Staatliches Gewerbeaufsichtsamt Hannover

EU GMP Requirements
Sterile medicinal product
Dr. Martin Melzer
GMP Training Course
20-21 October 2009
20.10.2009 Dr. Martin Melzer 2
Staatliches Gewerbeaufsichtsamt Hannover
Dr. Martin Melzer
Pharmacist / GMP Inspector
Tel.: + 49 (0) 511 9096 450
martin.melzer@gaa-h.niedersachsen.de
20.10.2009 Dr. Martin Melzer 3
Staatliches Gewerbeaufsichtsamt Hannover
Agenda
Relevant and legally binding documents
EU GMP annex 1
European Pharmacopoeia
PIC/ S
Other helpful documents
EN ISO 14644-1, -2
ISPE
FDA Aseptic Processing guide
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Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1
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20.10.2009 Dr. Martin Melzer 5
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1
Why is sterile manufacturing regulated in a separate annex ?
Annex 1 contains guidance to minimize the risk of contamination
- Microbes
- Particles
- Pyrogen
What is the not the goal of Annex 1 ?
- it must not be followed just by law
- others approached should not be forbidden by the CA
20.10.2009 Dr. Martin Melzer 6
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 7
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 8
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean Room Classification
Clean roomclassification A, B, C,
Particle limits at rest/ in operation
Microbiological limits in operation
Classification
Only particle contamination is used for classification purposes
Classification Monitoring
In accordance with EN ISO 14644 (Methodology)
During normal production, media fills (worst case scenario)
20.10.2009 Dr. Martin Melzer 9
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean Room Classification
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Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean Room Classification
US-FDA Requirements EU GMP Requirements !
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20.10.2009 Dr. Martin Melzer 11
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 12
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Monitoring
Principles
Routinely monitored in operation:
- Particles
- Microbiological count
- (+ temp + % rel. humidity)
Monitoring locations & frequency
- Based on formal risk analysis
- Alert and action limits
20.10.2009 Dr. Martin Melzer 13
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 14
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Technologies
The following Technologies are detailed:
Isolator
Blow/ Fill/ Seal
Terminally sterilized
Aseptic preparation
With regard to
Clean room classification / background
Monitoring

20.10.2009 Dr. Martin Melzer 15
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 16
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Personnel
Hygiene
Training
Clothing
Detailed for all clean room classes
20.10.2009 Dr. Martin Melzer 17
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 18
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Premises
Detailed for
General aspects
Sinks & drains
Changing rooms
Airlocks
Air supply

20.10.2009 Dr. Martin Melzer 19
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 20
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Equipment
Various regulations
20.10.2009 Dr. Martin Melzer 21
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 22
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Sanitation
Desinfectants/ Detergents
Fumigation
20.10.2009 Dr. Martin Melzer 23
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 24
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Processing
Media Fill
Details
Acceptance Table
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20.10.2009 Dr. Martin Melzer 25
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 26
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Sterilisation Methods
Principles ((moist) heat/ radiation/ ethylene oxide)
Validation
Biological Indicators for routine production
20.10.2009 Dr. Martin Melzer 27
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 28
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Aseptical filling
Filter 0.22 m
Filter integrity test before & after use
20.10.2009 Dr. Martin Melzer 29
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean roomclassification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009 Dr. Martin Melzer 30
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Finishing
Final closing under class A
Vial capping under class A (aseptic core) or class A
conditions (whatever that means )
100 % integrity testing (containers closed by fusion)
20.10.2009 Dr. Martin Melzer 31
Staatliches Gewerbeaufsichtsamt Hannover
European Pharmacopoeia
2.6.1 Sterility
Details of methods and sampling for sterility testing
5.1.1 Methods of preparation of sterile products
Sterility assurance level: 10
-6
, achived by
- Overkill methods
- F
0
-Concept
5.1.2 Biological indicators
5.1.5 Application of the F
0
Concept to steam sterilisation of
aqueous solutions
5.1.9 Guidance for using the test for sterility
20.10.2009 Dr. Martin Melzer 32
Staatliches Gewerbeaufsichtsamt Hannover
PIC/ S
(Pharmaceutical Inspection Convention)
Validation of aseptic processes (2009)
Recommendation of Sterility testing (2007)
Isolators used for aseptic processing and sterility
testing (2007)
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Staatliches Gewerbeaufsichtsamt Hannover
Other helpful documents
EN ISO 14644-1, -2
ISPE Guidelines
US FDA Aseptic processing guide
20.10.2009 Dr. Martin Melzer 34
Staatliches Gewerbeaufsichtsamt Hannover
Thank you !
20.10.2009 Dr. Martin Melzer 35
Staatliches Gewerbeaufsichtsamt Hannover
Link to documents
The Rules Governing Medicinal Products in the European Union
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/eudralex_en.htm
EU GMP
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol4_en.htm
PIC/ S
http://www.picscheme.org/
FDA (Aseptic Processing guide)
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM070342.pdf