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MCC PRESENTATION - GMP MCC PRESENTATION - GMP MANUFACTURING ENVIRONMENTSMANUFACTURING ENVIRONMENTS

Presented by :Presented by :

Deryck Smith Consulting Deryck Smith Consulting EngineersEngineers

Module 1

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GMP GMP MANUFACTURING ENVIRONMENTSMANUFACTURING ENVIRONMENTS

Presentation OutlinePresentation OutlineModule 1:Module 1: Introduction to GMP EnvironmentsIntroduction to GMP EnvironmentsModule 2:Module 2: Air Conditioning System ComponentsAir Conditioning System ComponentsModule 3:Module 3: Types & Configurations of AC SystemsTypes & Configurations of AC SystemsModule 4: Module 4: Pressure Cascades & building LayoutsPressure Cascades & building LayoutsModule 5:Module 5: Validation, Qualification & Maintenance Validation, Qualification & Maintenance

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GMP GMP MANUFACTURING ENVIRONMENTSMANUFACTURING ENVIRONMENTS

Topics for this ModuleTopics for this Module• What makes up the manufacturing What makes up the manufacturing

environment (not just Environmental environment (not just Environmental Control System)Control System)

• Contamination & cross-contaminationContamination & cross-contamination• How cleanrooms are definedHow cleanrooms are defined• Levels of Protection Levels of Protection ∆∆

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Module 1: Introduction to GMP Module 1: Introduction to GMP Manufacturing EnvironmentsManufacturing Environments

• The primary objective of manufacturing in an The primary objective of manufacturing in an ideal GMP environment is that this should lead ideal GMP environment is that this should lead to a high quality product being produced.to a high quality product being produced.

• Manufacturing in an ideal environment not only Manufacturing in an ideal environment not only leads to better quality products but should also leads to better quality products but should also result in :result in :

* Improved production rates.* Improved production rates.* Operator comfort, satisfaction and safety. * Operator comfort, satisfaction and safety. ∆∆

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Factors Factors Contributing to Contributing to Quality Quality ProductsProducts

Raw Materials

Personnel

Procedures

Validated processes

Equipment

Premises

Environment

Packing Materials

Validated processes

Equipment

Premises

Environment

The most important!

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Design considerationsDesign considerations for a manufacturing facility for a manufacturing facility

Preventcontact

with dust

Preventcontact

with fumes

Acceptablecomfort

conditions

cross-contamination

Protect fromproduct

Protect fromambient

contamination

contaminationPrevent

of staff

Correcttemperatureand humidity

Avoiddust

discharge

Avoidfume

discharge

Avoideffluent

discharge

PERSONNELPROTECTION

PRODUCTPROTECTION

ENVIRONMENTPROTECTION

GMP MANUFACTURINGENVIRONMENT

Three primary considerations to be addressed to ensure a safe and productive manufacturing facility

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The environment comprises aspects such as:

1. Light

2. Temperature

3. Humidity

4. Air movement

5. Microbial contamination

6. Particulate contamination

Uncontrolled environments can lead to:

� Product degradation & contamination � Loss of Product & Profit ∆

The manufacturing environment is critical for product quality

PIC/S PH 1/97 (Rev.3) #3.3 & 3.12

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Contaminants areContaminants are : :1.1.Products or substances other than Products or substances other than

product product manufactured manufactured 2.2.Foreign productsForeign products3.3.Particulate matterParticulate matter4.4.Micro-organismsMicro-organisms5.5.EndotoxinsEndotoxins (degraded micro-organisms) (degraded micro-organisms)

Cross-contamination is a particular case of Cross-contamination is a particular case of contaminationcontamination ∆∆

What are Contaminants ?

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What is Cross-What is Cross-Contamination ?Contamination ?Definit ion of CrossDefinit ion of Cross --ContaminationContamination

““Contamination of a starting material, Contamination of a starting material, oror of a of a product with another starting product with another starting material or product.material or product.””

Cross – Contamination (1)

PIC/S PH 1/97 (Rev.3) Pg. 134

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From wFrom w here does Cross-Contamination here does Cross-Contamination originate?originate?

