ICH_M7(R2)_2ndAddendum_Step_4_Presentation_2023_0516.pdf

ICH_M7(R2)_2ndAddendum_Step_4_Presentation

1. 1
ICH M7(R2): Assessment and Control
of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit
Potential Carcinogenic Risk
2
nd
Addendum
Step 4document –to be implemented
16 May 2023
International Council for Harmonisationof Technical Requirements
for Pharmaceuticals for Human Use

2. 2
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•
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•
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ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)
2

3. 3
Background
•
ThesecondrevisionofICHM7(R2)wasdevelopedbasedonthe
ConceptPaper(19September2018)
•
ICHM7(R2)includesa2
nd
AddendumtoICHM7complementingthe
firstAddendumpublishedinICHM7(R1).The2
nd
Addendumwas
signedoffasaStep2document(6October2021)tobeissuedbythe
ICHRegulatoryMembersforpublicconsultation
•
The2
nd
Addendumwasdevelopedtoincludeadditionalmonographs
for7mutagenicimpuritiesandderiveAcceptableIntakes(AIs)for
them
•
AdditionallyanupdatewasmadeinthemainM7guidelinetext
changingtheHIVtreatmentdurationfrom1-10yearsto>10years-
lifetime
•
AfterpublicconsultationandEWGdiscussions,thisdocumenthas
beensignedoffasa Step4document(3April2023)tobe
implementedbytheICHRegulatoryMembers
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

4. 4
Key Principles
•
This presentation provides a summary of the second addendum and
revisions of ICH M7(R1)
•
This presentation explains the merger of the first addendum with this
second addendum
•
The addendum is now a separate document to the core guideline and
both documents will be linked on the ICH website
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

5. 5
Guideline Objectives
•
ObjectivesremainthesameasindicatedinICHM7
guidelinefinalizedJune23
rd
2014•
Theguidelinerevision(R2)focusesonselectingadditional
relevantmutagenicimpuritiesanddevelopmonographs
withcompoundspecificAIstoincludeintheAddendum
•
Revise the main guideline
•
changing the HIV treatment duration from 1-10 years to > 10 years -
lifetime
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

6. 6
Table of Contents
•
List of Abbreviations•
Introduction
•
Methods
•
Acceptable Intakes (AIs) or Permissible Daily Exposures
(PDEs)
•
Monographs for 21 chemicals commonly occurring as
impurities in drug substances
o
Compiled monographs of chemicals with derived AIs or PDEs of the
first and second addendum
•
Notes 1-5
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

7. 7
List ofAbbreviationsusedin thispresentation
•
AI –AcceptableIntake
•
API –ActivePharmaceuticalIngredient
•
ATSDR –Agency for Toxic Substances and Disease Registry
•
CPDB –CarcinogenicityPotencyDatabase
•
EWG –Expert Working Group
•
HC –Health Canada, Canada
•
HPRT –Hypoxanthine-Guanine-Phosphoribosyltransferase
•
NTP-TR –National ToxicologyProgram-Technical Report
•
PDE –PermissibleDaily Exposure
•
TD
50
–Tumor Dose 50 (dose with50 % tumorbearinganimals)
•
US-EPA –United States Environmental ProtectionAgency
•
WHO-IPCS –World HealthOrganisation-International Programon Chemical
Safety
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

8. 8
Summary of Guideline Content
•
The addendum explains the development of chemical
specific AIs or PDEs (when appropriate)•
Methods used to develop AIs or PDEs and in which cases
an AI and in which cases a PDE should be developed
•
21 monographs developed for individual chemicals
according to methodology explained in the addendum
•
Change of HIV treatment duration from 1 -10 years to >10
years -lifetime in Note 7, table 4
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

9. 9
Results of Public Consultation
•
Addition of Note 3 to the addendum explaining how to apply
the limit for formaldehyde in products applied via inhalation
of 215 ppb or 8 mg/day whichever is lower
•
Addition of supporting references to some of the
monographs, e.g. EFSA 2020 (Ref 29) and ECHA 2021 (Ref
30) in styrene monograph
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

10. 10
Mutagenicimpuritiesaddedtotheaddendum
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)
CompoundCAS#
Chemical
Structure
LifetimeLimit
AI and/or PDE (µg/d)Acetaldehyde
75-07-0
PDE (oral) 2,000
AI 185 (all other
routes)
1,2-
dibromoethane
106-93-4 AI 2
Ethyl bromide
74-96-4 AI 32
Epichlorohydrin
106-89-8 AI 3
Formaldehyde
50-00-0
PDE (all other routes
10,000)
AI (inhalation) 8,000
or 215 ppb, whichever
is lower
Styrene
100-42-5 AI 154
Vinyl acetate
108-05-4
PDE (oral) 2,000
AI 758(all other
routes)

