Qualification of Cleanrooms and Environmental Monitoring - Practical Approaches in Europe

Transcription

1 Qualification of Cleanrooms and Environmental Monitoring - Practical Approaches in Europe 1

2 Dr. Doris Herrmann Zum Eselsbachtal Kaiserslautern Professional Background: Qualified Person since 1994 GMP Consultant since 2007 Owner of Company GMP- unlimited 2

3 Consultancy Service GMP/GP Facilities Design 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 raining Workshops Quality Management GMP Audits Obtaining licences from appropriate government institutions 3

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5 DIN EN ISO Cleanrooms and associated controlled environments Part 1: Classification of Air Cleanliness Part 2: Specification for esting and Monitoring to proove continued compliance Part 3: Measurement and esting echnology Part 4: Planning, Execution and Initial Operations (Annex F: Environmental Monitoring) ( published by Beuth Verlag Berlin 5

6 Environmental Control for a multi-functional, multi-product facility During manufacturing of cellular therapeutics Routine Monitoring of particles and germs should ensure the constant suitability of the cleanroom facilities and the hygienic appropriateness of the personnel. It should be demonstrated that there is no risk of contamination originating from the premises 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 operation Monitoring 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, 6

7 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

8 Limits for Air Borne Particles (including statistical evaluation) ISO European Max. Particles per cubic meter (in operation) Particles (at rest) > 0,5 µm > 5 µm > 0,5 > A B C D n.d. n.d Classification according to European GMP guidelines ool for early detection of failure Values should be achieved after Clean up period no longer than min. 8

9 Particles, in operation Instruments: Inv.-No.: Messuring done from: on date: Raum: (Präparationslabor) Ergebnis Zustand*: Sammelvolumen Partikel / m 3 soll ist soll ist soll ist L min L min 0,5 µm 0,5 µm 5 µm 5 µm 1) LF ) vor Durchreiche zum Laborflur ) auf/direkt vor unterem BS ) vor LF ) vor Zentrifuge ) vor Durchreiche zum C-Gang Raum: (Präparationslabor) Zustand*: 7) LF ) auf Arbeitstisch ) vor Zentrifuge ) vor LF (links) ) zwischen LF und ür ) vor Durchreiche zum C-Gang Raum: (Pers.Schleuse in B) Zustand*: 13) reine Seite vor ür zu ) reine Seite vor ür zu ) unreine Seite vor ür zum Gang ,5x *Description of work, how many people! limits reached: yes/no Actions: Date/Signature: 9

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11 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) Contact plates for surface sampling (diam 55mm) Glove prints 5 fingers Cfu /4 hours (b) Cfu/plate Cfu/glove A < 1 < 1 < 1 < 1 B C D a) hese are average values b) Individual settle plates maybe exposed less than 4 hours 11

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13 KS K R BS LF ZF R LF R R R LF ZF R BS KS K R ZF LF ZF R R R R unclass. Hallway Lock Class C Hallway Class C Locks Class B 4 Class B 13

14 Messuring points: particles ( square root of surface in m2) (in working height/10 cm over work area, not directly under supply air) 2 KS K R BS 3 LF 1 9 ZF 8 R LF R R R LF 16 ZF 18 R BS KS K R ZF LF 22 5 ZF 6 13 R R R R : able 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 and sensor not longer than 3 meters!) 14

15 Messuring points: microbiology (air germs, contact plates) 2 KS K ZF A2 R A1 3 4 A3 BS 1 LF ZF R A6 A5 6 7 R LF R R R LF ZF A9 12 R A8 13 BS KS K R A R ZF A11 14 LF A10 R A4 A7 11 R : able BS: Incubator LF: Laminar Flow KS: Refridgerator ZF: Centrifuge Locations: risk based approach = use common sense 15

16 esting frequencies according to previous testing values (in operation) Grades Particles Air germs Air germs Contact plates Personnel Settle plates Air sampler Incubation: 3-5 d R 3-5 d at 32,5 C +-2,5 C Incubation: 3-5 d R 3-5 d at 32,5 C +-2,5 C Incubation: 3-5 d at R 3-5 d at C Incubation: 3-5 d at R 3-5 d at C A During processing During processing After process Hand, Forarm B During process - 1/Month After process After process C based on risk analysis - based on risk analysis D - - based on risk analysis 16

17 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/ /20 Class B / /2900 Class C 3,20 Mio/ ,52 Mio/

18 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 -esting of supply air filters -esting of instrument for measuring -Check of lot of culture media, materials -Check of processing -Retraining of personnel - Machine set-up 18

19 Annual Cleanroom Qualification Requirements: - up dated Validation Master Plan - all Instruments, Equipement, Media must be qualified and maintained before starting! - Accessibiliy of technical installations in terms of a walk-in suspended ceiling above the cleanrooms and going around hallways! Measuring of physical Parameters: emperature, Humidity, Differential Pressure (Pressure difference between cleanroom classes), sound level, change of air ventilation per hour, air velocity, adequate lighting Confirmation of Cleanroom Classes according to DIN EN ISO , VDI , GMP Guide Annex 1 (based on defind measuring points at rest, in operation ) 19

20 Which kind of air flow? MS = urbulent Flow for class B AV= urbulent Dilution Flow Laminarflow for class A 20

21 Air Flow in Cleanrooms urbulent Flow Incoming air Intake Filter Exhaust Air Removal of emerging Particles: particles will be diluted by appropriate high air change per hour through air dilution cleaning of the room After breakdown of HVAC system recovery time of the cleanroom class should be below 20 min.! 21

22 urbulent Dilution Flow Cleanroom with 100 % Filter Fan Units on ceiling: Class A Parallele air stream Exhaust Air through ventilation double floor (elektronic) or areas at the bottom of cleanroom wall 22

23 Cleanroom Qualification Every 2 years: leaktest of terminal filter, primary filters must be checked routinely: testing of pressure difference and visual control, exchanged as needed! Filter Integrity test: test-socket for application of aerosol must be easily 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 is mandatory Analysis of Recovery ime = Self-cleaning time = time necessary to reduce particle concentration to 1 % of initial value Visualisation of Airflow for critical locations in operating areas to avoid crosscontamination (benches, 23 hatches for transfer of material, exhaust air near floor)

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25 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 testing 3. How many quarantine products 4. 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 investigations 7. Risk Analysis 25

26 Qualification and Monitoring of Cleanrooms Results Deviation reports OOS reports Change control reports Diagramm of pathogenic germs Effective follow up documentation of corrective and preventive actions Annual review report (not only for inspectors) 26

27 Make sure to work with secure equipment in a secure environment 27

28 hank you for your attention! 28