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Clean Area Classification

Rajendra Awasthi

Rajendra Awasthi

A clean room is a room with environmental control of particulate contamination, temperature and humidity, constructed and used in such away as to minimize the introduction, generation and retention of the particles inside the room.

Clean rooms are needed to reduce contaminations levels in the product or services performed.

Definition of clean area:

(a)Federal Standard 209 Definition of clean room

“A clean room is an enclosed area employing control over the particulate matter in air with temperature, humidity and pressure control as required. To meet the requirement of a ‘clean room’ as defined by this standard, all clean rooms must not exceed a particulate count as specified in the air cleanliness class.”

This standard first issued in 1963, has been used in the correct version 209B amendment since 1976. It is shortly to be reissued, entitled “airborne particulate cleanliness classes for clean room and clean zones.”

(b) BS 5295(British standard) definition of clean room:

This standard dates from 1976 and falls in to 3parts:

PART 1: Specification for control environmental clean rooms, work stations and clean air devices.

PART 2: Guide to construction and installation of clean rooms, work stations and clean air devices.

PART3: Guide to the operational procedure and disciplines applicable to clean rooms, work stations and clean air.

Objectives in cleaning a clean room:

The objectives in cleaning a clean room can vary between industries but the contamination that should be removed may one, two or all of the following types:

1.Particles and Fibers

2.Chemicals

3.Bacteria

4.Electrostatic Charges

In all types of clean rooms, particles and fibers are undesirable although the minimum size of particle, which is undesirable, will vary. In the pharmaceutical and medicinal devices industries it is though unwise to introduce particles into the patient.

In all types of clean rooms, spillage of chemicals from one part of the process may be undesirable in other part of the process. The Pharmaceutical industries are very concerned with bacteria because of the danger to the patient.

Many of the surfaces of clean room are poor conductors i.e. plastics and can develop and retain a high electrostatic charge. It may be necessary to clean these surfaces in such a way as to leave a film of antistatic agent to conduct the change away.

The Critical and General area of a clean room:

The clean room may be divided into:

  1. Critical Area
  2. General Area

The critical area is the area around the point of the production where contamination can gain direct access to the process. This is the area often protected by localized Laminar – Flow clean benches and workstations.

The “General” area is the rest of the clean room where contamination will not gain direct entry into the product but should be kept clean because of the transfer of contamination into the critical area.

It is necessary that the critical area be cleaned most often with the best cleaning ability without introducing contamination.

Cost effectiveness in relation to requirement can be best be achieved by considering the clean room in the “Critical” and “General” zones.

Classification Of Clean Rooms

The determination of how clean and areas is depends on classification that it has been designed to.

The classification of air cleanliness in FED standard 209 is very simple as the class is directly related to the number of particles per cubic foot of air equal to or greater than 0.5micron. The present British standard system designates 4 classes of environmental as class 1, 2, 3 and 4. Class 1 begins the highest class of cleanliness and in fact this is a slightly tighter specification than class 100 as 3000-particles/ m3 at 0.5µm.

Clean rooms are classified by the cleanliness of their air. The most recent 209E version has also accepted a metric nomenclature.

In the UK the British standard 5295, is also used to classify clean rooms.

209 define four classes of air cleanliness:

(1) Class 100,000: -particle count not to exceed a total of 100,000 particles per cubic foot of a

size 0.5µ and larger or 700 particles per cubic foot of size 5.0µ and larger.

(2) Class 10,000:- particle count not to exceed a total or 10,000 particles per cubic foot of a

size 0.5µ and larger or 65-70 particles per cubic foot of a size 5.0µ and larger.

(3) Class 1,000: - particles count not to exceed a total of 1000 particles per cubic foot of a size

0.5µ and larger or 10 particles per cubic foot of a size 5.0µ and larger.

(4) Class 100: - Particles count not to exceed a total of 100 particles per cubic foot of a size 0.5µ and larger.

