The document discusses the risks and regulatory frameworks surrounding nitrosamines in human medicinal products, highlighting their potential presence, risks of cancer, and regulatory limits set by entities like the EMA and FDA. It outlines the measures that manufacturers should undertake to assess and mitigate the presence of nitrosamines, including risk assessments, confirmatory testing, and compliance with acceptable intake limits. Additionally, it details the various sources and pathways through which nitrosamines can contaminate pharmaceuticals, urging manufacturers to implement control strategies accordingly.

1. NITROSAMINES IN HUMAN
MEDICINAL PRODUCTS
By-
Dr. Nityanand S. Zadbuke
DOI: 10.13140/RG.2.2.11844.96643
FEB 2021

2. QUALITY MEDICINES
• A quality product of any kind consistently meets the expectations of the user
• Medicines are no different
• Patients expect safe and effective medicine
• Quality- assuring every dose is safe and effective, free of contamination and defects
MEDICINES
EFFICACY
QUALITY
SAFETY
FEB 2021

3. REGULATORY MESSAGE
FEB 2021

4. NITROSAMINES- REGULATORY STATUS
REGULATORY
STATUS
(NITROSAMINES)
USP General
Chapter
Prospectus:
<1469>
EMA
Implemented
Guideline
Ph. Eur. Adopts
a new general
chapter
USFDA
Implemented
Guideline
FEB 2021

5. Has my
medication been
recalled ???
What is my
Risk of getting
cancer ???
How can I get
more information
about
Nitrosamines ???
I got a recall
notice. Am I in
danger ???
Should I stop
taking my
medication ???
STAY UP TO DATE WITH REGULATORY RESOURCES
STAY UP TO DATE
FEB 2021

6. IMPACT OF NITROSAMINES
Import
Alert
Product
Recall
Safety
&
Quality
Change in ROS /
Reformulation
Risk
Assessment
Business Loss
GLOBAL IMPACT
OF
PRESENCE NITROSAMINES IN MEDICINAL PRODUCTS
Drug
Shortage
Warning
Letters
FEB 2021

7. 2018
• Recalls of Angiotensin II Receptar Blockers (ARBs)
• Valsartan, Losartan & Irbesartan
2019
• Recalls of Ranitidine & Nizatidine Products
2020
• Recalls of Metformin Products
BACKGROUND
FEB 2021

8. BACKGROUND
ranitidine
valsartan metformin
nizatidine
losartan
Chemical Structures of APIs Reported In Literature To Contain Nitrosamines:
diphenhydramine
FEB 2021

9. BACKGROUND
N-Nitroso compound (NDMA) Formation In Metformin HCl
FEB 2021

10. N-Nitroso compound (NDMA) Formation In Aminophenazone
Hydrolysis Nitrosation
BACKGROUND
FEB 2021

11. NITROSAMINES
• Nitrosamines are organic compounds that we are
exposed to in our everyday lives
• They exist in low levels in:
 Meat
 Vegetables
 Dairy Products
 Water
• Regulatory alert- for presence of Nitrosamines in
human medicinal products
FEB 2021

12. • Nitrosamine- a class of compounds having the chemical structure of a nitroso group
bonded to an amine
• Nitrosamines can form by a nitrosating reaction between
• Amines (secondary, tertiary, or quaternary amines) &
• Nitrous acid (nitrite salts under acidic conditions)
NITROSAMINES
FEB 2021

13. RISKS OF NITROSAMINES
• People taking drugs that contain nitrosamines at or
below the acceptable daily intake (ADI) limits
everyday for 70 years are not expected to have an
increased risk of cancer.
NITROSAMINE
Exposure above
acceptable
levels
RISK OF CANCER
FEB 2021

14. • EMA & FDA has identified seven nitrosamine impurities that theoretically could be present
in drug products are:
NITROSAMINES
Sr. No. Nitrosamine Structure
1
N-nitrosodimethylamine
(NDMA)
2
N-nitrosodiethylamine
(NDEA)
3
N-nitroso-N-methyl-4-aminobutanoic acid
(NMBA)
4
N-nitrosoisopropylethyl amine
(NIPEA)
5
N-nitrosodiisopropylamine
(NDIPA)
6
N-nitrosodibutylamine
(NDBA)
7
N-nitrosomethylphenylamine
(NMPA) FEB 2021

