Cleanroom monitoring

보건산업진흥원/㈜아이비에스

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목 차

I 크린룸의 개괄

II 청정도

III 고려되어야 할 요소

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교과의 목표

크린룸에 대해 전체적인 이해를 구하고,

보호의 등급

청정도와 제조행위의 보호등급

청정도의 정의

각 규제기관 및 기구에서 정의한 청정도의 차이점을 이해

모니러링되어야하는 항목

일상적인 모니터링

적격성평가에 포함되어야 하는 항목

건설상태별 평가항목

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HVAC 시스템의 개괄-1

HVAC 시스템의 개념

제품의 보호

오염

교차오염

환경적인 조건

작업자 보호

편안한 조건 제공

접촉 방지: 호흡, 피부

환경 보호

사회에 위해성이 있는 물질

위해도에 따른 보호등급

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제품 보호의 등급 예시;

기관 및 기구에서 정의한 청정도의 형태

KGMP 1A, 1B, 2

WHO, EC, PIC/S: A, B, C, D

US FDA: Critical and controlled

Class100/class1,000/class10,000,

Class100,000

ISPE: Level 1, 2, 3

ISO: Class 5, 6, 7, 8

크린룸의 개괄-1

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크린룸의 개괄-2

의약품의 제조 시설 내에서 이루어지는 모든 행위에는 적절한 청정도로 보호해야 하며 여기에는 위생개념을 포함시킬 수 있음

예를 들면;

Description A B C D

Washing of containers X

Preparation of solution for terminal sterilisation

X

Preparation of solutions for aseptic filling

X X X

Depyrogenisation of containers X

Filling for terminal sterilisation X

Filling for aseptic process X

etc.

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크린룸의 개괄-3

작업자 및 환경보호

위해도에 따라 보호 정도에 차이

Biological Safety Level에 따라 보호조치가 달라짐.

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청정도-1

ISOClassificationNumber (N)

Maximum concentration limits (particles/m3 of air) for particles equal to and larger than the considered sizes shown below (concentration limits are calculated in accordance with equation (1) in 3.2)

0.1 μm 0.2 μm 0.3 μm 0.5 μm 1 μm 5 μm

ISO Class 1 10 2

ISO Class 2 100 24 10 4

ISO Class 3 1000 237 102 35 8

ISO Class 4 10000 2370 1020 352 83

ISO Class 5 100000 23700 10200 3520 832 29

ISO Class 6 1000000 237000 102000 35200 8320 293

ISO Class 7 352000 83200 2930

ISO Class 8 3520000 832000 29300

ISO Class 9 35200000 8320000 293000

NOTE Uncertainties related to the measurement process require that concentration data with no more than three significant figures be used in determining the classification level

ISO 14644 standard

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청정도-2

KGMPEU

GuidelinesWHO GMP

ISO 14644 FDA GFI Aseptic Processing 1)

1A Grade A Class 5 Class 100

- Grade B Class 6Class 100,

Class 1,000

1B Grade C Class 7 Class 10,000

2 Grade D Class 8 Class 100,000

1) Guidance for industry – sterile products produced by aseptic process. 2004. FDA

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청정도-3

Grade

At rest In operation

0.5㎛ 5㎛ 0.5㎛ 5㎛

A3,520 20 3,5200 20

B3,520 29 352,000 2,900

C352,000 2,900 3,520,000 29,000

D3,520,000 29,000 - -

Airborn Particulate (European Commission 1) Annex 1,

2008)

1) The Rules Governing Medicinal Products in the European Union Volume 4EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products

Maximum permitted number of particles/㎥ equal to or above

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청정도-4

FDA, CDER 2004 1) USP30(1116) 2007 2)

Class 0.5㎛ and larger 0.5㎛ and larger

100 3,520 3,530

1,000 35,200 35,300

10,000 352,000 353,000

100,0003,520,000

(Controlled areas)

3,530,000

Airborn Particulate(in operation)

1) Guidance for industry – sterile products produced by aseptic process. 2004. FDA

2) Microbiology Evaluation of Cleanrooms and Other Controlled Environments

FDA has not a standard for particle size larger than 0.5 micron.However, the total number of particles should not exceed it class.

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청정도-5

GradeAir sample

Cfu/㎥

Settle plates Φ90mm/4hrs

Contact plates Φ55m

Glove print 5 fingers

A <1 <1 <1 <1

B 10 5 5 5

C 100 50 25 -

D 200 100 50 -

Recommended limits for microbial contamination(in operation, EU)

These are average values.

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청정도-6

ClassFDA 1)

(cfu/m3)

USP30 2)

(cfu/m3)

USP30

(cfu/contact plate 3))

USP30

Glove 4)

USP30 clothing 3)

100 <1 < 3 < 3(including floor) < 3 < 5

1,000 <7 - - - -

10,000<10 < 20 < 5

< 10(floor)

< 10 < 20

100,000<100 < 100 < 100 - -

Regulatory standard for viable organism level (in operation)

1) Guidance for industry – sterile products produced by aseptic process. 2004. FDA

2) Microbiology Evaluation of Cleanrooms and Other Controlled Environments

Maximum number of colony forming units per unit air volume3) Area of contact plates vary from 24㎠ to 30 ㎠4) 5 Fingers print

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청정도-7

ISO 14644 EU Guidelines FDA

Class 5 Grade A IO : Class 100

Class 6AR : Grade BIO : Grade C

IO : Class 1,000

Class 7AR : Grade CIO : Grade D

IO : Class 10,000

Class 8AR : Grade DIO : ­ .

IO : Class 100,000

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고려되어야 할 요소-1

일상적으로 모니터되고 기록되는 운전변수

온도

습도

미립자 계수

부유미생물 혹은 settling plates

Contact plates

차압은 연속하여 문서화

적용이 어려운 경우에는 교대마다 주기적으로 측정하여기록하고 경보를 발생시켜 활용

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고려되어야 할 요소-2

Sampling Area Sampling Frequency

Class 100 or better room designations Each operating shift

Supporting areas immediately adjacent to Class 100 (e.g. Class 10,000) Each operating

shift

Other support areas (Class 100,000) Twice/week

Potential product/container contact areas Twice/week

Other support areas to aseptic processing areas but non-product contact (Class 100,000 or lower)

Once/week

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고려되어야 할 요소-3

적격성평가의 일부로 모니터링되는 항목일상적으로 모니터되고 기록되는 운전변수에 추가하여,

Room air flow pattern

환기회수

HEPA filter의 완전성; 반년주기

회복기간의 확인

작업시 제품의 노출정도

경보를 발생시키지 않는 문의 개방 기간

재적격성평가의 주기는 운전경험과 정책에 따름

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고려되어야 할 요소-4

Unidirectional air flow

Air flow pattern

작업위치에서 풍속 및 균일성

필터면에서 풍속 및 균일성

보호시험, 해당하는 경우

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고려되어야 할 요소-5

DefinitionInstallation

(construction)Production equipment

Material Personnel

As built ● X X X

At rest ● ● ● X

Operational

Dynamic 1)● ● ● ●

ISO 14644에서 상태의 정의

Installation은 건설이 완료되고 모든 서비스가 연결되고 기능하는 상태

1) ISO 14644에서의 operational condition과 동일한 의미이 용어는 UDFDA가 2004년에 발간한 “FDA guidance for

industry sterile drug products produced by aseptic processing”에서 사용

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