1.1. Poorly designed air handling systemPoorly designed air handling system ss and dust extraction systemsand dust extraction systems

2.2. Poorly operated and maintained air Poorly operated and maintained air handling systemhandling system ss and dust extraction and dust extraction systemssystems

3.3. Inadequate procedures for personnel and Inadequate procedures for personnel and equipmentequipment

4.4. Insufficiently cleaned equipmentInsufficiently cleaned equipment ∆∆

Cross – Contamination (2)

PIC/S PH 1/97 (Rev.3) # 3.14

1111

Cross-contamination (3)Cross-contamination (3)

Contamination

Contaminants from

Environment& Operators

Contaminants from

Equipment

CrossContamination

Productfrom

Environment& Operators

Productfrom

Equipment

PIC/S PH 1/97 # 5.10

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Cross-Contamination (4)Cross-Contamination (4)

Cross-contamination can be minimized byCross-contamination can be minimized by1.1. Personnel proceduresPersonnel procedures2.2. Adequate premisesAdequate premises3.3. Use of closed production systemsUse of closed production systems4.4. Adequate, validated cleaning Adequate, validated cleaning

proceduresprocedures5.5. Appropriate Appropriate Levels of Protection of Levels of Protection of

productproduct6.6. Correct air pressure cascade Correct air pressure cascade ∆∆

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How are Contaminants Removed?How are Contaminants Removed?

• By efficient filtration of supply air.By efficient filtration of supply air.• By dilution of contaminants or flushing By dilution of contaminants or flushing

contaminants by supplying adequate air contaminants by supplying adequate air quantities to the room. quantities to the room. ∆∆

More about this later!

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Where Do Contaminants Come From?Where Do Contaminants Come From?

• Outside air carries dust which is a contaminantOutside air carries dust which is a contaminant• People generate contaminants:People generate contaminants:

We completely shed our outer skin every 24 hrs.We completely shed our outer skin every 24 hrs. Particles of 0,3 micron & greater are liberated at a Particles of 0,3 micron & greater are liberated at a

rate varying between of 100 000 to 10 million per rate varying between of 100 000 to 10 million per minuteminute

A person walking will liberate 5000 bacteria/minute A person walking will liberate 5000 bacteria/minute and a single sneeze can produce up to 1 million and a single sneeze can produce up to 1 million bacteria.bacteria.

• The manufacturing process itself can generate The manufacturing process itself can generate contaminants eg paint off equipment, dust contaminants eg paint off equipment, dust from belt drives, etc from belt drives, etc ∆∆

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Why All the Concern About Dust?Why All the Concern About Dust?

Typical size relationship between

dust, bacteria and viruses

Virus

(0,006µm to 0,03µm)

Dust Particle

(0,5µm to 500µm)

Bacteria

(0,2µm to 2µm)

Dust Is a Bacteria Carrier

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Particle sizesParticle sizes

Airborne ContaminantsAirborne Contaminants

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Removal of BacteriaRemoval of Bacteria

• As dust is a carrier, dust must be As dust is a carrier, dust must be controlled.controlled.

• Ambient bacteria is removed by Ambient bacteria is removed by filtration.filtration.

• Internal bacterial distribution can be Internal bacterial distribution can be controlled by directional air flow and controlled by directional air flow and air flushing or dilution.air flushing or dilution.

• Surface bacteria is controlled by Surface bacteria is controlled by adherence to strict cleaning sop’s. adherence to strict cleaning sop’s. ∆∆

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Defining the EnvironmentDefining the Environment

• What is the manufacturing environment ?What is the manufacturing environment ?

• How does the manufacturing environment How does the manufacturing environment effect contamination and cross-effect contamination and cross-contamination ?contamination ?

• Cleanroom concept Cleanroom concept ∆∆

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What Is a Cleanroom ?What Is a Cleanroom ?

A cleanroom is an environment where the particulate contamination & bacterial contamination are limited to prescribed levels.

2020

How Are Cleanrooms How Are Cleanrooms Classified ?Classified ?

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Controlled Environment StandardsControlled Environment Standards

CONTROLLED ENVIRONMENT STANDARDSBS EN ISO 1 4644-1: 1999, Federal Standard and Approximate Equivalents.

 

-

-

-

•= Uni-directional (Laminar Flow) ** = Maximum number of viable microorganisms permitted per m³. Annex 1 # 3

200

2222

Facility Parameters That Facility Parameters That Need To Be ControlledNeed To Be Controlled

TemperatureTemperature

Humidity

Air Cleanliness

Room Pressure

Air movement

Lighting

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How Clean Should It Be?How Clean Should It Be?

Level of Protection Level of Protection ConceptConcept

1.1. Defines environmental requirements Defines environmental requirements

2.2. Working to defined environments hWorking to defined environments h elps prevent elps prevent contamination and cross-contaminationcontamination and cross-contamination

3.3. Allows production under optimal hygiene conditionsAllows production under optimal hygiene conditions

4.4. Takes into accountTakes into account• product sensitivity to contaminationproduct sensitivity to contamination • therapeutic risktherapeutic risk ∆∆

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Many Different Standards In UseMany Different Standards In Use

Levels of Protection & CleanroomLevels of Protection & Cleanroom Class Class definitions currently in use.definitions currently in use.

