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Dr. Paulo Eliandro
Application of chemistry concepts to risk mitigation of nitrosamines contamination in drug products: strategies and suitability of methods
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1. What is a nitrosamine?
CHEMISTRY
2. How is a nitrosamine formed?
QUALITY
3. How to evaluate the risk in drug products?
How is excipient playing a vital role?
ICH
Summary
The examples were created by Paulo for this presentation or obtained from literature
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What is a nitrosamine?
Nitrosamine impurities may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time, but a person taking a drug that contains nitrosamines at, or below, the acceptable daily intake limits every day for 70 years is not expected to have an increased risk of cancer.
N-nitrosodimethyllamine
(NDMA)
N-nitrosodiethylamine
(NDEA)
In total, 40.4 % of the analyzed APIs and 29.6 % of the API impurities are potential nitrosamine precursors.
(Schlingemann J, 2022)
~90% Drug Substance contain a Nitrogen atom
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Brazilian Scenario
Integra´s historical data
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Brazilian Scenario
No risk
61%
Risk NDRIs
36%
Risk in DS + DP 3%
Products of High priority
1 g/day and > 1 year treatment
12 months from 2022
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Brazilian Scenario
No risk
61%
Risk NDRIs
36%
Risk in DS + DP 3%
66% Low Risk
33% High risk
CPCA review
Products of High priority
> 1 g/day and > 1 year treatment
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Brazilian Scenario
Products of High priority
> 1 g/day and > 1 year treatment
No risk
80%
Risk NDRIs
20%
CPCA review
9
Brazilian Scenario
No risk
58%
Risk NDRIs
39%
Risk in DS + DP 3%
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How is a nitrosamine formed?�
2020 Lhasa Webinar: Controlling a cohort - Understanding the risk of nitrosamines within drug substance synthesis
Gaur, P., & Banerjee, S., Synthetic Communications 2019, 1–10. doi:10.1080/00397911.2019.1622733
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How is a nitrosamine formed?�
2020 Lhasa Webinar: Controlling a cohort - Understanding the risk of nitrosamines within drug substance synthesis
Gaur, P., & Banerjee, S., Synthetic Communications 2019, 1–10. doi:10.1080/00397911.2019.1622733
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How is a nitrosamine formed?�
Retrosynthesis
Amine or derivative
Nitrosating agent
Synthesis
Amine or
N-derivative
Nitrosating
agent
Conditions
How is a nitrosamine formed?�
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How is a nitrosamine formed?�
Retrosynthesis
Amine or derivative
Nitrosating agent
Oxidation :
M. Burns et al, Org. Process Res. Dev., 2020, 24 (9), 1558
How is a nitrosamine formed?
Gliclazide
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How is a nitrosamine formed?�
https://www.youtube.com/watch?v=XjUTaIYdDdA
https://www.youtube.com/c/PauloEliandro
Retrosynthesis
Step 1
Step 2
Step 3
How to evaluate the risk in drug products?
Step 1
Step 2
Step 3
How to evaluate the risk in drug products?
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
Risk Assessment
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
07
What is the control strategy?
Which one?
02
03
ICH M7 Classification
04
What is the limit?
05
Is the patient exposed?
CONFIRMATORY TEST?
06
WORKFLOW
NO RISK FOR THE PATIENT
NO
YES
01
A nitrosamine can be formed?
Risk Assessment
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
07
What is the control strategy?
Which one?
02
03
ICH M7 Classification
04
What is the limit?
05
Is the patient exposed?
CONFIRMATORY TEST?
06
WORKFLOW
NO RISK FOR THE PATIENT
NO
YES
01
A nitrosamine can be formed?
Risk Assessment
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
Risk Assessment
Nortriptyline HCl
Route of Synthesis
Created by Paulo for this presentation
ICH Q11?
KSM is corrected defined?
What is the LSM RoS?
Nortriptyline HCl
Route of Synthesis
Created by Paulo for this presentation
Synthesis or Degradation of Impurity?
Route of Synthesis
Evaluation of impurities profile
What synthetic impurities could be carried over to DP and be nitrosated?
Síntese
Purge Factor for API Impurities
Síntese
Purge Factor for API Impurities
Synthesis or Degradation of Impurity?
Drinking water
Peptides
Chemical synthesis procedure
1
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*EMA <Guideline on the Development and Manufacture of Synthetic Peptides> (Draft)
Drug DS-Semisynthetic method
Fermentation procedure
Biological process features
Synthetic properties
1
Biological impurities
Nitrosamine
Evaluation of reference manufacturing process
Route of Synthesis
Created by Paulo for this presentation
Step 1 ：Preparation of peptide resins
Semaglutide
Step 2 ：Cleavage of peptide resins
Step3 : Purification
Purge Factor Calculation
Need Restricted part
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
Where is the Nitrosating agent?
Risk Assessment of DRUG PRODUCT
Hattrem, 2017
API with N
Risk Assessment of Excipient
☐ Mined excipients, N-free products of fermentation or natural origin, …
☐ Synthetic origin and nitrogen containing
☐ Proteins, enzymes,
products of fermentation or extraction of biologic sources, ...
☐ N-free mineral acids or
bases, organic solvents, polymers, inorganic salts, small organic N-free entities, …
yes
Yes
No
No
Target Excipient: �Nitrogen containing?