The clean room class is generally achieved in the “AT REST” state when there are no people in the room.

Table: - 1 Measured particle size (micrometers) in different clean room classes

Class

 

Measured particle size (micrometers)

0.1 0.2 0.3 0.5 5.0

1

10

100

1,000

10,000

100,000

35 7.5 3 1 NA

350 75 30 10 NA

NA 750 300 100 NA

NA NA NA 1,000 7

NA NA NA 10,000 70

NA NA NA 100,000 700

In the new 209E published in 1992 the air borne concentration in the room are given in metric units i.e. per m3 and the classification of the room defined as the logarithm of the air born concentration of the particles ≥ 0.5µm.

E.g.: - a class M3 room has a particle limit for particles ≥0.5µm of 1000/m3.

BS 5295:

Class 1: The particle count shall not exceed a total of 3000 particles/m3of a size of

0.5 µ or greater. The greatest particle present in any sample shall not exceed 5 µ.

Class 2: The particle count shall not exceed a total of 3000 particles/m3of a size of 0.5

µ or greater; 2000 particles/m3 of size 0.5 µ or greater; 30 particles of a size 10 µ or greater

Class 3: The particle count shall not exceed a total of 1,000,000 particles of a size of 1 µ or greater; 20,000 particles/m3 of size 5 µ or greater; 4000 particles/m3 of a size 10 µ or greater; 300 particles of a size of 25 µ or greater

Class 4: The particle count shall not exceed a total of 200,000 particles of a size of 5 µ or greater; 40,000 particles/m3 of size 10 µ or greater; 4000 particles/m3 of a size 25 µ or greater.

ISO Standards for Clean Room

Because of the large number of clean rooms standard produced by individual countries it is very desirable that one worldwide standard of clean room classification is produced. The International Standards Organization (ISO) is producing such a document.

Table: - 2 Selected ISO 209 airborne particulate cleanliness classes for clean rooms and Clean zones

Numbers maximum concentration limits (particles/m3 of air) for Particles (N) equal and larger than the considered size

 

0.1 mm

0.2 mm

0.3 mm

0.5 mm

1.0 mm

5.0 mm

ISO 1

10

2

       

ISO 2

100

24

10

4

   

ISO 3

1000

237

102

35

8

 

ISO 4

10,000

2370

1020

352

83

 

ISO 5

100,000

23700

10200

3520

832

29

ISO 6

1,000,000

237000

102000

35200

8320

293

ISO7

     

352000

83200

2930

ISO 8

     

3520000

832000

29300

ISO 9

     

35200000

8320000

293000

The above classification derived from formula:

Cn = 10N × [0.1/D] 2.08

Cn= Maximum permitted concentration (particles/ m3 of air) of air born particles.

N = ISO classification number which shell not exceed the value of 9

D = Considered particle size in mm.

Pharmaceutical Clean Room Classification

European guidelines to GMP (Manufacture of sterile medicinal products)

The manufacture of sterile products should be carried out in clean areas, entry to which should be through air locks for personal and / or for equipment and materials.

The various operations of component preparations, product preparation and filling should be carried out in separate areas within the clean area.

Manufacturing operations are divided into two categories

1.Those where the product is terminally sterilized

2.Those which are conducted aseptically at some or all stages

Each manufacturing operation for sterile products require an appropriate environmental cleanliness level in the operational stage in order to minimize the risk of particulate or microbial; contamination of the product.

In order to meet “IN OPERATION” condition these areas should be designed to reach certain specified air- cleanliness level in the “At Rest” occupancy state.

The “AT REST” state is the condition where the installation is complete with production equipment installed and operating but with no operating personnel present

The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.

For the manufacture of sterile medicinal products normally 4 grades can be distinguished:

GRADE “A”: The local zone for high risk operations eg. Filling zone, stopper bowls, open ampules and vials , making aseptic connections. Normally such conditions are provided by a laminar airflow workstation. Laminar airflow system should provide a homogenous air speed of 0.45 m/s ±2.0% (guidance value) at the working position.

