Pharmaceutical industry best practices in lessons learned:
eln implementation of merck’s reaction review policy
Roger Sayle and john mayFIELD
Nextmove software, cambridge, uk
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
motivation
• Thepharmaceuticalindustryhasaninterestinreducinglaboratoryaccidentsbylearninglessonsfrompreviousincidents.
• ProjectssuchasthePistoiaAlliance’sChemicalSafetyLibrary(CSL)andiRAMP areexamplesfromthis.
• HerewepresentourexperienceimplementingMerck’spublishedrulesinanotherpharmaceuticalcompany’sELN.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Industry vs. academia
• Relativeriskdependsuponcontext...– Keepoutofreachofchildren.– Readlabelbeforeuse.– Donotpierceorburn,evenafteruse.– Donoteat,drinkorsmokewhenusingthisproduct.– Donotgetineyes,onskinoronclothing.– Avoidcontactduringpregnancy/whilenursing.– Ifmedicaladviceisneeded,haveproductcontainerathand.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Background of Merck’s RRP
• Priorto2009,Rahwaypreplaboratories(typically0.5-5kgscaleforintermediates/APIs)hadonlyan“adhoc”safetyreview.
• In2009,itwasdecidedtoformalizethisprocesstocomplementthePilotPlantreview.
• Thenecessityfora“HazardousReactionReview”forevenmuchsmallerscalewasrealizedwhenaseniorlevelscientistincurrentaserioushandinjuryuponisolatingadiazoniumsalton<5gscale.
• In2012,RRPwasextendedtoDiscoveryChemistry.254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Implementation architecture
PEI ELNDesktop Client
Mail Notification
Alert Ruleset
MailServer
Database AuditTrail
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Casandra
!
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Casandra
!
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
The influence of scale
• Differentthresholdsareappliedfor“bench”(typicallylabhood)vs.preplab(0.5– 5kg).
– Theamountofmaterialislarger– Heatremovalislessefficient– Timecyclesarelong;Becausethetimevs.temperatureprofileisincreased,decompositionexothermscantriggeredthatdon’tatsmallscale.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
ELN support for “vessel size”
• Merck’sRRPdefines“Prep.Labscale”tobedefinedasreactionsruninavessel>5L,eveniftheactualreactionvolumeisless.
• AnextrafieldwasaddedtotheCambridgesoft/PEIELNtocapture“ReactionVesselSize”– ≤100mL– >100ml– 5L– >5L
• ForexistingELNinstallations,“VesselSize”canbeapproximated/estimatedfrommaterialquantities.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Beware of Bretherick’s:1,3-dinitrobenzene
• Accidentsinvolvingmaintenanceofrailwaytankersareprobablynotrelevantatthelaboratoryscale.
Avesselcontainingdinitrobenzenefordrying,afterwashingoutstyphnic andpicricacidbyproductsinalkali,retainedaheelofsomehundredsoflitres,witharesidueofrust,afteremptying.Thiswascleanedoutwithlowpressuresteamat130°Ceverytwoyears.Duringcleaning,thetankburstandburntout.Itwassupposedthatresidualnitrophenol saltshadaccumulatedontherust,whichwasshowntothermallysensitisethem,anddeflagrated,initiatingthedinitrobenzene.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Avoiding alert fatigue
• OneusabilityaspectofCasandrawas(forsometypesofalerts)toavoidrepeatingwarningwithinaspecifiedperiodoftime.
• Alertsaboutuseofnon-greensolventsmayonlyfireatmostonceamonth.Alertsonpolicyandlaboratorycertificationmightonlyfireonceayear.
• Theservermaintainsalogofwhichalertshavebeenseenbywhichchemists.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
“Need to know” policy
• Dependinguponconfigurationsomealertsarereportedand/ore-mailedtothechemist,optionallye-mailedtohis/hersupervisor,andrarelytothesitemanagerorreactionreviewboard.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
