Lecture2-CurrentGoodManufacturingPrac5ces

1

cGMPBasicRequirements

QualitySystem

Defini5ons

Regula5ons

Requirements

QualityManagementSystem

QMS

PROCESSInput Output

ManagementResponsibility,ResourceManagement,ProductRealiza5on,Measurement,AnalysisandImprovement

RawMaterialsEnergyCostomerRequirement

Plan-Do-Check-ActPLAN

- Definethesystems- -Assesscurrentsitua5on

- Analyzecauses

DO- -Tryoutsystemorimprovetheory

CHECK-Studythesystemor

results

ACT- Standardizeimprovements

- Plancon5nuousimprovement

QMSandcGMPinBiopharmaceu5calCo.

SeniorManagementResponsibility

Toarchivethequalityobjec5ves,awell-establishanddocumentedsystemofQualityassurance(QA)

incorpora5ngGoodManufacturingPrac5ce(GMP)shouldbefollowed)

-Quality -Safety -Efficacy

QualityAssuranceandQualityControl

•  Isdefinedasthesumtotaloforganizedarrangementsmadewiththeobjec5veofensuringthattheproductsareofqualityrequiredfortheirintendeduse.

QA

•  ItisthepartofGMPwhichisconcernedwithsampling,specifica5ons,tes5ng,documenta5onandreleasewhichensuresthatnecessaryandrelevanttestsarecarriedoutandthatmaterials/productsarereleasedForuse/saleonlyaZertheirqualityisjudgedtobesa5sfactory.

QC

WhatQAsystemsshouldincludes?1.  GMPandGLParetakenintoaccountduringdesigninganddeveloping

products.2.  Allproduc5onandcontrolopera5onsareclearlyspecifiedand

documented.3.  Keypersonnelresponsibili5esareclearlydefined.4.  Allarrangementsforprocurementanduseofcorrectstar5ngmaterials

andpackagingmaterialsaremade.5.  Inprocesschecksandvalida5onsarecarriedoutinadefinedmanner.6.  Thefinalproductismanufactured,packedandcheckedasperdefined

procedures.7.  Regulatoryaspectsandinternalrequirementsforthefinalproductare

fulfilled.8.  Storage,handlinganddistribu5onproceduresforthefinalproductare

followedtoensuremaintenanceofqualitythroughoutshelflife.9.  Self-inspec5onproceduresaredefinedtoregularlymonitorthe

effec5venessofthequalityassurancesystem.10.  Correc5veac5ons11.  Sta5s5calprocesscontrol

WhatQCsystemsshouldincludes?1.  Appropriateprocedures,trainingpersonnelandadequatefacili5esforsampling,

inspec5onandtes5ngofstar5ngmaterials,intermediate,bulkandfinishedproducts.

2.  Validatedtestmethods

3.  Maintenanceofrecordstodemonstratethatallprocedureshavebeencarriedout.

4.  Cer5fica5onofstar5ngmaterialstobeofspecifiedqualityandpurity,andtheirstorageandadequatelabelingbeforeuseinfinalproduct.

5.  ReleaseofbatchofproductONLYaZercer5fica5onbyqualifiedpersonthatitmeetrequiredcriteriaorspecifica5ons.

6.  Maintainsufficientsamplesofstar5ngmaterialsandfinalproductforfutureexamina5on,ifnecessary.

7.  Recordingandinves5ga5onofoutofspecifica5onresults,changes,incidentsanddevia5ons.

cGMPGuidelinesforBiopharmaceu5cals1.  Allmanufacturingprocessareclearlydefined,systema5cally

reviewedinthelightofexperience,andshowntobecapableofconsistentlymanufacturingbiopharmaceu5calproductsoftherequiredqualityandspecifica5ons.

