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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 Environments

Module 2:Module 2: Air Conditioning System ComponentsAir Conditioning System Components

Module 3:Module 3: Types & Configurations of AC Types & Configurations of AC SystemsSystems

Module 4: Module 4: Pressure Cascades & building Pressure Cascades & building LayoutsLayouts

Module 5:Module 5: Validation, Qualification & Validation, Qualification & Maintenance 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-Contamination & cross-contaminationcontamination

• 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 ideal GMP environment is that this should lead to a high quality product being produced.lead to a high quality product being produced.

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

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

safety. 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- (degraded micro-

organisms)organisms)

Cross-contamination is a particular case Cross-contamination is a particular case of contaminationof contamination

What are Contaminants ?

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What is Cross-Contamination ?What is Cross-Contamination ?Definition of CrossDefinition 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 where does Cross-Contamination here does Cross-Contamination originate?originate?

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

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

3.3. Inadequate procedures for personnel Inadequate procedures for personnel and equipmentand equipment

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 by

1.1. Personnel proceduresPersonnel procedures

2.2. Adequate premisesAdequate premises

3.3. Use of closed production systemsUse of closed production systems

4.4. Adequate, validated cleaning Adequate, validated cleaning proceduresprocedures

5.5. Appropriate Appropriate Levels of Protection of Levels of Protection of productproduct

6.6. Correct air pressure cascade Correct air pressure cascade

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How are Contaminants How are Contaminants Removed?Removed?

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

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

More about this later!

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Where Do Contaminants Come Where Do Contaminants Come From?From?• Outside air carries dust which is a Outside air carries dust which is a

contaminantcontaminant• 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 Particles of 0,3 micron & greater are liberated at

a rate varying between of 100 000 to 10 million a rate varying between of 100 000 to 10 million per minuteper minute

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

• The manufacturing process itself can The manufacturing process itself can generate contaminants eg paint off generate contaminants eg paint off equipment, dust from belt drives, etc equipment, dust 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 controlled by directional air flow and air flushing or dilution.and 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 How does the manufacturing environment effect contamination and environment effect contamination and cross-contamination ?cross-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.

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How Are Cleanrooms How Are Cleanrooms Classified ?Classified ?

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Controlled Environment Controlled Environment StandardsStandards

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

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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 helps 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 Many Different Standards In UseUse

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, Cleanroom class (ISO 5, 6, etc.).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

Ma

nu

factu

ring

En

viro

nm

ent

req

uire

men

ts

Cle

anro

om

Cla

ss A

/ B

Cle

anro

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 Protection

Parameters to be definedParameters to be defined::1.1. Air cleanliness requirements (filter Air cleanliness requirements (filter

type and position,type and position, air changes, air changes, air air flow patterns, flow patterns, pressure differentials, pressure differentials, contamination levels bycontamination levels by particulate particulate matter and micro-organisms) matter and micro-organisms)

2.2. Personnel and material transfer Personnel and material transfer methodsmethods

3.3. 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 All operations within a pharmaceutical facilility must bemust be correlated to well-defined correlated to well-defined CleanroomCleanroom classesclasses..

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 zone

3.3. DDefinition of efinition of CleanroomCleanroom class class ((Contaminant Contaminant parameters, parameters, building materials, room requirements, building materials, room requirements, air handlingair handling systems ) systems )

4.4. Requirements for personnel and material in the different Requirements for personnel and material in the different classes 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 Number of micro-organisms in the air or

on surfaceson surfaces33 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 main tool for reaching

required parametersrequired parameters

• but are but are not sufficient as suchnot sufficient as such

Need for additional measures such asNeed for additional measures such asAppropriate gowning (type of clothing, Appropriate gowning (type of clothing,

proper changingproper changing rooms)rooms) Validated sanitationValidated sanitationAdequate transfer procedures for Adequate transfer procedures for

materials and personnelmaterials and personnel

Questions & AnswersQuestions & Answers