Qvents Template

Supplier Assessment and Risk Evaluation Templates for APIs

 

 

API Name

 

API Manufacturer Details

 

 

 

 

 

 

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.    

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

21.    

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

 

22.    

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

 

23.    

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

·        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

 

 

 

 

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  ¨ 

High if answer is Yes

2.       

Are nitrosating agents and secondary/tertiary amines present in the same manufacturing step of the API KSM process?

 

Yes ¨    /     No ¨        /        Not sure  ¨ 

High if answer is Yes

3.       

Are nitrosating agents and secondary/tertiary amines present in different manufacturing steps of the API process?

 

Yes ¨    /     No ¨        /        Not sure  ¨ 

Moderate if answer is Yes

4.       

Are nitrosating agents and secondary/tertiary amines present in different manufacturing steps of the KSM process?

Yes ¨    /     No ¨        /        Not sure  ¨ 

Moderate if answer is Yes

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  ¨ 

Moderate if answer is Yes

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  ¨ 

Minor if answer is Yes

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  ¨ 

High if answer is Yes

 

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  ¨ 

Moderate if answer is Yes

 

9.       

Are there shared equipment between this API and another product/intermediate with a Nitrosamine impurity risk?

 

(Due to nitrosating agents and secondary / tertiary amines or amide based solvents in same or different steps)

Yes ¨    /     No ¨        /        Not sure  ¨ 

Moderate if answer is Yes

 

10.    

Is recovered solvent used in API or KSM coming from a third party facility

Yes ¨    /     No ¨        /        Not sure  ¨ 

 

 

·        High, if third party site is used, but not evaluated.

·        Moderate / Minor, if third party site is used and evaluated

11.    

Is there potential for nitrosamine impurities to be carried into recovered solvent recovered at same facility.

  1. (If a site recover solvents from API or API KSM process where Nitrites and secondary / tertiary amine or amide based solvents are used in same or different steps, answer should be Yes)
  2. If a site recover 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, answer should be Yes

 

 

Yes ¨    /     No ¨        /        Not sure  ¨ 

 

 

·        High if for condition a answer is Yes

·        High to Moderate risk: if for condition b answer is Yes

·        Nil if there is no recovered solvent used in API/ KSM process.

 

12.    

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  ¨ 

·        Moderate to Minor (If answer is Yes)

 

 

 

13.    

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  ¨ 

 

14.    

Are solvents recovered from streams containing residual azides that are neutralized with nitrous acid?

Yes ¨    /     No ¨        /        Not sure  ¨ 

·        High if answer is Yes

15.    

Is there a risk of NDSRIs forming in the API or KSM process based on answers to Questions 21–23 in Questionnaire 1? Was Q21, 22 or 23 answered as Yes or Not sure?

Yes ¨    /     No ¨        /        Not sure  ¨ 

·        High if answer to Q21, 22 or 23 is Yes

·        Moderate if 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 / Chloramine / Nitrates with Ozone or Chlorine etc.

·        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

 

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, take action as per Moderate risk category.

·        If risk is Minor for any one of the questions, 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

Action

High
  • Identify the potential Nitrosamine impurity / NDSRI impurity that can be present
  • Implement specification controls for Nitrosamine / NDSRI impurities in both API 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
  • 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 both API and drug product
  • 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 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
  • 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 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.
  • If any incidence of results being above limit, implement specification control for Nitrosamines / NDSRIs in both API and 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.