Chapter 79 - Pharmaceutical Industry

10/10/2016 Chapter79PharmaceuticalIndustry
PartXIIChemicalIndustries Franais
Chapter79PharmaceuticalIndustry
PHARMACEUTICALINDUSTRY
KeithD.Tait
Definitions
Thesetermsareusedfrequentlyinthepharmaceuticalindustry:
Biologicsarebacterialandviralvaccines,antigens,antitoxinsandanalogousproducts,serums,
plasmasandotherbloodderivativesfortherapeuticallyprotectingortreatinghumansand
animals.
Bulksareactivedrugsubstancesusedtomanufacturedosageformproducts,processmedicated
animalfeedsorcompoundprescriptionmedications.
Diagnosticagentsassistthediagnosisofdiseasesanddisordersinhumansandanimals.
Diagnosticagentsmaybeinorganicchemicalsforexaminingthegastrointestinaltract,organic
chemicalsforvisualizingthecirculatorysystemandliverandradioactivecompoundsfor
measuringthefunctionoforgansystem.
Drugsaresubstanceswithactivepharmacologicalpropertiesinhumansandanimals.Drugsare
compoundedwithothermaterials,suchaspharmaceuticalnecessities,toproduceamedicinal
product.
Ethicalpharmaceuticalsarebiologicalandchemicalsagentsforpreventing,diagnosingor
treatingdiseaseanddisordersinhumansoranimals.Theseproductsaredispensedby
prescriptionorapprovalofamedical,pharmacyorveterinaryprofessional.
Excipientsareinertingredientswhicharecombinedwithdrugsubstancestocreateadosage
formproduct.Excipientsmayaffecttherateofabsorption,dissolution,metabolismand
distributioninhumansoranimals.
Overthecounterpharmaceuticalsaredrugproductssoldinaretailstoreorpharmacywhichdo
notrequireaprescriptionortheapprovalofamedical,pharmacyorveterinaryprofessional.
Pharmacyistheartandscienceofpreparinganddispensingdrugsforpreventing,diagnosingor
treatingdiseasesordisordersinhumansandanimals.
Pharmacokineticsisthestudyofmetabolicprocessesrelatingtotheabsorption,distribution,
biotransformation,andeliminationofadruginhumansoranimals.
Pharmacodynamicsisthestudyofdrugactionrelatingtoitschemicalstructure,siteofaction,
andthebiochemicalandphysiologicalconsequencesinhumansandanimals.
Thepharmaceuticalindustryisanimportantcomponentofhealthcaresystemsthroughouttheworlditiscomprisedofmanypublicandprivateorganizationsthat
discover,develop,manufactureandmarketmedicinesforhumanandanimalhealth(Gennaro1990).Thepharmaceuticalindustryisbasedprimarilyuponthescientific
researchanddevelopment(R&D)ofmedicinesthatpreventortreatdiseasesanddisorders.Drugsubstancesexhibitawiderangeofpharmacologicalactivityand
toxicologicalproperties(Hardman,GilmanandLimbird1996Reynolds1989).Modernscientificandtechnologicaladvancesareacceleratingthediscoveryand
developmentofinnovativepharmaceuticalswithimprovedtherapeuticactivityandreducedsideeffects.Molecularbiologists,medicinalchemistsandpharmacistsare
improvingthebenefitsofdrugsthroughincreasedpotencyandspecificity.Theseadvancescreatenewconcernsforprotectingthehealthandsafetyofworkerswithinthe
pharmaceuticalindustry(Agius1989Naumannetal.1996SargentandKirk1988Teichman,FallonandBrandtRauf1988).
Manydynamicscientific,socialandeconomicfactorsaffectthepharmaceuticalindustry.Somepharmaceuticalcompaniesoperateinbothnationalandmultinational
markets.Therefore,theiractivitiesaresubjecttolegislation,regulationandpoliciesrelatingtodrugdevelopmentandapproval,manufacturingandqualitycontrol,
marketingandsales(Spilker1994).Academic,governmentandindustryscientists,practisingphysiciansandpharmacists,aswellasthepublic,influencethe
pharmaceuticalindustry.Healthcareproviders(e.g.,physicians,dentists,nurses,pharmacistsandveterinarians)inhospitals,clinics,pharmaciesandprivatepracticemay
prescribedrugsorrecommendhowtheyshouldbedispensed.Governmentregulationsandhealthcarepoliciesonpharmaceuticalsareinfluencedbythepublic,advocacy
groupsandprivateinterests.Thesecomplexfactorsinteracttoinfluencethediscoveryanddevelopment,manufacturing,marketingandsalesofdrugs.
Thepharmaceuticalindustryislargelydrivenbyscientificdiscoveryanddevelopment,inconjunctionwithtoxicologicalandclinicalexperience(seefigure79.1).Major
differencesexistbetweenlargeorganizationswhichengageinabroadrangeofdrugdiscoveryanddevelopment,manufacturingandqualitycontrol,marketingandsales
andsmallerorganizationswhichfocusonaspecificaspect.Mostmultinationalpharmaceuticalcompaniesareinvolvedinalltheseactivitieshowever,theymay
specializeinoneaspectbaseduponlocalmarketfactors.Academic,publicandprivateorganizationsperformscientificresearchtodiscoveranddevelopnewdrugs.The
biotechnologyindustryisbecomingamajorcontributortoinnovativepharmaceuticalresearch(SwarbickandBoylan1996).Often,collaborativeagreementsbetween
researchorganizationsandlargepharmaceuticalcompaniesareformedtoexplorethepotentialofnewdrugsubstances.
Figure79.1Drugdevelopmentinthepharmaceuticalindustry
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Manycountrieshavespecificlegalprotectionsforproprietarydrugsandmanufacturingprocesses,knownasintellectualpropertyrights.Ininstanceswhenlegal
protectionsarelimitedordonotexist,somecompaniesspecializeinmanufacturingandmarketinggenericdrugs(MedicalEconomicsCo.1995).Thepharmaceutical
industryrequireslargeamountsofcapitalinvestmentduetothehighexpensesassociatedwithR&D,regulatoryapproval,manufacturing,qualityassuranceandcontrol,
marketingandsales(Spilker1994).Manycountrieshaveextensivegovernmentregulationsaffectingthedevelopmentandapprovalofdrugsforcommercialsale.These
countrieshavestrictrequirementsforgoodmanufacturingpracticestoensuretheintegrityofdrugmanufacturingoperationsandthequality,safetyandefficacyof
pharmaceuticalproducts(Gennaro1990).
Internationalanddomestictrade,aswellastaxandfinancepoliciesandpractices,affecthowthepharmaceuticalindustryoperateswithinacountry(SwarbickandBoylan
1996).Significantdifferencesexistbetweendevelopedanddevelopingcountries,regardingtheirneedsforpharmaceuticalsubstances.Indevelopingcountries,where
malnutritionandinfectiousdiseasesareprevalent,nutritionalsupplements,vitaminsandantiinfectivedrugsaremostneeded.Indevelopedcountries,wherethediseases
associatedwithageingandspecificailmentsareprimaryhealthconcerns,cardiovascular,centralnervoussystem,gastrointestinal,antiinfective,diabetesand
chemotherapydrugsareinthegreatestdemand.
HumanandanimalhealthdrugssharesimilarR&Dactivitiesandmanufacturingprocesseshowever,theyhaveuniquetherapeuticbenefitsandmechanismsfortheir
approval,distribution,marketingandsales(SwarbickandBoylan1996).Veterinariansadministerdrugstocontrolinfectiousdiseasesandparasiticorganismsin
agriculturalandcompanionanimals.Vaccinesandantiinfectiveandantiparasiticdrugsarecommonlyusedforthispurpose.Nutritionalsupplements,antibioticsand
hormonesarewidelyemployedbymodernagriculturetopromotethegrowthandhealthoffarmanimals.TheR&Dofpharmaceuticalsforhumanandanimalhealthare
oftenallied,duetoconcurrentneedstocontrolinfectiousagentsanddisease.
HazardousIndustrialChemicalsandDrugrelatedSubstances
Manydifferentbiologicalandchemicalagentsarediscovered,developedandusedinthepharmaceuticalindustry(Hardman,GilmanandLimbird1996Reynolds1989).
Somemanufacturingprocessesinthepharmaceutical,biochemicalandsyntheticorganicchemicalindustriesaresimilarhowever,thegreaterdiversity,smallerscaleand
specificapplicationsinthepharmaceuticalindustryareunique.Sincetheprimarypurposeistoproducemedicinalsubstanceswithpharmacologicalactivity,manyagents
inpharmaceuticalR&Dandmanufacturingarehazardoustoworkers.Propercontrolmeasuresmustbeimplementedtoprotectworkersfromindustrialchemicalsand
drugsubstancesduringmanyR&D,manufacturingandqualitycontroloperations(ILO1983Naumannetal.1996Teichman,FallonandBrandtRauf1988).
Thepharmaceuticalindustryusesbiologicalagents(e.g.,bacteriaandviruses)inmanyspecialapplications,suchasvaccineproduction,fermentationprocesses,
derivationofbloodbasedproductsandbiotechnology.Biologicalagentsarenotaddressedbythisprofileduetotheiruniquepharmaceuticalapplications,butother
referencesarereadilyavailable(SwarbickandBoylan1996).Chemicalagentsmaybecategorizedasindustrialchemicalsanddrugrelatedsubstances(Gennaro1990).
Thesemayberawmaterials,intermediatesorfinishedproducts.SpecialsituationsarisewhenindustrialchemicalsordrugsubstancesareemployedinlaboratoryR&D,
qualityassuranceandcontrolassays,engineeringandmaintenance,orwhentheyarecreatedasbyproductsorwastes.
Industrialchemicals
Industrialchemicalsareusedinresearchinganddevelopingactivedrugsubstancesandmanufacturingbulksubstancesandfinishedpharmaceuticalproducts.Organicand
inorganicchemicalsarerawmaterials,servingasreactants,reagents,catalystsandsolvents.Theuseofindustrialchemicalsisdeterminedbythespecificmanufacturing
processandoperations.Manyofthesematerialsmaybehazardoustoworkers.Sinceworkerexposurestoindustrialchemicalsmaybehazardous,occupationalexposure
limits,suchasthresholdlimitvalues(TLVs)havebeenestablishedbygovernment,technicalandprofessionalorganizations(ACGIH1995).
Drugrelatedsubstances
Pharmacologicallyactivesubstancesmaybecategorizedasnaturalproductsandsyntheticdrugs.Naturalproductsarederivedfromplantandanimalsources,while
syntheticdrugsareproducedbymicrobiologicalandchemicaltechnologies.Antibiotics,steroidandpeptidehormones,vitamins,enzymes,prostaglandinsand
pheromonesareimportantnaturalproducts.Scientificresearchisfocusingincreasinglyonsyntheticdrugsduetorecentscientificadvancesinmolecularbiology,
biochemistry,pharmacologyandcomputertechnology.Table79.1liststheprincipalpharmaceuticalagents.
