Qvents Template
Nitrosamines and NDSRI Risk Assessment of Drug Products
Drug Product Name:		Drug Product Manufacturer Details:
Number of APIs involved in the Process
1	API Name:	API Vendor Details:
2	API Name:	API Vendor Details:
3	………..	……………………………
Number of Excipients involved in the Process
1	Excipient Name:	Excipient Vendor Details:
2	Excipient Name:	Excipient Vendor Details:
4	……………………….	……………………………………..
Number of Primary Packing Materials (PPM) involved
1	PPM Name:	PPM Vendor Details:
2	………………..	………………………………...

Nitrosamine Risk Assessment of Drug Products Questionnaire
S. No.	Questions	Answers	Nitrosamines / NDSRI Risk Category
Nitrosamine Carry over from API / Excipients / Water / Packing Material
1.	Risk of Nitrosamine Carry over from API	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨
2.	Risk of NDSRIs Carry over from API	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨
3.	Risk of Nitrosamines Carry over from Excipients	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨
4.	Risk of Nitrosamines Carry over from Water used in process	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨
5.	Risk of Nitrosamines from Printed Packing Material: Is there possibility for Nitrosamine generation (NDMA / NDEA) due to interaction of nitrocellulose in lidding foil with primary amines in printing ink	Yes ¨ / No ¨ / Not sure ¨
Risk of Nitrosamines formation in the Drug Product Manufacturing process
6.	Is there potential for secondary amines / tertiary amine residues carry over in APIs	Yes ¨ / No ¨ / Not sure ¨
7.	Is there potential for Nitrites carry over in APIs	Yes ¨ / No ¨ / Not sure ¨
8.	Are Nitrites/ Nitrosating impurities possible from excipients used in process	Yes ¨ / No ¨ / Not sure ¨
9.	Are secondary amines / tertiary amine residues possible from excipients used in process	Yes ¨ / No ¨ / Not sure ¨
10.	Does Water used in the drug product manufacturing have Nitrite / Nitrosating impurities risk	Yes ¨ / No ¨ / Not sure ¨
11.	Does Water used in the drug product manufacturing have amine residues risk	Yes ¨ / No ¨ / Not sure ¨
12.	Are any Manufacturing equipment shared with other products at risk of formation of Nitrosamines	Yes ¨ / No ¨
Risk of NDSRI Formation in the Drug Product Manufacturing process
13.	Does the APIs used in process or API impurities have secondary or tertiary amine functional group	Yes ¨ / No ¨
14.	Can degradation of API used in the process or the API impurities produce secondary or tertiary amine functional groups	Yes ¨ / No ¨
15.	Risk of NDSRI: 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 Formulation	Yes ¨ / No ¨ / Not sure ¨
16.	Are any Manufacturing equipment shared with other products at risk of formation of NDSRI impurities	Yes ¨ / No ¨
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.

Nitrosamines Risk Categorisation

High

· When possibility for both Nitrites and Secondary / Tertiary Amines residues from APIs, Excipients are High

· When risk of carryover of Nitrosamines from API or Excipients or Water is High

Moderate

· When possibility for Nitrites or Amines from APIs, Excipients or Water are Moderate

· When risk of carryover of Nitrosamines from API or Excipients or Water is Moderate

Minor

· When risk of carryover of Nitrosamines from API or Excipients or Water is Minor

· When manufacturing equipment are shared with other products at risk of Nitrosamine impurities

Nil

· When possibility of Nitrites or Amines from APIs, Excipients, Process Water are Nil

· When risk of carryover of Nitrosamines from API or Excipients or Water is Nil

NDSRI Risk Categorisation

High

· When risk of carry over of NDSRI impurities from API is High

· When APIs used in process or API impurities have secondary or tertiary amine functional group and risk of Nitrites is high

· When there is possibility for formation of the NDSRI impurities listed in the USFDA Guidance Control of Nitrosamines in Human Drugs and / or EMA/CMDh: Appendix 1 for Nitrosamines

Moderate

· When risk of carry over of NDSRI impurities from API is Moderate

· When APIs used in process or API impurities have secondary or tertiary amine functional group and risk of Nitrites is Moderate

· When degradation of API used in the process or the API impurities produce secondary or tertiary amine functional groups and risk of Nitrites is High

Minor

· When risk of carry over from API is Minor (Q2 is Minor)

· When degradation of API used in the process or the API impurities produce secondary or tertiary amine functional groups is Yes and risk of Nitrites is Moderate

· When manufacturing equipment are shared with other products at risk of NDSRI impurities formation

Nil

· When risk of carryover of NDSRIs from API is Nil and risk of formation of NDSRIs in the Formulation is Nil

Nitrites risk is considered High when related responses are answered Yes and Moderate when answered Not sure

Amines risk is considered High when related responses are answered Yes and Moderate when answered Not sure

Overall Risk Categorization & Actions

A. Risk Categorization

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

· If risk is High for any one of the questions, take action as per High risk category.

· If risk is Moderate for any one of the questions, and if there is no High risk category, take action as per Moderate risk category.

· If risk is Minor for any one of the questions and there is no High or Moderate risk category, take action as per Minor risk category.

· If risk is NIL against all questions, 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	Action
High	Identify the potential Nitrosamine impurity / NDSRI impurity that can be present Implement specification controls for Nitrosamine / NDSRI impurities in API (where applicable), excipients (where applicable) and drug product Establish alert and action limits for Nitrites / Amines for Process Water if water has a Nitrites risk or Amines risk Initiate mitigation measures to reduce / prevent nitrosamine impurities risk Initiate stability monitoring of batches for Nitrosamines / NDSRI impurities
Moderate	Identify the potential Nitrosamine impurity / NDSRI impurity that can be present Evaluate representative batches of API (where applicable), Excipients (where applicable) and Drug product for Nitrosamine / NDSRI impurities Implement specification controls in APIs and Excipients if detectable amounts of Nitrosamine / NDSRI impurities are observed If nitrosamines / NDSRI exceed 10% of Acceptable Intake (AI) in drug product batches establish specification controls for drug product and also initiate stability monitoring of drug product batches Establish alert and action limits for Nitrites / Amines for Process Water if water has a Nitrites risk or Amines risk Where specification controls are not warranted, monitor representative batches annually. There shall be no out of specifications
Minor	Identify the potential Nitrosamine impurity / NDSRI impurity that can be present Evaluate representative batches of API (where applicable), Excipients (where applicable) and Drug product for Nitrosamine / NDSRI impurities Implement specification controls for Nitrosamines / NDSRIs if impurities are observed at higher than 10% of the Acceptable Intake (AI) limits in drug product and initiate stability monitoring of the batches Establish alert and action limits for Nitrites / Amines for Process Water if water has a Nitrites risk or Amines risk Where specification controls are not warranted, monitor representative batches annually. There shall be no out of specifications
Nil	Nil Risk Document the risk assessment with all supporting documents. Perform periodic reassessment.