Qvents Template

Nitrosamines and NDSRIs Risk Assessment Template for Drug Products

API Name	API Vendor Details
Excipient 1	Vendor Details
Excipient 2	Vendor Details
…………..
Excipient (n)
Primary packing material (PPM1)	Vendor detail
Primary packing material (PPM1)	Vendor Detail

Risk Assessment Matrix (Categorise risk as High / Moderate / Minor / Nil)

S. No.	Questions	Answers	Nitrosamine Risk Evaluation Matrix
Nitrosamine Carry over from API / Excipients / Water / Packing Material
1.	Risk of Nitrosamine Carry over from API	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨	· (As per API Nitrosamine Questionnaire and assessment)
2.	Risk of NDSRIs Carry over from API	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨	· (As per API Nitrosamine Questionnaire and assessment)
3.	Risk of Nitrosamines Carry over from Excipients	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨	· (As per Excipients Nitrosamine Questionnaire and assessment)
4.	Risk of Nitrosamines Carry over from Water used in process	High ¨ / Moderate ¨ / Minor ¨ / Nil ¨	· (As per Nitrosamine Risk Assessment of Process Water)
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 ¨	· Moderate if answer is Yes or Not Sure · Nil if answer is No
Risk of Nitrosamines formation in the Drug Product Manufacturing process
6.	Is there potential for secondary amines / tertiary amine residues carry over in API	Yes ¨ / No ¨ / Not sure ¨	· High if answer is Yes and Nitrite impurities are possible in excipients or water · Moderate if answer is Not sure and Nitrite impurities are possible in excipients or water · Nil if answer is No · Nil if answer is Yes but Nitrite / Nitrosating impurities are not possible in excipients or water
7.	Is there potential for nitrites carry over in API	Yes ¨ / No ¨ / Not sure ¨	· High if answer is Yes and amine residues are possible in excipients or water · Moderate if answer is Not sure and amine residuea are possible in excipients or water · Nil if answer is No · Nil if answer is Yes but amine impurities are not possible in excipients or water
8.	Are Nitrites/ Nitrosating impurities possible from excipients used in process	Yes ¨ / No ¨ / Not sure ¨	· High if answer is Yes and amine residues are possible in API or water · Moderate if answer is Not sure and amine residuea are possible in API or water · Nil if answer is No · Nil if answer is Yes but amine impurities are not possible in API or water
9.	Are secondary amines / tertiary amine residues possible from excipients used in process	Yes ¨ / No ¨ / Not sure ¨	· High if answer is Yes and Nitrite /Nitrosating residues are possible in API or water · Moderate if answer is Not sure and Nitrite / Nitrosating residue are possible in API or water · Nil if answer is No · Nil if answer is Yes but Nitrite / Nitrosating impurities are not possible in excipients or water
10.	Can Water used in the drug product manufacturing have Nitrite / Nitrosating impurities	Yes ¨ / No ¨ / Not sure ¨	· High if answer is Yes and amine residues are possible in API or excipients · Moderate if answer is Not sure and amine residuea are possible in API or excipients · Nil if answer is No
11.	Can Water used in the drug product manufacturing have amine residues	Yes ¨ / No ¨ / Not sure ¨	· High if answer is Yes and Nitrite residues are possible in API or excipients · Moderate if answer is Not sure and Nitrite residue are possible in API or excipients · Nil if answer is No
12.	Risk of NDSRI Formation in the Drug Product Manufacturing process.
13.	Does the API / API impurities have secondary or tertiary amine functional group	Yes ¨ / No ¨ / Not sure ¨	· High if answer is Yes and Nitrite / Nitrosating impurities are possible in excipients or water · Moderate if answer is Not sure and Nitrite / Nitrosating impurities are possible in excipients or water · Nil if answer is No · Nil if answer is Yes, but Nitrite / Nitrosating impurities are not possible in excipients or water
14.	Can the degradation API /API impurities produce secondary or tertiary amine functional groups	Yes ¨ / No ¨ / Not sure ¨	· Moderate if answer is Yes / Not sure and Nitrite / Nitrosating impurities are possible in excipients or water · Nil if answer is No · Nil if answer is Yes, but Nitrite / Nitrosating impurities are not possible in excipients or water
· If response to all questions are No proceed to Overall Risk Categorization as Nil Risk. · Wherever response is Not Sure, treat it as High Risk 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

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 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 Evaluate the API / Excipient / Water for nitrites and amines impurities as applicable (where this is a possible carry over impurity). Establish specifications controls such that formation of Nitrosamines / NDSRI will not cause product failure Initiate mitigation measures to reduce / prevent nitrosamine impurities risk If the risk of formation of NDSRI impurities are High, stability monitoring of batches for formation of NDSRI impurities to be initiated
Moderate	Identify the potential Nitrosamine impurity / NDSRI impurity that can be present Evaluate the batches for Nitrosamine / NDSRI impurities in API(where applicable), excipients (where applicable) and drug product If detectable amounts of Nitrosamine impurities are observed in API batches or Excipient batches implement specification controls for Nitrosamine / NDSRI impurities in API batches and Excipient batches. 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 Evaluate the API / Excipient / Water for nitrites and amines impurities as applicable (where this is a possible carry over impurity). Establish specifications controls such that formation of Nitrosamines / NDSRI will be in control in drug product. If NDSRI impurities are observed during testing initiate stability studies to monitor NDSRI impurities Where specification controls are not implemented, 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 the API and /or Excipients batches (as applicable) 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. If detectable amounts of Nitrosamines are observed in the excipient, establish scientifically sound specification limits for the Nitrosamines in the excipient such that carry over of the impurity into drug product will not cause product failure Evaluate the API / Excipient / Water for nitrites and amines impurities as applicable (where this is a possible carry over impurity). If the evaluation of drug product shows show that the level of impurity is more than 10% of acceptable intake (AI) levels,, implement specification controls for the impurities in API, Excipients, Water where applicable Evaluate the drug product batches for Nitrosamine / NDSRI impurities in API(where applicable), excipients (where applicable) and drug product 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 NDSRI impurities are observed during testing initiate stability studies to monitor NDSRI impurities
Nil	Nil Risk Document the risk assessment with all supporting documents. Perform periodic reassessment of the API.

B. Actions required

Summaries the actions required on Drug Product / API / Excipient(s) / Water

Area	Actions
Drug Product	1. ……………………………………………………………………………………………………………………………………. 2. ……………………………………………………………………………………………………………………………………. 3. …………………………………………………………………………………………………………………………………….
API	1. ……………………………………………………………………………………………………………………………………. 2. ……………………………………………………………………………………………………………………………………. 3. …………………………………………………………………………………………………………………………………….
Excipient(s)	1. ……………………………………………………………………………………………………………………………………. 2. ……………………………………………………………………………………………………………………………………. 3. …………………………………………………………………………………………………………………………………….
Water	1. ……………………………………………………………………………………………………………………………………. 2. ……………………………………………………………………………………………………………………………………. 3. …………………………………………………………………………………………………………………………………….