Wed Sayles Pharmaceutical industry best practices in ... · Pharmaceutical industry best practices...

transcript

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.

Industry vs. academia

• Relativeriskdependsuponcontext...– Keepoutofreachofchildren.– Readlabelbeforeuse.– Donotpierceorburn,evenafteruse.– Donoteat,drinkorsmokewhenusingthisproduct.– Donotgetineyes,onskinoronclothing.– Avoidcontactduringpregnancy/whilenursing.– Ifmedicaladviceisneeded,haveproductcontainerathand.

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

Casandra

The influence of scale

• Differentthresholdsareappliedfor“bench”(typicallylabhood)vs.preplab(0.5– 5kg).

– Theamountofmaterialislarger– Heatremovalislessefficient– Timecyclesarelong;Becausethetimevs.temperatureprofileisincreased,decompositionexothermscantriggeredthatdon’tatsmallscale.

ELN support for “vessel size”

• Merck’sRRPdefines“Prep.Labscale”tobedefinedasreactionsruninavessel>5L,eveniftheactualreactionvolumeisless.

• AnextrafieldwasaddedtotheCambridgesoft/PEIELNtocapture“ReactionVesselSize”– ≤100mL– >100ml– 5L– >5L

• ForexistingELNinstallations,“VesselSize”canbeapproximated/estimatedfrommaterialquantities.

Beware of Bretherick’s:1,3-dinitrobenzene

• Accidentsinvolvingmaintenanceofrailwaytankersareprobablynotrelevantatthelaboratoryscale.

Avesselcontainingdinitrobenzenefordrying,afterwashingoutstyphnic andpicricacidbyproductsinalkali,retainedaheelofsomehundredsoflitres,witharesidueofrust,afteremptying.Thiswascleanedoutwithlowpressuresteamat130°Ceverytwoyears.Duringcleaning,thetankburstandburntout.Itwassupposedthatresidualnitrophenol saltshadaccumulatedontherust,whichwasshowntothermallysensitisethem,anddeflagrated,initiatingthedinitrobenzene.

Avoiding alert fatigue

• OneusabilityaspectofCasandrawas(forsometypesofalerts)toavoidrepeatingwarningwithinaspecifiedperiodoftime.

• Alertsaboutuseofnon-greensolventsmayonlyfireatmostonceamonth.Alertsonpolicyandlaboratorycertificationmightonlyfireonceayear.

• Theservermaintainsalogofwhichalertshavebeenseenbywhichchemists.

“Need to know” policy

• Dependinguponconfigurationsomealertsarereportedand/ore-mailedtothechemist,optionallye-mailedtohis/hersupervisor,andrarelytothesitemanagerorreactionreviewboard.

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

ghs pictograms are not enough

• Unfortunately,GHSlabelsareinsufficient.• Bothmethanolanddimethylmercuryarelabelledwithwarningsindicatingtoxicandhealthhazardifswallowedorexposedtoskinrespectively.

Merck Solution: ghs categories

• ThesolutionistoonlyalertonGHScategory1orNFPAcategory4hazards(bydefault).

• Thesereflectunusualorunanticipatedhazards.– Unstableexplosive,andexplosivevs.firehazard/mayexplodeinfire.– Extremelyflammablegas(H220)vsFlammablegas(H221)– Extremelyflammableliquid(H224)vsFlammableliquid(H225)– Fatalifinhaled(H330)

Challenge: data coverage

• Unfortunately,SDS/MSDSdatasheetsexistforaverysmallfractionchemicals.

• Ofthe91McompoundsinPubChem,Safetyinformationisavailablefor11487(~0.01%),andGHSinformationfor5060(~0.006%).

• Additionally,unlikehigh-schoolandundergraduatepracticals,pharmaceuticalmedicinalchemistryR&Dproducespreviouslyunsynthesizedcompounds.

• It’simportanttocheckreactantsand products.

Solution: deriving categories

• GHSandNFPAcategoriesare(mostly)derivedfromphysicalpropertiesmeasuredbyexperimentaltestingandlegallymandatedthresholds.

• Thesemayalsobelookedupinadatabaseorcalculatedalgorithmicallytocategorize/triagecompounds.

• FlorA.Quintero,SuhaniJ.Patel,FelipeMuñozandM.Sam.Mannan,“ReviewofExistingQSAR/QSPRModelsDevelopedforPropertiesusedinHazardousChemicalsClassificationSystem”,IndustrialandEngineeringChemistryResearch,Vol.51,pp.16101-16115,2012.

Effectively Adding ghs diamonds

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

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.

Case study #2: h330

• GHShazardH330is“Fatalifinhaled”.• Applicabletopoisongassessuchasphosgene.• Thesetofgassesisfinite,butthiscategorizationisalsotovapours,dustsandmists.

• ThiscategorizationisbasedonLC50 inppm/V.• AsurprisediscoverywasthatthenaturalproductAconitine(MW~646)iscategorizedasH330,eventhoughusedtherapeutically,andnoreportedLC50.

• Itturnsoutthiscategorizationisrequiredbylaw!?

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.

Oxygen balance

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

Structures aren’t enough

Future work: mixture handling

• BecausetheOEB/GHScategorycandependuponconcentration,phaseandphysicalstateeffortsarebeingmadetocapturethismoreaccuratelyintheELN/Casandrasystem.

• ItishopedthatrecentworkbyIUPAContheMInChI(MixtureInChI)maysolvemanyoftheremainingrepresentationalchallenges.

Future work: property prediction

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.

19% 11%

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).

acknowledgements

• BharathRamandran andJenSonnenberg-RhimatAmgen(ThousandOaksandSouthSanFran,CA).

• DanaVanderwall,RameshDurvasula,DongLiandCarolMcnab fromBristol-MyersSquibb.

• LeahMcEwen,EvanBoltonandRalphStuartatiRAMP.

• ChemicalSafetyLibrary(CSL)project,PistoiaAlliance.• TherestoftheteamatNextMove Software.

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.

H280: irrelevant to pubchem?

• HazardcodeH280is“Containsgasunderpressure;mayexplodeifheated”.

• Thiswarningconcernsthecontainerthataproductmayshippedin,andisn’tafundamentalhazardofthechemicalitself.

• Anygasat200kPa(i.e.inagascylinder)hasthishazard.

• Currently,88PubChemCIDshavethis“feature”,includingCID1119(Sulfurdioxide).

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