Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of...
Transcript of Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of...
![Page 1: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/1.jpg)
Use of Mirabilis based purge calculations to understand
MI related risk and control strategy options
Case study examples (including management of N-nitrosamines)
CEO
chrisbarberlhasalimitedorg
Chris BarberACEM-JEMS
Tokyo Nov 2019
Acknowledgement
bull This presentation contains slides from
Dr Andy Teasdale of AZ who was
originally due to present
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenges of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
ICH M7 and the value of purge-based arguments
Is the impurity mutagenic
Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
bull Assessment and control of DNA reactive (mutagenic) impurities in
pharmaceuticals to limit potential carcinogenic risk
Analytical or in silico methods
ICH M7 and the value of purge-based arguments
bull Most syntheses introduce mutagenic impurities during drug synthesis
bull Proof that mutagenic impurities are absent in the final drug product can be obtained experimentally
bull Develop sensitive analytical techniques and measure in batches
bull Estimated by one medium sized organisation to be gt10000 hours year
bull ICH M7 allows the use of theory-based arguments for purge
bull This can save time (and money) without increasing patient risk
Reactive reagents
and intermediates
Are deliberately introduced to enable high-yielding syntheses
If present in the final drug product these may react with DNA
Are often rapidly lost in subsequent reaction or purification steps
Typically projects have ~5 potential mutagenic impurities to assess
Is Avoidance of Genotoxic IntermediatesImpurities Tenable for Complex Multistep Syntheses Elder Org Process Res Dev 2015 19 1437
ICH M7 and the value of purge-based arguments
bull The guidelines (section 8) define a series of control options for potentially mutagenic impurities
bull Theoretical methods can support options 3 and 4
Option 1
bull Test to show impurity levels below acceptable
level in final drug substance
Option 2
bull Test to show impurity levels below acceptable
level in raw material intermediatehellip
Option 3bull Test shows impurity levels above acceptable
level in a raw material intermediate PLUS
bull Evidence that subsequent purges will result in
final levels below acceptable level
Option 4
bull Sufficient knowledge that the purge is so high
that no testing is required
ICH M7 and the value of purge-based arguments
bull Purge-based approaches are written into the ICH M7 guidelines
bull Theoretical methods can support purge arguments
bull Must show an understanding of the fate of the impurity
bull Must be evidence-based
bull Chemical understanding of reactivitysolubility under the conditions used
bull Supported by relevant experimental data
bull Should be conservative in approach
bull Are commonly used in regulatory submissions
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 2: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/2.jpg)
Acknowledgement
bull This presentation contains slides from
Dr Andy Teasdale of AZ who was
originally due to present
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenges of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
ICH M7 and the value of purge-based arguments
Is the impurity mutagenic
Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
bull Assessment and control of DNA reactive (mutagenic) impurities in
pharmaceuticals to limit potential carcinogenic risk
Analytical or in silico methods
ICH M7 and the value of purge-based arguments
bull Most syntheses introduce mutagenic impurities during drug synthesis
bull Proof that mutagenic impurities are absent in the final drug product can be obtained experimentally
bull Develop sensitive analytical techniques and measure in batches
bull Estimated by one medium sized organisation to be gt10000 hours year
bull ICH M7 allows the use of theory-based arguments for purge
bull This can save time (and money) without increasing patient risk
Reactive reagents
and intermediates
Are deliberately introduced to enable high-yielding syntheses
If present in the final drug product these may react with DNA
Are often rapidly lost in subsequent reaction or purification steps
Typically projects have ~5 potential mutagenic impurities to assess
Is Avoidance of Genotoxic IntermediatesImpurities Tenable for Complex Multistep Syntheses Elder Org Process Res Dev 2015 19 1437
ICH M7 and the value of purge-based arguments
bull The guidelines (section 8) define a series of control options for potentially mutagenic impurities
bull Theoretical methods can support options 3 and 4
Option 1
bull Test to show impurity levels below acceptable
level in final drug substance
Option 2
bull Test to show impurity levels below acceptable
level in raw material intermediatehellip
Option 3bull Test shows impurity levels above acceptable
level in a raw material intermediate PLUS
bull Evidence that subsequent purges will result in
final levels below acceptable level
Option 4
