Basics of Contamination Control This product was funded by a grant awarded under the President’s High Growth Job Training Initiative as implemented by

Basics of Contamination Control

Basics of Basics of Contamination Contamination

ControlControl

This product was funded by a grant awarded under the President’s High Growth Job Training This product was funded by a grant awarded under the President’s High Growth Job Training Initiative as implemented by the U.S. Department of Labor’s Employment & Training Administration. Initiative as implemented by the U.S. Department of Labor’s Employment & Training Administration.

The information contained in this product was created by a grantee organization and does not The information contained in this product was created by a grantee organization and does not necessarily reflect the official position of the U.S. Department of Labor. All references to non-necessarily reflect the official position of the U.S. Department of Labor. All references to non-

governmental companies or organizations, their services, products, or resources are offered for governmental companies or organizations, their services, products, or resources are offered for informational purposes and should not be construed as an endorsement by the Department of Labor. informational purposes and should not be construed as an endorsement by the Department of Labor.

This product is copyrighted by the institution that created it and is intended for individual This product is copyrighted by the institution that created it and is intended for individual organizational, non-commercial use only organizational, non-commercial use only


AudienceAudience ManufacturingManufacturing Quality ControlQuality Control Quality Quality

Assurance/RegulatoryAssurance/Regulatory Facilities/EngineeringFacilities/Engineering Materials Materials

Management/WarehouseManagement/Warehouse


AgendaAgenda Define Contamination ControlDefine Contamination Control

Sources of ContaminationSources of Contamination Review Regulations Relating to Review Regulations Relating to

Contamination Control Contamination Control 21 CFR Part 21121 CFR Part 211

Components of a Contamination Control Components of a Contamination Control Program Program

Best Practices in Developing & Best Practices in Developing & Maintaining a Contamination Maintaining a Contamination Control ProgramControl Program

Review CitationsReview Citations


Training GoalsTraining Goals To provide participants the information To provide participants the information

that will aid in establishing and that will aid in establishing and maintaining a Contamination maintaining a Contamination

Control Program.Control Program. Gain a better understanding of the Gain a better understanding of the

aspects of product manufacturing aspects of product manufacturing that have the potential to that have the potential to contribute to product contribute to product contamination.contamination.

Make employees aware of areas they Make employees aware of areas they can assist in reducing the potential can assist in reducing the potential

of product contaminationof product contamination


What is Contamination What is Contamination Control?Control? DefinitionDefinition

Proactive prevention of contaminationProactive prevention of contamination Contamination is considered any foreign Contamination is considered any foreign environmental, chemical and biological environmental, chemical and biological

matter.matter. To ensure:To ensure:

Product free of foreign matterProduct free of foreign matter Appropriate control measures exist to Appropriate control measures exist to

prevent product contamination. prevent product contamination. Environments & product contact areas do Environments & product contact areas do

not contribute to product not contribute to product contaminationcontamination

Gowning practicesGowning practices Materials/containers/closures do not Materials/containers/closures do not

contribute to product contamination contribute to product contamination Appropriate documentation system of Appropriate documentation system of

such practices such practices


Sources of Sources of ContaminationContamination

PRODUCT

PEOPLE

Equipment

Air &

Surfaces

Water

Raw M

ater

ials


Cleanroom Contamination Cleanroom Contamination ClassificationClassification

SubstanceSubstance

EnergyEnergyPhysicalPhysical ChemicalChemical BiologicBiologic

DustDust Organic Organic CompoundsCompounds BacteriaBacteria ThermalThermal

DirtDirt Inorganic SaltsInorganic Salts FungusFungus LightLight

GritGrit VaporVapor SporeSpore Electromagnetic Electromagnetic (EMI)(EMI)

FiberFiber MistMist PollenPollen Electrostatic(ESElectrostatic(ESD)D)

LintLint FumeFume VirusVirus RadiationRadiation

JewelryJewelry SmokeSmoke Human SkinHuman Skin ElectricalElectrical

Cells/HairCells/HairLiving creaturesLiving creatures


Size of ParticulatesSize of Particulates

Courtesy of C. Bolotin Contamination Control Winter ‘06Courtesy of C. Bolotin Contamination Control Winter ‘06


ISO 14644-1 Cleanroom Standards

Particle SizeParticle Size

ClassClass 0.1 µm0.1 µm 0.2 µm0.2 µm 0.3 µm0.3 µm 0.5 µm0.5 µm 1 µm1 µm 5 µm5 µm

ISO ISO 11

1010 22

ISO ISO 22

100100 2424 1010 44

ISO ISO 33

1,0001,000 237237 102102 3535 88

ISO ISO 44

10,00010,000 2,3702,370 1,0201,020 352352 8383

ISO ISO 55

100,000100,000 23,70023,700 10,20010,200 3,5203,520[100][100] 832832 2929

ISO ISO 66

1,000,001,000,0000

237,00237,0000

102,00102,0000

35,200 35,200 [1000][1000] 8,3208,320 293293

ISO ISO 77

352,000 352,000 [10,000][10,000] 83,20083,200 2,9302,930

ISO ISO 88

3,520,000 3,520,000 [100,000][100,000] 832,000832,000 29,30029,300

ISO ISO 99

35,200,00035,200,000 8,320,008,320,0000

293,000293,000

Notes: Number of particles per cubic meter (m3) or ft3



People - Greatest FactorPeople - Greatest Factor General hygiene, microbiology, poor clean/ General hygiene, microbiology, poor clean/

controlled room controlled room practices, unhealthy, untrained, practices, unhealthy, untrained, not following procedures etc. not following procedures etc.