Table79.1Majorcategoriesofpharmaceuticalagents
Centralnervous Renaland Gastrointestinal Antiinfectivesand Immunesystem Chemotherapy Bloodandblood Endocrine

system cardiovascularsystem system targetorgans formingorgans
Analgesics Antidiabetics Gastrointestinal Systemicanti Analgesics Antineoplastics Bloodmodifiers Diagnostic
agents infectives
Acetaminophen Biguanides Nonsteroidal Adjunct Anticoagulants
Salicylates Glycosidase Antacids AIDStherapies anti therapy Antiplatelet
inhibitors Antiflatulents Amebicides inflammatory Alkylating agents
Anaesthetics Insulins Antidiarrhoeals Anthelmintics agents(NSAIDs) agents Colony
Sulphotryforeas Antiemetics Antibiotics Antibiotics stimulating
Antispasmodics Antifungals Antimetabolites factors
Generaland Cardioprotective Laxatives Antimalarials Biologicalresponse Hormones Haemantinics
local agents Prostaglandins Sulphonamides modifiers Immuno Haemostatics
Cephalosporins, modulators Plasma
Anticonvulsants Adrenergic penicillins, Alphaproteinase fractions Hormones
blockers tetracyclines, inhibitors
Barbituates Stimulants etc. Antitoxins Vasodilators
Benzodiazepine Angiotensin Immuneserums
inhibitors Respiratoryagents Toxoids Cerebral
Migrainepreparations Antiarrhythmics Vaccines vasodilators
Calcium Antitussives
Betaadrenergic channel Bronchodilators Antifibrosistherapy
blockingagents blockers Decongestants
Serotonin Diuretics Expectorants Immunodilatorsand
receptor Vasodilators immunosuppressives
antagonists Vasodepressors Skinandmucous
membraneagents Multiplesclerosis
Narcotics management
Acne
Opates preparations Prostaglan
Allergans
Psychotherapeutics Antiinfectives
Burn
Antianxiety preparations
agents
Emollients
Antidepressants
Urinarytractagents
Sedativesand
hypnotics Antiinflectives
Antispasmodics
Barbituates
Benzodiazepine Vaginalpreparations
Antifungals
Activedrugsubstancesandinertmaterialsarecombinedduringpharmaceuticalmanufacturingtoproducedosageformsofmedicinalproducts(e.g.,tablets,capsules,
liquids,powders,creamsandointments)(Gennaro1990).Drugsmaybecategorizedbytheirmanufacturingprocessandtherapeuticbenefits(EPA1995).Drugsare
medicinallyadministeredbystrictlyprescribedmeans(e.g.,oral,injection,skin)anddosages,whereasworkersmaybeexposedtodrugsubstancesbyinadvertently
breathingairbornedustorvapoursoraccidentallyswallowingcontaminatedfoodsorbeverages.Occupationalexposurelimits(OELs)aredevelopedbytoxicologistsand
occupationalhygieniststoprovideguidanceonlimitingworkerexposurestodrugsubstances(Naumannetal.1996SargentandKirk1988).
Pharmaceuticalnecessities(e.g.,binders,fillers,flavouringandbulkingagents,preservativesandantioxidants)aremixedwithactivedrugsubstances,providingthe
desiredphysicalandpharmacologicalpropertiesinthedosageformproducts(Gennaro1990).Manypharmaceuticalnecessitieshavenoorlimitedtherapeuticvalueand
arerelativelynonhazardoustoworkersduringdrugdevelopmentandmanufacturingoperations.Thesematerialsareantioxidantsandpreservatives,colouring,
flavouringanddilutingagents,emulsifiersandsuspendingagents,ointmentbases,pharmaceuticalsolventsandexcipients.
PharmaceuticalOperations,RelatedHazardsandWorkplaceControlMeasures
Pharmaceuticalmanufacturingoperationsmaybecategorizedasbasicproductionofbulkdrugsubstancesandpharmaceuticalmanufacturingofdosageformproducts.
Figure79.2illustratesthemanufacturingprocess.
Figure79.2Manufacturingprocessinthepharmaceuticalindustry
Basicproductionofbulkdrugsubstancesmayemploythreemajortypesofprocesses:fermentation,organicchemicalsynthesis,andbiologicalandnaturalextraction
(TheodoreandMcGuinn1992).Thesemanufacturingoperationsmaybediscretebatch,continuousoracombinationoftheseprocesses.Antibiotics,steroidsandvitamins
areproducedbyfermentation,whereasmanynewdrugsubstancesareproducedbyorganicsynthesis.Historically,mostdrugsubstanceswerederivedfromnatural
sourcessuchasplants,animals,fungiandotherorganisms.Naturalmedicinesarepharmacologicallydiverseanddifficulttoproducecommerciallyduetotheircomplex
chemistryandlimitedpotency.
Fermentation
Fermentationisabiochemicalprocessemployingselectedmicroorganismsandmicrobiologicaltechnologiestoproduceachemicalproduct.Batchfermentation
processesinvolvethreebasicsteps:inoculumandseedpreparation,fermentation,andproductrecoveryorisolation(TheodoreandMcGuinn1992).Aschematicdiagram
ofafermentationprocessisgiveninfigure79.3.Inoculumpreparationbeginswithasporesamplefromamicrobialstrain.Thestrainisselectivelycultured,purifiedand
grownusingabatteryofmicrobiologicaltechniquestoproducethedesiredproduct.Thesporesofthemicrobialstrainareactivatedwithwaterandnutrientsinwarm
conditions.Cellsfromtheculturearegrownthroughaseriesofagarplates,testtubesandflasksundercontrolledenvironmentalconditionstocreateadensesuspension.
Figure79.3Diagramofafermentationprocess
Thecellsaretransferredtoaseedtankforfurthergrowth.Theseedtankisasmallfermentationvesseldesignedtooptimizethegrowthoftheinoculum.Thecellsfrom
theseedtankarechargedtoasteamsterilizedproductionfermentor.Sterilizednutrientsandpurifiedwaterareaddedtothevesseltobeginthefermentation.During
aerobicfermentation,thecontentsofthefermentorareheated,agitatedandaeratedbyaperforatedpipeorsparger,maintaininganoptimumairflowrateandtemperature.
Afterthebiochemicalreactionsarecomplete,thefermentationbrothisfilteredtoremovethemicroorganisms,ormycelia.Thedrugproduct,whichmaybepresentinthe
filtrateorwithinthemycelia,isrecoveredbyvarioussteps,suchassolventextraction,precipitation,ionexchangeandabsorption.
Solventsusedforextractingtheproduct(table79.2)generallycanberecoveredhowever,smallportionsremainintheprocesswastewater,dependingupontheir
solubilityandthedesignoftheprocessequipment.Precipitationisamethodtoseparatethedrugproductfromtheaqueousbroth.Thedrugproductisfilteredfromthe
brothandextractedfromthesolidresidues.Copperandzincarecommonprecipitatingagentsinthisprocess.Ionexchangeoradsorptionremovestheproductfromthe
brothbychemicalreactionwithsolidmaterials,suchasresinsoractivatedcarbon.Thedrugproductisrecoveredfromthesolidphasebyasolventwhichmaybe
recoveredbyevaporation.
Table79.2Solventsusedinthepharmaceuticalindustry
Solvents Processes
Acetone C F B
Acetonitrile C F B
Ammonia(aqueous) C F B
nAmylacetate C F B
Amylalcohol C F B
Aniline C
Benzene C
2Butanone(MEK) C
nButylacetate C F
nButylalcohol C F B
Chlorobenzene C
Chloroform C F B
Chloromethene C
Cyclohexane C
oDichlorobenzene(1,2 C
Dichlorobenzene)
1,2Dichloroethane C B
Diethylamine C B
Diethylether C B
N,NDimethylacetamide C
Dimethylamine C
N,Ndimethylaniline C
N,Ndimethylformamide C F B
Dimethylsulphoxide C B
1,4Dioxane C B
Ethanol C F B
Ethylacetate C F B
Ethyleneglycol C B
Formaldehyde C F B
Formamide C
Furfural C
nHeptane C F B
nHexane C F B
Isobutyraldehyde C
Isopropanol C F B
Isopropylacetate C F B
Isopropylether C B
Methanol C F B
Methylamine C
Methylcellosolve C F
Methylenechloride C F B
Methylformate C
Methylisobutylketone(MIBK) C F B
2Methylpyridine C
Petroleumnaphtha C F B
Phenol C F B
Polyethyleneglycol600 C
nPropanol C B
Pyridine C B
Tetrahydrofuran C
Toluene C F B
Trichlorofluoromethane C
Triethylamine C F
Xylenes C
C=chemicalsynthesis,F=fermentation,B=biologicalornaturalextraction.Source:EPA1995.
Workerhealthandsafety
Workersafetyhazardsmaybeposedbymovingmachinepartsandequipmenthighpressuresteam,hotwater,heatedsurfacesandhotworkplaceenvironmentscorrosive
andirritatingchemicalsheavymanualhandlingofmaterialsandequipmentandhighnoiselevels.Workerexposurestosolventvapoursmayoccurwhenrecoveringor
isolatingproducts.Workerexposurestosolventsmayresultfromuncontainedfiltrationequipmentandfugitiveemissionsforleakingpumps,valvesandmanifoldstations
duringextractionandpurificationsteps.Sincetheisolationandgrowthofmicroorganismsareessentialforfermentation,biologicalhazardsarereducedbyemploying
nonpathogenicmicrobes,maintainingclosedprocessequipmentandtreatingspentbrothbeforeitsdischarge.
Generally,processsafetyconcernsarelessimportantduringfermentationthanduringorganicsynthesisoperations,sincefermentationisprimarilybaseduponaqueous
chemistryandrequiresprocesscontainmentduringseedpreparationandfermentation.Fireandexplosionhazardsmayariseduringsolventextractionshowever,the
flammabilityofsolventsisreducedbydilutionwithwaterinfiltrationandrecoverysteps.Safetyhazards(i.e.,thermalburnsandscalding)areposedbythelargevolumes
ofpressurizedsteamandhotwaterassociatedwithfermentationoperations.
Chemicalsynthesis
Chemicalsynthesisprocessesuseorganicandinorganicchemicalsinbatchoperationstoproducedrugsubstanceswithuniquephysicalandpharmacologicalproperties.
Typically,aseriesofchemicalreactionsareperformedinmultipurposereactorsandtheproductsareisolatedbyextraction,crystallizationandfiltration(Kroschwitz
1992).Thefinishedproductsareusuallydried,milledandblended.Organicsynthesisplants,processequipmentandutilitiesarecomparableinthepharmaceuticaland
finechemicalindustries.Aschematicdiagramofanorganicsynthesisprocessisgiveninfigure79.4.
Figure79.4Diagramofanorganicsynthesisprocess
Pharmaceuticalchemistryisbecomingincreasinglycomplexwithmultistepprocessing,wheretheproductfromonestepbecomesastartingmaterialforthenextstep,
untilthefinisheddrugproductissynthesized.Bulkchemicalswhichareintermediatesofthefinishedproductmaybetransferredbetweenorganicsynthesisplantsfor
varioustechnical,financialandlegalconsiderations.Mostintermediatesandproductsareproducedinaseriesofbatchreactionsonacampaignbasis.Manufacturing
processesoperatefordiscreteperiodsoftime,beforematerials,equipmentandutilitiesarechangedtoprepareforanewprocess.Manyorganicsynthesisplantsinthe
pharmaceuticalindustryaredesignedtomaximizetheiroperatingflexibility,duetothediversityandcomplexityofmodernmedicinalchemistry.Thisisachievedby
constructingfacilitiesandinstallingprocessequipmentthatcanbemodifiedfornewmanufacturingprocesses,inadditiontotheirutilityrequirements.
