Qvents Template
Supplier Assessment and Risk Evaluation Templates for Excipients

Excipient

Supplier Details

Nitrosamine Risk Assessment as High / Moderate / Minor / Nil

S. No.	Questions	Options	Nitrosamine Risk Evaluation
1.	Is sodium nitrite (NaNO₂) or any other nitrite or nitrosating agent: i. Used in any steps in the manufacturing process as reagents/catalyst? ii. Known to be used in the preparation of raw materials or intermediates used in the manufacturing process? iii. Known to be used in the preparation of reagents/catalysts/processing aids used in the manufacturing process? iv. Known to be generated as impurities during the manufacturing process? v. Deliberately added to the process, including components of cell culture media or for fermentation?	i. Yes ¨ / No ¨ / Don’t know ¨ ii. Yes ¨ / No ¨ / Don’t know ¨ iii. Yes ¨ / No ¨ / Don’t know ¨ iv. Yes ¨ / No ¨ / Don’t know ¨ v. Yes ¨ / No ¨ / Don’t know ¨
2.	Have you analysed, and are the results available for the excipient for: i. Nitrites? ii. Nitrates? iii. Nitrosamines? (Provide test result details as annexure)	i. Yes ¨ / No ¨ / NA ¨ ii. Yes ¨ / No ¨ / NA ¨ iii. Yes ¨ / No ¨ / NA ¨	(Supporting Info)
3.	Is water used in the manufacturing process? If “Yes”: i. Is the water used prepared by distillation, by ion exchange or by reverse osmosis? ii. If ‘no’ and potable water is used, where possible, please report the maximum level of nitrite. iii. Is the water used involve chloramine treatment (Nitrite is a controlled impurity in potable water with a WHO guideline limit of 3 mg/L and a European limit of 0.5 mg/L.)	Yes ¨ / No ¨ / NA ¨ i. Distillation ¨ / Ion exchange ¨ / Reverse osmosis ¨ ii. Potable water: Yes ¨ / No ¨ / NA ¨ iii. Chloramine treatment: Yes ¨ / No ¨ / NA ¨
4.	1. Are there any secondary and/or tertiary amines present in the manufacturing process as: i. Raw material? ii. Intermediate? iii. Reagent? iv. Processing aids? v. Catalyst /Base? vi. Solvent? 2. If yes, are those amines present in the - Same - Previous - Subsequent step as any nitrosating agent mentioned in S. No. 1?	1. Secondary / tertiary amines: i. Yes ¨ / No ¨ / Don’t know ii. Yes ¨ / No ¨ / Don’t know iii. Yes ¨ / No ¨ / Don’t know iv. Yes ¨ / No ¨ / Don’t know v. Yes ¨ / No ¨ / Don’t know vi. Yes ¨ / No ¨ / Don’t know 2. Same / Previous / Subsequent step as any nitrosating agent S.No.1 i. same ¨ / previous ¨ / subsequent ¨ ii. same ¨ / previous ¨ / subsequent ¨ iii. same ¨ / previous ¨ / subsequent ¨ iv. same ¨ / previous ¨ / subsequent ¨ v. same ¨ / previous ¨ / subsequent ¨ vi. same ¨ / previous ¨ / subsequent ¨
5.	Is there any amide, primary amine or ammonium salt used or present in the substance manufacturing process as; Raw material Intermediate Reagent Processing aid Catalyst / Base Solvent Washing Fluid Please provide any relevant information about the chemical name / structure of amine(s): …………………………………………………… ……………………………………………………	i. Yes ¨ / No ¨ / Don’t know ii. Yes ¨ / No ¨ / Don’t know iii. Yes ¨ / No ¨ / Don’t know iv. Yes ¨ / No ¨ / Don’t know v. Yes ¨ / No ¨ / Don’t know vi. Yes ¨ / No ¨ / Don’t know vii. Yes ¨ / No ¨ / Don’t know
6.	Recycled/recovered Solvents: - Are recycled / recovered nitrogen containing solvents used in the manufacturing process?	Yes ¨ / No ¨ / Don’t know
7.	Equipment: Is the excipient produced in multipurpose equipment? In case of multipurpose equipment, is the equipment used for manufacturing of any material involving nitrites, nitrosating agents or material with identified risk of formation of nitrosamines? Are chloramines used as part of cleaning procedures used for manufacturing equipment?	i. Yes ¨ / No ¨ / Don’t know ii. Yes ¨ / No ¨ / Don’t know iii. Yes ¨ / No ¨ / Don’t know
· *Note* 1: Risk of formation of nitrosamines and risk of carry over of Nitrites and / or secondary or tertiary amines to be assessed independent of each other · *Note* 2: Nitrosating agents to be considered : 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 nitrates · Note 3: Other sources of secondary amines: Amide containing solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-methyl pyrrolidinone (NMP), quaternary ammonium salts such as tetrabutylammonium bromide (TBAB), primary amines such as methylamine. Presence of such reagents along with nitrosating agents in the process lead to Moderate risk of nitrosamine · Note 4: Specification control for Nitrites / Nitrosating agents / amines in Excipients to be implemented based on the Nitrosamines and NDSRI Risk Assessment of Drug Products