EC, PIC/S, TGA, WHOEC, PIC/S, TGA, WHO,, etc. : etc. : A, B, C, D.A, B, C, D.US FDA : US FDA : CCritical and ritical and CControlledontrolled or or

Class 100, 1000, etcClass 100, 1000, etc..ISPE :ISPE : Level 1, 2 or 3 or Level 1, 2 or 3 or

Cleanroom class (ISO 5, 6, etc.).Cleanroom class (ISO 5, 6, etc.).Companies : Companies : Various Various othersothers such as White, Grey, such as White, Grey,

Black, Green, etcBlack, Green, etc..

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Therapeutic risks

Man

ufa

cturin

g E

nviro

nm

ent

req

uirem

en

ts

Cle

an

roo

m C

lass

A / B

Clea

nro

om

Cla

ss C

Cle

anrm

. Cla

ss D

Oth

ers

Cleanroom Class Required Is Dependant on Manufacturing Process Being Carried Out !

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Levels of ProtectionLevels of ProtectionParameters to be definedParameters to be defined ::

1.1. Air cleanliness requirements (filter type Air cleanliness requirements (filter type and position,and position, air changes, air changes, air flow air flow patterns, patterns, pressure differentials, pressure differentials, contamination levels bycontamination levels by particulate matter particulate matter and micro-organisms) and micro-organisms)

2.2. Personnel and material transfer methodsPersonnel and material transfer methods3.3. Permitted operationsPermitted operations4.4. Building design & finishes Building design & finishes ∆∆

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Levels of ProtectionLevels of Protection

All operations within a pharmaceutical facilility must beAll operations within a pharmaceutical facilility must be correlated to well-defined correlated to well-defined CleanroomCleanroom classes classes..

Example:Example:

ISO 14644-1 ISO 5U ISO 5T ISO 7 ISO 8

Washing of Containers X

Preparation of solution for terminal sterilization X

Preparation of solutions for aseptic filling X X X

Depyrogenisation of containers X

Filling for terminal sterilization X

Filling for aseptic process X

Etc.

U = Uni-directional

T = TurbulentAnnex 1, # 3, Pg 41

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Based on the Based on the CleanroomCleanroom Class Requirements, Class Requirements, various Levels of Protection have to various Levels of Protection have to be be created, includingcreated, including ::

1.1. Correlation between process operations and Correlation between process operations and CleanroomCleanroom classes classes 2.2. Type of operation permitted in each Type of operation permitted in each Level of Protection zoneLevel of Protection zone3.3. DDefinition of efinition of CleanroomCleanroom class class ((Contaminant Contaminant parameters, building parameters, building

materials, room requirements, materials, room requirements, air handlingair handling systems ) systems )4.4. Requirements for personnel and material in the different classes Requirements for personnel and material in the different classes

(clothing, training, type of materials, etc. )(clothing, training, type of materials, etc. )5.5. Requirements on entry conditions for personnel and material Requirements on entry conditions for personnel and material

(change (change & clean-down & clean-down procedures )procedures ) ∆∆

Levels of Protection

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Parameters Influencing the Parameters Influencing the Level of Protection (1)Level of Protection (1)

Air Handling System

Production RoomWith

DefinedRequirements

SupplyAir

OutletAir

How does an Air Handling System influence the Cleanroom Class or Level of Protection ?

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Parameters Influencing the Parameters Influencing the Level of Protection (2)Level of Protection (2)

11 Number of particles in the airNumber of particles in the air22 Number of micro-organisms in the air or on Number of micro-organisms in the air or on

surfacessurfaces33 Number of air changesNumber of air changes for each room for each room44 Air velocityAir velocity55 Air flow patternAir flow pattern66 Filters ( type, position )Filters ( type, position )77 Air Air Pressure differentials between roomsPressure differentials between rooms88 Temperature, humidityTemperature, humidity ∆∆

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Parameters Influencing the Parameters Influencing the Level of Protection (3)Level of Protection (3)

Cleanroom Classdefined by

Critical Parameters

Air HandlingSystem

Additional Measures

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Parameters Influencing the Parameters Influencing the Level of Protection (4)Level of Protection (4)

Air handling systemsAir handling systems::• are the are the main tool for reaching required main tool for reaching required

parametersparameters

• but are but are not suff icient as suchnot suff icient as such

Need for additional measures such asNeed for additional measures such as� Appropriate gowning (type of clothing, proper Appropriate gowning (type of clothing, proper

changingchanging rooms)rooms) � Validated sanitationValidated sanitation� Adequate transfer procedures for materials and Adequate transfer procedures for materials and

personnelpersonnel ∆∆∆∆

Questions & AnswersQuestions & Answers