2.  Allstepsofmanufacturingprocessesandanysignificantchangesmadetotheprocessarevalidated.

3.  Allnecessaryfacili5esareprovided,including:–  Appropriatequalifiedandtrainedpersonnel–  Adequatepremisesandspace–  Suitableequipmentandservices–  Correctmaterials,containersandlabels–  Approvedproceduresandinstruc5ons–  Suitablestorageandtransport–  Adequatepersonnel,laboratoriesandequipmentforin-process

controlundertheresponsibilityoftheproduc5onmanagement.

cGMPGuidelinesforBiopharmaceu5cals(cont)

4.  Instruc5onsandproceduresarewrijeninclearlanguage,specificallyapplicabletothefacili5esprovided.

5.  Operatorsaretrainedtocarryoutprocedurescorrectly

6.  Recordsaremade(Manually,withsignatureorrecordinginstruments)duringmanufacturingtoshowthatallstepsrequiredbythedefinedprocedureshavebeentakenandtheexpectedquan5tyandqualitywerereached.Anysignificantdevia5onsarefullyrecordedandinves5gated.

7.  Recordscoveringmanufacturinganddistribu5on,whichenablethecompletehistoryofabatchtobetraced,areretainedinacomprehensibleform.

8.  Properstorageanddistribu5onoftheproductsminimizedanyrisktotheirquality

9.  Asystemisavailabletorecallanybatchorproductfromsaleorsupply

10.  Complainsaboutmarketedproductsareexamined,thecausesofqualitydefectsinves5gated,andappropriatemeasurementstakeninrespectofthedefec5veproduct(s)andtopreventrecurrence.

Informa(onandmaterialflowinpharmaceu(cal/biopharmaceu(calproduc(onprocess

ThecGMPRegula5ons

•  Firstissued:June1963

•  Current=Dynamicroles(standarsdevolveover5me)

cGMPforfinisedPharmaceu5cals21CFR210,211

www.fda.gov/cder/dmpq

ExamplesofcGMPcodes(FDA)Building,Facili5es,Equipments(21CFR211.42-72)EquipmentIden5fica5on(21CFR211.105)Equipmentcleaninganduse(21CFR211.182)Electronicrecords,electronicsignature(21CFRPart11)Processvalida5on(GeneralcodeofFDAprocess

valida5on)Rubberar5clesforrepeateduse(21CFR177.2600)

BuildingsandFacili5es

a)  Anybuildingorbuildingsusedinthemanufacture,processing,packingorholdingofdrugproductshallbeofsuitablesize,construc5onandloca5ontofacili5escleaning,maintenance,andproperopera5on

ExternalEnvironmentandInternalEnvironment

211.42DesignandConstruc5onfeatures

Siteprepara5onandPlantdesign

v  Sitearrangementandover-alllayoutdesign(greenspacesparking,traffic,recrea5onarea,tanks,siteu5li5es,etc..)

v  Watersupplyandwastemanagementarea(wastecontractor!!)

v  Sitesecurityandaccess(fences,guard,cameras,etc..)

v  U5li5esdesign,layout,backup(cri5calu5li5esbackup)v  Equipment-design,layout,spares,capacity

v  Safety(personnelandequipment),emergencyservicesaccess.

v  Externalarchitectureshouldtakeinaccountthelocalenvironment(temperature,humidity,wind,etc..)

v  Easeofmaintenance(serviceducts,catfloor,etc..)

v  Projectmanagement(managers,consultants,etc..)

v  Valida5onPlansandaneffec5vechangecontrolprocedures.Provisionofdesignand(asbuilds)drawing.

v  Contractor(Experiencedcontractor)

b)  Anysuchbuildingshallhaveadequatespacefortheorderlyplacementofequipment,drugproductcontainers,closures,labeling,in-processmaterials,ordrugproducts,andtopreventcontamina5on.Theflowofcomponents,drugproductcontainers,closures,labeling,in-processmaterials,anddrugproductsthroughthebuildingsshallbedesignedtopreventcontamina5on.