11. 11
Acetaldehyde
•
MutagenicinHypoxantine-Phosphoribosyl-Transferase(HPRT)assay
inmammaliancells,whilenegativeintheAmestest
•
Route-specificdifferencesincarcinogenicresponse
•
Oralexposure–norelevantcarcinogenicresponseinrats
•
Highestdoses:males246mg/kg/day,females260mg/kg/day
•
Inhalationexposure–carcinogenicinrat
•
Nasaladenocarcinomasignificantlyincreasedatalldosestested
•
Effectofdetoxificationinnasalmucosaisunclear
•
Carcinogeniceffectpossiblylimitedtositeofcontact
•
Thresholdmodeofactionisunclearforinhalation
•
Significanthumanexposure
•
Endogenouslyformedasmetaboliteofcarbohydrates
•
Exposureviafood
•
Efficientlydetoxifiedbyaldehydedehydrogenase
•
Thresholdassumed
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

12. 12
Acetaldehyde-PDE (oral) 2 mg/day–AI (all
otherroutes) 185 µg/day
•
OralPDEof2mg/daywasdetermined
o
Basedonaveragedailyintakefromfood(Uebelacker&Lachenmeier,
2011)
•
ForallotherroutestheAIis185µg/day
o
28monthinhalationstudyinrat(Woutersenetal.1986)considered
themostrelevantstudy
o
Relevantoutcome:nasaladenocarcinoma
o
TD
50
calculatedbyCPDB=185mg/kg/day
o
AI=(185mg/kg/d/50,000)x50kg=185µg/day
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

13. 13
1,2 Dibromoethane–AI 2 µg/day
•
Mutagenic in Ames test and HPRT test in Chinese Hamster
Ovary (CHO), cells
•
Carcinogenic in mouse and rat
•
By oral exposure –most sensitive forestomach
•
By inhalation –most sensitive lung and nasal cavity
•
Most robust study for derivation of AI
•
National Toxicology Program (NTP) inhalation study in F344 rats
(NTP TR-210)
•
TD
50
calculated by CPDB = 2.33 mg/kg/day; –similar to TD
50
of most
robust oral study in mice
•
AI = (2.33 mg/kg/day / 50,000) x 50 kg = 2.33 µg/day
•
AI rounded to 2 µg/day
•
One AI for all routes justified due to similar TD
50
values for inhalation
and oral application
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

14. 14
Epichlorohydrin–AI 3 µg/day
•
MutagenicinAmestestandmouselymphomatest•
Carcinogenicatsiteofcontact
o
Forestomachandoralcavitytumorsfororaladministration
o
Nasaltumorsforinhalation
o
Injectionsitesarcomasforsubcutaneousinjection
•
MostrobuststudyforderivationofAI
o
Oralstudyinrat(Westeretal.,1985)
o
TD
50
calculatedbyCPDB=2.55mg/kg/day
o
AI=(2.55mg/kg/day/50,000)x50kg=2.55µg/day
o
AIroundedto3µg/day
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

15. 15
Ethyl Bromide
•
EthylbromideisanalkylatingagentandmutagenicinAmes
asagas•
CarcinogenicinNTPinhalationstudiesinmiceandrats
(NTP-TR363)
o
Targetorganswere:uterus,adrenalglandinmalesandliverinboth
sexes
o
Mostsensitiveendpointwasadrenalglandpheochromocytomasin
malerat–significantincreaseatalldosescomparedtocontrol
o
Lackofdose-dependentincrease,trendanalysisnegative,TD
50
calculatedbyCPDBnotstatisticallysignificantandnotconsidered
appropriate
o
TheExpertWorkingGroup(EWG)calculatedTD
50
valuesforeach
doseseparately.Allcalculatedvalueswerestatisticallysignificant
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

16. 16
Ethyl Bromide –AI 32 µg/day
•
DerivationoftheAI
o
NTPinhalationstudy(NTP-TR363)
o
TD
50
calculatedbyCPDBnotconsideredappropriate
o
TheEWGcalculatedaTD
50
foreachdose(seeNote2inthe
addendumforreference)
o
TheEWGchosethemostsenstitiveTD
50
=32.2mg/kg/dayfor
calculatingtheAI
o
AI=(32.2mg/kg/day/50,000)x50kg=32.2µg/day
o
AIroundedto32µg/day
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

17. 17
Note 2
•
Note2demonstratesthecalculationofTD
50
valuesforeach
oftheethylbromidedoselevelsintheNTP-TR363study:
•
ThelowdoseprovidesthemostconservativeTD
50
•
TD
50
=0.693/0.0215055234=32.2mg/kg/day
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