bull Sufficient knowledge that the purge is so high
that no testing is required
ICH M7 and the value of purge-based arguments
bull Purge-based approaches are written into the ICH M7 guidelines
bull Theoretical methods can support purge arguments
bull Must show an understanding of the fate of the impurity
bull Must be evidence-based
bull Chemical understanding of reactivitysolubility under the conditions used
bull Supported by relevant experimental data
bull Should be conservative in approach
bull Are commonly used in regulatory submissions
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 3: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/3.jpg)
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenges of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
ICH M7 and the value of purge-based arguments
Is the impurity mutagenic
Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
bull Assessment and control of DNA reactive (mutagenic) impurities in
pharmaceuticals to limit potential carcinogenic risk
Analytical or in silico methods
ICH M7 and the value of purge-based arguments
bull Most syntheses introduce mutagenic impurities during drug synthesis
bull Proof that mutagenic impurities are absent in the final drug product can be obtained experimentally
bull Develop sensitive analytical techniques and measure in batches
bull Estimated by one medium sized organisation to be gt10000 hours year
bull ICH M7 allows the use of theory-based arguments for purge
bull This can save time (and money) without increasing patient risk
Reactive reagents
and intermediates
Are deliberately introduced to enable high-yielding syntheses
If present in the final drug product these may react with DNA
Are often rapidly lost in subsequent reaction or purification steps
Typically projects have ~5 potential mutagenic impurities to assess
Is Avoidance of Genotoxic IntermediatesImpurities Tenable for Complex Multistep Syntheses Elder Org Process Res Dev 2015 19 1437
ICH M7 and the value of purge-based arguments
bull The guidelines (section 8) define a series of control options for potentially mutagenic impurities
bull Theoretical methods can support options 3 and 4
Option 1
bull Test to show impurity levels below acceptable
level in final drug substance
Option 2
bull Test to show impurity levels below acceptable
level in raw material intermediatehellip
Option 3bull Test shows impurity levels above acceptable
level in a raw material intermediate PLUS
bull Evidence that subsequent purges will result in
final levels below acceptable level
Option 4
bull Sufficient knowledge that the purge is so high
that no testing is required
ICH M7 and the value of purge-based arguments
bull Purge-based approaches are written into the ICH M7 guidelines
bull Theoretical methods can support purge arguments
bull Must show an understanding of the fate of the impurity
bull Must be evidence-based
bull Chemical understanding of reactivitysolubility under the conditions used
bull Supported by relevant experimental data
bull Should be conservative in approach
bull Are commonly used in regulatory submissions
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 4: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/4.jpg)
ICH M7 and the value of purge-based arguments
Is the impurity mutagenic
Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
bull Assessment and control of DNA reactive (mutagenic) impurities in
pharmaceuticals to limit potential carcinogenic risk
Analytical or in silico methods
ICH M7 and the value of purge-based arguments
bull Most syntheses introduce mutagenic impurities during drug synthesis
bull Proof that mutagenic impurities are absent in the final drug product can be obtained experimentally
bull Develop sensitive analytical techniques and measure in batches
bull Estimated by one medium sized organisation to be gt10000 hours year
bull ICH M7 allows the use of theory-based arguments for purge
bull This can save time (and money) without increasing patient risk
Reactive reagents
and intermediates
Are deliberately introduced to enable high-yielding syntheses
If present in the final drug product these may react with DNA
Are often rapidly lost in subsequent reaction or purification steps
Typically projects have ~5 potential mutagenic impurities to assess
Is Avoidance of Genotoxic IntermediatesImpurities Tenable for Complex Multistep Syntheses Elder Org Process Res Dev 2015 19 1437
ICH M7 and the value of purge-based arguments
bull The guidelines (section 8) define a series of control options for potentially mutagenic impurities
bull Theoretical methods can support options 3 and 4
Option 1
bull Test to show impurity levels below acceptable
level in final drug substance
Option 2
bull Test to show impurity levels below acceptable
level in raw material intermediatehellip
Option 3bull Test shows impurity levels above acceptable
level in a raw material intermediate PLUS
bull Evidence that subsequent purges will result in
final levels below acceptable level
Option 4
bull Sufficient knowledge that the purge is so high
that no testing is required
ICH M7 and the value of purge-based arguments