211.42DesignandConstruc(onfeatures

c)  Opera5onsshallbeperformedwithinspecificallydefinedareasofadequatesize.Thereshallbeseparateordefinedareasorothersuchcontrolsystemsforthefirm’sopera5onsasarenecessarytopreventcontamina5onormix-upsduringthecourseofthefollowingprocedures:1.  Receipt,iden5fica5on,storageandwithfoldingfromuseofcomponents,drug

productcontainers,closuresandlabeling,pendingtheappropriatesampling,tes5ng,orexamina5onbyqualitycontrolunitbeforereleaseformanufacturingorpackaging.

2.  Holdingrejectedcomponents,drugproductcontainers,closuresandlabelingbeforedispersion.

3.  Storageofreleasedcomponents,drugproductcontainers,closuresandlabeling4.  Storageofin-processmaterials5.  Manufacturingandprocessingopera5ons6.  Packagingandlabelingopera5ons7.  Quaran5nestoragebeforereleaseofdrugproducts8.  StorageofdrugproductsaZerrelease9.  Controlandlaboratoryopera5on

211.42DesignandConstruc(onfeatures

10. Asep5cprocessing,whichincludeasappropriate:

i.  Floors,walls,andceilingsofsmooth,hardsurfacestheeasilycleanable

ii.  Temperatureandhumiditycontrolsiii.  Anairsupplyfilteredthroughhigh-efficiencypar5cularair

filtersunderposi5vepressure,regardlessofwhetherflowislaminarornon-laminar

iv.  Asystemformonitoringenvironmentalcondi5onsv.  Asystemforcleaninganddisinfec5ngtheroomand

equipmenttoproduceasep5ccondi5onsvi.  Asystemformaintaininganyequipmentusedtocontrol

theasep5ccondi5ons.

211.42DesignandConstruc(onfeaturesPart(c)cont

Construc5onMaterials

•  Provideordinarymovementofmaterialsandpersonnel•  Provideacceptablenoiselevelduringopera5on•  Smoothsurface,cleanable,non-porous•  Flushwithoutanyprojec5ons•  Usuallymadeofepoxy,enamelorprefabricatedsmoothmaterials•  (roundedfloortowalljunc5on)

walls

• Durable,cleanable,acid/baseresistance,non-porous,smooth• Usuallymadeofepoxymaterials.Subsurfacefinish!!• Ceramicandvinyl5lesarenotrecommended

Floors

• Smoothfinishsurface• Allceilingfixtures(light,fiqng,airoutletsandreturns,etc..)shoulddesignedtoensureeasecleaningandtominimizedustaccumula5on

• Cat-floorintheproduc5onareaisessen5alformaintenanceduringopera5on.Ceilings

TypicalfinishingmaterialsinBiopharmaceu5calfacili5es

Walls Floors Ceiling

Warehouse Sanitarypain5ng Hard,sealed(pref.epoxy)

Clean,painted

Dispensary EpoxyCoved

EpoxyorinsituterrazzoCoved

EpoxyCoved

Manufacturing EpoxyCoved

EpoxyorinsituterrazzoCoved

EpoxyCoved

Packaging EpoxyCoved

EpoxyorinsituterrazzoCoved

EpoxyCoved

d)  Opera5onsrela5ngtothemanufacture,processingandpackingofPENICILINshallbeperformedinfacili5esseparatefromthoseusedforotherdrugproductsforhumanuse

211.42DesignandConstruc(onFeatures

Adequateligh5ngshallbeprovidedinallarea

The amount of light reaching the working surface of each area involved in the production chain should be defined (lux or foot-candles) Normally, for public standard, a range of 30-50 candles is necessary to ensure worker comfort and ability to perform efficiently and effectively One hundred (100) foot-candles is required in some area such as inspection and filling area Lighting should measured periodically and the results recorded. Routine replacement of light sources on some schedule to ensure that light levels do not drop below the established minimum.

211.44Ligh(ng

a)  Adequate ventilation should be provided.

b)  Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product

c)  Air filtration system, including pre-filters and particulate matter air filters, shall be used when appropriate on air supplies to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems adequate to control contaminants.

d)  Air-handling systems for the manufacture, processing and packing of PENICILIN shall be completely separate from those for other drug, products for human use.