GRADE “B”: In case of aseptic preparation and filling, the background environment for grade “A” zone.

GRADE “C” &”D”: Clean areas for carrying out less critical stages in the manufacture of sterile products.

Table: - 3 Air borne particulate classification for Grade A, B, C & D

 

Maximum permitted number of particles /m3

Grade

At rest

In n operation

 

0.5mm

5mm

0.5mm

5mm

A

3500

0

3500

0

B

3500

0

350,000

2000

C

350,000

2,000

3,500,000

20,000

D

3,500,000

20,000

Not defined

Not defined

(a) In order to reach the B, C, & D air grades, the number of air changes should be related to the size of the room and equipment and personnel present in the room. The air system should be provided with appropriate filters such as HEPA for grade A, B, & C.

(b) The guidance given for the maximum permitted number of particles in the “at rest” conditions corresponds approximately to the US. Federal Standards 209E and the ISO classification as follows.

GRADE “A” & “B” correspondence with class 100, M 3.5, ISO 5

GRADE “C” with class 10,000, M 5.5, ISO 7

GRADE “D” with class 100,000, M 6.5, ISO 8

Isolator and Blow fill technology:

The air classification required for the background environment depends on the design of the isolator and its application .It should be controlled and aseptic processing is at least grade “D”.

The blow / fill / seal equipment used for aseptic production which is fitted with an effective grade ”A” air shower may be installed in at least a grade “C” environment, provided that grade “A”/“B” clothing is used.

Terminally sterilized products:

Preparation of components and most products should be done at least a grade “D” environment.

Filling of products for terminal sterilization should be done at least a grade “C” environment.

Aseptic preparation:

Components after washing should be handled in at least a grade “D” environment.

Handling of sterile starting materials and components unless subjected to sterilization or filtration n through a microorganism remaining after later in the process, should be done in a grade “A” environment with a grade “B” background.

Preparation of solutions which are to be sterile, filtered during the process should be done in a grade “C” environment; if not filtered, the preparation of materials and product should be done in a grade “A” environment with a grade “B” background..

Preparation and filling of sterile Ointment, Creams, Suspensions and Emulsions should be done in a grade “A” with a grade “B” background, when the product is exposed and is not subsequently filtered.

Table: - 4 Comparison of various standards:

Country & standard

USA 209D

USA 209E

Britain BS5295

Australia AS1386

France AFNORX44101

Germany VDI2083

ISO standard

Date of current issue

1988

1992

1989

1989

1972

1990 onwards

1997

Class

1

M1.5

C

0.035

-

1

3

10

M2.5

D

0.35

-

2

4

100

M3.5

E or F

3.5

4,000

3

5

1,000

M4.5

G or H

35

-

4

6

10,000

M5.5

J

350

400,000

5

7

100,000

M6.5

K

3500

4,000,000

6

8

References:

  1. Scott SO. 1993, Handbook of International Environmental Standards.
  2. Knovel (Firm), Bill Bennell,Graham C. 2003, Pharmaceutical Production and Engineering Guide.
  3. Roy SB. 2001, The clean air act.
  4. Winfield AJ. ,Richards RME., 2004, Pharmaceutical Practice.
  5. Nigel A. Halls.1994, Achieving Sterility in Medical and Pharmaceutical products.
  6. Kenneth EA. 1993, Pharmaceutical dosage forms: Parenteral Medications
  7. Graham C. 1998,Pharmaceutical Production Facilities: Design and Applications.

About Authors:

Rajendra Awasthi

Rajendra Awasthi
Faculty of pharmacy, Dept. of Pharma. Technology, MIET, Meerut (U.P.) INDIA
E. mail ID: r_pharma7@rediffmail.com, awasthi02@gmail.com

Kamal Dua

Kamal Dua

Faculty of pharmacy, D. J. College of Pharmacy, Modinagar, (U.P.) INDIA

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