Multipurposereactorsaretheprimaryprocessingequipmentinchemicalsynthesisoperations(seefigure79.5).Theyarereinforcedpressurevesselswithstainless,glass
ormetalalloylinings.Thenatureofchemicalreactionsandphysicalpropertiesofmaterials(e.g.,reactive,corrosive,flammable)determinethedesign,featuresand
constructionofreactors.Multipurposereactorshaveexternalshellsandinternalcoilswhicharefilledwithcoolingwater,steamorchemicalswithspecialheattransfer
properties.Thereactorshellisheatedorcooled,basedupontherequirementsofthechemicalreactions.Multipurposereactorshaveagitators,bafflesandmanyinletsand
outletsconnectingthemtootherprocessvessels,equipmentandbulkchemicalsupplies.Temperature,pressureandweightsensinginstrumentsareinstalledtomeasure
andcontrolthechemicalprocessinthereactor.Reactorsmaybeoperatedathighpressuresorlowvacuums,dependingupontheirengineeringdesignandfeaturesandthe
requirementsoftheprocesschemistry.
Figure79.5Diagramofachemicalreactorinorganicsynthesis
Figure79.6Examplesofsteroidalandnonsteroidaloestrogenstructure
Figure79.7Typicaloralcontraceptivetabletmanufacturingprocessflow
Heatexchangersareconnectedtoreactorstoheatorcoolthereactionandcondensesolventvapourswhentheyareheatedabovetheirboilingpoint,creatingarefluxor
recyclingofthecondensedvapours.Airpollutioncontroldevices(e.g.,scrubbersandimpingers)canbeconnectedtotheexhaustventsonprocessvessels,reducinggas,
vapouranddustemissions(EPA1993).Volatilesolventsandtoxicchemicalsmaybereleasedtotheworkplaceoratmosphere,unlesstheyarecontrolledduringthe
reactionbyheatexchangersoraircontroldevices.Somesolvents(seetable79.2)andreactantsaredifficulttocondense,absorboradsorbinaircontroldevices(e.g.,
methylenechlorideandchloroform)duetotheirchemicalandphysicalproperties.
Bulkchemicalproductsarerecoveredorisolatedbyseparation,purificationandfiltrationoperations.Typically,theseproductsarecontainedinmotherliquors,as
dissolvedorsuspendedsolidsinasolventmixture.Themotherliquorsmaybetransferredbetweenprocessvesselsorequipmentintemporaryorpermanentpipesor
hoses,bypumps,pressurizedinertgases,vacuumorgravity.Transferringmaterialsisaconcernduetotheratesofreaction,criticaltemperaturesorpressures,featuresof
processingequipmentandpotentialforleaksandspills.Specialprecautionstominimizestaticelectricityarerequiredwhenprocessesuseorgenerateflammablegases
andliquids.Chargingflammableliquidsthroughsubmergeddiptubesandgroundingandbondingconductivematerialsandmaintaininginertatmospheresinsideprocess
equipmentreducetheriskofafireorexplosion(CrowlandLouvar1990).
Manyworkerhealthandsafetyhazardsareposedbysynthesisoperations.Theyincludesafetyhazardsfrommovingmachineparts,pressurizedequipmentandpipes
heavymanualhandlingofmaterialsandequipmentsteam,hotliquids,heatedsurfacesandhotworkplaceenvironmentsconfinedspacesandhazardousenergysources
(e.g.,electricity)andhighnoiselevels.
Acuteandchronichealthrisksmayresultfromworkerexposurestohazardouschemicalsduringsynthesisoperations.Chemicalswithacutehealtheffectscandamagethe
eyesandskin,becorrosiveorirritatingtobodytissues,causesensitizationorallergicreactionsorbeasphyxiants,causingsuffocationoroxygendeficiency.Chemicals
withchronichealtheffectsmaycausecancer,ordamagetheliver,kidneysorlungsoraffectthenervous,endocrine,reproductiveorotherorgansystems.Healthand
safetyhazardsmaybecontrolledbyimplementingappropriatecontrolmeasures(e.g.,processmodifications,engineeringcontrols,administrativepractices,personaland
respiratoryprotectiveequipment).
Organicsynthesisreactionsmaycreatemajorprocesssafetyrisksfromhighlyhazardousmaterials,fire,explosionoruncontrolledchemicalreactionswhichimpactthe
communitysurroundingtheplant.Processsafetycanbeverycomplexinorganicsynthesis.Itisaddressedinseveralways:byexaminingthedynamicsofchemical
reactions,propertiesofhighlyhazardousmaterials,design,operationandmaintenanceofequipmentandutilities,trainingofoperatingandengineeringstaff,and
emergencypreparednessandresponseofthefacilityandlocalcommunity.Technicalguidanceisavailableonprocesshazardanalysisandmanagementactivitiesto
reducetherisksofchemicalsynthesisoperations(CrowlandLouvar1990Kroschwitz1992).
Biologicalandnaturalextraction
Largevolumesofnaturalmaterials,suchasplantandanimalmatter,maybeprocessedtoextractsubstanceswhicharepharmacologicallyactive(Gennaro1990
SwarbickandBoylan1996).Ineachstepoftheprocess,thevolumesofmaterialsarereducedbyaseriesofbatchprocesses,untilthefinaldrugproductisobtained.
Typically,processesareperformedincampaignslastingafewweeks,untilthedesiredquantityoffinishedproductisobtained.Solventsareusedtoremoveinsolublefats
andoils,therebyextractingthefinisheddrugsubstance.ThepH(acidity)oftheextractionsolutionandwasteproductscanbeadjustedbyneutralizingthemwithstrong
acidsandbases.Metalcompoundsfrequentlyserveasprecipitatingagents,andphenolcompoundsasdisinfectants.
Someworkersmaydevelopallergicand/orskinirritationfromhandlingcertainplants.Animalmattermaybecontaminatedwithinfectiousorganismsunlessappropriate
precautionsaretaken.Workersmaybeexposedtosolventsandcorrosivechemicalsduringbiologicalandnaturalextractionoperations.Fireandexplosionrisksareposed
bystoring,handling,processingandrecoveringflammableliquids.Movingmechanicalpartshotsteam,water,surfacesandworkplacesandhighnoiselevelsarerisksto
workersafety.
Processsafetyissuesareoftenreducedbythelargevolumesofplantoranimalmaterials,andsmallerscaleofsolventextractionactivities.Fireandexplosionhazards,
andworkerexposurestosolventsorcorrosiveorirritatingchemicalsmayoccurduringextractionandrecoveryoperations,dependinguponthespecificchemistryand
containmentofprocessequipment.
Pharmaceuticalmanufacturingofdosageforms
Drugsubstancesareconvertedintodosageformproductsbeforetheyaredispensedoradministeredtohumansoranimals.Activedrugsubstancesaremixedwith
pharmaceuticalnecessities,suchasbinders,fillers,flavouringandbulkingagents,preservativesandantioxidants.Theseingredientsmaybedried,milled,blended,
compressedandgranulatedtoachievethedesiredpropertiesbeforetheyaremanufacturedasafinalformulation.Tabletsandcapsulesareverycommonoraldosage
formsanothercommonformissterileliquidsforinjectionorophthalmicapplication.Figure79.8illustratestypicalunitoperationsformanufacturingofpharmaceutical
dosageformproducts.
Figure79.8Pharmaceuticalmanufacturingofdosageformproducts
Pharmaceuticalblendsmaybecompressedbywetgranulation,directcompressionorsluggingtoobtainthedesiredphysicalproperties,beforetheirformulationasa
finisheddrugproduct.Inwetgranulation,theactiveingredientsandexcipientsarewettedwithaqueousorsolventsolutionstoproducecoursegranuleswithenlarged
particlesizes.Thegranulesaredried,mixedwithlubricants(e.g.,magnesiumstearate),disintegrantsorbinders,thencompressedintotablets.Duringdirectcompression,
ametaldieholdsameasuredamountofthedrugblendwhileapunchcompressesthetablet.Drugsthatarenotsufficientlystableforwetgranulationorcannotbedirectly
compressedareslugged.Sluggingordrygranulationblendsandcompressesrelativelylargetabletswhicharegroundandscreenedtoadesiredmeshsize,then
recompressedintothefinaltablet.Blendedandgranulatedmaterialsmayalsobeproducedincapsuleform.Hardgelatincapsulesaredried,trimmed,filledandjoinedon
capsulefillingmachines.
Liquidsmaybeproducedassterilesolutionsforinjectionintothebodyoradministrationtotheeyesliquids,suspensionsandsyrupsfororalingestionandtincturesfor
applicationontheskin(Gennaro1990).Highlycontrolledenvironmentalconditions,containedprocessequipmentandpurifiedrawmaterialsarerequiredfor
manufacturingsterileliquidstopreventmicrobiologicalandparticulatecontamination(Cole1990SwarbickandBoylan1996).Facilityutilities(e.g.,ventilation,steam
andwater),processequipmentandworkplacesurfacesmustbecleanedandmaintainedtopreventandminimizecontamination.Waterathightemperaturesandpressures
isusedtodestroyandfilterbacteriaandothercontaminantsfromthesterilewatersupplywhenmakingsolutionsforinjection.Parenteralliquidsareinjectedby
intradermal,intramuscularorintravenousadministrationintothebody.Theseliquidsaresterilizedbydryormoistheatunderhighpressurewithbacteriaretainingfilters.
Althoughliquidsolutionsfororalortopicalusedonotrequiresterilization,solutionstobeadministeredtotheeyes(ophthalmic)mustbesterilized.Oralliquidsare
preparedbymixingtheactivedrugsubstanceswithasolventorpreservativetoinhibitmoldandbacterialgrowth.Liquidsuspensionsandemulsionsareproducedby
colloidmillsandhomogenizers,respectively.Creamsandointmentsarepreparedbyblendingorcompoundingactiveingredientswithpetrolatum,heavygreasesor
emollientsbeforepackaginginmetalorplastictubes.
Workerhealthandsafetyrisksduringpharmaceuticalmanufacturingarecreatedbymovingmachineparts(e.g.,exposedgears,beltsandshafts)andhazardousenergy
sources(e.g.,electrical,pneumatic,thermal,etc.)manualhandlingofmaterialandequipmenthighpressuresteam,hotwaterandheatedsurfacesflammableand
corrosiveliquidsandhighnoiselevels.Workerexposurestoairbornedustsmayoccurduringdispensing,drying,millingandblendingoperations.Exposureto
pharmaceuticalproductsisaparticularconcernwhenmixturescontaininghighproportionsofactivedrugsubstancesarehandledorprocessed.Wetgranulation,
compoundingandcoatingoperationsmaycreatehighworkerexposurestosolventvapours.
Processsafetyissuesprimarilyrelatetotherisksoffireorexplosionduringpharmaceuticalmanufacturingofdosageforms.Manyoftheseoperations(e.g.,granulation,
blending,compoundinganddrying)useflammableliquids,whichmaycreateflammableorexplosiveatmospheres.Sincesomepharmaceuticaldustsarehighly
explosive,theirphysicalpropertiesshouldbeexaminedbeforetheyareprocessed.Fluidbeddrying,millingandsluggingareaparticularconcernwhentheyinvolve
potentiallyexplosivematerials.Engineeringmeasuresandsafeworkpracticesreducetherisksofexplosivedustsandflammableliquids(e.g.,vapouranddusttight
electricalequipmentandutilities,groundingandbondingofequipment,sealedcontainerswithpressurereliefandinertatmospheres).
