Qualification of Cleanrooms and Environmental Monitoring- Practical Approaches in Europe

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Dr. Doris HerrmannZum Eselsbachtal 2067657 Kaiserslautern

Doris.Herrmann@GMP-unlimited.dewww.gmp-unlimited.com

Professional Background:

Qualified Person since 1994GMP Consultant since 2007Owner of Company GMP- unlimited

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GMP/GTP FacilitiesDesign and planning of cleanrooms, adjacent technical infrastructure, Installation-Qualification and Process-Validation for the operational commissioning

Process- Product- Development

Regulatory Requirements regarding GMP Compliance

Education and Training Workshops

Quality Management

GMP Audits

Obtaining licences from appropriate government institutions

Consultancy Service ……………………………………………………………………………………………………………………………………………

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DIN EN ISO 14644Cleanrooms and associated controlled environments

• Part 1: Classification of Air Cleanliness

• Part 2: Specification for Testing and Monitoring to proove continuedcompliance

• Part 3: Measurement and Testing Technology

• Part 4: Planning, Execution and Initial Operations

(Annex F: Environmental Monitoring)

(www.beuth.de) published by Beuth Verlag Berlin

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Environmental Control for a multi-functional, multi-product facility

“During manufacturing of cellular therapeutics “Routine Monitoring” ofparticles and germs should ensure the constant suitability of the cleanroomfacilities and the hygienic appropriateness of the personnel. It should bedemonstrated that there is no risk of contamination originating from thepremises and personnel for the products in operation conditions”

„Cleanroom and clean air devices should be classified in accordance with EN DIN ISO 14644, classification should be clearly differentiated from operational EM“.„Cleanroom and clean air devices should be routinely monitored in operationMonitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms…“

„In operation“ = Routine Manufacturing, simulated operations, Media Fills„At rest“ = complete equipment installed and operating, no personnel

Annex 1, Medicinal Products for Human Use, EU GMP Guide, http://ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf

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Cleanroom Monitoring for 4 grades

Grade A Zone: for high risk operations

Particle monitoring for full duration of critical processing, including

equipment except where justified by contaminants in the process

presenting a hazard, sampling methodes used should not interfere with zone

protection, results should be considered for finished product release

Laminar air flow (air velocity 0,36-0,54m/s)

Grade B Zone: for aspetic preparations and fillings

Similiar system, sample freqency decreased

Grade C and D: for less critical stages

Performance in accordance with the principles of quality risk management,

dependent on the nature of operations carried out

(Monitoring also for physical parameters: temperature and humidity if critical for the

product, pressure, HVAC-System, equipment, media) 7

Limits for Air Borne Particles(including statistical evaluation)

ISO European Max. Particles per cubic meter

(in operation)

> 0,5 µm > 5 µm

Particles

(at rest)

> 0,5 > 5

5

6

7

8

A

B

C

D

3500 20

352.000 2.900

3.520.000 29.000

n.d. n.d.

3520 20

3521 29

352.000 2900

3.520.000 29.000

Classification accordingto European GMP guidelines

Tool for early detection offailure

Values should be achieved after Clean up period no longer than15-20 min.

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Particles, in operationInstruments:Inv.-No.:Messuring done from: on date:

Ergebnis Sammelvolumen Partikel / m3

soll ist soll ist

Raum: 3.123 (Präparationslabor) Zustand*:

soll L │ min

ist L │ min ≥0,5 µm 0≥,5 µm 5 ≥µm ≥5 µm

1) LF 1000 │ 36 3 500 1 2) vor Durchreiche zum Laborflur 100 │ 4 350 000 2 000 3) auf/direkt vor unterem BS 100 │ 4 350 000 2 000 4) vor LF 100 │ 4 350 000 2 000 5) vor Zentrifuge 100 │ 4 350 000 2 000 6) vor Durchreiche zum C-Gang 100 │ 4 350 000 2 000 Raum: 3.126 (Präparationslabor) Zustand*:

7) LF 1000 │ 36 3 500 1 8) auf Arbeitstisch 100 │ 4 350 000 2 000 9) vor Zentrifuge 100 │ 4 350 000 2 000 10) vor LF (links) 100 │ 4 350 000 2 000 11) zwischen LF und Tür 100 │ 4 350 000 2 000 12) vor Durchreiche zum C-Gang 100 │ 4 350 000 2 000 Raum: 3.125 (Pers.Schleuse in B) Zustand*:

