MCC PRESENTATION - GMP MANUFACTURING ENVIRONMENTS Module 1

Presented by :
Deryck Smith Consulting Engineers
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GMP MANUFACTURING ENVIRONMENTS

Presentation Outline
Module Module Module Module Module 1: 2: 3: 4: 5: Introduction to GMP Environments Air Conditioning System Components Types & Configurations of AC Systems Pressure Cascades & building Layouts Validation, Qualification & Maintenance

GMP MANUFACTURING ENVIRONMENTS

Topics for this Module What makes up the manufacturing environment (not just Environmental Control System) Contamination & cross-contamination How cleanrooms are defined Levels of Protection
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Module 1: Introduction to GMP Manufacturing Environments

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

Manufacturing in an ideal environment not only

leads to better quality products but should also result in : * Improved production rates. * Operator comfort, satisfaction and safety.

Factors Contributing to Quality Products

Personnel
Validated processes Validated processes Procedures

Raw Materials

The most important!

Equipment Equipment

Packing Materials

Premises Environment Environment

Design considerations for a manufacturing facility

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

PERSONNEL PROTECTION

PRODUCT PROTECTION

ENVIRONMENT PROTECTION

Prevent contact with dust Prevent contact with fumes

Protect from product cross-contamination Protect from ambient contamination

Avoid dust discharge Avoid fume discharge

Acceptable comfort conditions

Prevent contamination of staff

Correct temperature and humidity

Avoid effluent discharge

The manufacturing environment is critical for product quality

The environment comprises aspects such as:
1.
2. 3. 4. 5. 6.

Light
Temperature Humidity Air movement Microbial contamination Particulate contamination

Uncontrolled environments can lead to:

Product degradation & contamination

Loss of Product & Profit
PIC/S PH 1/97 (Rev.3) #3.3 & 3.12
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What are Contaminants ?

Contaminants are : 1. Products or substances other than product manufactured 2. Foreign products 3. Particulate matter 4. Micro-organisms 5. Endotoxins (degraded micro-organisms) Cross-contamination is a particular case of contamination
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Cross Contamination (1)

What is Cross-Contamination ? Definition of CrossContamination Contamination of a starting material,
or of a product with another starting material or product.

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

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Cross Contamination (2)

From where does Cross-Contamination originate? 1. Poorly designed air handling systems and dust extraction systems 2. Poorly operated and maintained air handling systems and dust extraction systems 3. Inadequate procedures for personnel and equipment 4. Insufficiently cleaned equipment
PIC/S PH 1/97 (Rev.3) # 3.14
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Cross-contamination (3)
Contaminants from Environment & Operators

Contamination

Contaminants from Equipment

Product from Environment & Operators

Cross Contamination

Product from Equipment

PIC/S PH 1/97 # 5.10
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Cross-Contamination (4)
Cross-contamination can be minimized by 1. Personnel procedures 2. Adequate premises 3. Use of closed production systems 4. Adequate, validated cleaning procedures 5. Appropriate Levels of Protection of product 6. Correct air pressure cascade
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How are Contaminants Removed?

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

contaminants by supplying adequate air quantities to the room.

More about this later!

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Where Do Contaminants Come From?

Outside air carries dust which is a contaminant People generate contaminants:
We completely shed our outer skin every 24 hrs. Particles of 0,3 micron & greater are liberated at a rate varying between of 100 000 to 10 million per minute A person walking will liberate 5000 bacteria/minute and a single sneeze can produce up to 1 million bacteria.

The manufacturing process itself can generate

contaminants eg paint off equipment, dust from belt drives, etc

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Why All the Concern About Dust?

Dust Is a Bacteria Carrier
Virus

(0,006m to 0,03m)

Dust Particle (0,5m to 500m)

Bacteria (0,2m to 2m)

Typical size relationship between

dust, bacteria and viruses

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Airborne Contaminants
Particle sizes

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Removal of Bacteria
As dust is a carrier, dust must be
controlled. Ambient bacteria is removed by filtration. Internal bacterial distribution can be controlled by directional air flow and air flushing or dilution. Surface bacteria is controlled by adherence to strict cleaning sops.
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Defining the Environment

What is the manufacturing environment ? How does the manufacturing environment
effect contamination and crosscontamination ?

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Cleanroom concept

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 Classified ?

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Controlled Environment Standards

200

= Uni-directional (Laminar Flow)

** = Maximum number of viable microorganisms permitted per m.

Annex 1 # 3
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CONTROLLED ENVIRONMENT STANDARDS

BS EN ISO 1 4644-1: 1999, Federal Standard and Approximate Equivalents.

Facility Parameters That Need To Be Controlled

Temperature
Humidity

Air

Cleanliness
Pressure

Room

Air

movement

Lighting
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How Clean Should It Be?

Level of Protection Concept
1. 2. 3. 4. Defines environmental requirements Working to defined environments helps prevent contamination and cross-contamination Allows production under optimal hygiene conditions Takes into account

product sensitivity to contamination therapeutic risk

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Many Different Standards In Use

Levels of Protection & Cleanroom Class definitions currently in use.
EC, PIC/S, TGA, WHO, etc. : A, B, C, D. US FDA : Critical and Controlled or Class 100, 1000, etc. ISPE : Level 1, 2 or 3 or Cleanroom class (ISO 5, 6, etc.). Companies : Various others such as White, Grey, Black, Green, etc.
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Cleanroom Class Required Is Dependant on Manufacturing Process Being Carried Out !

Manufacturing Environment requirements

Cleanroom Class A / B

Cleanroom Class C

Cleanrm. Class D

Therapeutic risks
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Others

Levels of Protection
Parameters to be defined:
1. Air cleanliness requirements (filter type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter and micro-organisms) 2. Personnel and material transfer methods 3. Permitted operations 4. Building design & finishes
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Levels of Protection
All operations within a pharmaceutical facilility must be correlated to well-defined Cleanroom classes. Example:
ISO 14644-1 ISO 5U ISO 5T ISO 7 ISO 8 X X X X X X X X

Washing of Containers Preparation of solution for terminal sterilization Preparation of solutions for aseptic filling Depyrogenisation of containers Filling for terminal sterilization Filling for aseptic process

Etc.
U = Uni-directional T = Turbulent

Annex 1, # 3, Pg 41
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Levels of Protection
Based on the Cleanroom Class Requirements, various Levels of Protection have to be created, including: 1. Correlation between process operations and Cleanroom classes 2. Type of operation permitted in each Level of Protection zone 3. Definition of Cleanroom class (Contaminant parameters, building 4.
materials, room requirements, air handling systems ) Requirements for personnel and material in the different classes (clothing, training, type of materials, etc. ) Requirements on entry conditions for personnel and material (change & clean-down procedures )

5.

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Parameters Influencing the Level of Protection (1)

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

Supply Air

Production Room With Defined Requirements

Outlet Air

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Parameters Influencing the Level of Protection (2)

1 2
3 4 5 6 7 8

Number of particles in the air Number of micro-organisms in the air or on surfaces Number of air changes for each room Air velocity Air flow pattern Filters ( type, position ) Air Pressure differentials between rooms Temperature, humidity
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Parameters Influencing the Level of Protection (3)

Cleanroom Class defined by Critical Parameters

Air Handling System

Additional Measures

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Air handling systems: are the main tool for reaching required
parameters

Parameters Influencing the Level of Protection (4)

but are not sufficient as such

Need for additional measures such as
Appropriate gowning (type of clothing, proper changing rooms) Validated sanitation Adequate transfer procedures for materials and personnel Questions & Answers
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