15. NITROSAMINES- REGULATORY CONSIDERATIONS
- QUALITY
a. Root causes for presence of N-nitrosamines and proposed measures to mitigate it
b. Consideration for analytical method development to identify and quantify N-nitrosamines
in drug substances and medicinal products
- QUALITY
a. As Low As Reasonably Achievable/Practicable
(ALARA/ALARP)
- SAFETY
a. Setting a limit based on toxicological data
(AI- Acceptable Intake)
(LTL- Less-Than-Lifetime Exposure)
- SAFETY
a. Setting a limit based on technical capability
(LOQ- Limit of Quantification)
1
2
3
4
FEB 2021

16. ACCEPTABLE INTAKE (AI) LIMITS OF NITROSAMINES
• EMA & FDA recommends the following AI limits for the nitrosamine impurities:
Sr. No. Nitrosamine
AI Limit
ng/day
1 N-nitrosodimethylamine (NDMA) 96.00
2 N-nitrosodiethylamine (NDEA) 26.50
3 N-nitroso-N-methyl-4-aminobutyric acid (NMBA) 96.00
4 N-Nitrosomethylphenylamine (NMPA) 26.50
5 N-nitrosoisopropylethyl amine (NIPEA) 26.50
6 N-nitrosodiisopropylamine (NDIPA) 26.50
• These limits are applicable only if a drug product contains a single nitrosamine
FEB 2021

17. DERIVATION OF THE INTERIM LIMITS FOR ACCEPTABLE INTAKE (AI)
• Nitrosamines are classified as Class 1 mutagenic impurities
• AI Limit is a daily exposure to a compound such as NDMA, NDEA, NMBA,NMPA,
NIPEA, or NDIPA that approximates a 1:100,000 cancer risk after 70 years of
exposure:
EXAMPLE- Using an AI of 96 ng/day for the target Nitrosamine
Name Acceptable Concentration (ng/gm)
Nitrosamine 1
50 mg dose
(0.050 gm)
100 mg dose
(0.100 gm)
250 mg dose
(0.250 gm)
1000 mg dose
(1.000 gm)
1920 960 384 96
FEB 2021

18. CONVERSION OF AI LIMITS INTO PPM
• Conversion of AI limit into ppm varies by product and is calculated
based on a drug’s maximum daily dose (MDD)
• EXAMPLE-
 NDMA acceptable intake (AI) = 96.0 ng/day*
 Maximum daily dose (MDD) of Metformin HCl = 3 gm
• Converted Limit In Metformin HCl-
• * Value from Carcinogenic Potency Database (CPDB)
FEB 2021

19. ACCEPTABLE INTAKE (AI) LIMITS OF NITROSAMINES
If more than one
nitrosamine
impurities
identified,
detected
Total quantity of
nitrosamine
exceeds 26.5
ng/day based on
the maximum
daily dose (MDD)
The
manufacturer
should contact
regulatory
agency for
evaluation
FEB 2021

20. ACCEPTABLE INTAKE (AI) LIMITS OF NITROSAMINES
For drug
products with
MDD
less than
880 mg/day
For drug
products with
MDD
above
880 mg/day
f
f
Limit for total nitrosamines 0.03 ppm (30 ng/day) is considered
acceptable
Limit for total nitrosamines should be adjusted so as not to exceed
the recommended limit of 26.5 ng/day
FEB 2021

21. ACCEPTABLE INTAKE (AI) LIMITS OF NITROSAMINES
Manufacturers
should contact
the regulatory
agency about
the
acceptability of
any proposed
limit
Acceptability
Should use the
approach
outlined in ICH
M7(R1) to
determine the
risk associated
with the
nitrosamine
Manufacturers
Found in drug
product
Nitrosamines
without AI limit
ICH
M7(R1)
How to set
a
limit
????
FEB 2021

22. WHAT TO DO ????-
API & DRUG PRODUCT MANUFACTURERS
1. Assess the risk of nitrosamine impurities in APIs, marketed
drug products, and products under approved and pending
applications.
2. Conduct confirmatory testing when there is any risk for the
presence of nitrosamine impurities.
3. If a risk of nitrosamine impurities is identified, confirmatory
testing of batches should be conducted using sensitive and
appropriately validated methods.
4. Report changes implemented to prevent or reduce nitrosamine
impurities in APIs and drug products to regulatory agency
FEB 2021

