potable Water: Yes ¨ / No ¨ / NA ¨ ii. Water with Ion exchange process: Yes ¨ / No ¨ / NA ¨ iii. Chloramine in process water: Yes ¨ / No ¨ / NA ¨
13.	Does the manufacturing process involve nitrosating agents and bases like N-methylmorpholine (NMM) or tributylamine (TBA), which can form Nitrosamine derivatives in same or different manufacturing steps?	Yes ¨ / No ¨ / Not sure ¨
14.	Does the process involve nitrosating agents and reagents like quaternary ammonium salts (e.g., TBAB) or primary amines that can produce secondary/tertiary amines in same or different steps? (	Yes ¨ / No ¨ / Not sure ¨
15.	Are solvents recovered and reused from streams containing residual azides that are neutralized with nitrous acid?	Yes ¨ / No ¨ / Not sure ¨
16.	Is there a risk of NDSRIs forming in the API or KSM process based on answers to Questions 22–24 in Questionnaire 1? Was Q22, 23 or 24 answered as Yes or Not sure?	Yes ¨ / No ¨ / Not sure ¨
· For Questionnaire 2, wherever answer is Not Sure, consider risk as High, unless supported with additional scientific rationale to categorize as Moderate, Minor or Nil. · Nitrosating agents: Nitrites (e.g., sodium nitrite, NaNO2) and nitrous acid (HNO2), nitric oxide (NO), nitric oxide due to nitric acid, nitrosyl halides (e.g., ClNO, BrNO), dinitrogen trioxide (N2O3), dinitrogen tetroxide (N2O4) and organic nitrites (e.g., t-BuONO), Ozone with amines leading to nitrites, Chloramine Other sources of secondary amines: Amide based solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-methyl pyrrolidinone (NMP), quaternary ammonium salts such as tetrabutylammonium bromide (TBAB), tertiary amine bases, primary amines such as methylamine, azides. · Consider each question as independent of each other for performing the evaluation for specific aspect. Overall Risk Categorization shall be considering the risk categorization against each question.

Overall Risk Categorization & Actions

Risk of formation or carryover of Nitrosamines / NDSRIs from the process:

High:

1. If Nitrites and Secondary / Tertiary Amines are in same step in manufacturing process for API or Key starting material (If Not sure consider Moderate risk)

2. If third party sites are involved in solvent recovery and no risk assessment is done or risk assessment shows that there is risk of nitrosamine impurity carry over risk from third party site

3. If there is risk of NDSRIs formation in API due to secondary / tertiary amine functional groups in API / degradation of API, Intermediates, starting materials which interact with nitrites in the process or product (If Not sure consider Moderate risk)

Moderate

4. If Nitrites and Secondary / Tertiary Amines are in different manufacturing steps in manufacturing process for API or Key starting material (If Not sure consider Minor risk)

5. If Nitrosating agents and amide based solvents which can generate secondary amines present in same manufacturing steps (If Not sure, Minor risk

6. If there are shared equipment between the API and other products (API or intermediate) with Nitrosamine impurity risk (If Not sure, Minor risk)

7. If solvents are recovered at the same facility from APIs or API KSMs at risk of Nitrosamine impurities and reused in the process

8. If process use Potable water and solvents with potential for secondary /tertiary amines to be present are also used in the process in same or different steps

9. If process has potential for nitrites and also has has potential for formation of secondary / tertiary amines due to process reagents like NMM, TBA, Quarternary ammonium salts, primary amines (If Not sure Minor)

10. If solvents are recovered from streams containing residual azides neutralized with nitrous acid and reused

Minor

11. If Nitrosating agents and amide based solvents which can generate secondary amines present in different manufacturing steps

12. If process use water generated by ion exchange process and process also has potential for presence of nitrites

13. If Chloramine is used in the treatment of process water used in the process

Nil Risk

14. If third party sites are involved in solvent recovery and risk assessment shows that there is no risk of nitrosamine impurity carry over risk from third party site or there is no use of third party facilities for recovery of solvents

15. Other responses indicating there is no risk of secondary amines / tertiary amines and nitrites interacting in same or different steps of the process.

Carryover risk of Nitrites /Amines:

· Carryover risk of Nitrites: Yes if Sodium Nitrate or any other Nitrosating agents involved in the Route of Synthesis (ROS) for the API (Question 1 response Yes or Not sure)

· Carryover risk of Amines: Yes if Secondary or Tertiary Amines used in API ROS (Questions 3 response is Yes or Not sure)

Based on the supplier evaluation and risk categorization take actions as below..

· If risk is High due to any one of the conditions, take action as per High risk category.

· If risk is Moderate due to any one of the conditions, take action as per Moderate risk category.

· If risk is Minor due to any one of the conditions, take action as per Minor risk category.

· If risk is NIL, no further evaluation or testing required. Perform periodic reassessment of the vendor and if risk category changes, take action as per appropriate risk category.

Risk Category for Formation of Nitrosamines	Action
High	Identify the potential Nitrosamine impurity / NDSRI impurity that can be present Implement specification controls for Nitrosamine / NDSRI impurities in API · Evaluate API and Drug Product batches for Nitrosamine / NDSRI impurity. If nitrosamine levels in the Drug product are not more than 10% of the recommended Acceptable Intake (AI) limit, a formal specification limit is not needed in Drug product. If nitrosamines exceed 10% but are still within the AI limit, establish specifications controls in both the release and stability specifications for the Drug product Initiate, stability monitoring of batches for Nitrosamines / NDSRI impurities Initiate mitigation measures to reduce / prevent nitrosamine impurities risk
Moderate	Identify the potential Nitrosamine impurity / NDSRI impurity that can be present · Evaluate API and Drug Product batches for Nitrosamine / NDSRI impurity. If any incidence of Nitrosamine impurities higher than 10% of the limits in API batches implement specification controls for Nitrosamine / NDSRI impurities in API batches. Initiate, stability monitoring of batches for Nitrosamines / NDSRI impurities If nitrosamine levels in the drug product are not more than 10% of the recommended Acceptable Intake (AI) limit, a formal specification limit is not needed in Drug product. If nitrosamines exceed 10% but are still within the AI limit, specifications should be established in both the release and stability specifications for the Drug product If specification controls are not warranted, keep monitoring a representative number of batches of APIs and Drug product for Nitrosamine / NDSRI impurities annually. There shall be no incidence of any impurities being out of specifications
Minor	Identify the potential Nitrosamine impurity / NDSRI impurity that can be present Evaluate API batches for the impurity. If any incidence of Nitrosamine impurities higher than 10% of the limits in API batches implement specification controls for Nitrosamine / NDSRI impurities in API batches. Initiate, stability monitoring of batches for Nitrosamines / NDSRI impurities If any incidence of results being above limit, implement specification control for Nitrosamines / NDSRIs in both API and drug product. Document the risk assessment with all supporting documents. Perform periodic reassessment of the API.
Nil	Nil Risk Document the risk assessment with all supporting documents. Perform periodic reassessment of the API.
Carryover Potential for Nitrites is Yes	Assess risk of formation of Nitrosamines / NDSRIs in the Drug product due to API carrying nitrites
Carryover Potential for Secondary / Tertiary Amines is Yes	Assess risk of formation of Nitrosamines / NDSRIs in the Drug product due to API carrying Secondary / Tertiary Amines