18. 18
Formaldehyde
•
FormaldehydeismutagenicintheAmestestandintheHPRTtestin
mammalian(TK6)cells
•
Carcinogenicity
o
Carcinogenicinanimalsbyinhalationroute;tumorsinthenasalcavity
o
Wasnotconsideredcarcinogenicinstudiesviatheoralroute
-
Oneoutofthreestudieswaspositiveforleukemia/lymphosarcoma,however
inappropriateanddeficientstudydesignandanalysesinvalidatedtheuseofthis
study
•
Carcinogenicmodeofaction
o
Formaldehydeisconsideredtobeasite-of-contactcarcinogenactingmainly
bycytolethality/regenerativecellularproliferation
o
FormationofDNA-proteincrosslinksbyformaldehydeisinvolvedin
cytolethalityhowever,thismaynotbetheprimarymodeofaction
o
Conollyetal.(2004)describedamodeltocalculatehumancancerriskof
formaldehydeinhalationusingnon-linear-basedandlinear-basedmechanisms
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

19. 19
Formaldehyde
•
Significant
humanexposure
o
Endogenouslyformed–bodyturnoverisupto50g/day
o
Componentofmanyfoods–dailyoralintakerange1.5-14mg/day
•
Regulatorylimits
o
US-EPA,WHO-IPCS,ATSDR,HClimitformaldehydeviaoral
exposureto0.2mg/kg/dayor10mg/dayfora50kgpersonbasedon
non-cancerendpoint
o
ForinhalationHCrecommendsalimitof100ppbinairasa1hour
averageandWHOrecommends77ppbinairasa30minaverageto
protecthumansfromlocalirritationandsensitizationeffects
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

20. 20
Formaldehyde AI (inhalation) = 8 mg/day or 215
ppb whichever is lower
•
EWGconsideredtheConollyetal.(2004)modelasthemost
suitabletoderiveanAI
•
TheAIisderivedbycalculatingthecumulativedaily
formaldehydedoseinhaledattheformaldehydeairconcentration
associatedwith1:100,000cancerrisk.Thiscummulativedaily
doseis8.2mg/day,roundedto8.0mg/dayandrepresentsan
upperlimitovera24hourperiod.AI=8mg/day
•
However,inhaling8mgformaldehydewithonebreathe.g.withan
inhalationdrugtakenonceperdayviaaninhaler,isnot
consideredappropriate.
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

21. 21
Formaldehyde AI (inhalation) = 8 mg/day or 215
ppb whichever is lower
•
Toprotectpatientsfromlocalirritationandsensitizationeffectsof
formaldehydetheEWGcalculatedaconcentrationlimitfor
inhalationofformaldehydeindrugproducts
•
Theconcentrationlimitwasderivedbycalculatingthe
formaldehydeconcentrationinairwheninhaling8mgovera24h
breathingperiod.
•
With an average human breathing volume of 28.8 m
3
/day and
weight of air of 1293 g/m
3
the concentrationiscalculated:
215 ppb = (0.008g/day/ 28.8 m
3
/day) x 1/1293 g/m
3
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

22. 22
Note 3 -ApplicationofformaldehydeAI (inhalation) =
8 mg/day or 215 ppb whichever islower
•
Forformaldehydethelimitis215ppbor8mg/daywhicheveris
lower
•
Example1:albuterolactuatorwithformaldhydeasimpurityinAPI
o
delivers90µgAPI/actuator.
o
Tidalvolumeinhaledwitheachactuatoris400-500ml(female/maleadult)
o
CalculationofformaldehydelimitinAPI:
-
215 ppb offormaldehydein 400 ml tidalvolume:
0.215 x 30 g/mol/ 24.45 = 0.263 mg/m
3
. 0.263 mg/m
3
x 1000 L x 0.4 L = 0.105 µg
formaldehyde. Formaldehyde in API: 0.105 µg formaldehyde/ 90 µg API = 0.12 %
•
Example2: Albuterolsulfateactuatorwithformaldehydeasa drug
productimpurity
o
delivers35 mg drugproduct/actuator
o
Calculationofformaldehydelimitin drugproduct:
-
withthe215 ppb in airlimit, theallowedformaldehydeamountis0.105 µg
-
0.105 µg formaldehyde / 35 mg drug product = 3 ppm
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

23. 23
Formaldehyde PDE (all otherroutes) = 10 mg/day
•
Forallotherroutes,aPDEof10mg/dayisrecommended
o
BasedonthelimitsetbyUS-EPA,WHO-IPCS,HCandATSDR
o
Consideredbroadlyacceptedandjustifiedbyenvironmentalexposure
ranges
o
Carcinogenicityofformaldehydeisconsideredspecifictothe
inhalationroute
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

