Biosafety in Cleanroom/GMP Environments · Biosafety in Cleanroom/GMP Environments ... environment ISO 8 to 4.8, ... Gowning/degowning Procedure . some conflict

Biosafety in Cleanroom/GMP Environments SBNet Applied Biosafety Meeting, Basel, 24 August 2017

Biosafety in Cleanroom/GMP Environments

Squaring the Circle: Is it so difficult?

Biosafety in Cleanroom/GMP Environments 2

GMP

Biosafety

"Containment" principles in a nutshell

Bio-Exclusion: _ Clean-room, SPF

Containment (Bio-Inclusion): _ Pathogens _ GMO _ Invasive Neobiota Combination inclusion&exclusion:

_ GMP (vaccine production)

Source: Basler & Hofmann

3 Biosafety in Cleanroom/GMP Environments

GMP / cleanroom classifications

_ GMP standards are a set of manufacturing protocols designed to ensure that every batch of products meets the required quality standards.

_ Depending on the product or process, validation and monitoring of cleanliness are required.

_ GMP for sterile and clean products requires cleanroom conditions and clean air.

_ These specifications differ slightly between different standards.


GMP Harmonisation


https://www.worldmapsonline.com (Map)

WHO and PIC/S EU ASEAN USA

https://www.worldmapsonline.com

Example: EU GMP / cleanroom requirements


EU Grades Grade A: High risk Grade B: Background for Grade A Grade C: Less critical Grade D: Less critical

Source: https://ec.europa.eu/health/documents/eudralex/vol-4_en

Cleanroom ISO 14644-1 ~ ISO 4.8 ~ ISO 5 ~ ISO 7 at rest ~ ISO 8 in operation ~ ISO 8

Example GMP processes



GMP architectural requirements

_ Rooms/spaces in sequence to separate cleanroom/ GMP zones/areas.

_ Outfitting with floor, ceiling and wall systems that prevents build-up of dust and is easy to clean.

_ Furnishing that prevents build-up of dust and is easy to clean.


GMP ventilation requirements

_ Heating, ventilation and air-conditioning (HVAC) is an important area of technical support for a pharmaceutical production unit: _ To ensure that the process is not negatively affected by any kind of

climatic changes.

_ To provide comfortable working conditions for the operating staff.

_ The prevention of contamination and cross-contamination (e.g. by use of pressure cascades) is an essential design consideration of the HVAC system.


Example: EU GMP / cleanroom requirements


Sources: − EN ISO 14644 Standards that define Airborne Particulate Cleanliness Classes in Cleanrooms and Clean

Zones. − ASHRAE Handbook (American Society of Heating, Refrigerating and Air-Conditioning Engineers, Inc., a

non-profit technical organisation)

Do we need cleanroom conditions in BSL labs?


EU Grades Grade A: High risk Grade B: Background for Grade A Grade C: Less critical Grade D: Less critical


Cleanroom ISO 14644-1 ~ ISO 4.8 ~ ISO 5 ~ ISO 7 at rest ~ ISO 8 in operation ~ ISO 8

Microbiological lab Depends Depends Depends Depends

Normally not required in diagnostic and research settings

Biosafety Cabinets or other containment devices provide clean work environment ISO 8 to 4.8, depending on the background

BSL-2 settings requiring cleanroom conditions

_ Very strict aseptic work, for example _ Medicinal products derived from blood (blood banks)

_ Cell/tissue cultures for medical purposes (stem cells for clinical trials)

_ Bacterial cultures for medical purposes

_ Vaccine production using live microorganisms

_ Quality control of the above


Contamination prevention in BSL-2 labs

_ Sterile / clean supplies

_ Hand washing

_ PPE selection and usage (gloves, garments, donning)

_ Procedures and Practices (“aseptic work techniques”)

_ BSC location (doors, windows, passage ways, exposure to ventilation air draughts)

_ BSC performance (tested against EN 12469)

_ Housekeeping (dust, tidiness)