23. NITROSAMINES- RISK ASSESSMENT
IDENTIFICATION
CONTROL
RISK
ASSESSMENT
QUANTIFICATION
FEB 2021

24. NITROSAMINES- RISK ASSESSMENT
Implement a Control Strategy
Is the impurity present in final API ???
Is the impurity mutagenic ???
What are potential impurities ???
Analytical or
In Silico Methods
ICH
M7
Assessment & Control of DNA reactive
mutagenic impurities in pharmaceuticals to
limit potential carcinogenic risk
FEB 2021

25. CONTENT OF NITROSAMINES RISK ASSESSMENT
1. MATERIALS
a) Raw Materials
b) Recovered Solvents
c) Recovered Materials
d) Water
2. MACHINE
a) Chain of equipment used
b) Equipment cleaning procedures- Cross contamination
c) Cleaning solvents (such as dimethylformamide should be considered in the risk assessment)
3. METHOD (MANUFACTURING PROCESS & REACTION CONDITIONS)
a) Temperature
b) pH
c) Carbon treatment
d) Chemical reaction
e) Excess of alcohol
f) Possibility of carry overs
g) Use of Nitrosating agent
h) Primary Packaging- attention paid to the material with additives such as antistatic packaging
4. MEASUREMENT
a) Conduct confirmatory using sensitive and appropriately validated methods
b) ICH Q2(R1) –Validation of Analytical Procedures: Text and Methodology guideline for Limit Testing
5. MOTHER ENVIRONMENT
a) Dedicated facility with a dedicated in-house solvent recovery systems
b) Different manufacturing locations
6. MAN
a) Trained & Qualified Personnel (cGMP & ICH Q7)
FEB 2021

26. NITROSAMINES- RISK ASSESSMENT
Risk assessment can
be performed
Through a yes/no
questionnaire
Through a FMEA-type
tool with different
scores assigned to
various risk levels
FEB 2021

27. NITROSAMINES- RISK ASSESSMENT
Yes/No Questionnaire:
1) Is sodium nitrite (NaNO2) or any other nitrite or
nitrosating agent1
:
- used in any steps in the manufacturing
process2
as reagents/catalyst?
- known to be used in the preparation of
raw materials or intermediates used in the
manufacturing process?
- known to be used in the preparation of
reagents/catalysts/processing aids used in
the manufacturing process?
- Known to be generated as impurities
during the manufacturing process?
YES ☐
YES ☐
YES ☐
YES ☐
NO ☐
NO ☐
NO ☐
NO ☐
Information
not available
☐
☐
☐
2) Have you analysed, and are the results available
for the excipient for:
- Nitrites?
- Nitrates?
- Nitrosamines?
If yes, please provide test results for the tested
analyte and a general indication of the applied test
method and indicate if testing was performed in-
house or contracted out.
YES ☐
YES ☐
YES ☐
NO ☐
NO ☐
NO ☐
Test result,
if available
FEB 2021

28. NITROSAMINES- RISK ASSESSMENT
Yes/No Questionnaire:
3) If water is used in the manufacturing processError!
Bookmark not defined.
, is it prepared by distillation, by ion
exchange or by reverse osmosis?
If “No”, please inform about the maximum level of
- Nitrites
- Nitrates
(Note: Purified water according Ph. Eur. complies with a
nitrates level of maximum 0.2 ppm)
YES ☐
____ ppm
____ ppm
NO ☐
Not
specified
☐
☐
Not applicable
☐
☐
☐
4) Is there any secondary and/or tertiary amine1
present in the manufacturing process asError! Bookmark not
defined.
:
- Raw material2
?
- Intermediate?
- Reagent?
- Processing aids?
- Catalyst / Base?
- Solvent?
If yes, are those amines present in the
- Same
- Previous
- Subsequent
step as any nitrosating agent mentioned in section 1?
Information about the chemical name / structure of
amine(s):
……………………………………………………
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
Not applicable
☐
☐
☐
FEB 2021

29. NITROSAMINES- RISK ASSESSMENT
Yes/No Questionnaire:
5) Is there any amide, primary amine or ammonium
salt1
used or present in the substance manufacturing
process as:
- Raw material
- Intermediate
- Reagent
- Processing aid
- Catalyst / Base
- Solvent
- Washing Fluid
Information about the chemical name / structure:
……………………………………………………
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
YES ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
NO ☐
6) Recycled/recovered Solvents:
- Are recycled / recovered nitrogen containing
solvents used in the manufacturing process?
YES ☐ NO ☐
7) Multipurpose Equipment6
:
- Is the substance 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?
YES ☐
YES ☐
NO ☐
NO ☐
Not applicable
☐
FEB 2021

