Contamination Control for Pharmaceutical Industry

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Manufacture of sterile medical product

Grade A : The local zone for high risk operation e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections Grade B : For aseptic preparation and filling Grade C : Clean areas for preparation of solutions when unusually at risk Grade D : Clean areas for preparation of solutions and components for subsequent filling
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Airborne Particulate Classification

Max. permitted number of particles/m3 equal to or above ( EN/ISO 14644-1 ) Size (m) Grade A Grade B Grade C Grade D 0.5 at rest 5.0 at rest 3,500 3,500 350,000 3,500,000 1 1 2,000 20,000 0.5 in operation 5.0 in operation 3,500 350,000 3,500,000 not defined 1 2,000 20,000 not defined

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Cleanroom Control
ENVIRONMENT
ISO 14644-1, -2 FS 209 E GMP, cGMP FDA Guidelines ISO 14644-3

Verification

Monitoring

PROCESS
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PEOPLE
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Monitoring Vs. Verification

Monitoring (FDA or GMP) focus: parameters during operation
Dynamic or in operation Potential effect on product is critical issue

Verification is normally done during idle time

Infrequent but thorough check of the environment as-built at rest
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Cleanroom Monitoring
In Operation or Dynamic Only Relates to Process and Product Quality Data needed for Product Release Average only count data from same location
each point must be below limit on the average but not necessarily each sample may be OK to delay ALERT or ACTION until 3rd or 5th consecutive high reading

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Cleanroom monitoring
Monitoring is intended to insure that the product exposure is controlled within limits because even with a good environment . . .

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People as Contamination
5 to 10 million cells per day 2300 micro-organisms per square cm Filter efficiency of clothing is highly variable

. . . People and Process can contaminate the Product.

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Cleanroom Verification
Initial and periodic certification
Federal Standard 209E ISO 14644-1, -2

Three states
As-built At Rest Operational / Dynamic

Averaging of Data from all positions

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Clean room Standards

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Particle counting regulations and specifications

FDA
The FDA stipulates that particle counts must be monitored in critical fill areas. Critical fill areas are where drugs are being dispensed into containers.

Federal Standard 209E

Fed Std 209E defines clean room classifications Clean Room classes are based on the numbers of 0.5 and larger, particles per cubic foot. The classifications are as follows:

Class 1 to Class 100,000

Class 1 and 10 are typically used in semiconductor manufacturers clean rooms. Class 100 and 1000 are typically used in pharmaceutical applications. Critical fill areas are class 100. Class 10,000 and class 100,000 are used in manufacturing environments.
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ISO Regulations
ISO 14644-1 Cleanroom Design (new 209E)

will eventually replace FS209E, even in USA (3 - 5 years)

EU GMP Annex I - Sterile Products

requires monitoring of 5 um particles as well as 0.5 um

ISO 13408

Aseptic Guidelines
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very similar to FDA version for liquid filling

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Recent ISO Documents related to cleanrooms

ISO Document ISO-14644-1 ISO-14644-2 ISO-14644-3 ISO-14644-4 ISO-14644-5 ISO-14644-6 ISO-14644-7 ISO-14644-8 ISO-14698-1 ISO-14698-2 ISO-14698-3 Title Classification of Air Cleanliness Cleanroom Testing for Compliance Methods for Evaluating & Measuring Cleanrooms & Associated Controlled Environments Cleanroom Design & Construction Cleanroom Operations Terms, Definitions & Units Enhanced Clean Devices Molecular Contamination Biocontamination: Control General Principles Biocontamination: Evaluation & Interpretation of Data Biocontamination: Methodology for Measuring Efficiency of Cleaning Inert Surfaces Status Active Active Draft Active Draft Draft Draft Draft Active Active Active
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Verification: ISO 14644-1

ISO 14644-1
ISO Class

FED STD 209E

English Metric

ISO 14644-1 adds

2 ultra-clean classes
ISO Class 1 ISO Class 2

1 2 3 4 5 6 7 8 9 1 10 100 1,000 10,000 100,000 M1.5 M2.5 M3.5 M4.5 M5.5 M6.5

1 very dirty class

ISO Class 9

Total of 9 classes Counts / cubic meter Must specify room status

as-built / at rest / in operation
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Verification: ISO 14644-1 versus FS 209E

Parameter Minimum sample volume FS 209E ISO 14644-1

2.83 liter 2.0 liter (0.1 cubic foot) (0.07 cubic foot) not specified 1 minute

Minimum sample time Minimum number of samples at each location

Note: Typical sample volume may be larger than minimum listed above especially for smaller size particles in very clean areas (better than ISO Class 5 or FS 209E Class 100)
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Particle Counter and Theory of Operation

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Theory of Particle Counter

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Theory of Particle Counter

There are three basic elements in all particle counting systems: 1) The sensor
The sensor is the device that detects particles using a light scattering method of detection.

2) The sample delivery system

The sample is delivered to the sensor by the use of a vacuum pump.

3) The counting electronics

The particle counts are processed and displayed by on board circuitry or in software.
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Sensor

Counting Electronics

Sample Delivery System (pump)

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The Sensor
Columnating lens Laser diode

Reflector

Light trap

Quiet State, no particles present.

Photo detector

Particle in the view volume.

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Sample Delivery
A vacuum pump is used to pull the sample air through the sensor. The flow is measured in cubic feet per minute (cfm). 1.0cfm pump 0.1cfm pump

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Counting Electronics
+V Threshold Circuit
This circuitry is duplicated from one channel up to six channels depending on the model counter

CH3

+V

CH2

Digital signals to counting circuitry

Analog Signal in +V

CH. 3 CH. 2 CH. 1

CH1

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Particle Sizing
The larger the particle , the larger the corresponding output pulse from the sensor.

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Counting Modes
Cumulative Differential

Size 3 Size 2 Size 1

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Block Diagram for Airborne Particle Counter

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Airborne Particle Counter

Sensitivities 0.1 to 25 micron

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Particle Counter Calibration Methods

Count Correlation
Compare to a standard reference instrument Compare to a standard count standard media

Size Calibration
Calibrate to a NIST traceable particle (mono-dispersed) Requires volumetric full stream or known view volume sensors

Count Correlation Calibration

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Size Size Calibration

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THANK YOU FOR YOUR ATTENTION

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