GMP room schematic for less critical process

Hand wash

Lockers

Benc

h

Personnel airlock ISO 8

Material airlock ISO 8

Cabinets

Grade D Room with ISO 8 background

BSC

Laminar flow Isolator

Grade C

ISO 7


Low grade clean

Medium grade clean

Unclassified area

Unclassified area

GMP Airflow / Differential pressure, DP

++ +

Personnel airlock ISO 8 Grade D Room with ISO 8 background



Directional airflow +, ++ Differential pressure

Unclassified area

Unclassified area

BSC

Laminar flow Isolator

Grade C

ISO 7

Non containment zone

BSL-2 room schematic

Hand wash

Lockers

BSL-2 Laboratory Changing area/zone

Lab coat, gloves

BSC


Low grade clean

Non containment zone

BSL-2 Airflow / Differential pressure

Lockers

BSL-2 Laboratory Changing area/zone

-


Directional airflow - Differential pressure

BSC

Hand wash

GMP/BSL-2 Schematic for less critical process

Hand wash

Lockers

Benc

h



Cabinets

Grade D / BSL-2 Room with ISO 8 background

Hand wash


Low grade clean

Medium grade clean

Unclassified area

Unclassified area

BSC

Grade C

ISO 7


GMP/BSL-2 Airflow / Differential pressure, DP

+ ++

Personnel airlock ISO 8 Grade D / BSL-2 Room with ISO 8 background


Directional airflow +, ++ Differential pressure

Unclassified area

Unclassified area

BSC

Grade C

ISO 7

GMP/BSL-3 Airflow / Differential pressure, DP

Personnel airlock ISO 8 Grade D / BSL-3 Room with ISO 8 background



- -

Directional airflow - -, -, + Differential pressure

Unclassified area

Unclassified area

BSC

Grade C

ISO 7

+ -

GMP room schematic for critical process

BSC / Isolator

Grade A ISO 4.8

Lockers

Grade B Room with ISO 5 background

Benc

h



Cabinets

Hand wash

Lockers

Benc

h


Cabinets


ISO 8

ISO 8

Unclassified area

Unclassified area


Low grade clean High grade clean

Medium high grade clean

BSC / Isolator

Grade A ISO 4.8


ISO 8

GMP Airflow / Differential pressure, DP




+++ ++ +


Directional airflow +, ++, +++ Differential pressure

ISO 8


Unclassified area

Unclassified area

GMP / BSL-2 room schematic for critical process

BSC / Isolator

Grade A ISO 4.8

Lockers


Benc

h


Cabinets

Hand wash

Lockers

Benc

h

Cabinets


Hand wash


Low grade clean High grade clean

Medium high grade clean

ISO 8

Material airlock ISO 5 Material airlock ISO 8

ISO 8

Unclassified area

Unclassified area

BSC / Isolator

Grade A ISO 4.8


GMP / BSL-2 Airflow / Differential pressure, DP

Personnel airlock ISO 5 Personnel airlock ISO 8

+++ ++ + -


ISO 8

Material airlock ISO 5 Material airlock ISO 8

ISO 8

Directional airflow -, +, ++, +++ Differential pressure

Unclassified area

Unclassified area

Monitoring GMP Environment / Quality Control


_ GMP requires monitoring of environment and a tight quality control of the products

_ Additional safety measures need to assure that pathogenic organisms are not released from the containment _ Analysis in the certified area (if space available)

_ Closed transport to point of analysis

_ Concept for documentation (electronic, paper?)

_ Cleaning and maintenance of sampling (and analysis) equipment

Competent authorities, policies/SOPS

_ Biosafety (national and cantonal authorities) _ Cantons

_ BAG / BAFU / BLV / SUVA

_ GMP (national and international authorities) _ Swissmedic

_ Inspectorates of countries where products are going to be sold/used


BSL versus cleanroom/GMP requirements; legal aspects Guidelines

_ BSL (national legislation) _ ESV, StFV, SAMV

_ EU: Directive 2009/41/EC on the contained use of genetically modified micro-organisms

_ CWA 15973 (Laboratory Biorisk Management) and CWA 16393 (Guidelines for implementation of CWA 15973)

_ GMP-standards issued by (international legislation) _ Switzerland (AMBV with reference to EU legislation)

_ EU (Directive 2003/94/EC, 1991/412/EEC, Eudralex Volume 4)

_ US (21 CFR 210 und 21 CFR 211), ASEAN, WHO, PIC/S



Measure Synergy GMP / Biosafety

Laboratory Design

Segregation of Production Areas

yes

Easy Cleaning yes Separate Airlock for personnel and material

yes

Room Pressure

no (pressure bubble)

Equipment Validation yes (different focus)

Choice of Equipment yes (closed systems)

CIP, SIP yes

Maintenance

some conflict (decontamination procedure)

Summary of Synergies




Personnel Awareness yes

Training, Qualification yes

Choice of PPE may need adaptation

Restricted Access, Minimize Movements

yes

Material Qualification of Suppliers yes

Sampling

Special Solution (analysis of samples)

Monitoring environment Special Solution (analysis of samples)

HVAC Direction of Airflow no




Processes Minimize (Cross-) Contamination

yes (closed system)

Validation and Control of Processes

yes

Gowning/degowning Procedure

some conflict (hand washing)

Documentation yes

Change Management yes

Risk Assessment / Quality Risk Management

yes

Inactivation of MOs some conflict (e.g. attenuated / live microorganisms)

Squaring the Circle: Is it so difficult?


GMP

Biosafety

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Thank you Basler & Hofmann Switzerland


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Biosafety in Cleanroom/GMP Environments · Biosafety in Cleanroom/GMP Environments ... environment ISO 8 to 4.8, ... Gowning/degowning Procedure . some conflict