Controlmeasures
Fireandexplosionpreventionandprotectionprocesscontainmentofhazardoussubstances,machinehazardsandhighnoiselevelsdilutionandlocalexhaustventilation
(LEV)useofrespirators(e.g.,dustandorganicvapourmasksand,insomecases,poweredairpurifyingrespiratorsorairsuppliedmasksandsuits)andpersonal
protectiveequipment(PPE)andworkertrainingonworkplacehazardsandsafeworkpracticesareworkplacecontrolmeasuresapplicableduringallofthevarious
pharmaceuticalmanufacturingoperationsdescribedbelow.Specificissuesinvolvesubstitutinglesshazardousmaterialswheneverpossibleduringdrugdevelopmentand
manufacturing.Also,minimizingmaterialtransfers,unsealedoropenprocessingandsamplingactivitiesdecreasesthepotentialforworkerexposures.
Theengineeringdesignandfeaturesoffacilities,utilitiesandprocessequipmentcanpreventenvironmentalpollutionandreduceworkerexposurestohazardous
substances.Modernpharmaceuticalmanufacturingfacilitiesandprocessequipmentarereducingenvironmental,healthandsafetyrisksbypreventingpollutionand
improvingthecontainmentofhazards.Workerhealthandsafetyandqualitycontrolobjectivesareachievedbyimprovingtheisolation,containmentandcleanlinessof
pharmaceuticalfacilitiesandprocessequipment.Preventingworkerexposurestohazardoussubstancesandpharmaceuticalproductsishighlycompatiblewiththe
concurrentneedtopreventworkersfromaccidentallycontaminatingrawmaterialsandfinishedproducts.Safeworkproceduresandgoodmanufacturingpracticesare
complementaryactivities.
Facilitydesignandprocessengineeringissues
Theengineeringdesignandfeaturesofpharmaceuticalfacilitiesandprocessequipmentinfluencesworkerhealthandsafety.Theconstructionmaterials,process
equipmentandhousekeepingpracticesgreatlyaffectthecleanlinessoftheworkplace.DilutionandLEVsystemscontrolfugitivevapoursanddustemissionsduring
manufacturingoperations.Fireandexplosionpreventionandprotectionmeasures(e.g.,vapouranddusttightelectricalequipmentandutilities,extinguishingsystems,
fireandsmokedetectorsandemergencyalarms)areneededwhenflammableliquidsandvapoursarepresent.Storageandhandlingsystems(e.g.,storagevessels,portable
containers,pumpsandpiping)areinstalledtomoveliquidswithinpharmaceuticalmanufacturingfacilities.Hazardoussolidscanbehandledandprocessedinenclosed
equipmentandvessels,individualbulkcontainers(IBCs)andsealeddrumsandbags.Theisolationorcontainmentoffacilities,processequipmentandhazardous
materialspromotesworkerhealthandsafety.Mechanicalhazardsarecontrolledbyinstallingbarrierguardsonmovingmachineparts.
Theprocessequipmentandutilitiesmaybecontrolledbymanualorautomaticmeans.Inmanualplants,chemicaloperatorsreadinstrumentsandcontrolprocess
equipmentandutilitiesneartheprocessequipment.Inautomatedplants,theprocessequipment,utilitiesandcontroldevicesarecontrolledbydistributedsystems,
allowingthemtobeoperatedfromaremotelocationsuchasacontrolroom.Manualoperationsareoftenemployedwhenmaterialsarechargedortransferred,products
aredischargedandpackagedandwhenmaintenanceisperformedornonroutineconditionsarise.Writteninstructionsshouldbeprepared,todescribestandardoperating
proceduresaswellasworkerhealthandsafetyhazardsandcontrolmeasures.
Verificationofworkplacecontrols
Workplacecontrolmeasuresareevaluatedperiodicallytoprotectworkersfromhealthandsafetyhazardsandminimizeenvironmentalpollution.Manymanufacturing
processesandpiecesofequipmentarevalidatedinthepharmaceuticalindustrytoensurethequalityofproducts(Cole1990Gennaro1990SwarbickandBoylan1996).
Similarvalidationpracticesmaybeimplementedforworkplacecontrolmeasurestoensurethattheyareeffectiveandreliable.Periodically,processinstructionsandsafe
workpracticesarerevised.Preventivemaintenanceactivitiesidentifywhenprocessandengineeringequipmentmayfail,therebyprecludingproblems.Trainingand
supervisioninformsandeducatesworkersaboutenvironmental,healthandsafetyhazards,reinforcingsafeworkpracticesandtheuseofrespiratorsandpersonal
protectiveequipment.Inspectionprogrammesexaminewhethersafeworkplaceconditionsandworkpracticesaremaintained.Thisincludesinspectingrespiratorsandto
ensuretheyareproperlyselected,wornandmaintainedbyworkers.Auditprogrammesreviewthemanagementsystemsforidentifying,evaluatingandcontrolling
environmental,healthandsafetyhazards.
Pharmaceuticalunitoperations
Weighinganddispensing
Weighinganddispensingofsolidsandliquidsisaverycommonactivitythroughoutthepharmaceuticalindustry(Gennaro1990).Usuallyworkersdispensematerialsby
handscoopingsolidsandpouringorpumpingliquids.Weighinganddispensingareoftenperformedinawarehouseduringbulkchemicalproductionorinapharmacy
duringpharmaceuticaldosageformmanufacturing.Duetothelikelihoodofspills,leaksandfugitiveemissionsduringweighinganddispensing,properworkplacecontrol
measuresarenecessarytoprotectworkers.Weighinganddispensingshouldbeperformedinapartitionedworkplaceareawithgooddilutionventilation.Thework
surfacesinareaswherematerialsareweighedanddispensedshouldbesmoothandsealed,permittingtheirpropercleaning.LEVwithbackdraftorsidedrafthoods
preventsthereleaseofaircontaminantswhenweighinganddispensingdustysolidsorvolatileliquids(Cole1990).Weighinganddispensinghighlytoxicmaterialsmay
requireadditionalcontrolmeasuressuchaslaminarventilationhoodsorisolationdevices(e.g.,gloveboxesorglovebags)(Naumannetal.1996).
Charginganddischargingsolidsandliquids
Solidsandliquidsarefrequentlychargedanddischargedfromcontainersandprocessequipmentinpharmaceuticalmanufacturingoperations(Gennaro1990).Charging
anddischargingofmaterialsareoftenperformedmanuallybyworkershowever,othermethodsareemployed(e.g.,gravity,mechanicalorpneumatictransfersystems).
Containedprocessequipment,transfersystemsandengineeringcontrolspreventworkerexposuresduringcharginganddischargingofhighlyhazardousmaterials.
Gravitychargingfromenclosedcontainersandvacuum,pressureandpumpingsystemseliminatefugitiveemissionsduringcharginganddischargingoperations.LEV
withflangedinletscapturesfugitivedustsandvapourswhicharereleasedatopentransferpoints.
Liquidseparations
Liquidsareseparatedbasedupontheirphysicalproperties(e.g.,density,solubilityandmiscibility)(Kroschwitz1992).Liquidseparationsarecommonlyperformed
duringbulkchemicalproductionandpharmaceuticalmanufacturingoperations.Hazardousliquidsshouldbetransferred,processedandseparatedinclosedvesselsand
pipingsystemstoreduceworkerexposurestoliquidspillsandairbornevapours.Eyewashesandsafetyshowersshouldbelocatednearoperationswherehazardous
liquidsaretransferred,processedorseparated.Spillcontrolmeasuresandfireandexplosionpreventionandprotectionareneededwhenusingflammableliquids.
Transferringliquids
Liquidsareoftentransferredbetweenstoragevessels,containersandprocessequipmentduringpharmaceuticalmanufacturingoperations.Ideally,facilityand
manufacturingprocessesaredesignedtominimizetheneedfortransferringhazardousmaterials,therebydecreasingthechanceofspillsandworkerexposures.Liquids
maybetransferredbetweenprocessvesselsandequipmentthroughmanifoldstations,areaswheremanypipeflangesarelocatedclosetogether(Kroschwitz1992).This
allowstemporaryconnectionstobemadebetweenpipingsystems.Spills,leaksandvapouremissionsmayoccuratmanifoldstationsthereforepropergasketsandtight
sealsonhosesandpipesareneededtopreventenvironmentalpollutionandworkplacereleases.Drainagesystemswithsealedtanksorsumpscapturespilledliquidsso
theycanbereclaimedandrecovered.Sealedvesselsandcontainersandpipingsystemsarehighlydesirablewhentransferringlargevolumesofliquids.Special
precautionsshouldbetakenwhenusinginertgasestopressurizetransferlinesorprocessequipment,sincethismayincreasethereleaseofvolatileorganiccompounds
(VOCs)andhazardousairpollutants.Recirculationorcondensationofexhaustgasesandvapoursreducesairpollution.
Filtration
Solidsandliquidsareseparatedduringfiltrationoperations.Filtershavedifferentdesignsandfeatureswithvaryingcontainmentandcontrolofliquidsandvapours
(Kroschwitz1992Perry1984).Whenopenfiltersareusedforhazardousmaterials,workersmaybeexposedtoliquids,wetsolids,vapoursandaerosolsduringloading
andunloadingoperations.Closedprocessequipmentcanbeusedtofilterhighlyhazardousmaterials,reducingvapouremissionsandpreventingworkerexposures(see
figure79.9).FiltrationshouldbeperformedinareaswithspillcontrolandgooddilutionandLEV.Volatilesolventvapourscanbeexhaustedthroughventsonsealed
processequipmentandcontrolledbyairemissionsdevices(e.g.,condensers,scrubbersandadsorbers).
Figure79.9Asparklerfilter
Compounding
Solidsandliquidsaremixedincompoundingoperationstoproducesolutions,suspensions,syrups,ointmentsandpastes.Containedprocessequipmentandtransfer
systemsarerecommendedwhencompoundinghighlyhazardousmaterials(Kroschwitz1992Perry1984).Bufferingagents,detergentsandgermicidesthatare
neutralizing,cleaningandbiocidalagentsmaybehazardoustoworkers.Eyewashesandsafetyshowersreduceinjuries,ifworkersaccidentallycontactcorrosiveor
irritatingsubstances.Duetothewetsurfacesincompoundingareas,workersneedtobeprotectedfromelectricalhazardsofequipmentandutilities.Thermalhazardsare
posedbysteamandhotwaterduringcompoundingandcleaningactivities.Workerinjuriesfromburnsandfallsarepreventedbyinstallinginsulationonhotsurfacesand
maintainingdrynonslipfloors.
Granulation
Dryandwetsolidsaregranulatedtochangetheirphysicalproperties.Granulatorshavedifferentdesignsandfeatureswithvaryingcontainmentandcontrolofmechanical
hazardsandairbornedustsandvapours(Perry1984SwarbickandBoylan1996).Enclosedgranulatorscanbeventedtoaircontroldevices,reducingemissionsof
solventvapoursorduststotheworkplaceandatmosphere(seefigure79.10).Materialhandlingconcernsarisewhenloadingandunloadinggranulators.Mechanical
equipment(e.g.,elevatedplatforms,lifttablesandpalletjacks)assistsworkerstoperformheavymanualtasks.Eyewashesandsafetyshowersareneeded,ifworkers
accidentallycontactsolventsorirritatingdusts.