Sources of Sources of ContaminationContamination PeoplePeople

Shedding cells, skins, oilsShedding cells, skins, oils Inappropriate gowningInappropriate gowning

Exposed skin, hair, clothing etcExposed skin, hair, clothing etc Ex. Incorrectly wearing cleanroom Ex. Incorrectly wearing cleanroom

attire attire

Bringing additional items Bringing additional items into clean areas into clean areas

Jewelry, shoes, clothing, purses, Jewelry, shoes, clothing, purses, keys, cell phones keys, cell phones



EquipmentEquipment Improper design, improper and Improper design, improper and

ineffective cleaning (cross ineffective cleaning (cross contamination), inadequate contamination), inadequate maintenancemaintenance

Facilities Facilities Inappropriate designInappropriate design Pest ControlPest Control

Materials/Containers/ClosuresMaterials/Containers/Closures Contaminated, mishandled, Contaminated, mishandled,

improper improper storagestorage

EnvironmentEnvironment Air, surfaces, temperature, Air, surfaces, temperature,

humidity, water, humidity, water, insufficient cleaninginsufficient cleaning

Cardboard, wood pallets, etcCardboard, wood pallets, etc



Goal: Prevent or minimize Goal: Prevent or minimize

external particulates from external particulates from entering the entering the clean/controlled areasclean/controlled areas..

Monitor & ControlMonitor & Control


Why Monitor?Why Monitor? Regulatory RequirementRegulatory Requirement

We must!We must! Safe ProductSafe Product

Ensure product safetyEnsure product safety Data to support satisfactory Data to support satisfactory

operation of facility, operation of facility, equipment quality systemsequipment quality systems Validation, Statistical Process Validation, Statistical Process

Control (SPC) & Proof Control (SPC) & Proof that we do itthat we do it

Confirm absence of objectionable Confirm absence of objectionable organisms organisms


GMP Regulations 21 CFR GMP Regulations 21 CFR Part 211Part 211

211.42 Design and construction 211.42 Design and construction featuresfeatures

211.56 Sanitation211.56 Sanitation 211.63, 211.65, 211.68 211.63, 211.65, 211.68

Equipment design, construction Equipment design, construction & maintenance & maintenance

211.84 Testing and approval or 211.84 Testing and approval or rejection of components, rejection of components, drug product containers, and closuresdrug product containers, and closures

211.113 Control of microbiological 211.113 Control of microbiological contaminationcontamination

211.146 Ventilation, air filtration, 211.146 Ventilation, air filtration,

air heating and coolingair heating and cooling 211.165 Testing and release for 211.165 Testing and release for

distributiondistribution


Components of a Contamination Components of a Contamination Control ProgramControl Program

Compliance Assessment Compliance Assessment Product TestingProduct Testing Environmental MonitoringEnvironmental Monitoring

Viable/Non-Viable MonitoringViable/Non-Viable Monitoring Utility Monitoring – Gases, Water, Utility Monitoring – Gases, Water,

Compressed Air Compressed Air Materials/Components/Materials/Components/

Containers/ Containers/ ClosuresClosures

Equipment Qualification & Equipment Qualification & Cleaning Cleaning ValidationValidation

Facility DesignFacility Design Disinfectant PracticesDisinfectant Practices TrainingTraining


Compliance AssessmentCompliance Assessment Consult with Guidelines &

Regulations US & Foreign Agencies

Evaluation of Processes Oral Solid Dose vs Liquid Toxic Compounds Generation of particles (Dusty

Operations) Open vs Closed Operations

Evaluation of Facilities & Equipment Site location Facility & Equipment Design Multi-use vs Dedicated Operations Room Classifications, Clean Rooms,

Barriers or Isolators Disinfectants


Product TestingProduct Testing Assess chemical and microbiological

purity Compendial methods (USP, EP, JP

Testing) Method Development

Use validated methods of analysis Methods are appropriate for evaluating

product over relevant ranges. Development of appropriate specifications Adherence to SOPs/Batch Records

Operations & Equipment Maintenance/Calibration

Incubation times

Sample Handling & Storage


Environmental Environmental MonitoringMonitoring

Viable Monitoring – TSA & SDA MediaViable Monitoring – TSA & SDA Media Air

Active Air Sampling Passive Air Sampling

Settling Plates Surfaces

Contact Plates Swab

Static (no activity) vs Dynamic (with activity)