highly toxic/dangerous reagenT
1. Unusuallytoxicsolids(typicallyIDLH<30ppm)– Cyanide,OsO4,phosgene/diphosgene/triphosgene,iodine,PCl5.
2. Unusuallytoxicliquids(typicallyIDLH<30ppm)– MeI,HF,SOCl2,oxalylchloride,bromine,Hg(allforms),CS2,fumingH2SO4.
3. Knownorstronglysuspectedcarcinogens– Benzene,CCl4,Cr(VI)reagents,dimethylsulfate
4. Pyrophoricmaterials– AlR3,BR3,PR3,ZnR2,RLi,RMgX,95%NaH,LiAlH4,Na,K,Li,RaneyNi
5. Unusuallystrongoxidizers– >30%H2O2,ozone,conc.HNO3,O2.
6. Knownorsuspectedsensitizers– DCC,formicacid,bromobenzylbromide,limonene,omeprazole,beta-lactams.
7. OEB5orcomparablematerials254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Oeb 5 = GHS category 1
• Explosives:H200,H201,H202,H203,H204,H205• Desensitizedexplosives:H206• Flammability:H220,H222,H224,H228,H229• PhysicalHazard:H250,H251,H260,H270,H290.• Toxicity:H300,H304,H310,H314,H317,H318,H330,H334,H340,H350,H360,H370,H372
• Environmentalhazards:H400,H410,H420
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
ghs pictograms are not enough
• Unfortunately,GHSlabelsareinsufficient.• Bothmethanolanddimethylmercuryarelabelledwithwarningsindicatingtoxicandhealthhazardifswallowedorexposedtoskinrespectively.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Merck Solution: ghs categories
• ThesolutionistoonlyalertonGHScategory1orNFPAcategory4hazards(bydefault).
• Thesereflectunusualorunanticipatedhazards.– Unstableexplosive,andexplosivevs.firehazard/mayexplodeinfire.– Extremelyflammablegas(H220)vsFlammablegas(H221)– Extremelyflammableliquid(H224)vsFlammableliquid(H225)– Fatalifinhaled(H330)
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Challenge: data coverage
• Unfortunately,SDS/MSDSdatasheetsexistforaverysmallfractionchemicals.
• Ofthe91McompoundsinPubChem,Safetyinformationisavailablefor11487(~0.01%),andGHSinformationfor5060(~0.006%).
• Additionally,unlikehigh-schoolandundergraduatepracticals,pharmaceuticalmedicinalchemistryR&Dproducespreviouslyunsynthesizedcompounds.
• It’simportanttocheckreactantsand products.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Solution: deriving categories
• GHSandNFPAcategoriesare(mostly)derivedfromphysicalpropertiesmeasuredbyexperimentaltestingandlegallymandatedthresholds.
• Thesemayalsobelookedupinadatabaseorcalculatedalgorithmicallytocategorize/triagecompounds.
• FlorA.Quintero,SuhaniJ.Patel,FelipeMuñozandM.Sam.Mannan,“ReviewofExistingQSAR/QSPRModelsDevelopedforPropertiesusedinHazardousChemicalsClassificationSystem”,IndustrialandEngineeringChemistryResearch,Vol.51,pp.16101-16115,2012.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Effectively Adding ghs diamonds
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Evolution of Hazard alerting
1. ChemicalCompound/Substance(MSDS)Lookup1a. Exactname/MFCD/Synonymcomparison1b. Name-to-structurecanonicalmatch(spellingcorrection)1c. Normalizedrepresentation(InChI)match
2. ChemicalIncompatibilityLookup3. SubstructurePatterns4. ChemicalClassIncompatibility5. ReactionMechanismRecognition6. PhysicalPropertyThresholds
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Case study #1: h224
• GHShazardH224is“Extremelyflammable”.• Thelogicforthiscategorizationis:
• Flashpoint<23°Candboilingpoint£ 35°C=H224(1)• Flashpoint<23°Candboilingpoint>35°C=H225(2)• Flashpoint³ 23°Cand£ 60°C=H226(3)• Flashpoint>60°C=(4)
• Hencetrans-2-pentene(SIAL111260)whichhasaNISTreportedboilingpointof36.25± 0.5°C(NISTWebbook)can’tpossiblybeH224.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Case study #2: h330
• GHShazardH330is“Fatalifinhaled”.• Applicabletopoisongassessuchasphosgene.• Thesetofgassesisfinite,butthiscategorizationisalsotovapours,dustsandmists.
• ThiscategorizationisbasedonLC50 inppm/V.• AsurprisediscoverywasthatthenaturalproductAconitine(MW~646)iscategorizedasH330,eventhoughusedtherapeutically,andnoreportedLC50.
• Itturnsoutthiscategorizationisrequiredbylaw!?