Chemical Synthetic Manufacturing Process? �including processes to introduce chemically synthesized fragments to biological products or substances of natural origin
IPEC. Questionnaire for Excipient Nitrosamines Risk Evaluation – version 3
MOST OF THE TIMES THERE IS NO INFORMATION
Risk Assessment of Excipient
10.1081/DDC-120030419
Manufacturing Process Risk
Packing Material Risk
Known risk : Nitrocellulose risk
NO AMINE
NO EXCIPIENT
18 ng/day
AI = 0,0000045 ppm
(4 L/dia)
Elastomer disk
< 0.1%
NDBzA
Rubber risk
Voloshenko, Anna & Rimma, Shelkov & Lev, Ovadia & Gun, Jenny. (2011). Analytica chimica acta. 685. 162-9. 10.1016/j.aca.2010.11.026.
Medical devices?
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
Risk Assessment
Quality Risk
Cross contamination
Cleaning Validation
Detergent
Water
Useful tool
What nitrosamines could come from the DS and what impurities could be carried out to DP?
RISK IN THE API
DP RISK
POTENTIAL IMPURITIES RISK (SYNTHESIS AND DEGRADATION)
Impureza ou Degradação do IFA
Are there other degradation of Impurities?
- Theoretical Forced Degradation study
Could it be formed?
Could it be formed?
Could it be formed?
No risk
No risk
No risk
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
07
What is the control strategy?
Which one?
02
03
ICH M7 Classification
04
What is the limit?
05
Is the patient exposed?
CONFIRMATORY TEST?
06
WORKFLOW
NO RISK FOR THE PATIENT
NO
YES
01
A nitrosamine can be formed?
Risk Assessment
SIM
Nitrosamine on the list for Annex I?
Anexo I compliant limit
NÃO
Harmonized limit between EMA, FDA and HC?
SIM
Use Harmonized Limit
NÃO
There are data from�carcinogenicity?
SIM
Limit from TD50
NÃO
Choose one of the options
CPCA
Read across
TTC nitrosamines(18 ng/day)
NÃO
Mutagenicity in vivo negative?
SIM
According to Q3A (upon agency approval)
NÃO
Negative optimized Ames test?
SIM
Use TTC �1.5 ug/day
Limits for nitrosamines
Fernanda Waechter
Chem. Res. Toxicol. 2022, 35, 1997−2013
Org. Process Res. Dev. 2020, 24, 1558−1585
What influences the potency of nitrosamines?
WORKFLOW
CPCA
https://integraconsultancy.com.br/pontuacao-cpca/
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
07
What is the control strategy?
Which one?
02
03
ICH M7 Classification
04
What is the limit?
05
Is the patient exposed?
CONFIRMATORY TEST?
06
WORKFLOW
NO RISK FOR THE PATIENT
NO
YES
01
A nitrosamine can be formed?
Risk Assessment
How much could be formed?
Risk Assessment of Excipient
Worst Scenario
TOTAL OF NITRITES AND NITRATES
Risk Assessment of Excipient
TOTAL OF NITRITES AND NITRATES
Does exceed the limit, and the API contains secondary amine
In the worst scenario,
Does not exceed TTC if converted
LIMITING REAGENT ?
RISK
NO RISK
1 Mol
1 Mol
1 Mol
0.1 Mol
0.1 Mol
1 Mol
Optimal condition: Excess of Nitrite
Cálculo de cinética reacional
Kinetic Simulation
[NO2] = Total of Nitrites from Worst Scenario Calculation and Literature
Solution simulation
Ashworth · 2020
DP RISK
POTENTIAL IMPURITIES RISK
Cálculo de cinética reacional
Kinetic Simulation
Plot worst case scenario for solid = more conservative
High Risk
39 ppm to 193
Cálculo de cinética reacional
Kinetic Simulation
Cálculo de cinética reacional
Kinetic Simulation
| [Predicted] (ppm) | AI (ppm) | Risk |
1 | 8971 | 260 | High |
Antioxidant System:
Citric acid and sodium citrate
Cálculo de cinética reacional
Kinetic Simulation
| [Experimental] | AI (ppm) | Risk |
1 | < 2 ppb | 260 | Low |
Antioxidant System:
Citric acid and sodium citrate
Cálculo de cinética reacional
Kinetic Simulation
| [Nitrite] (M) | [Predicted] (ppm) | AI (ppm) | Risk |
1 | 0.00004 | 283 | 6.67 | High |
Cálculo de cinética reacional
Kinetic Simulation
| [Nitrite] (M) | [Predicted] (ppm) | AI (ppm) | Risk |
1 | 0.00004 | 283 | 6.67 | High |
0.000001 | 0.09 | Low |
Nitrite quantification
5 ppb
| [Experimental] | AI (ppm) | Risk |
1 | < 2 ppb | 6.67 | Low |
DS
DP
Route of Synthesis
Water
Intermediate
KSM
Reagents
Solvents
Materials recovery
Cross contamination
Cleaning validation
Packing material
Solvents
DP Process
Cross contamination
Excipient
Excipient compatibility
Degradation
Degradation
Packing material
07
What is the control strategy?
Which one?
02
03
ICH M7 Classification
04
What is the limit?
05
Is the patient exposed?
CONFIRMATORY TEST?
06
WORKFLOW
NO RISK FOR THE PATIENT
NO
YES
01
A nitrosamine can be formed?
Risk Assessment
WORKFLOW
What´s coming next?
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paulo@integraconsultancy.com.br
+55 16 99449 3113