13) reine Seite vor Tür zu 3.123 100 │ 4 350 000 2 000 14) reine Seite vor Tür zu 3.126 100 │ 4 350 000 2000 15) unreine Seite vor Tür zum Gang 100 │ 4 3,5x106 20 000

*Description of work, how many people !limits reached: yes/noActions: Date/Signature:

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Limits for microbial contamination (a)(Air, Surface and personnel monitored frequently after critical operations)

European

Grades

Volumetric Air samples cfu/m3

Settle Plates (diameter 90mm)

Cfu /4 hours (b)

Contact plates forsurface sampling

(diam 55mm)

Cfu/plate

Glove prints

5 fingers

Cfu/glove

A

B

C

D

< 1

10

100

200

< 1

5

50

100

< 1

5

25

50

< 1

5

a) These are average values

b) Individual settle plates maybe exposed less than 4 hours

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LF LFLF

LF

BSBS

ZF

ZF

ZF ZF

TTT

T

T

TKSTKKS

TK

TR 3.123

R 3.132

R 3.133R 3.131

R 3.130

R 3.127

R 3.128

R 3.129

R 3.124

R 3.125

R 3.126

unclass. Hallway

Hallway Class C

Locks Class B

4 Class B

Lock Class C

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Messuring points: particles ( √ square root of surface in m2)

(in working height/10 cm over work area, not directly under supply air)

LF LFLF

LF

BSBS

ZF

ZF

ZF ZF

TTT

T

T

TKSTKKS

TK

TR 3.123

R 3.132

R 3.133R 3.131

R 3.130

R 3.127

R 3.128

R 3.129

R 3.124

R 3.125

R 3.126

1

2

4

5

6

7

8

3

9

10

11

12

13 14

15

16

17

18

19

20

21

22

2324

25

26

27

28 29

30

31

32

33

34 35 3637 38

39

40

41 42

43

44LF LFLF

LF

BSBS

ZF

ZF

ZF ZF

TTT

T

T

TKSTKKS

TK

TR 3.123

R 3.132

R 3.133R 3.131

R 3.130

R 3.127

R 3.128

R 3.129

R 3.124

R 3.125

R 3.126

LF LFLF

LF

BSBS

ZF

ZF

ZF ZF

TTT

T

T

TKSTKKS

TK

TR 3.123

R 3.132

R 3.133R 3.131

R 3.130

R 3.127

R 3.128

R 3.129

R 3.124

R 3.125

R 3.126

1

2

4

5

6

7

8

3

9

10

11

12

13 14

15

16

17

18

19

20

21

22

2324

25

26

27

28 29

30

31

32

33

34 35 3637 38

39

40

41 42

43

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T: Table BS: Incubator ZF: Centrifuge LF: Laminar Flow KS: Refridgerator

When using Continous Particle Monitoring, measuring points:LF and background class B (attention: tubing between measuring point andsensor not longer than 3 meters !) 14

Messuring points: microbiology (air germs, contact plates)

LF LFLF

LF

BSBS

ZF

ZF

ZF ZF

TTT

T

T

TKSTKKS

TK

TR 3.123

R 3.132

R 3.133R 3.131

R 3.130

R 3.127

R 3.128

R 3.129

R 3.124

R 3.125

R 3.126

2

3

4

5

6

1

7

8

9

1012

1314

15

11

16

1718

19

2423

2221

20

25

A4

A5

A6A3

A2

A1

A7

A8A9 A12

A11

A10

LF LFLF

LF

BSBS

ZF

ZF

ZF ZF

TTT

T

T

TKSTKKS

TK

TR 3.123

R 3.132

R 3.133R 3.131

R 3.130

R 3.127

R 3.128

R 3.129

R 3.124

R 3.125

R 3.126

LF LFLF

LF

BSBS

ZF

ZF

ZF ZF

TTT

T

T

TKSTKKS

TK

TR 3.123

R 3.132

R 3.133R 3.131

R 3.130

R 3.127

R 3.128

R 3.129

R 3.124

R 3.125

R 3.126

2

3

4

5

6

1

7

8

9

1012

1314

15

11

16

1718

19

2423

2221

20

25

A4

A5

A6A3

A2

A1

A7

A8A9 A12

A11

A10

T: Table BS: Incubator LF: Laminar Flow KS: Refridgerator ZF: Centrifuge

Locations: risk based approach = use common sense15

Testing frequencies according to previous testing values

(in operation)