30. NITROSAMINES- RISK ASSESSMENT
Packaging b
Solvents/Water b Drug Substance a
Formation
during storage c
Manufacturing
Process b Excipients b
Nitrosamines
In
Drug Product
Ishikawa (Fishbone) Diagram:
Potential sources of nitrosamine impurities in drug product
a- Primary/predominant source of potential nitrosamines
b- Secondary source of potential nitrosamines
c- Formed by a mechanism other than degradation of the drug substance FEB 2021

31.  In Silico Tool
 Number of advantages over the paper based approach
 Systematic layout- consistent approach
 Purge analyses can quickly identify and dismiss risks
 Access to detailed information that makes / assists
predictions
 ICH M7 allows the use of theory based arguments for purge
Use of Purge Calculations:
NITROSAMINES- RISK ASSESSMENT
FEB 2021

32. NITROSAMINES- RISK ASSESSMENT
• ICH M7 guideline (section 8) define a series of control options for potentially mutagenic
impurities
• Theoretical methods can support options 3 and 4
• Option 4 is especially useful for those impurities that are introduced early in the
synthesis and are effectively purged
OPTION 1
- Test to show impurity levels below acceptable level in
final drug substance
OPTION 2
- Test to show impurity levels below acceptable level in
raw material, intermediate…
OPTION 3
- Test shows impurity levels above acceptable level in a
raw material, intermediate... PLUS
- Evidence that subsequent purges will result in final
levels below acceptable level
OPTION 4
- Sufficient knowledge that the purge is so high that no
testing is required
ICH M7
FEB 2021

33. NITROSAMINES- RISK ASSESSMENT
Purge Factor & Purge Ratio:
FEB 2021

34. NITROSAMINES- RISK ASSESSMENT
Purge Factor & Purge Ratio:
FEB 2021

35. NITROSAMINES- RISK ASSESSMENT
Impurity requires management as (potentially) mutagenic impurities
(P)MI
Determine Purge Ratio (PR) in Current API route for (P)MI
Predicted purge factor for (P)M
Purge Ratio (PR) = -----------------------------------------------------------------------
Required purge factor to achieve PDE for P(MI)
Select initial ICH M7 control strategy for (P)MI during development based on
Purge Ratio. Implement recommended experimental data collection and
regulatory reporting strategies based upon Purge Ratio (next slide)
Does Final
Package Support
Commercial ICH
M7 Option 4
Strategy ???
Purge Prediction Decision Tree:
Select ICH M7 Option 1,2
or 3 commercial strategy,
as appropriate
Select ICH M7 Option 4
commercial strategy NO
YES
FEB 2021

36. SOURCE/PATHWAYS FOR PRESENCE OF NITROSAMINES
API
EXCIPIENT
SOLVENT
MANUFACTURING
PROCESS
DRUG PRODUCT
STABILITY
HEAT
HYDROLYSIS
WATER
HYDROLYTIC/THERMAL
DEGRADATION
CONTAINER-
CLOSURE SYSTEM
NITROSATION
FEB 2021

37. SOURCE/PATHWAYS FOR PRESENCE OF NITROSAMINES
Sr. No.
Source/Pathway For Presence
Nitrosamines
Observed Risk
1 Impurities In Solvents
 Presence of residual dialkyl amines or tri-substituted amines that can
degrade to form dialkyl amines (e.g., triethylamine)
 Presence of nitrites (NaNO2) or other nitrosating agents
 Presence of acid
 Limited controls/specification limits for recycled solvents
 Poor quality water or solvents
2 Impurities In Water
 Presence of residual dialkyl amines or tri-substituted amines that can
degrade to form dialkyl amines (e.g., triethylamine)
 Presence of nitrites (NaNO2) or other nitrosating agents
 Presence of acid
3 Impurities In Excipients  Presence of nitrites or other nitrosating agents
4 Impurities In Drug Substance/API
 Use of sodium azide and nitrite for azide quenching in the synthesis in
acid media
 Use of di- or tri-alkylamines and amides (e.g., dimethylformamide
[DMF], dimethylamine [DMA], triethylamine [TEA], N-
methylpyrrolidone [NMP]) in the presence of nitrites and acid media
 Use of recycled solvents that may contain nitrosamines or their
precursors
 Use of sanitized water (e.g., chloramines)
 Need of additional purification steps (e.g., crystallization)
FEB 2021