bull Purge-based approaches are written into the ICH M7 guidelines
bull Theoretical methods can support purge arguments
bull Must show an understanding of the fate of the impurity
bull Must be evidence-based
bull Chemical understanding of reactivitysolubility under the conditions used
bull Supported by relevant experimental data
bull Should be conservative in approach
bull Are commonly used in regulatory submissions
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 5: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/5.jpg)
ICH M7 and the value of purge-based arguments
bull Most syntheses introduce mutagenic impurities during drug synthesis
bull Proof that mutagenic impurities are absent in the final drug product can be obtained experimentally
bull Develop sensitive analytical techniques and measure in batches
bull Estimated by one medium sized organisation to be gt10000 hours year
bull ICH M7 allows the use of theory-based arguments for purge
bull This can save time (and money) without increasing patient risk
Reactive reagents
and intermediates
Are deliberately introduced to enable high-yielding syntheses
If present in the final drug product these may react with DNA
Are often rapidly lost in subsequent reaction or purification steps
Typically projects have ~5 potential mutagenic impurities to assess
Is Avoidance of Genotoxic IntermediatesImpurities Tenable for Complex Multistep Syntheses Elder Org Process Res Dev 2015 19 1437
ICH M7 and the value of purge-based arguments
bull The guidelines (section 8) define a series of control options for potentially mutagenic impurities
bull Theoretical methods can support options 3 and 4
Option 1
bull Test to show impurity levels below acceptable
level in final drug substance
Option 2
bull Test to show impurity levels below acceptable
level in raw material intermediatehellip
Option 3bull Test shows impurity levels above acceptable
level in a raw material intermediate PLUS
bull Evidence that subsequent purges will result in
final levels below acceptable level
Option 4
bull Sufficient knowledge that the purge is so high
that no testing is required
ICH M7 and the value of purge-based arguments
bull Purge-based approaches are written into the ICH M7 guidelines
bull Theoretical methods can support purge arguments
bull Must show an understanding of the fate of the impurity
bull Must be evidence-based
bull Chemical understanding of reactivitysolubility under the conditions used
bull Supported by relevant experimental data
bull Should be conservative in approach
bull Are commonly used in regulatory submissions
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 6: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/6.jpg)
ICH M7 and the value of purge-based arguments
bull The guidelines (section 8) define a series of control options for potentially mutagenic impurities
bull Theoretical methods can support options 3 and 4
Option 1
bull Test to show impurity levels below acceptable
level in final drug substance
Option 2
bull Test to show impurity levels below acceptable
level in raw material intermediatehellip
Option 3bull Test shows impurity levels above acceptable
level in a raw material intermediate PLUS
bull Evidence that subsequent purges will result in
final levels below acceptable level
Option 4
bull Sufficient knowledge that the purge is so high
that no testing is required
ICH M7 and the value of purge-based arguments
bull Purge-based approaches are written into the ICH M7 guidelines
bull Theoretical methods can support purge arguments
bull Must show an understanding of the fate of the impurity
bull Must be evidence-based
bull Chemical understanding of reactivitysolubility under the conditions used
bull Supported by relevant experimental data
bull Should be conservative in approach
bull Are commonly used in regulatory submissions
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 7: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/7.jpg)
ICH M7 and the value of purge-based arguments
bull Purge-based approaches are written into the ICH M7 guidelines
bull Theoretical methods can support purge arguments
bull Must show an understanding of the fate of the impurity
bull Must be evidence-based
bull Chemical understanding of reactivitysolubility under the conditions used
bull Supported by relevant experimental data
bull Should be conservative in approach
bull Are commonly used in regulatory submissions
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 8: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/8.jpg)
ICH M7 and the value of purge-based arguments
bull Examples of purge-based arguments have been published
bull Best practice defined by large consortia of experts with regulatory input
bull Key publications
bull A consortium-driven framework to guide the
implementation of ICH M7 Option 4 control strategies
Barber C Reg Tox and Pharmacol 2017 90 22
bull New Semi-Automated Computer-Based System for
Assessing the Purge of Mutagenic Impurities
Burns M OPRD 2019
bull Short video available here httpsyoutubeOnclED3e4jc
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 9: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/9.jpg)