Figure79.10Ahighsteamgranulator
Drying
Waterorsolventwetsolidsaredriedduringmanypharmaceuticalmanufacturingoperations.Dryershavedifferentdesignsandfeatureswithvaryingcontainmentand
controlofvapoursanddusts(seefigure79.11).Flammablesolventvapoursandexplosiveairbornedustsmaycreateflammableorexplosiveatmosphereexplosionrelief
ventingisparticularlyimportantoncontaineddryers.DilutionandLEVreducestheriskoffireorexplosion,inadditiontocontrollingworkerexposurestosolvent
vapourswhenhandlingwetcakes,ortoairbornedustswhenunloadingdriedproducts.Heavymaterialhandlingmaybeinvolvedwhenloadingorunloadingdryertrays,
binsorcontainers(seefigure79.12).Mechanicalequipment(e.g.,drumjacks,liftsandworkplatforms)assiststhesemanualtasks.Eyewashesandsafetyshowersshould
belocatednearby,incaseworkersaccidentallycontactsolventsanddusts.
Figure79.11Arotaryvacuumdryer
GlattAirTechniques,Inc.
Figure79.12Avacuumshelfdryer
Source:EPA1993
Milling
Drysolidsaremilledtochangetheirparticlecharacteristicsandproducefreeflowingpowders.Millshavedifferentdesignsandfeatureswithvaryingcontainmentand
controlofmechanicalhazardsandairbornedusts(Kroschwitz1992Perry1984).Priortomillingmaterials,theirphysicalpropertiesandhazardsshouldbereviewedor
tested.Explosionpreventionandprotectionmeasuresinvolveinstallingdusttightelectricalequipmentandutilities,groundingandbondingequipmentandaccessoriesto
eliminateelectrostaticsparking,installingsafetyreliefvalvesonenclosedmills,andconstructingblastreliefpanelsinwalls.Thesemeasuresmaybenecessaryduetothe
explosivityofsomedrugsubstancesandexcipients,highdustlevelsandenergiesassociatedwithmillingoperations.
Blending
Drysolidsareblendedtoproducehomogeneousmixtures.Blendershavedifferentdesignsandfeatureswithvaryingcontainmentandcontrolofmechanicalhazardsand
airbornedusts(Kroschwitz1992Perry1984).Workerexposurestodrugsubstances,excipientsandblendsmayoccurwhenloadingandunloadingblendingequipment.
LEVwithflangedinletsreducesfugitivedustemissionsduringblending.Heavymaterialhandlingmayberequiredwhencharginganddischargingsolidsfromblenders.
Mechanicalequipment(e.g.,workplatforms,hoistsanddrumandpalletjacks)reducesthephysicaldemandsofheavymaterialhandling.
Compression
Drysolidsarecompressedorsluggedtocompactthem,changingtheirparticleproperties.Compressionequipmenthasdifferentdesignsandfeatureswithvarying
containmentandcontrolofmechanicalhazardsandairbornedusts(Gennaro1990SwarbickandBoylan1996).Compressionequipmentmayposeseriousmechanical
hazardsifinadequatelyguarded.Highnoiselevelsmayalsobeproducedbycompressionandsluggingoperations.Enclosingimpactsources,isolatingvibrating
equipment,rotatingworkersandusinghearingprotectivedevices(e.g.,earmuffsandplugs)reducetheimpactofnoiseexposures.
Soliddosageformmanufacturing
Tabletsandcapsulesarethemostcommonoraldosageforms.Compressedormouldedtabletscontainmixturesofdrugsubstancesandexcipients.Thesetabletsmaybe
uncoatedorcoatedwithsolventmixturesoraqueoussolutions.Capsulesaresoftorhardgelatinshells.Tabletpresses(seefigure79.13),tabletcoatingequipmentand
capsulefillingmachineshavedifferentdesignsandfeatureswithvaryingcontainmentandcontrolofmechanicalhazardsandairbornedusts(Cole1990).Workersmaybe
exposedtosolventvapourswhenspraycoatingtablets.Moderntabletcoatingequipmentishighlycontainedhowever,LEVcanbeinstalledinolderopencoatingpansto
controlfugitivesolventvapours.TabletcoatingequipmentcanbeventedtoairemissiondevicestocontrolVOCsfromtheprocess(seefigure79.14).Wheneverpossible,
recoveredsolventsshouldbereusedbytheprocessoraqueousmixturessubstitutedforsolventmixturesfortabletcoating.Moderntabletpressesandcapsulefilling
machinesareenclosedbyinterlockedpanels,reducingthehazardsoffastmovingparts,highnoiselevelsanddustemissionsduringtheiroperation.Hearingprotective
devicescanreduceworkernoiseexposuresduringtabletandcapsuleoperations.
Figure79.13Tabletpresswithloadhopperandspiraldustpickupsforproductrecovery
Figure79.14Atabletcoatingmachine
Source:Perry1984
Sterilemanufacturing
Sterileproductsaremanufacturedinpharmaceuticalmanufacturingplantswithmodulardesign(seefigure79.15),cleanworkplaceandequipmentsurfaces,andhigh
efficiencyparticulateair(HEPA)filteredventilationsystems(Cole1990Gennaro1990).Theprinciplesandpracticesofcontrollingcontaminationinsterileliquid
manufacturingaresimilartothoseinthemicroelectronicsindustry.Workerswearprotectiveclothingtopreventthemfromcontaminatingproductsduringsterile
manufacturingoperations.Sterilepharmaceuticaltechnologiestocontrolcontaminationinvolvefreezedryingproducts,usingliquidgermicidesandsterilizinggases,
installinglaminarflowventilation,isolatingmoduleswithdifferentialairpressuresandcontainingmanufacturingandfillingequipment.
Figure79.15Diagramofasterileliquidmanufacturingfacility
Chemicalhazardsareposedbytoxicgermicides(e.g.,formaldehydeandglutaraldehyde)andsterilizinggases(i.e.,ethyleneoxide).Wheneverpossible,lesshazardous
agentsshouldbeselected(e.g.,alcohols,ammoniumcompounds).Sterilizationofrawmaterialsandequipmentmaybeperformedbyhighpressuresteamortoxicgases
(i.e.,dilutedethyleneoxidegasmixtures)(SwarbickandBoylan1996).Sterilizationvesselscanbelocatedinseparateareaswithremoteinstrumentandcontrolsystems,
nonrecirculatedairandLEVtoextracttoxicgasemissions.Workersshouldbetrainedonstandardoperatinginstructions,safeworkpracticesandappropriateemergency
response.Gassterilizationchambersshouldbefullyevacuatedundervacuumandpurgedwithairtominimizefugitiveworkplaceemissionsbeforesterilizedgoodsare
removed.Gasemissionsfromsterilizationchamberscanbeventedtoaircontroldevices(e.g.,carbonadsorptionorcatalyticconverters)toreduceatmosphericemissions.
Occupationalhygienemonitoringmeasuresworkerexposurestochemicalgermicidesandsterilizinggases,helpingtoassesstheadequacyofcontrolmeasures.Safety
hazardsinvolvehighpressuresteamandhotwater,movingmachinepartsinwashing,filling,cappingandpackagingequipment,highnoiselevelsandrepetitivemanual
tasks.
Cleaningandmaintenanceactivities
Nonroutinetasksmayoccurwhencleaning,repairingandmaintainingequipment,utilitiesandworkplaces.Althoughuniquehazardsmayariseduringnonroutinetasks,
recurringhealthandsafetyconcernsareencountered.Workplaceandequipmentsurfacesmaybecontaminatedbyhazardousmaterialsanddrugsubstances,requiring
themtobecleanedbeforeunprotectedworkersconductservicingormaintenancework.Cleaningisperformedbywashingorwipingliquidsandsweepingorvacuuming
dusts.Drysweepingandblowingsolidswithcompressedairarenotrecommended,sincetheycreatehighworkerexposurestoairbornedusts.Wetmoppingand
vacuumingreduceworkerexposurestodustsduringcleaningactivities.VacuumcleanerswithHEPAfiltersmaybeneededwhencleaninghazardoussubstancesandhigh
potencydrugs.Explosionproofequipmentandconductivematerialsmayberequiredinvacuumsystemsforexplosivedusts.EyewashesandsafetyshowersandPPE
reducetheeffectofworkersaccidentalcontactwithcorrosiveandirritatingdetergentsandcleaningliquids.
Hazardousmechanical,electrical,pneumaticorthermalenergymayneedtobereleasedorcontrolledbeforeequipmentandutilitiesareserviced,repairedormaintained.
Contractworkersmayperformspecialproductionorengineeringtasksinpharmaceuticalplantswithoutadequatetrainingonsafetyprecautions.Carefulsupervisionof
contractworkersisimportant,sotheydonotviolatesafetyrulesorperformworkthatcreatesafire,explosionorotherserioushealthandsafetyhazards.Special
contractorsafetyprogrammesarerequiredwhenworkingwithhighlyhazardousmaterials(e.g.,toxic,reactive,flammableorexplosive)andprocesses(e.g.,exothermic
orhighpressure)inbulkpharmaceuticalanddosageformmanufacturingfacilities.
Packaging
Pharmaceuticalpackagingoperationsareperformedwithaseriesofintegratedmachinesandrepetitivemanualtasks(Gennaro1990SwarbickandBoylan1996).
Finisheddosageformproductsmaybepackagedinmanydifferenttypesofcontainers(e.g.,plasticorglassbottles,foilblisterpacks,pouchesorsachets,tubesandsterile
vials).Themechanicalequipmentfills,caps,labels,cartonsandpacksthefinishedproductsinshippingcontainers.Workerproximitytopackagingequipment
necessitatesbarrierguardingonmovingmachineparts,accessiblecontrolswitchesandemergencystopcablesandemployeetrainingonmachinehazardsandsafework
practices.Enclosureandisolationofequipmentreducessoundandvibrationlevelsinpackagingareas.Useofhearingprotectivedevices(e.g.,earmuffsandplugs)
reducesworkerexposurestonoise.Goodindustrialdesignpromotestheproductivity,comfortandsafetyofemployees,byaddressingergonomichazardsfrompoorbody
postures,materialhandlingandhighlyrepetitivetasks.
Laboratoryoperations
Laboratoryoperationsinthepharmaceuticalindustryarediverse.Theymayposebiological,chemicalandphysicalhazards,dependinguponthespecificagents,
operations,equipmentandworkpracticesemployed.Majordistinctionsexistbetweenlabswhichconductscientificresearchandproductandprocessdevelopmentand
thosewhichevaluatequalityassuranceandcontrolactivities(SwarbickandBoylan1996).Labworkersmayconductscientificresearchtodiscoverdrugsubstances,
developmanufacturingprocessesforbulkchemicalanddosageformproductsoranalyzerawmaterials,intermediatesandfinishedproducts.Labactivitiesshouldbe
evaluatedindividually,althoughgoodlabpracticesapplytomanysituations(NationalResearchCouncil1981).Clearlydefinedresponsibilities,trainingandinformation,
safeworkpracticesandcontrolmeasuresandemergencyresponseplansareimportantmeansforeffectivelymanagingenvironmental,healthandsafetyhazards.