Grades Particles Air germs

Settle plates

Incubation:

3-5 d RT

3-5 d at 32,5°C

+-2,5° C

Air germs

Air sampler

Incubation:

3-5 d RT

3-5 d at 32,5°C

+-2,5° C

Contact plates

Incubation:

3-5 d at RT

3-5 d at 30-35°C

Personnel

Incubation:

3-5 d at RT

3-5 d at 30-35°C

A During processing During processing

After process Hand, Forarm

B During process - 1/Month After process After process

C based on riskanalysis

- based on riskanalysis

D - - based on riskanalysis

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Alert (discussion of cause)Definition based on results during qualification, monitoring statistic, or 50 % of Actions limit

Actions limits (deviation report with corrective actions)

Particles/m3 >0,5µ >5µ >0,5µ >5µ

Alert limit Action limit

Class A 2800/10 3520/20

Class B 280.000/2400 352.000/2900

Class C 3,20 Mio/15.000 3,52 Mio/29.000

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Reaching Alert Limits:Discussion of cause with all the employees

Reaching Action Limit:Directly repetition of sampling is possible, if again over limit:

Investigations and Deviation report to find reasons of contamination:

-Instruments on/off

-Arrangements for new Cleaning and Disinfection

-Check of coating and channeling into the cleanrooms

-Testing of supply air filters

-Testing of instrument for measuring

-Check of lot of culture media, materials

-Check of processing

-Retraining of personnel

- Machine set-up

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Annual Cleanroom QualificationRequirements: - up dated Validation Master Plan - all Instruments, Equipement, Media must bequalified and maintained before starting !

- Accessibiliy of technical installations in termsof a walk-in suspended ceiling above thecleanrooms and going around hallways !

Measuring of physical Parameters:Temperature, Humidity, Differential Pressure(Pressure difference between cleanroomclasses), sound level, change of air ventilationper hour, air velocity, adequate lighting

Confirmation of Cleanroom Classes accordingto DIN EN ISO 14644 - 3, VDI 2083 – 3,GMP Guide Annex 1 (based on defind measuring points “at rest”, “in operation”) 19

Which kind of air flow ?

TAV= Turbulent Dilution Flow „Laminarflow“ for class A

TMS = Turbulent Flow for class B

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Removal of emerging Particles: particles will be diluted byappropriate high air change per hour through air dilution „cleaning of the room“

After breakdown of HVAC systemrecovery time of the cleanroomclass should be below 20 min.!

Turbulent FlowAir Flow in Cleanrooms

Intake Filter

Exhaust AirIncoming air

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Cleanroom with 100 % Filter Fan Units on ceiling: Class A

Parallele air stream

Exhaust Air throughventilation double floor(elektronic) or areas at the bottom ofcleanroom wall

Turbulent Dilution Flow

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Cleanroom Qualification

Every 2 years: leaktest of terminal filter, primaryfilters must be checked routinely: testing of pressuredifference and visual control, exchanged as needed !Filter Integrity test: test-socket for application of aerosol must beeasily accessible

Reserve capacity/redundancy of HVAC System (pressure differences are kept ?)

Reduced air changes during the night: check pressure system during/after restart to 100 % and recovery time, 2-stage volume flow rate regulation ismandatory

Analysis of Recovery Time = Self-cleaning time = time necessary to reduceparticle concentration to 1 % of initial value

Visualisation of Airflow for critical locations in operating areas to avoid crosscontamination (benches,

hatches for transfer of material, exhaust air near floor)

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Product Impact (Results from monitoring and qualification should be considered when

reviewing batch documentation for product release !)

Corrective and preventive Action results should lead to:

Acceptability of operations or products ?

1. Review of manufacturing records (how many products ?)2. Repeat product sterility testing3. How many quarantine products4. Discarding of products if not irrecoverable

(discussions with responsible physicians !)5. How many products of these infused already ?6. Notify physicians, recipient, follow up of clinical

investigations7. Risk Analysis

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Qualification and Monitoring of Cleanrooms Results

• Deviation reports

• OOS reports

• Change control reports

• Diagramm of pathogenic germs

Effective follow up documentation of correctiveand preventive actions

Annual review report (not only for inspectors)

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Make sure to work with secure equipment in a secure environment

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……………………………………………………………………………………………………………………………………………

Thank you for your attention !

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