38. Sr. No.
Source/Pathway For Presence
Nitrosamines
Observed Risk
5 Manufacturing Process
 Contamination
 Use of poor quality or recycled solvents that may contain nitrosamines
or their precursors
 Poor quality solvents
 Presence of nitrous oxides in air used to dry the API or drug product
6 Drug Product (including stability)
 Secondary or tertiary amine group in molecule
 Presence of nitrate counter ions (potentially as an impurity)
 Potential reactions within the formulation matrix during stability/shelf
life (e.g., presence or generation of acidic conditions, moisture, and
heat)
7 Impurities In Container–Closures
 Thermal decomposition of nitrocellulose to produce nitrites followed
by migration to the drug product (e.g.- Blister packs with lidding foil
containing nitrocellulose)
 Biodegradation of nitrocellulose during the blister heat-sealing process
to produce nitrites followed by migration to the drug product
 Low molecular weight amines present either in printing ink
SOURCE/PATHWAY FOR PRESENCE OF NITROSAMINES
FEB 2021

39. NITROSAMINES- CONTROL STRATEGY
STRAT
Conduct Risk Assessment of manufacturing process
Address potential modes of contamination as possible
Potential
Nitrosamine
source is
identified ??
Take necessary measures to control risk as appropriate
(e.g.- reevaluate/modify process, supply materials
Risk
Acceptance
??
Establish control strategy to remain in state of control
(e.g- Change in management is an integral part of the
control strategy)
END
NO
NO
Process 1
Process 2
Process 3
YES
Decision 2
Decision 1
FEB 2021

40. • Should be controlled in ingredients
Identified as
impurities in
ingredients
• Should be controlled in drug product
Identified as
degradation product
• Should be controlled in manufacturing
process to achieve acceptable levels or
the elimination of nitrosamine impurities
in the drug product
Identified in the
manufacturing
process
NITROSAMINES- CONTROL STRATEGY
FEB 2021

41. NITROSAMINES- RISK ASSESSMENT OUTCOME
Outcome of the risk
assessment can be
- High/Medium/Low
- Risk Mitigation Plan
- Negligible outcome
Risk is Confirmed
Control Strategy
&
Decision to proceed to analytical testing FEB 2021

42. NITROSAMINES- RISK QUANTIFICATION
CHOICE OF ANALYTICAL METHOD
CHALLENGES IN QUANTIFICATION
OF NITROSAMINES
RECOMMENDED
ANALYTICAL METHODS
FOR
QUANTIFICATION OF
NITROSAMINES
• Has to guarantee the unambiguous
determination
• Specificity and selectivity
• Validated
• Physicochemical properties
• Low molecular weight
• high selectivity and sensitivity
required down to the picomole
range
• GC-MS
• GC-MS/MS
• LC-MS/MS
• HPLC–HRMS
FEB 2021

43. RECOMMENDATIONS TO API MANUFACTURERS
1. Mitigating the Presence of Nitrosamine Impurities in APIs:
Optimize
Route of Synthesis
(ROS)
Controlled
Reaction
Conditions
(pH, Temp, Time)
Avoid
Secondary,
Tertiary,
Quaternary
Bases
CAUTION-
ROS involves
amide solvents
-Control on
Raw/Starting
Materials &
Intermediates
-Replace Nitrites
Process with
Nitrosamine
Purge Study
Analyze nitrite
and nitrosamine
levels in water
FEB 2021

44. RECOMMENDATIONS TO API MANUFACTURERS
2. Control of Nitrosamine Impurities in APIs:
NITROSAMINE
ABOVE
LOQ
Develop control
strategy to keep
nitrosamines
within AI limit
Conduct testing
of each batch
Any batch with
nitrosamine
above AI limit
should not be
released for
distribution
Include
specification
limit
FEB 2021

45. RECOMMENDATIONS TO DRUG PRODUCT MANUFACTURERS
API
Manufacturers
Drug Product
Manufacturers
Evaluation of
Degradation
Pathway
Nitrosamine
Risk
Assessment In
Drug Product
No Potential
For
Nitrosamine
Impurities
No need to
take further
action
FEB 2021