211.46Ven(la(on,airfiltra(on,airhea(ngandcooling

Considera5onofAir-HandlingSystem Placement of air inlet and outlet ports. These should be sited to minimize the entry of airbone

particles or odors from the surrounding areas. Outlets should not be sited near inlet. Where recirculation of air acceptable, adequate precautions must be taken to ensure that

particulates from a processing area are removed. This will usually require an alarm system or an automatic cutoff in the event that a filter develops a hole. Dust extraction systems should be provided, where appropriate, to further minimize this potential problem.

The degree of filtration and air volumes should be matched to the operations involved. Temperature and humidity conditions should provide personnel comfort- to enhance performance Temperature and humidity conditions should be within the optimal condition of equipment

operation Where differential pressures are required between adjacent areas, suitable monitoring equipment

must be provided. The siting of final air filters close to each room being serviced eliminates concerns regarding the

possibility of small leaks in the air duct system. Air usually enters rooms near the ceiling and leaves from the opposite side near the floor.

211.48Plumbing

a)  Potablewatershallbesuppliedundercon5nuousposi5vepressureinaplumbingsystemfreeofdefectsthatcouldcontributecontamina5ontoanydrugproduct.PotablewatershallmeetthestandardprescribedintheEnvironmentalProtec5onAgency’sPrimaryDrinkingWaterRegula5onsetin40CFRPart141.waternotmee5ngsuchstandardsshallnotbepermijedinthepotablewatersystems.

b)  Drainsshallbeofadequatesizeand,whereconnecteddirectlytoasewer,shallbeprovidedwithairbreakorothermechanicaldevicetopreventback-siphonage

FDA usually not inquire documents that the potable water is meeting the standard if the manufacturer connects the potable waterline to a public supply that meet the standard

The water can lose quality in transmission through the public

piping system and through the manufacturer’s system If potable water is obtained from wells under the control of

manufacturer, periodic testing is mandatory. In case of providing potable water storage system, an

automatic chlorination system should be installed, usually at 2-3ppm

211.50Sewageandrefuse

Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner

Product disposal: any product requiring disposal should initially be separated from packaging. Disposal procedures should involve agents with a proven record of dealing with such sensitive material from plant to disposal. Printed packaging disposal: labels, inserts and cartons poses usually no health risk. For public. However, this may rise the public concern that product may be associated with the packaging. Incineration of such materials is preferred. General trash and sewage: an internal procedures should be established to ensure that product and packaging waste does not get intermixed. Containers used wiyhin the plant to accumulate waste materials should be clearly marked to denote their designated use.

FacilityRequirementsReview(Building)

NON-GMParea GMPfacility(Produc(onarea)

Wallpain5ng PVApaints Epoxyorenamel

Flooring Normalfloor(non-porous) Homogenoussealedfloor;Epoxyfinishorweldedvinyl

Windows Windowss5ll(openable) Flushgluzedwindows(preferablydoubleglass,notopened)

Floordrain Openfloordrain Hygienicdrains

Ceiling Withjoints Smoothsealedceiling

Ligh5ng Exposedopenlightfiqng Flushlightfiqngs

Furniture Woodenisallowed Mustbeofnon-porousmaterials(stainlesssteelorMelamine)

211.52Washingandtoiletfacili(es

Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and

clean toilet facilities easily accessible to working areas.

Separatestoiletfacilityforeachsexexceptwhereindividuallockedtoiletroomsareavailable(thenumberisbasedonthenumberusers)Suggestedaddi5onalemphasis.Ea5ngfacility:Ea5ng,drinkingarepermijedinseparateareaandwellsegregatedfromallproduc5onareas.Prominentsignindica5ngthisroleattheentranceofproduc5onareas.Enforcementproceduresagainstviola5onaretakenbymanagementInproduc5onarea:Tissuesandlooseddisposalcontainersarereadilyavailable.Lavoratoriesandlockers:Adequatenumberforpersonnelemployed,hotshowerfacility,disinfectantsoaps,adequateashandwastereceptaclesareprovided,periodiccleaningofareaduringeachshiZ,completedailycleaningusingdisinfectant,specificrestareaforfemaleemployeesshouldprovided,areasseparatedfromallasep5cspacesbyanairlock.