24. 24
Styrene
•
StyreneismutagenicintheAmestestonlywithmetabolic
activationandmutagenicinvivoinlymphocytesofexposed
workers
o
Metabolitestyrene7,8-oxideisconsideredthemutageniccompound
o
Styrene7,8-oxideformscovalentadductswithDNA,adductsidentified
invitro,invivoand,inexposedhumans
•
Carcinogenicpotential
o
Carcinogenicinmiceviaoralandinhalationroutes
o
Carcinogenicinratsonlyinasinglestudyviainhalation(relevance
questionableduetostudylimitations)butnegativeinanother
inhalationstudyandalloralstudies
o
Styrene7,8-oxideiscarcinogenicinmicebyoralanddermal
applicationand,inratviaoralandtransplacentalexposure
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

25. 25
Styrene–AI 154 µg/day
•
Carcinogenicmodeofaction
o
Metabolitestyrene7,8-oxideconsideredthemainmutagenicagent
o
Styreneinducedoxidativestress,immunosuppressionandchronic
inflammationarethepotentialcontributingfactors
•
DerivationoftheAI
o
Mouselungtumorsareconsideredthemostrelevanttumors
o
Themostsensitiveandrobuststudy(Cruzanetal.2001)providesa
TD
50
calculatedbyCPDBof154mg/kg/day
o
AI=(154mg/kg/day/50,000)x50kg=154µg/day
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

26. 26
Vinyl Acetate
•
Genotoxicpotential
o
VinylacetateisnotmutagenicinAmestest,butgenotoxiccausing
chromosomaldamageinhumanlymphocytes
o
Extensiveevidencethatgenotoxicityismediatedviaitsmetabolite,
acetaldehyde
•
Carcinogenicity
o
FourstudiesarelistedinCPDB
-
Twomousestudies,onewithoralonewithinhalation
-
Tworatstudies,onewithoralonewithinhalation
-
Tumorsobservedwereuterine,espophagealandforestomachtumorsin
mouseandliver,thyroid,uterineandnasaltumorsinrat
o
Inotherpublishedoralstudiesinmiceandrattumorsobservedinthe
oralcavity,esophagusandforestomach
o
Vinylacetatewasnegativeinaninhalationstudyinmice,andpositive
fornasaltumorsinratsatthehighdose
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

27. 27
Vinyl Acetate PDE (oral) 2mg/day–AI 758 µg/day
forall otherroutes
•
PDE(oral)–Vinylacetateundergoesrapidhydrolysisto
formaceticacidandacetaldehyde.Basedonthesame
considerationasforacetaldehydethePDEfororalrouteis
setto2mg/day
•
AI(allotherroutes):The2yearinhalationstudyinrats
listedinCPDB(Bogdanffyetal.1994)wasconsideredthe
mostrobustandappropriateforderivationofanAI.TD
50
calculatedbyCPDBwas758mg/kg/day
AI=(758mg/kg/day/50,000)x50kg=758µg/day
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

28. 28
Implementation of the change of the HIV treatment
duration from 1-10 years to > 10 years -lifetime
For regulatory submissions 18 months after the date that the
M7(R2) reached Step 4 (3 April 2023), the 1.5 μg/day or other
appropriate acceptable intake would be applied in situations
that are explained in detail in the ICH M7(R2) Q&As document
in Q&A 7.4
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

29. 29
Considerations
•
ICHM72
nd
addendumshouldbereadinconjunction
withthemainguidelineICHM7(R2),theICHM7Q&A
documentandtheM7(R1)Trainingmaterialvideo
presentation
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)

30. 30
Conclusions
•
ICHM7(R2)hasrevisedtheformatofM7intotwolinkedseparate
documents
o
Firstdocumentisthecoreguidelineincludingatableofall
monographs,thatareincludedintheaddendumandhyperlinkedto
theseconddocument
o
Seconddocumentistheaddendumcontainingallmonographsof
mutagenicimpuritiesassessedbytheEWG
•
HIVtreatmentdurationchangedfrom1-10yearsto>10years-
lifetimeinmainM7guidelinetext
•
Sevennewmonographsformutagenicimpuritiesaddedplustwo
additionalNotes(Note2and3)toexplainderivationofAIforethyl
bromideanduseofconcentration/exposurelimitsforformaldehyde
indrugsforinhalation
•
ListofCompounds(Appendix3)updatedtoincludeallmonographs
•
Grammaticaleditingandformattinge.g.updatingURLs
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)
International Council for Harmonisationof Technical Requirements
for Pharmaceuticals for Human Use

31. 31
Contact
•
For any questions please contact the ICH Secretariat:
[email protected]
ICH M7(R2) –Assessment And Control Of DNA
Reactive (Mutagenic) Impurities In Pharmaceuticals
To Limit Potential Carcinogenic Risk (Step 4)