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Staatliches Gewerbeaufsichtsamt Hannover EU GMP Requirements Sterile medicinal product Dr. Martin Melzer GMP Training Course 20-21 October 2009
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Requirements
Sterile medicinal product
Dr. Martin Melzer
GMP Training Course20-21 October 2009
20.10.2009 Dr. Martin Melzer 2
Staatliches Gewerbeaufsichtsamt Hannover
Dr. Martin Melzer
Pharmacist / GMP Inspector
Tel.: + 49 (0) 511 9096 450
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
20.10.2009 Dr. Martin Melzer 4
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1Coming into operation: 1.3.2009
Coming into operation (capping of freeze-dried vials): 1.3.2010
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 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� 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 ElementsClean 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 9
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic ElementsClean Room Classification
Particles
Microbes/ cfu
20.10.2009 Dr. Martin Melzer 10
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic ElementsClean Room Classification
� US-FDA Requirements � EU GMP Requirements !
EU GMP Annex 1
FDA Aseptic
Process
ing Guide
cGMP
20.10.2009 Dr. Martin Melzer 11
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 12
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic ElementsMonitoring
� 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 room classification� 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 ElementsTechnologies
� 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 room classification� 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 ElementsPersonnel
� 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 room classification� 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 ElementsPremises
� 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 room classification� 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 ElementsEquipment
� Various regulations
20.10.2009 Dr. Martin Melzer 21
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
� Clean room classification� Monitoring� Technologies� Personnel� Premises� Equipment� Sanitation� Processing� Sterilisation Methods� Aseptical Filling� Finishing
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Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic ElementsSanitation
� Desinfectants/ Detergents� Fumigation
20.10.2009 Dr. Martin Melzer 23
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic Elements
� Clean room classification� Monitoring� Technologies� Personnel� Premises� Equipment� Sanitation� Processing� Sterilisation Methods� Aseptical Filling� Finishing
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Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic ElementsProcessing
� Media Fill� Details� Acceptance Table
Harmonized withUS FDAand
PIC/Srequirements
20.10.2009 Dr. Martin Melzer 25
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 26
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic ElementsSterilisation 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 room classification� 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 ElementsAseptical filling
� Filter 0.22 µm� Filter integrity test before & after use
20.10.2009 Dr. Martin Melzer 29
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 30
Staatliches Gewerbeaufsichtsamt Hannover
EU GMP Annex 1- Basic ElementsFinishing
� 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- 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 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
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Staatliches Gewerbeaufsichtsamt Hannover
Thank you !
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Staatliches Gewerbeaufsichtsamt Hannover
Link to documents
The Rules Governing Medicinal Products in the European Unionhttp://ec.europa.eu/enterprise/pharmaceuticals/eudralex/eudralex_en.htm
EU GMPhttp://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol4_en.htm
PIC/ Shttp://www.picscheme.org/
FDA (Aseptic Processing guide)http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM070342.pdf
