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CROSS CONTAMINATION IN PHARMACEUTICALS

Jitendra J. Jagtap (M.Pharm)

THE MANUFACTURING ENVIRONMENT IS CRITICAL FOR PRODUCT QUALITY1. Light

2. Temperature

3. Humidity

4. Air movement

5. Microbial contamination

6. Particulate contamination

7. Uncontrolled environment can lead to product degradation

product contamination

loss of product and profit

Jitendra J. Jagtap (M.Pharm)

CROSS-CONTAMINATION

What is Cross-Contamination ?

Definition of Cross-Contamination:

“Contamination of a starting material, intermediate product, or finished product with another starting material or product during production.” (WHO)

Jitendra J. Jagtap (M.Pharm)

CROSS-CONTAMINATION

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

Jitendra J. Jagtap (M.Pharm)

Contamination

Contaminant from

EnvironmentOperators

Contaminant from

Equipment

CrossContamination

Productfrom

EnvironmentOperators

Productfrom

Equipment

CROSS-CONTAMINATION

Jitendra J. Jagtap (M.Pharm)

CROSS - CONTAMINATION

Jitendra J. Jagtap (M.Pharm)

CROSS - CONTAMINATION

Jitendra J. Jagtap (M.Pharm)

CROSS CONTAMINATION - RISK

Jitendra J. Jagtap (M.Pharm)

CROSS CONTAMINATION – CHEMICAL ANALYSIS

Jitendra J. Jagtap (M.Pharm)

CROSS- CONTAMINATION

Cross-contamination can be minimized by:

1. Personnel procedures (Skilled Manpower, Technical Awareness)

2. Adequate premises (Proper Lay out, Area Classification)

3. Use of closed production systems (Man & Material movement)

4. Adequate, validated cleaning procedures5. Appropriate levels of protection of product6. Correct air pressure cascade (HVAC design & Air Distribution)

Jitendra J. Jagtap (M.Pharm)

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”

Jitendra J. Jagtap (M.Pharm)

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

Jitendra J. Jagtap (M.Pharm)

WHERE DO CONTAMINANTS COME FROM?Outside air carries dust which is a contaminantPeople 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 bacteriaThe manufacturing process itself can generate contaminants e.g. paint off equipment, dust from belt drives, etc

Jitendra J. Jagtap (M.Pharm)

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

Jitendra J. Jagtap (M.Pharm)

Particle sizes

AIRBORNE CONTAMINANTS

Jitendra J. Jagtap (M.Pharm)

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

Jitendra J. Jagtap (M.Pharm)

DEFINING THE ENVIRONMENT

What is the manufacturing environment ?

How does the manufacturing environment effect

contamination and cross-contamination ?

Clean room concept

Jitendra J. Jagtap (M.Pharm)

WHAT IS A CLEANROOM ?

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

Jitendra J. Jagtap (M.Pharm)

HOW ARE CLEANROOMS CLASSIFIED ?

Jitendra J. Jagtap (M.Pharm)

CONTROLLED ENVIRONMENT STANDARDS

-

-

-

•= Uni-directional (Laminar Flow) ** = Maximum number of viable microorganisms permitted per m³

200

Jitendra J. Jagtap (M.Pharm)

FACILITY PARAMETERS THAT NEED TO BE CONTROLLED

Temperature

Humidity

Air CleanlinessRoom Pressure

Air movementLighting

Jitendra J. Jagtap (M.Pharm)

HOW CLEAN SHOULD IT BE?

Level of Protection Concept

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

Jitendra J. Jagtap (M.Pharm)

MANY DIFFERENT STANDARDS IN USE

Levels of Protection & Clean room 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.

Jitendra J. Jagtap (M.Pharm)

Therapeutic risks

Man

ufactu

ring

Environ

men

t requ

iremen

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 !

Jitendra J. Jagtap (M.Pharm)

LEVELS OF PROTECTION

PARAMETERS TO BE DEFINED: Air cleanliness requirements (filter type and

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

Personnel and material transfer methods Permitted operations Building design & finishes

Jitendra J. Jagtap (M.Pharm)

Based on the Clean room 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 Clean room 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 )

LEVELS OF PROTECTION

Jitendra J. Jagtap (M.Pharm)

PARAMETERS INFLUENCING THE LEVEL OF PROTECTION

Air Handling System

Production RoomWith

DefinedRequirements

SupplyAir

OutletAir

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

Jitendra J. Jagtap (M.Pharm)

1 Number of particles in the air2 Number of micro-organisms in the air or on surfaces3 Number of air changes for each room4 Air velocity5 Air flow pattern6 Filters ( type, position )7 Air Pressure differentials between rooms8 Temperature, humidity

PARAMETERS INFLUENCING THE LEVEL OF PROTECTION

Jitendra J. Jagtap (M.Pharm)

Cleanroom Classdefined by

Critical Parameters

Air HandlingSystem

Additional Measures

PARAMETERS INFLUENCING THE LEVEL OF PROTECTION

Jitendra J. Jagtap (M.Pharm)

Air handling systems:are the main tool for reaching required

parametersbut 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

PARAMETERS INFLUENCING THE LEVEL OF PROTECTION

Jitendra J. Jagtap (M.Pharm)

Jitendra J. Jagtap (M.Pharm)