Nitrosamine Risk Assessment

· Risk Categorisation of formation of Nitrosamine: High Risk, Moderate Risk, Minor Risk, Nil Risk

· High Risk:

o If Nitrites /Nitrosating agents as well as Secondary / Tertiary Amines are present in the same step in manufacturing process

· Moderate Risk:

o If Nitrites /Nitrosating agents and Secondary / Tertiary Amines are present in the in manufacturing process, but in different steps

o If Nitrites /Nitrosating agents are present in the manufacturing process and other contributing factors for secondary amines/ tertiary amines are present in the process. This include amides, primary amines or ammonium salt used or present in the substance manufacturing process, use of recycled / recovered nitrogen containing solvents in the manufacturing process,

o Potable Water which has potential to contribute Nitrites involved in the manufacturing process along with secondary amines / tertiary amines or other contributing factors for secondary amines/ tertiary amines

o If Water used is from distillation or reverse osmosis treatment possibility for Nitrites which can contribute to Nitrosamine formation may be considered Nil.

o If Water used is from ion exchange treatment consider possibility for amines which can contribute to Nitrosamine formation.

· Minor Risk:

o Use of Chloramine in Water treatment

o Use of Chloramine in Equipment cleaning procedures

o Use of multipurpose manufacturing equipment which is used in manufacture of material having risk of Nitrosamine formation

o Use of Water from Ion exchange treatment in process and presence of secondary amines / tertiary amines or other contributing factors for secondary amines/ tertiary amines

· Nil Risk: No possibility of Nitrites or Nitrosating factors along with Secondary / Tertiary amines or other contributing factors for secondary amines/ tertiary amines are present in the process. Process water by distillation or reverse osmosis process may be considered to have Nil possibility for presence of Nitrites.

· Uncertainty in responses: Where responses are Don’t Know, consider the contribution to risk of formation to Nitrosamines one step lower than when the responses are Yes. For example, If response to queries on Secondary / Tertiary Amines in the process with Nitrites in the same step is Don’t Know, the risk categorization may be considered Moderate. If response to use of Potable water which can contribute to presence of Nitrites is used in process along with use of Secondary / Secondary Amines is Don’t know, risk categorization may be considered Minor. Uncertainty brings down risk level one step lower in the case of High Risk and Moderate risk, but not for Minor risk. (High to Moderate, Moderate to Minor, But Minor will remain Minor).

· Carryover potential for Nitrites / Nitrosating factors:

· Where the process involves direct use of Nitrites / Nitrosating agents. For both Yes and Don’t Know responses consider carryover potential.

· Possibility for presence of Nitrites due to indirect factors (Potable water in process, use of multipurpose manufacturing equipment) may not be considered to have potential for Nitrites carry over.

· Carryover potential for Secondary / Tertiary Amines:

· Where the process involves direct use of Secondary amines / Tertiary amines/ amides / primary amines or ammonium salts, consider carry over risk of amines. For both Yes and Don’t Know responses consider carryover potential.

· Possibility for presence of secondary amines / tertiary amines due to indirect factors (use of recovered solvents, multipurpose equipment, water treatment by ion-exchange process) may not be considered to have potential for secondary amines / tertiary amines carryover.

Overall Risk Categorization & Actions

Risk Category for Formation of Nitrosamines	Action
High	· Identify the potential Nitrosamine impurity that can be present · Evaluate the batches for Nitrosamine impurities. · 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
Moderate	· Identify the potential Nitrosamine impurity that can be present · Evaluate the batches for Nitrosamine impurities. · 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 · Where specification controls are not implemented, keep monitoring a representative number of batches of excipients for Nitrosamine impurities annually. There shall be no incidence of any impurities being out of specifications
Minor	· Identify the potential Nitrosamine impurity that can be present · Evaluate the excipient batches for Nitrosamine impurities. · 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 · Where specification controls are not implemented, keep monitoring a representative number of batches of excipients for Nitrosamine impurities annually. There shall be no incidence of any impurities being out of specifications
Nil	· No further actions · Document the risk assessment with all supporting documents. Perform periodic reassessment of the excipient.
Carryover Potential for Nitrites is Yes	· Assess risk of formation of Nitrosamines / NDSRIs in the Drug product due to excipients carrying nitrites
Carryover Potential for Secondary / Tertiary Amines is Yes	· Assess risk of formation of Nitrosamines / NDSRIs in the Drug product due to excipients carrying Secondary / Tertiary Amines