211.56Sani(za(ona)  Anybuildingusedinthemanufacture,processing,packing,orholdingofadrugproductshall

bemaintainedinacleanandsanitarycondi5on.Anysuchbuildingshallbefreeofinfesta5onby rodents, birds, insects, and other vermin (other than laboratory animals). Trash andorganicwastemajershallbeheldanddisposedofina5melyandsanitarymanner.

b)  Thereshallbewrijenproceduresassigningresponsibilityforsani5za5onanddescribing insufficient detail the cleaning schedules,methods, equipment andmaterials to be used incleaningthebuildingandfacili5es;suchwrijenproceduresshouldbefollowed.

c)  There shall bewrijen procedure for use of suitable roden5cides, insec5cides, fungicides,fumigita5onagents,andcleaningandsani5za5onagents.Suchwrijen,proceduresshallbedesigned procedures should be designed to prevent the contamina5on of equipment,components, drug product containers, closures, packaging, labeling materials, or drugproductandshallbefollowed.Roden5cides,insec5cides,fungicidesshallnotbeusedunlessregisteredandusedinaccordancewiththeFederal Insec5cide,Fungicide,andRoden5cideAct(7U.S.C.135).

d)  Sanita5on procedures shall apply to work performed by contractors or temporaryemployeesaswellasworkperformedbyfull-5meemployeesduringtheordinarycourseofopera5ons.

Any building used in the manufacture, processing, packing or holding of a drug product shall be maintained

in a good state of repair

Deterioration of buildings not only presents poor image of the facility, but also can influence product quality. Cracks in ceiling, hole in wall or floor crack is potential source of insects, microbial contaminations. Water leakage can cause significant damage for materials and equipment, give rise to electrical failure and fires and result in damage to the basic structure of the building. Holes in the roof or near the tops of building proved ready access to birds, which may then be encourages to nest within the building.

211.58Maintenance

Equipment

211.62Equipmentdesign,sizeandloca(on

Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

211.65Equipmentconstruc(on

Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identify, strength, quality, or purity of the drug product beyond that official or other established requirements.

Any substance required for operation, such as lubricants or

coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity strength, quality, or purity of the drug product beyond the official or other established requirements.

211.67Equipmentcleaningandmaintenancea)  Equipmentandutensilsshallbecleaned,maintainedandsani5zedatappropriate

intervalstopreventmalfunc5onsorcontamina5onthatwouldalterthesafety,iden5ty,strength,quality,orpurityofthedrugproductbeyondtheofficialorotherestablishedrequirements.

b)  Wrijenproceduresshallbeestablishedandfollowedforcleaningandmaintenanceofequipment,includingutensils,usedinthemanufacture,processing,packing,orholdingofadrugproduct.TheseProcedureshallinclude,butnotnecessarilylimitedtothefollowing:1)Assignmentofresponsibilityforcleaningandmaintainingequipment.2)Maintenanceandcleaningschedule,including,whereappropriate,sani5zingschedule.3)Adescrip5oninsufficientdetailofthemethods,equipmentandmaterialsusedincleaningandmaintenanceopera5ons,andthemethodsofdissemblingequipmentasnecessarytoassurepropercleaningandmaintenance.4)Removalofoblitera5onofpreviousbatchiden5fica5on5)Protec5onofcleanequipmentfromcontamina5onpriortouse6)inspec5onofequipmentforcleanlinessimmediatelybeforeuse.

c)  Recordsshallbekeptofmaintenance,cleaning,sani5zingandinspec5onasspecifiedin211.180and211.182

211.68Automa(c,mechanical,andelectronicequipment

a)  Automatic, mechanical or electrical equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.

