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

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

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

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 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

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

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

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

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

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

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

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-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

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

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

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

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

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

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