Thehealthandsafetyhazardsofflammableandtoxicmaterialsarereducedbyminimizingtheirinventoriesinlabsandstoringtheminseparatecabinets.Labassaysand
operationswhichmayreleaseaircontaminantscanbeperformedinventilatedexhaustfumehoodstoprotectworkers.Biologicalsafetyhoodsprovidedownwardand
inwardlaminarflow,preventingthereleaseofmicroorganisms(Gennaro1990SwarbickandBoylan1996).Workertrainingandinformationdescribesthehazardsof
labwork,safeworkpracticesandproperemergencyresponsetofiresandspills.Foodandbeveragesshouldnotbeconsumedinlabareas.Labsafetyisenhancedby
requiringsupervisorstoapproveandmanagehighlyhazardousoperations.Goodlabpracticesseparate,treatanddisposeofbiologicalandchemicalwastes.Physical
hazards(e.g.,radiationandelectromagneticenergysources)areoftencertifiedandoperated,accordingtospecificregulations.
GeneralHealthandSafetyHazards
Ergonomicsandmaterialhandling
Thematerialsshipped,stored,handled,processedandpackagedinthepharmaceuticalindustryrangefromlargequantitiesofrawmaterialstosmallpackagescontaining
pharmaceuticalproducts.Rawmaterialsforbulkchemicalproductionareshippedinbulkcontainers(e.g.,tanktrucks,railcars),metalandfibredrums,reinforcedpaper
andplasticbags.Pharmaceuticalproductionusessmallerquantitiesofrawmaterialsduetothereducedscaleoftheoperations.Materialhandlingdevices(e.g.,forklift
trucks,palletlifts,vacuumhoistsanddrumjacks)assistmaterialhandlingduringwarehousingandproductionoperations.Heavymanualworkmaycreateergonomic
riskswhenmovingmaterialsandequipmentifmechanicaldevicesarenotavailable.Goodindustrialengineeringandfacilitymanagementpracticesreduceinjuriesfrom
materialhandlingbyimprovingthedesignandfeaturesofequipmentandtheworkplaceanddecreasingthesizeandweightofcontainers(Cole1990).Engineering
controlmeasures(e.g.,ergonomicdesignoftools,materialsandequipment)andadministrativepractices(e.g.,rotatingworkers,providingworkertraining)reducethe
risksofcumulativetraumainjuriesduringhighlyrepetitiveproductionandpackagingoperations.
Machineguardingandcontrolofhazardousenergy
Unguardedmovingmachinepartsinpharmaceuticalmanufacturingandpackagingequipmentcreatemechanicalhazards.Exposedcrushandnippointsinopen
equipmentmayseriouslyinjureworkers.Mechanicalhazardsareexacerbatedbythelargenumbersanddifferentdesignsofequipment,crowdedworkplaceconditions
andfrequentinteractionsbetweenworkersandequipment.Interlockedguards,controlswitches,emergencystopdevicesandoperatortrainingareimportantmeansof
reducingmechanicalhazards.Loosehair,longsleevedclothing,jewelleryorotherobjectsmaybecometrappedinequipment.Routineinspectionandrepairactivities
identifyandcontrolmechanicalhazardsduringproductionandpackagingoperations.Hazardouselectrical,pneumaticandthermalenergymustbereleasedorcontrolled
beforeworkingonactiveequipmentandutilities.Workersareprotectedfromsourcesofhazardousenergybyimplementinglockout/tagoutprocedures.
Noiseexposures
Highsoundlevelsmaybegeneratedbymanufacturingequipmentandutilities(e.g.,compressedair,vacuumsourcesandventilationsystems).Duetotheencloseddesign
ofpharmaceuticalworkplacemodules,workersareoftenlocatedclosetomachinesduringmanufacturingandpackagingoperations.Workersobserveandinteractwith
productionandpackagingequipment,therebyincreasingtheirexposuretonoise.Engineeringmethodsreducesoundlevelsbymodifying,enclosinganddampeningnoise
sources.Employeerotationanduseofhearingprotectivedevices(e.g.,earmuffsandplugs)reduceworkersexposuretohighnoiselevels.Comprehensivehearing
conservationprogrammesidentifynoisesources,reduceworkplacesoundlevels,andtrainworkersonthehazardsofnoiseexposureandproperuseofhearingprotective
devices.Noisemonitoringandmedicalsurveillance(i.e.,audiometry)assessworkerexposurestonoiseandtheirresultinglossofhearing.Thishelpstoidentifynoise
problemsandevaluatetheadequacyofcorrectivemeasures.
Solventvapourandpotentcompoundexposures
Specialconcernsmayarisewhenworkersareexposedtotoxicsolventvapoursandpotentdrugsasairbornedusts.Workerexposurestosolventvapoursandpotent
compoundsmayoccurduringvariousmanufacturingoperations,whichneedtobeidentified,evaluatedandcontrolledtoensurethatworkersareprotected.Engineering
controlsarethepreferredmeansofcontrollingtheseexposures,duetotheirinherenteffectivenessandreliability(Cole1990Naumannetal.1996).Enclosedprocess
equipmentandmaterialhandlingsystemspreventworkerexposures,whileLEVandPPEsupplementthesemeasures.Increasedfacilityandprocesscontainmentis
neededforcontrollinghighlytoxicsolvents(e.g.,benzene,chlorinatedhydrocarbons,ketones)andpotentcompounds.Positivepressurerespirators(e.g.,poweredair
purifyingandsuppliedair)andPPEareneededwhenhighlytoxicsolventsandpotentcompoundsarehandledandprocessed.Specialconcernsareposedbyoperations
wherehighlevelsofsolventvapours(e.g.,compounding,granulatingandtabletcoating)anddusts(e.g.,drying,millingandblending)aregenerated.Lockerandshower
rooms,decontaminationpracticesandgoodsanitarypractices(e.g.,washingandshowering)arenecessarytopreventorminimizetheeffectsofworkerexposuresinside
andoutsidetheworkplace.
Processsafetymanagement
Processsafetyprogrammesareimplementedinthepharmaceuticalindustryduetothecomplexchemistry,hazardousmaterialsandoperationsinbulkchemical
manufacturing(CrowlandLouvar1990).Highlyhazardousmaterialsandprocessesmaybeemployedinmultisteporganicsynthesisreactionstoproducethedesired
drugsubstance.Thethermodynamicsandkineticsofthesechemicalreactionsmustbeevaluated,sincetheymayinvolvehighlytoxicandreactivematerials,lachrymators
andflammableorexplosivecompounds.
Processsafetymanagementinvolvesconductingphysicalhazardtestingofmaterialsandreactions,performinghazardanalysisstudiestoreviewtheprocesschemistry
andengineeringpractices,examiningpreventivemaintenanceandmechanicalintegrityoftheprocessequipmentandutilities,implementingworkertrainingand
developingoperatinginstructionsandemergencyresponseprocedures.Specialengineeringfeaturesforprocesssafetyincludeselectingproperpressureratedvessels,
installingisolationandsuppressionsystems,andprovidingpressurereliefventingwithcatchtanks.Processsafetymanagementpracticesaresimilarinthepharmaceutical
andchemicalindustrieswhenmanufacturingbulkpharmaceuticalsasspecialityorganicchemicals(CrowlandLouvar1990Kroschwitz1992).
EnvironmentalIssues
Thedifferentpharmaceuticalmanufacturingprocesseseachhavetheirownenvironmentalissues,asdiscussedbelow.
Fermentation
Fermentationgenerateslargevolumesofsolidwastewhichcontainsmyceliaandspentfiltercakes(EPA1995TheodoreandMcGuinn1992).Filtercakescontain
mycelia,filtermediaandsmallamountsofnutrients,intermediatesandresidualproducts.Thesesolidwastesaretypicallynonhazardous,yettheymaycontainsolvents
andsmallamountsofresidualchemicalsdependinguponthespecificchemistryofthefermentationprocess.Environmentalproblemsmaydevelopiffermentation
batchesbecomeinfectedwithaviralphagewhichattacksthemicroorganismsinthefermentationprocess.Althoughphageinfectionsarerare,theycreateasignificant
environmentalproblembygeneratinglargeamountsofwastebroth.
Spentfermentationbrothcontainssugars,starches,proteins,nitrogen,phosphatesandothernutrientswithhighbiochemicaloxygendemand(BOD),chemicaloxygen
demand(COD)andtotalsuspendedsolids(TSS)withpHvaluesrangingfrom4to8.Fermentationbrothscanbetreatedbymicrobiologicalwastewatersystems,afterthe
effluentisequalizedtopromotethestableoperationofthetreatmentsystem.Steamandsmallamountsofindustrialchemicals(e.g.,phenols,detergentsanddisinfectants)
maintainthesterilityoftheequipmentandproductsduringfermentation.Largevolumesofmoistairareexhaustedfromfermentors,containingcarbondioxideand
odourswhichmaybetreatedbeforetheyareemittedtotheatmosphere.
Organicsynthesis
Wastesfromchemicalsynthesisarecomplexduetothevarietyofhazardousmaterials,reactionsandunitoperations(Kroschwitz1992TheodoreandMcGuinn1992).
Organicsynthesisprocessesmaygenerateacids,bases,aqueousorsolventliquors,cyanidesandmetalwastesinliquidorslurryform.Solidwastesmayincludefilter
cakescontaininginorganicsalts,organicbyproductsandmetalcomplexes.Wastesolventsinorganicsynthesisareusuallyrecoveredbydistillationandextraction.This
allowsthesolventstobereusedbyotherprocessesandreducesthevolumeofliquidhazardouswastestobedisposedof.Residuesfromdistillation(stillbottoms)needto
betreatedbeforetheyaredisposed.Typicaltreatmentsystemsincludesteamstrippingtoremovesolvents,followedbymicrobiologicaltreatmentofotherorganic
substances.Volatileorganicandhazardoussubstanceemissionsduringorganicsynthesisoperationsshouldbecontrolledbyairpollutioncontroldevices(e.g.,condensers,
scrubbers,venturiimpingers).
Wastewaterfromsynthesisoperationsmaycontainaqueousliquors,washwater,dischargesfrompumps,scrubbersandcoolingsystems,andfugitiveleaksandspills
(EPA1995).Thiswastewatermaycontainmanyorganicandinorganicsubstanceswithdifferentchemicalcompositions,toxicitiesandbiodegradabilities.Traceamounts
ofrawmaterials,solventsandbyproductsmaybepresentinaqueousmotherliquorsfromcrystallizationsandwashlayersfromextractionsandequipmentcleaning.
ThesewastewatersarehighinBOD,CODandTSS,withvaryingacidityoralkalinityandpHvaluesrangingfrom1to11.
Biologicalandnaturalextraction
Spentrawmaterialsandsolvents,washwaterandspillsaretheprimarysourcesofsolidandliquidwastes(TheodoreandMcGuinn1992).Organicandinorganic
chemicalsmaybepresentasresiduesinthesewastestreams.Usually,wastewatershavelowBOD,CODandTSS,withrelativelyneutralpHvaluesrangingfrom6to8.