The purge factor and purge ratio
bull Purge factor =119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119887119890119891119900119903119890 119886 119904119905119890119901
119888119900119899119888119890119899119905119903119886119905119894119900119899 119900119891 119894119898119901119906119903119894119905119910 119886119891119905119890119903 119886 119904119905119890119901
bull A step is a reaction or a purification step
bull Overall purge = product of purge factors for individual steps
bull The fold-loss in impurity over all steps
bull Purge ratio = 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
bull The excess purge over that necessary
transformation
or purification
Impurity at
100ppm
Impurity at
1ppm
Purge factor =100
1= 100
100
10
1
Overall purge factor = 100 x 10 x 1 = 1000The purge factor can be measured or predicted
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 10: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/10.jpg)
Potential sources of purge
Physicochemical
parameter
Scale of purge factor
Reactivity
Highly reactive = 100
Moderately reactive = 10
Low reactivityunreactive = 1
Solubility
Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility
Boiling point gt20 degC below that of the reaction process solvent = 10
Boiling point within plusmn20 degC of that of the reactionprocess solvent = 3
Boiling point gt20 degC above that of the reaction process solvent = 1
pKa pKbIonisation potential of GTI significantly different from that of the desired
product
Physical processes
chromatography
Chromatography 10minus100 based on extent of separation
Physical processes eg other
scavenger resins
Evaluated on an individual basis
New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities Burns OPRD 2019
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 11: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/11.jpg)
A conservative approach to purgebull Recommended thresholds when making regulatory submissions under Option 4
Purge ratio (PR)Purge ratio =
119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
The excess purge over that necessary
Option 4 supported
Provide purge ratio
Option 4 supported
Provide full purge calculation and literature evidence andor non-trace analytical data to support
key purges
Option 4 supported only with
strong supporting data Full purge calculation literature
evidence and trace level
dataexperiments (eg spiking)
Option 4 not supported
Options 3 2 or 1 required
PR gt 1000 1000 gtPR gt 100 100 gt PR gt 1 PR lt 1
A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies Barber Reg Tox and Pharmacol 2017 90 22
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 12: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/12.jpg)
Introducing Mirabilis
bull Mirabilis can support the expert assessment and reporting of purge values for ICH M7
bull Using knowledge to conservatively estimate purges
bull Developed from a paper-based approach with a broad industry consortium and regulatory
engagement
bull Key benefits
bull Reproducible and efficient
bull Built around industry-defined best practice approach
bull Creates standardized reports that meet the requirements of regulators
bull Trusted and transparent
bull Robust and validated approach
bull Built around a knowledge base containing expert commentary experimental data
literature references mechanismshellip
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 13: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/13.jpg)
Introducing Mirabilis
bull A collaborative tool that
allows the expert to track
an impurity through
synthetic steps
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 14: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/14.jpg)
Introducing Mirabilis
bull Allows the assignment of
purge values using
expert knowledge
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 15: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/15.jpg)
Introducing Mirabilis
bull Create a report showing
impurities purges
calculations and
supporting information
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 16: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/16.jpg)
Agenda
bull ICH M7 and the value of purge-based arguments
bull Introducing Mirabilis ndash a tool to support expert
assessment of purge values
bull Recent challenge of nitrosamines amp implications
bull Conclusions
Purge-based arguments for the presence of mutagenic impurities
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 17: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/17.jpg)
N-Nitrosamines - status amp implications
bull Some N-nitrosamines are mutagenic carcinogens
bull Have been found to be present in some marketed drugs resulting in recall and regulatory demands
N-Nitroso dimethylamine
CH3+
DNA
P450
methyldiazohydroxide
diazomethane
carbonium ion
httpswwwsciencedirectcomtopicsneurosciencenitrosamines
NDMA
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 18: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/18.jpg)
N-Nitroso dimethylamine
Valsartan
