Good Manufacturing Practice (GMP)

MANUFACTURING ENVIRONMENTS

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 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. 

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Factors Contributing to Quality
Products

Personnel

Validated processes
Validated processes
Procedures

Raw Materials
The most important!
Equipment
Equipment

Packing Materials
Premises

Environment
Environment

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

PERSONNEL PRODUCT ENVIRONMENT

PROTECTION PROTECTION PROTECTION

Prevent Protect from Avoid

contact product dust
with dust cross-contamination discharge

Prevent Protect from Avoid

contact ambient fume
with fumes contamination discharge

Acceptable Prevent Avoid

comfort contamination effluent
conditions of staff discharge

Correct
temperature
and humidity
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 The manufacturing environment is
critical for product quality

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 

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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 Cross-Contamination

“Contamination of a starting material, or of

a product with another starting material or
product.”

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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 
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Cross-contamination (3)

Contaminants
Contaminants
from
Contamination from
Environment
Equipment
& Operators

Product
Product
from Cross
from
Environment Contamination
Equipment
& Operators

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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. 

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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
(0,006µm to 0,03µm)

Dust Particle Bacteria

(0,5µm to 500µm) (0,2µm to 2µm)

Typical size relationship between

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dust, bacteria and viruses
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 sop’s. 

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Defining the Environment

• What is the manufacturing environment ?

• How does the manufacturing environment

effect contamination and cross-
contamination ?

• Cleanroom concept 

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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 m³.

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Facility Parameters That Need
To Be Controlled
 Temperature

Humidity

Air Cleanliness

Room Pressure

Air movement

Lighting
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How Clean Should It Be?

Level of Protection Concept

1. Defines environmental requirements

2. Working to defined environments helps prevent

contamination and cross-contamination

3. Allows production under optimal hygiene conditions

4. Takes into account

• product sensitivity to contamination
• therapeutic risk 

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

Cleanroom Class A / B
requirements

Cleanroom Class C
Cleanrm. Class D
Others

Therapeutic risks
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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
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 = 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
materials, room requirements, air handling systems )
4. Requirements for personnel and material in the different classes
(clothing, training, type of materials, etc. )
5. Requirements on entry conditions for personnel and material
(change & clean-down procedures ) 

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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

Production Room
Supply With Outlet
Air Defined Air
Requirements

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Parameters Influencing the
Level of Protection (2)
1 Number of particles in the air
2 Number of micro-organisms in the air or on
surfaces
3 Number of air changes for each room
4 Air velocity
5 Air flow pattern
6 Filters ( type, position )
7 Air Pressure differentials between rooms
8 Temperature, humidity 

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Parameters Influencing the
Level of Protection (3)

Cleanroom Class
defined by
Critical Parameters

Air Handling Additional Measures

System

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Parameters Influencing the
Level of Protection (4)
Air handling systems:
• are the main tool for reaching required
parameters

• 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 

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