Pharmaceuticalmanufacturingofdosageforms
Pharmaceuticalmanufacturingofdosageformproductsgeneratessolidandliquidwastesduringcleaningandsterilization,andfromleaksandspillsandrejectedproducts
(TheodoreandMcGuinn1992).Drying,millingandblendingoperationsgenerateatmosphericandfugitivedustemissions.Theseemissionscanbecontrolledand
recycledtothemanufacturingofdosageformproductshowever,qualitycontrolpracticesmaypreventthisifotherresiduesarepresent.Whensolventsareusedduring
wetgranulation,compoundingandtabletcoating,VOCsandhazardousairpollutantsmaybereleasedtotheatmosphereorintheworkplaceasprocessorfugitive
emissions.Wastewatersmaycontaininorganicsalts,sugars,syrupsandtracesofdrugsubstances.ThesewastewatersusuallyhavelowBOD,CODandTSS,with
neutralpHvalues.Someantiparasiticorantiinfectivedrugsforhumansandanimalsmaybetoxictoaquaticorganisms,requiringspecialtreatmentofliquidwastes.
Environmentalpollutionprevention
Wasteminimizationandpollutionprevention
Goodengineeringandadministrativepracticesminimizetheenvironmentalimpactofbulkchemicalproductionandpharmaceuticalmanufacturingoperations.Pollution
preventionemploysmodifyingprocessesandequipment,recyclingandrecoveringmaterialsandmaintaininggoodhousekeepingandoperatingpractices(Theodoreand
McGuinn1992).Theseactivitiesenhancethemanagementofenvironmentalissues,aswellasworkerhealthandsafety.
Processmodifications
Processesmaybemodifiedtoreformulateproductsbyusingmaterialsthatarelesshazardousorpersistentorchangingmanufacturingoperationstoreduceairemissions,
liquideffluentsandsolidwastes.Reducingtheamountandtoxicityofwastesiswise,sinceitimprovestheefficiencyofmanufacturingprocessesandreducesthecosts
andimpactsofwastedisposal.Governmentdrugapprovalregulationsmaylimittheabilityofpharmaceuticalmanufacturerstochangehazardousmaterials,
manufacturingprocesses,equipmentandfacilities(Spilker1994).Drugmanufacturersmustanticipatetheenvironmental,healthandsafetyimpactsofselecting
hazardousmaterialsanddesigningmanufacturingprocessatanearlystage.Itbecomesincreasinglydifficulttomakechangesduringthelaterstagesofdrugdevelopment
andregulatoryapproval,withoutconsiderablelossoftimeandexpense.
Itisverydesirabletodevelopmanufacturingprocesseswithlesshazardoussolvents.Ethylacetate,alcoholsandacetonearepreferabletohighlytoxicsolventssuchas
benzene,chloroformandtrichloroethylene.Wheneverpossible,somematerialsshouldbeavoidedduetotheirphysicalproperties,ecotoxicityorpersistenceinthe
environment(e.g.,heavymetals,methylenechloride)(CrowlandLouvar1990).Substitutingaqueouswashesforsolventsduringfiltrationsinbulkchemicalproduction
reducesliquidwastesandvapouremissions.Also,substitutingaqueousforsolventbasedsolutionsduringtabletcoatingreducesenvironmental,healthandsafety
concerns.Pollutionpreventionispromotedbyimprovingandautomatingprocessequipment,aswellasperformingroutinecalibration,servicingandpreventive
maintenance.Optimizingorganicsynthesisreactionsincreasesproductyields,oftendecreasingthegenerationofwastes.Incorrectorinefficienttemperature,pressureand
materialcontrolsystemscauseinefficientchemicalreactions,creatingadditionalgaseous,liquidandsolidwastes.
Thefollowingareexamplesofprocessmodificationsinbulkpharmaceuticalproduction(TheodoreandMcGuinn1992):
Minimizethequantitiesofhazardousmaterialsusedandselectmaterialswhosewastescanbecontrolled,recoveredandrecycled,wheneverpossible.
Developandinstallsystemsforrecyclingrawmaterials(e.g.,solvents),intermediates,wastesandutilitymaterials(e.g.,coolingwater,heattransferliquids,
lubricants,steamcondensate).
Examinereactants,solventsandcatalyststooptimizetheefficiencyofchemicalreactions.
Modifythedesignandfeaturesofprocessingequipmenttominimizepollutionandwastes.
Improveprocessestomaximizeproductyieldsanddesiredproperties,eliminatingadditionalprocessing(e.g.,recrystallization,dryingandmilling).
Considerusingmultipurposeequipment(e.g.,reactors,filtersanddryers)toreducepollutionandwastesduringtransfers,cleaningandadditionalprocesssteps.
Useappropriateinstruments,automatedcontrolsystemsandcomputerprogramstomaximizetheefficiencyofprocessesandreducepollutionandwastes.
Resourcerecoveryandrecycling
Resourcerecoveryuseswasteproductsandreclaimsmaterialsduringprocessingbyseparatingwasteimpuritiesfromdesiredmaterials.Solidwastesfromfermentation
(e.g.,mycelia)maybeaddedtoanimalfeedsasanutritionalsupplementorassoilconditionersandfertilizers.Inorganicsaltsmayberecoveredfromchemicalliquors
producedduringorganicsynthesisoperations.Spentsolventsareoftenrecycledbyseparationanddistillation.Airemissioncontroldevices(e.g.,condensers,compression
andrefrigerationequipment)greatlyreduceemissionsofvolatileorganiccompoundstotheatmosphere(EPA1993).Thesedevicescapturesolventvapoursby
condensation,enablingthereuseofsolventsasrawmaterialsorforcleaningvesselsandequipment.Scrubbersneutralizeorabsorbacid,causticandsolublegasesand
vapours,dischargingtheireffluentstowastetreatmentsystems.
Recycledsolventsmaybereusedasmediaforperformingreactionsandextractions,andcleaningoperations.Differenttypesofsolventsshouldnotbemixed,sincethis
reducestheirabilitytoberecycled.Somesolventsshouldbesegregatedduringprocessing(e.g.,chlorinatedandnonchlorinated,aliphaticandaromatic,aqueousand
flammablesolvents).Dissolvedandsuspendedsolidsareextractedorseparatedfromthesolvents,beforethesolventsarerecovered.Laboratoryanalysisidentifiesthe
compositionandpropertiesofwastesolventsandrecycledrawmaterials.Manynewwastepreventionandcontroltechnologiesarebeingdevelopedforsolid,liquidand
gaseouswastes.
Generalhousekeepingandoperatingpractices
Writtenoperatingprocedures,materialhandlinginstructionsandwastemanagementpracticesreducethegenerationandimprovethetreatmentofwastes(Theodoreand
McGuinn1992).Goodoperatingandhousekeepingpracticesidentifyspecificresponsibilitiesforgenerating,handlingandtreatingwastes.Trainingandsupervisionof
operatingstaffincreasestheirabilitytoimproveandmaintainefficientmanufacturingandwastemanagementoperations.Workersshouldbetrainedonthehazardsof
wastemanagementpracticesandthepropermeansofrespondingtoemergencyspills,leaksandfugitiveemissions.Workertrainingshouldaddressmaterialhandling,
cleaningorneutralizingwastesandwearingrespiratorsandPPE.Spillandleakdetectiondevicespreventpollutionbyroutinelymonitoringproductionequipmentand
utilities,identifyingandcontrollingfugitiveemissionsandleaks.Theseactivitiesmaybesuccessfullyintegratedwithpreventivemaintenancepracticestoclean,
calibrate,replaceandrepairequipmentthatcreatespollution.
Writteninstructionsdescribingnormaloperatingprocedures,aswellasstartup,shutdownandemergencyprocedures,preventpollutionandreduceriskstoworker
healthandsafety.Carefulmanagementofmaterialinventoriesdecreasestheexcessivepurchasingofrawmaterialsandgenerationofwastes.Computersystemscanassist
theeffectivemanagementofplantoperations,maintenancepracticesandmaterialinventories.Automaticweighing,monitoringandalarmsystemscanbeinstalledto
improvethemanagementofmaterialsandequipment(e.g.,storagetanks,processequipmentandwastetreatmentsystems).Moderninstrumentandcontrolsystemsoften
increasetheproductivityofoperations,reducingpollutionandhealthandsafetyhazards.Comprehensivepollutionpreventionprogrammesexamineallwastesgenerated
atafacilityandexaminetheoptionsforeliminating,reducingortreatingthem.Environmentalauditsexaminethestrengthsandweaknessesofpollutionpreventionand
wastemanagementprogrammes,seekingtooptimizetheirperformance.
EFFECTSOFSYNTHETICOESTROGENSONPHARMACEUTICALWORKERS:AUNITEDSTATESEXAMPLE
Background
Oestrogensusedinthepharmaceuticalindustrycangenerallybeclassifiedasnaturalor
syntheticandassteroidalornonsteroidal.Allsteroidaloestrogens,bothnatural(e.g.,oestrone)
andsynthetic(e.g.,ethynyloestradiolandmoestranol)haveatypicalmultiringstructure,as
depictedinfigure79.6Diethylstilboestrol(DES)anddienoestrolareexamplesofthenon
steroidaloestrogens.Theprincipalusesofoestrogeniccompoundsareinoralcontraceptive
tabletsandtabletsintendedforoestrogenreplacementtherapy.Thepurecompounds(naturally
derivedorsynthesized)arenolongermanufacturedintheUnitedStates,butareimported.
Manufacturingprocesses
Thefollowingdescriptionisageneralized,andcomposite,descriptionofthemanufacturing
processusedinmanyUSpharmaceuticalcompanies.Specificproductprocessesmaynotfollow
theflowexactlyasdescribedbelowsomestepsmaybeabsentinsomeprocesses,and,inother
cases,additionalstepsmaybepresentthatarenotdescribedhere.
Aswithmostdryproductdrugs,pharmaceuticalproductsmadefromoestrogeniccompounds
aremanufacturedinastepwisebatchoperation(figure79.7).Themanufacturingstepsbegin
withtheassemblyandpreweighingofbothactiveingredientsandexcipients(inactive
ingredients)inanisolatedroomunderlocalexhaustventilation.Whenneeded,theingredients
aremovedtoablendingroomequippedwithmechanicalblenders.Excipientsareusually
loadeddryfromahopperabovetheblender.Theactiveingredientsarealmostalwaysdissolved
firstinanalcohol,andareaddedmanuallyorarefedthroughtubingthroughthesideofthe
blender.Theinitialblendingoftheingredientsisdoneinawetstate.Attheendofthewet
blendingprocess,thegranulationistypicallymovedtoawetmill,whereparticlesinthemixare
reducedtoaspecificsize.Themilledgranulationisthendriedusingafluidbeddrieroristray
driedinovensdesignedforthepurpose.Thedriedgranulationmayormaynotundergothe
additionofalubricantbeforedryblendingand/ordrymilling,dependingonthespecific
productandprocess.Thefinalgranulation,readytobemadeintotablets,isthenstoredinsealed
containers.Therawmaterialsandgranulation,andsometimestheintermediateproducts,are
typicallysampledandassayedbyqualitycontrolpersonnelpriortobeingmovedtothenext
processstep.
Whenneeded,thegranulationismovedtoacompressionroom,whereitismadeintotabletsby
meansofatabletpress.Thegranulationistypicallyfedfromthestoragecontainer(typicallya
plasticlinedfibredrumoralinedstainlesssteelcontainer)intothetabletpresshopperby
gravityorpneumaticallybymeansofavacuumwand.Formedtabletsexitfromthemachine
throughtubingattheside,anddropintoplasticlineddrums.Whenfilled,thedrumsare
sampledandinspected.Afterassaybyqualitycontrolpersonnel,thedrumsaresealed,stored
andstagedforpackagingoperations.Sometabletsalsoundergoacoatingprocess,inwhich
layersofediblewaxandsometimessugarsareusedtosealthetablet.