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 19: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/19.jpg)
Purge ratio
= 119901119906119903119892119890 119891119886119888119905119900119903 119891119900119903 119905ℎ119890 119894119898119901119906119903119894119905119910
119903119890119902119906119894119903119890119889 119901119906119903119892119890 119891119886119888119905119900119903 119879119879119862 119900119903 119875119863119864
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 20: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/20.jpg)
Key conclusions
bull Valsartan was shown to contain NDMA
bull It is likely that this was introduced during the formation of the tetrazole ring
bull This was formed at final stage of synthesis
bull Limited opportunity for it to be purged
bull The tetrazole ring in Candesartan was formed much earlier in the synthesis
bull 4 further steps provides purging opportunities
bull High predicted purge of dimethylamine predicted before nitrite introduced (gt 1015)
bull High predicted purge of NDMA after any possible formation ( gt 104)
bull Confirmed in analytical experiments
bull Purge analyses can quickly identify and dismiss risks
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 21: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/21.jpg)
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
EMA Press release 5-7-2018 FDA recall
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 22: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/22.jpg)
Impact of discovering NDMA contamination
bull The discovery of NDMA in Valsartan has
resulted in the recall of some batches
bull This has been followed by a wider recall
of other sartans
bull Widened further by recall of other drugs with
NDMA risks
EMA1896342019
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 23: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/23.jpg)
Evaluation of nitrosamine risks for all drugs
bull 26 9 2019
bull ldquoEMArsquos human medicines committee
(CHMP) is requesting as a matter of
precaution that marketing authorisation
holders for human medicines
containing chemically synthesised
active substances review their
medicines for the possible presence of
nitrosamines and test all products at
riskrdquo
httpswwwemaeuropaeuennewsema-advises-companies-steps-take-avoid-nitrosamines-human-medicines
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 24: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/24.jpg)
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamineshellip
bull NDMA may result from solvent recycling (if not properly cleaned)
bull This is a GMP issue
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 25: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/25.jpg)
Other potential sources of nitrosamineshellip
bull The science is still emerging around the presence of nitrosamines hellip
bull NDMA may be a degradant formed during the analysis of Ranitidine
bull D Light (Valisure) notes that Ranitidine can degrade to NDMA under the
analytical conditions used to quantify it (10mol formed at 130oC 15mins)
bull FDA also note that this method is lsquonot suitable for testing ranitidinersquo
httpswwwchemistryworldcomnewsnitrosamine-contamination-withdrawals-spread-to-new-drugs4010505article
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine Carcinogenesis 2016 37 625
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 26: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/26.jpg)
Conclusions
bull ICH M7 allows the use of purge-based arguments to understand the risk of
mutagens present during synthesis surviving into the final drug product
bull Strong arguments on the purge of intermediates can replace testing
Is the impurity mutagenic Is the impurity present in the final API
What are the potential impurities
Implement a control strategy
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 27: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/27.jpg)
Conclusions
bull There is acceptance of purge-based arguments that remove the need to test
bull Significant costtime savings without increasing patient risk
bull Mirabilis is a tool to support expert assessment of purge
bull Developed with a broad consortium and regulatory engagement
bull Scientific principles and application published in peer reviewed journals
bull Emerging risks of nitrosamine contamination has implication for marketed drugs
bull Assessment of potential sources for nitrosamines needed
bull Purge-based analysis can inform where analytical testing is necessary
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems
![Page 28: Use of Mirabilis based purge calculations to understand MI ... · ICH M7 and the value of purge-based arguments • The guidelines (section 8) define a series of control options for](https://reader034.fdocuments.us/reader034/viewer/2022042319/5f090e067e708231d42503a2/html5/thumbnails/28.jpg)
Thank you
Established in 1983
HQ located in Leeds United Kingdom
Not-for-profit amp Educational Charity
Facilitate collaborative data sharing projects in the chemistry-related industries
Controlled by our members
Creators of knowledge base statistical and database systems