Staatliches Gewerbeaufsichtsamt Hannover
GMP Training Course
20-21 October 2009
EU GMP Requirements
Sterile medicinal product
Dr. Martin Melzer
Staatliches Gewerbeaufsichtsamt Hannover
Dr. Martin Melzer
Pharmacist / GMP Inspector
Tel.: + 49 (0) 511 9096 450
[email protected]
20.10.2009
Dr. Martin Melzer
2
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
20.10.2009
Dr. Martin Melzer
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Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1
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20.10.2009
Dr. Martin Melzer
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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
5
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
6
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
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 Room Classification
Clean room classification 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
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Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean Room Classification
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20.10.2009
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rob
Dr. Martin Melzer
9
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean Room Classification
US-FDA Requirements
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EU GMP Requirements !
20.10.2009
Dr. Martin Melzer
10
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
11
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
12
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
13
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
14
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
15
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
16
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
17
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
18
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
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Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Equipment
Various regulations
20.10.2009
Dr. Martin Melzer
20
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
21
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Sanitation
Desinfectants/ Detergents
Fumigation
20.10.2009
Dr. Martin Melzer
22
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
23
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Processing
Harm
onize
d
US F with
DA
Media Fill
Details
Acceptance Table
and
PIC
requ /S
ireme
nts
20.10.2009
Dr. Martin Melzer
24
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
25
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
26
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
27
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Aseptical filling
Filter 0.22 µm
Filter integrity test before & after use
20.10.2009
Dr. Martin Melzer
28
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
Clean room classification
Monitoring
Technologies
Personnel
Premises
Equipment
Sanitation
Processing
Sterilisation Methods
Aseptical Filling
Finishing
20.10.2009
Dr. Martin Melzer
29
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
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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
- F0-Concept
5.1.2 Biological indicators
5.1.5 Application of the F0 Concept to steam sterilisation of
aqueous solutions
5.1.9 Guidance for using the test for sterility
20.10.2009
Dr. Martin Melzer
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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)
20.10.2009
Dr. Martin Melzer
32
Staatliches Gewerbeaufsichtsamt Hannover
Other helpful documents
EN ISO 14644-1, -2
ISPE Guidelines
US FDA Aseptic processing guide
20.10.2009
Dr. Martin Melzer
33
Staatliches Gewerbeaufsichtsamt Hannover
Thank you !
20.10.2009
Dr. Martin Melzer
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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
20.10.2009
Dr. Martin Melzer
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