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Energetic substructures
• UNrecommendationson“TransportofDangerousGoods”liststhefollowingfunctiongroupsasbeingassociatedwithexplosiveproperties:– C-Cunsaturation:Acetylenes,acetylides,1,2-dienes.– C-Metal,N-Metal:Grignardreagents,organo-lithiumcompounds.– N-N:Azides,aliphaticazocompounds,diazoniumsalts,hydrazines,
sulfonylhydrazides.– O-O:Peroxides,ozonides.– N-O:Hydroxylamines,nitrates,nitrocompounds,nitrosocompounds,
N-oxides,1,2-oxazoles.– N-Halogen:Chloramines,fluoramines.– O-Halogen:Chlorates,perchlorates,iodosylcompounds.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Oxygen balance
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Theoretical DSC OF TNT
• HeatofDecomposition– C7H5N3O6 →2.5H2O+1.75CO2 +5.25C+1.5N2
Hf=-63.2→Hf=2.5*-240.6+1.75*-393.5=-1290.12kJ/molΔHd =-1226.92kJ/mol
• HeatofCombustion– C7H5N3O6 +5.25O2 →2.5H2O+7CO2 +1.5N2
Hf=-63.2→Hf=2.5*-240.6+7*-393.5=-3356kJ/molΔHc =-3292.8kJ/mol
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Structures aren’t enough
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Future work: mixture handling
• BecausetheOEB/GHScategorycandependuponconcentration,phaseandphysicalstateeffortsarebeingmadetocapturethismoreaccuratelyintheELN/Casandrasystem.
• ItishopedthatrecentworkbyIUPAContheMInChI(MixtureInChI)maysolvemanyoftheremainingrepresentationalchallenges.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Future work: property prediction
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Future work: namerxn integration
1. J.Carey,D.Laffan,C.Thomson,M.Williams,Org.Biomol.Chem. 2337,2006.2. S.RoughleyandA.Jordan,J.Med.Chem.54:3451-3479,2011.
29%
19% 11%
3% 2%
13%
5%
2% 9%
4% 3% Heteroatomalkylationandarylation
Acylationandrelatedprocesses
C-Cbondformations
Heterocycleformation
Protections
Deprotections
Reductions
Oxidations
Functionalgroupconversion
Functionalgroupaddition
Resolution
Future work: ontogrep integration
• nitrogencontainingheterocycles• cationicringsystems• cyclicalkanes• branchedacyclicalkanes• transuranicelements• zinccompounds• binarycompounds• Lewisacids• atropisomers• polyspiro ringsystems• polyatomicelements• inorganicsalts
• radioactivecompounds• radioactiveelements• monocyclicringsystems• neutralcompounds• unchargedcompounds• zwitterioniccompounds• carboncontaininginorganics• zincoxides• metalchlorides• ironhalides• inorganicsalts
Conclusions/insights
• Thetechnologyexiststoalert/flagexperimentsinELNsagainstpublished“bestpractice”guidance.
• Merck’sreactionreviewpolicyrequiresmodifyinganELNtomorefields,suchasreactionvesselsize.
• ApplicabilityofthesealertscanbeextendedbyQSARmodels(algorithmsforcompoundpropertyprediction).
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
acknowledgements
• BharathRamandran andJenSonnenberg-RhimatAmgen(ThousandOaksandSouthSanFran,CA).
• DanaVanderwall,RameshDurvasula,DongLiandCarolMcnab fromBristol-MyersSquibb.
• LeahMcEwen,EvanBoltonandRalphStuartatiRAMP.
• ChemicalSafetyLibrary(CSL)project,PistoiaAlliance.• TherestoftheteamatNextMove Software.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
Derek lowe vs. common sense
• “IgnoranceisNoDefence:InAChemistryLab,Whatyoudon’tknowreallycanhurtyou”,byDerekLowe,ChemistryWorld,14th January2015.https://www.chemistryworld.com/opinion/ignorance-is-no-defence/8150.article
• Listsashazardousboth:1. Dimethylmercury2. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)
• Theexposurerisksofeacharenotreallycomparable:1. Hazardouswhenhandlingevenwithgloves.2. Hazardousifinjectedintravenously.
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
H280: irrelevant to pubchem?
• HazardcodeH280is“Containsgasunderpressure;mayexplodeifheated”.
• Thiswarningconcernsthecontainerthataproductmayshippedin,andisn’tafundamentalhazardofthechemicalitself.
• Anygasat200kPa(i.e.inagascylinder)hasthishazard.
• Currently,88PubChemCIDshavethis“feature”,includingCID1119(Sulfurdioxide).
254th ACSNationalMeeting,WashingtonDC,USA,Wednesday23rd August2017