Temperature & Relative Humidity (R/H) Pressures Procedure to detail what can and can not

be brought into manufacturing areas. No cardboard, wood products/pallets,

packing materials



Water – Purified Water Water – Purified Water &WFI&WFI Viable Counts - BioburdenViable Counts - Bioburden

FiltrationFiltration Pour PlatesPour Plates

Chemistry AnalysisChemistry Analysis pHpH ConductivityConductivity TOCTOC



Evaluation of incoming goodsEvaluation of incoming goods Raw materialsRaw materials

Meet COA and internal Meet COA and internal specificationsspecifications

Vendor selectionVendor selection QualityQuality

Bioburden (microbial limits)Bioburden (microbial limits) IdentityIdentity

Containers, closures etc.Containers, closures etc. Certificate of Analysis (COA)Certificate of Analysis (COA) CleanlinessCleanliness

Storage & HandlingStorage & Handling


Equipment Qualification & Cleaning Equipment Qualification & Cleaning ValidationValidation

Documented studies to supportDocumented studies to support Equipment is of appropriate designEquipment is of appropriate design

Materials of construction, suitable for Materials of construction, suitable for environmentenvironment

Meets intended needMeets intended need Effective equipment cleaning & Effective equipment cleaning &

maintenance procedures maintenance procedures Cleaning historyCleaning history Maintenance historyMaintenance history Compatibility of cleaning agentsCompatibility of cleaning agents Confirm removal of cleaning agentConfirm removal of cleaning agent


Facilities Design & Facilities Design & ControlControl

Segregation of process areas Segregation of process areas from mechanical/utility areasfrom mechanical/utility areas

Orderly operational flows for Orderly operational flows for

personnel, materials and personnel, materials and processesprocesses

Group similar type operationsGroup similar type operations Sanitary designSanitary design Pest controlPest control

Baits, trapsBaits, traps Clean & orderlyClean & orderly


Cleaning & Disinfectant Cleaning & Disinfectant PracticesPractices

Understand the Understand the environmentenvironment Cleanliness requiredCleanliness required Type and amount of organic Type and amount of organic

matter/microorganisms matter/microorganisms presentpresent

Surface typeSurface type Potential for deterioration or Potential for deterioration or

corrosioncorrosion Type of water availableType of water available Contact timeContact time


Cleaning & Disinfecting Cleaning & Disinfecting DefinitionsDefinitions

AntisepticAntiseptic Inhibits or destroys microorganism. Inhibits or destroys microorganism. No sporicidal activityNo sporicidal activity

BiocideBiocide Kills all living microorganisms including Kills all living microorganisms including

sporesspores DecontaminationDecontamination

Removal of microorganisms; not Removal of microorganisms; not quantifiablequantifiable

DisinfectionDisinfection Process to remove or eliminate all Process to remove or eliminate all

pathogenic organisms except spores.pathogenic organisms except spores. SanitationSanitation

Process of bringing contamination to a safe Process of bringing contamination to a safe level typically applies to cleaning of level typically applies to cleaning of inanimate objectsinanimate objects


Decontamination Decontamination PracticesPractices

Expectation that Expectation that companiescompanies Document/data to Document/data to

support effectiveness of support effectiveness of cleaning practicescleaning practices

Document/data to Document/data to support satisfactory support satisfactory changeover and changeover and

line clearance activitiesline clearance activities


Training ProgramTraining Program Training, Training, Training

Operators, lab personnel, engineers, support groups

Periodic training General GMP Contamination Control & What Impacts

the Environment Gowning practices Clean room Behavior

What not to do in manufacturing areas What not to bring in manufacturing area How to transport materials in

manufacturing areas SOPs to support all the above and GMP

related activities


ControlsControls Method ValidationMethod Validation Equipment Validation Equipment Validation Cleaning ValidationCleaning Validation Disinfectant ValidationDisinfectant Validation Environmental Environmental

MonitoringMonitoring PeoplePeople

Facility Design & Facility Design & Process FlowProcess Flow

Materials ManagementMaterials Management Well written Policies & Well written Policies &

Standard Operating Standard Operating Procedures (Controlled Procedures (Controlled Documents)Documents)

TrainingTraining


Basics of Contamination Control Basics of Contamination Control SummarySummary

FDA expects systems to support proactive contamination control Standard operating procedures (SOPs) & data to

support the systems designed to monitor and control the environment;

Sanitation practices Cleaning & disinfecting of facility & equipment

surfaces Facility Design and Process Flow Good hygiene, gowning practices & clean room behavior Evaluation of incoming materials, containers & closures Controlled processes for movement of materials to and from clean rooms Product evaluation and testing of in-process and

release samples Environmental monitoring

HVAC - Viable/Non-Viable Particulate, Temperature, R/H, Pressures

Training