Thetabletsarepackagedbysealingtheminblisterpacksorbottled,dependingonthenatureof
theproduct.Inthisprocess,thecontainersoftabletsaremovedtothepackagingarea.The
tabletsmaybemanuallyscoopedintothepackagingmachinehopperorfedbymeansofa
vacuumwand.Thetabletsaretheneitherimmediatelysealedbetweenlayersofaluminiumfoil
andplasticfilm(blisterpackaging)ortheyarebottled.Theblisterpacksorbottlesarethen
conveyedalongalineonwhichtheyareinspectedandplacedinpouchesorboxedwith
appropriateinserts.
Healtheffectsonmaleandfemalepharmaceuticalworkers
Reportsofoccupationalexposuresandtheeffectsonmaleshavebeenrelativelyfew,compared
withtheconsiderableliteraturethatexistsregardingacuteandchroniceffectsofoestrogensin
womenasaresultofnonoccupationalexposures.Thenonoccupationalliteratureisprimarilya
resultofwidespreadcontraceptiveandothermedicalusesofoestrogenicpharmaceuticals(but
alsoenvironmentalpollutantswithoestrogenicproperties,suchastheorganochlorines)and
focusesparticularlyontherelationshipsbetweenthatexposureandavarietyofhumancancers,
suchasthatoftheendometrium,cervixandbreastinwomen(Hoover1980Houghtonand
Ritter1995).Intheoccupationalliterature,thehyperoestrogenicsyndromeinbothmaleand
femaleworkershasbeenassociatedwithexposurestoDESanditsderivatives,naturalor
conjugatedoestrogens,hexoestrolanditsderivativesandsteroidalsyntheticssuchas
ethynyloestradiolandmoestranol.Shortlyaftertheinitiationofcommercialproductionof
oestrogens,reportsbegantosurfaceoftheireffects,suchasgynaecomastia(abnormal
enlargementofthebreastsinamale)anddecreasedlibidoamongmaleworkers,andmenstrual
disorders(increasedfloworintermenstrualspotting)amongfemaleworkers(ScarffandSmith
1942Fitzsimons1944Klavis1953Pagani1953Watrous1947WatrousandOlsen1959
Pacynskietal.1971BurtonandShumnes1973Meyer,PeteetandHarrington1978
Katzenellenbogen1956Dunn1940StopplemanandvanValkenburg1955Goldzieherand
Goldzieher1949Fisk1950).Therehavealsobeenafewreportsoftoxicitysyndrome
associatedwithsomeprogoestogeniccompounds,includingacetoxyprogoesterone(Suciuetal.
1973),andvinyloestrenoloneincombinationwithethynyloestradiol(Gambini,Farineand
Arbosti1976).
Atotalof181casesofhyperoestrogenisminbothmalesandfemales(occurringovertheperiod
19401978)wererecordedandreportedbycompanyphysiciansin10pharmaceutical
companies(13plantsites)intheUnitedStates(Zaebst,TanakaandHaring1980).The13plant
sitesincluded9sitesmanufacturingprimarilyoralcontraceptivescontainingvarioussynthetic
oestrogensandprogoestogens,onefirmmanufacturingoestrogenreplacementpharmaceuticals
fromnaturalconjugatedoestrogensandonefirmmanufacturingpharmaceuticalsfromDES
(whichhadinearlieryearsalsosynthesizedDES).
InvestigatorsfromtheUSNationalInstituteforOccupationalSafetyandHealth(NIOSH)
conductedapilotindustrialhygieneandmedicalstudyin1984ofmaleandfemaleworkersin
twoplants(TanakaandZaebst1984).Measurableexposuresweredocumentedtoboth
moestranolandnaturalconjugatedoestrogens,bothinsideandoutsidetherespiratoryprotective
equipmentused.However,nostatisticallysignificantchangesinoestrogenstimulated
neurophysins(ESN),corticosteroidbindingglobulins(CBG),testosterone,thyroidfunction,
bloodclottingfactors,liverfunction,glucose,bloodlipidsorgonadotropichormoneswere
notedintheseworkers.Onphysicalexamination,noadversephysicalchangeswerenotedin
eithermaleorfemaleworkers.However,intheplantusingmoestranolandnorethindroneto
manufactureoralcontraceptivetablets,serumethynyloestradiollevelsappearedtoshow
possibleoestrogenexposureandabsorptiondespitetheuseofrespirators.Insiderespiratorair
samplesobtainedatthisplantsuggestedlesseffectiveworkplaceprotectionfactorsthan
expected.
Hyperoestrogenicsymptomsinmalesreportedinthesestudieshaveincludednipplesensitivity
(manifestedastinglingortendernessofthenipple)orafeelingofpressureinthebreastarea
and,insomecases,breasthyperplasiaandgynaecomastia.Additionalsubjectivesymptoms
reportedbysomeofthemaleworkersalsoincludeddecreasedlibidoand/orsexualpotency.
Findingsinfemalesincludedirregularmenstruation,nausea,headaches,breastpain,
leucorrhoea(thick,whitishdischargefromthevaginaorcervicalcanal)andankleoedema.
Therehavebeennolongtermfollowupstudiesinpersonsoccupationallyexposedto
oestrogensorprogoestogens.
Hazardsandcontrolofexposure
Oneofthemostserioushazardsinthemanufactureofoestrogenicpharmaceuticalsisinhalation
(andtosomeextentoralingestion)ofthepureactiveoestrogeniccompoundduringweighing,
assemblyandqualityassurancetesting.However,substantialinhalationofthedry,blendeddust
(whichcontainsalowpercentageofactiveingredient)mayalsooccurtoworkersduring
granulation,compressionandpackagingoperations.Skinabsorptionmayalsooccur,
particularlyduringthewetphasesofgranulation,sincealcoholsolutionsareused.Quality
controlandlaboratorypersonnelarealsoatriskofexposurewhilesampling,assayingor
otherwisehandlingpureoestrogenicsubstances,granulationortablets.Maintenancepersonnel
canbeexposedwhilecleaning,repairingorinspectingmixers,hoppers,mills,vacuumlinesand
ventilationsystems,orchangingfilters.NIOSHinvestigatorshaveconductedanindepth
evaluationofengineeringcontrolswhichhavebeenusedduringthemanufacturingoforal
contraceptivetablets(Anastas1984).Thisreportprovidesadetailedreviewofcontrolsandan
evaluationoftheireffectivenessforgranulation,milling,materialtransfers,powderandtablet
feedequipment,andgeneralandlocalexhaustventilationsystems.
Thefourmainelementsofhazardcontrolemployedinplantsusingoestrogenicpharmaceuticals
are:
1.Engineeringcontrols.Theseincludeisolationofprocessingequipmentrooms,controlof
airflowwithinafacilityfromleastcontaminatedareastomostcontaminated,localexhaust
ventilationatanyopentransferpoints,enclosureofmachines,sealedprocessstreamsand
enclosedpowderfeedsystems.Frequently,implementationofengineeringcontrols,suchas
generalorlocalexhaustventilation,iscomplicatedbythefactthatgoodmanufacturing
regulations(suchasthoserequiredbytheUSFoodandDrugAdministration),whichare
designedtoensureasafeandeffectiveproduct,conflictwiththebesthealthandsafety
practices.Forexample,pressuredifferentialsachievedbygeneralventilationsystems,designed
toprotectworkersoutsidethehazardousprocess,conflictwiththeregulatoryrequirementto
preventcontaminationoftheproductbydustorcontaminantsexternaltotheprocess.Becauseit
eliminatesdirectcontactbetweenpeopleandthehazardouscontaminants,processorequipment
containmentisoftenthebestoption.
2.Goodworkpractices.Theseincludeseparatecleanandcontaminatedlockerrooms
separatedbyshowers,changesofclothing,washingorshoweringbeforeexitingcontaminated
areasand,whereitisfeasibleandappropriate,systematicrotationsofallworkersbetween
exposedandnonexposedareas.Appropriatetrainingandeducationregardingthehazardsof
oestrogens,andgoodworkpractices,areanintegralpartofaneffectiveworkerprotection
programme.Thebestengineeringcontrolsandpersonalprotectiveequipmentcanbedefeatedif
theoperatorsarenotknowledgeableaboutthehazardsandcontrols,andiftheyarenotproperly
trainedtotakeadvantageofthecontrolsandtousethepersonalprotectiveequipmentprovided.
3.Aggressiveenvironmentalandmedicalmonitoringofexposedworkers.Inadditionto
normallyadministeredphysicals,routinescreeningshould,ataminimum,includereviewfor
symptoms(breasttenderness,libidochangeandsoon),examinationsofthebreastandaxillary
nodesandmeasurementofareolae.Thescreeningfrequencywillvary,dependingonthe
severityoftheexposurehazard.Ofcourse,medicalscreeningandmonitoring(e.g.,physical
exams,healthquestionnairesortestingofbodyfluids)shouldbeimplementedwiththeutmost
sensitivitytoworkersoverallwelfare,theirhealthandtheirprivacy,sincetheircooperationand
assistanceinsuchaprogrammearecriticaltoitssuccess.Monitoringofworkerexposurestothe
activeoestrogenicorprogoestogenicsubstancesshouldbedoneregularlyandshouldinclude
notonlybreathingzonesamplingforaircontaminants,butalsoevaluationsofskin
contaminationandtheeffectivenessofpersonalprotectiveequipment.
4.Useofappropriatepersonalprotectiveequipment:Personalprotectiveequipmenttypically
includesdisposableorlaunderablecoverallsseparatesteroidareashoes,socks,underclothing
andrubberglovesandeffectiverespiratorstailoredtothedegreeofhazard.Inthemost
hazardousareas,airsuppliedrespiratoryprotectiveequipmentandimpervious(todustsand/or
organicsolvents)suitsmayberequired.
5.Becauseofthepotencyoftheoestrogenicsubstances,particularlythesyntheticonessuch
asmoestranolandethynyloestradiol,allofthesemeasuresareneededtocontrolexposures
adequately.Theuseofpersonalprotectiveequipmentalonemaynotprovidecomplete
protection.Primaryrelianceshouldbeplacedoncontrollingexposuresatthesource,byprocess
containmentandbyisolation.
Monitoringmethods
Bothhighperformanceliquidchromatographyandradioimmunoassayprocedureshavebeen
usedtodetermineoestrogensorprogoestogensinenvironmentalsamples.Serumsampleshave
beenanalysedfortheexogenousactivecompound,itsmetabolite(e.g.,ethynyloestradiolisthe
mainmetaboliteofmoestranol),oestrogenstimulatedneurophysinsoranyofanumberofother
hormones(e.g.,gonadotropichormonesandCBGs)consideredappropriateforthespecific
processandhazard.Airbornemonitoringusuallyincludesbreathingzonepersonalmonitoring,
butareasamplingcanbeusefulindetectingdeparturesfromexpectedvaluesovertime.
Personalmonitoringhastheadvantagesofdetectingbreakdownsorproblemswithprocessing
equipment,personalprotectiveequipmentorventilationsystemsandcanprovideanearlier
warningofexposure.Biologicalmonitoring,ontheotherhand,candetectexposureswhichmay
bemissedbyenvironmentalmonitoring(e.g.,skinabsorptionoringestion).Ingeneral,good
practicecombinesbothenvironmentalandbiologicalsamplingtoprotectworkers.
DennisD.Zaebst
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