b) Appropriate controls shall be exercised over a computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. Input and output from the computer or related system of formulas or other records data shall be checked for accuracy. The degree and frequency of input/output verification shall be maintained except where certain data, such as calculations performed in connection with laboratory analysis, are eliminated by computerization or other automated processes. In such instances a written record of the program shall be maintained along with appropriate validation data. Hard copy or alternative systems, such as duplicate, stapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss shall be maintained

211.68Automa(c,mechanical,andelectronicequipment

211.70Filters

Filtersforliquidfiltra5onusedinmanufacture,processing,orpackingofinjec5bledrugproductsintendedforhumanuseshallnotreleasefibersintosuchproducts.Fiber-releasingfiltersmaynotbeusedinthemanufacture,processing,orpackingoftheseinjectabledrugproductswithouttheuseofsuchfilters.Ifuseofafiber-releasingfilterinnecessary,anaddi5onalnon-fiberreleasingfilterof0.22micronmaximummeanporosity(0.45micronifthemanufacturingcondi5onssodictate)shallsubsequentlybeusedtoreducethecontentofpar5clesintheinjectabledrugproduct.Useofanasbestos-containingfilter,withorwithoutsubsequentuseofaspecificnon-fiberreleasingfilter,ispermissibleonlyuponsubmissionofprooftotheappropriatebureauoftheFoodandDrugAdministra5onthatuseofanon-fiber-releasingfilterwill,orislikelyto,compromisethesafetyoreffec5venessoftheinjec5bledrugproduct

FiltersinBiopharmaceu5calsFactory

Airfilters HEPA/ULPAfilters-  pre-filters/filter-  MicrobiologicalFilters(Filterdefectcausecontamina2on)-Airfilterforopera5on(pneuma5cvalves)(Filterdefectisdestruc2veforthevalvesystem)-  Airfilterforprocess(aera5onandtransfer)(Filterdefectcausecontamina2on)

FiltersinBiopharmaceu5calsFactory(cont.)

A- For Cooling line I.  Prefilter II.  Filter (Filter defect is destructive for heat exchanger and valve on the

cooling line) B- For Process water I.  Water filtration before distillation II.  Medium filtration (sterilization) III.  WFI for buffer and product formulation (Pyrogen free) (Filter defect directly affecting process and product Quality,

depending on the filter position) C- For media preparation I.  Microbiological filter (Filter defect cause direct contamination)

41

Liquid filters

-  Process steam: (heating, sterilization of double jacketed vessels (Filter defect make damage in heat exchangers and also

for steam valves) -  Sterilization steam (direct steam injection): (for sterilization of empty vessels such as for media

transfer tanks and holding tanks), or SIP equipments (Filter defect make damage for filter and direct

contamination of products by foreign particle!)

42

FiltersinBiopharmaceu5calsFactory(cont.)

(Filteringsteamfromsolidpar5cles)Steamfilters

-  Process steam: (heating, sterilization of double jacketed vesels) (Filter defect make damage in heat exchangers and steam

valves) -  Sterilization steam (direct steam injection) (for sterilization of empty vessels such as for media transfer

tanks and holding tanks), or SIP equipments. (Filters defect make valve damage and direct contamination

of products by foreign particle!)

43

FiltersinBiopharmaceu5calsFactory(cont.)

(Filtering steam from solid particles) Steam filters

•  Usedforproteinsepara5onbasedonmembranemolecularweightcut-off.Differentfiltersystemsareusuallyapplied.Thecommonusedare1000/10000/50000/100000Daltons

(Filtersdefectcauseimproperproteinsepara5onandleakageandlossoftotalproteinproduc5on)

44

FiltersinBiopharmaceu5calsFactory(cont.)

Ultrafiltra5onsystem(proteinconcentrator)

•  Assignment1.  Designstagesindrugapprovalprocess.2.  Post-marke5ngevalua5on.3.  CompareandcontrastQAandQC.

Stagesinanewproductlaunch(simplified)