46. RECOMMENDATIONS TO DRUG PRODUCT MANUFACTURERS
Control of Nitrosamine Impurities in Drug Product:
NITROSAMINE
ABOVE
LOQ
Develop control
strategy to keep
nitrosamines
within AI limit
Conduct testing
of each batch
Any batch with
nitrosamine
above AI limit
should not be
released for
distribution
Include
specification
limit
FEB 2021

47. RECOMMENDATIONS TO DRUG PRODUCT MANUFACTURERS
CONTROL
STRATEGY
Eliminate
Source of
Contamination
(Sources)
Evaluate At-risk
APIs
Manufacturing
Process
Evaluate
consistency of
API Supplier
Through
Continuous
Testing of Lots
Evaluate
Nitrosamines in
Drug Product
Over Shelf Life
FEB 2021

48. RECOMMENDATIONS TO API & DRUG PRODUCT MANUFACTURERS
CONTROL STRATEGY
LIFECYCLE
ICH Q10
Pharmaceutical
Quality System
ICH M7(R1)
Assessment and
Control of DNA
Reactive (Mutagenic)
Impurities in
Pharmaceuticals To
Limit Potential
Carcinogenic Risk
ICH Q9
Quality Risk
Management
FEB 2021

49. RECOMMENDATIONS TO API & DRUG PRODUCT MANUFACTURERS
REPORTING CHANGES
TO
REGULATORY
AUTHORITY
Change in route of synthesis (ROS)
of API #
Reprocessed or reworked batch of
API
Change in manufacturing process
of approved or marketed drug
product (DP) #
Change in API supplier of
approved or marketed drug
product (DP) #
Conduct a risk assessment in API,
DP & confirmatory testing prior to
submission
If nitrosamines detected above the
LOQ but is within the AI limit
#- All changes should be handled through the change management process as part of the organization quality management system
FEB 2021

50. CONCLUSION
Presence of
Nitrosamines
Control
Strategy
FEB 2021

51. REFERENCES
1. General Chapter: ˂2.5.42˃ N-Nitrosamines in active substances Ph.Eur. (Adopted by the European
Pharmacopoeia Commission (Dec 2020)
2. General Chapter: <1469> Nitrosamine Impurities USP-NF (Jan 2021)
3. ICH guidance for industry Q9 Quality Risk Management (June 2006)
4. ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009)
5. ICH guidance for industry Q11 Development and Manufacture of Drug Substances (November 2012)
6. ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active 23 Pharmaceutical Ingredients
(September 2016)
7. ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in
Pharmaceuticals To Limit Potential Carcinogenic Risk (March 2018)
8. EMA/189634/2019 - Information on Nitrosamines for Marketing Authorization Holders
9. Health Canada - Information to Marketing Authorization Holders (MAH) of Human Pharmaceutical Products
Regarding Nitrosamines Impurities (Letter- October 2019)
10. EFPIA decision tree “Drug substance manufacturing process risk assessment for presence of Nnitrosamines”
11. IPEC Europe. Questionnaire for Excipient Nitrosamines Risk Evaluation. Guidance, Conducting purge assessments
12. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-
impurities
13. APIC Additional guidance on the assessment on the risk assessment for presence of N-nitrosamines in APIs
(2020)
14. Dr Andrew Teasdale, AstraZeneca, Presentation On “N-Nitrosamines Status / Implications” (Jan 2020)
15. Michael J. Burns, Andrew Teasdale, Eric Elliott, and Chris G. Barber, Controlling a Cohort: Use of Mirabilis-Based
Purge Calculations to Understand Nitrosamine-Related Risk and Control Strategy Options, Org. Process Res. Dev.
2020, 24, 1531−1535.
16. Chris Barber, Lhasa Ltd, Presentation On “Use of Mirabilis based purge calculations to understand
17. MI related risk and control strategy options” (Nov 2019)
18. https://www.fda.gov/about-fda/fda-pharmacy-student-experiential-program/nitrosamine-impurities-drugs-
what-health-care-professionals-need-know FEB 2021

52. THANK YOU
FOR YOUR ATTENTION
NITROSAMINE
CONTROL IN
MEDICINAL
PRODUCTS
TEAM WORK
FEB 2021