Foreword
Introduction
1 Scope
2 Normative references
3 Terms and definitions
4 Quality management systems
5 Personnel
5.1 Personnel management
5.2 Training for APA qualification
5.3 General employee health
5.4 Monitoring of personnel
5.5 Gowning
5.5.1 Gowning training
5.5.2 Gowning requirements
5.5.3 Control of gowned personnel
6 Premises
7 Process-related media
7.1 Water
7.1.1 Potable water
7.1.2 Treated potable water
7.1.3 Purified water
7.1.4 Water for Injections (WFI)
7.2 Other media
7.2.1 Vacuum systems
7.2.2 Gases
7.2.3 Clean steam
8 Qualification of equipment and utilities, and process
validation
8.1 General
8.2 Requalification and revalidation
9 Processes
9.1 Cleaning and disinfection of the APA
9.1.1 Disinfectants and cleaning agents
9.1.2 Validation of disinfection procedures
9.1.3 Monitoring of cleaning and disinfection
effectiveness
9.2 Bioburden
9.3 Endotoxins
9.4 Sterilization, assembly and use of filling equipment
and utensils
9.5 Clean in place (CIP)
9.6 Steam in Place (SIP)
9.7 Feeding sterilized container components and product
to the filling line
9.8 Sterile filtration
9.8.1 Pore size rating
9.8.2 Liquid filtration
9.8.3 Gas filtration
9.9 Aseptically-produced suspensions
9.10 Filling process: interventions, rejects
9.11 Freeze drying
9.12 Sealing and final packaging
10 Environmental monitoring and controls
10.1 Particulate monitoring programme
10.2 Microbiological monitoring programme
10.2.1 General
10.2.2 Alert and action levels
10.2.3 Review of data
10.3 Environmental monitoring trend analysis
10.4 Investigations and reports
10.4.1 Investigation action plans
10.4.2 Investigation testing
10.4.3 Investigation report
11 Media fills (process simulation tests)
12 Finished product sterility testing
12.1 General
12.2 Investigation of sterility test positives
12.3 Sampling plans
13 Product release
Annex A (normative) Conventional cleanrooms
A.1 Facility design features
A.2 Facility design review
A.3 Material flow
A.4 Aseptic processing area (APA)
A.5 Critical processing zones
A.6 Other processing zones within the APA
A.7 Support areas outside the APA
A.8 Environmental air systems and controls
A.8.1 Temperature and humidity
A.8.2 Air
A.8.3 HEPA filter integrity
A.8.4 Air handling
A.9 Facility design
A.10 Preparation areas
Annex B (normative) Isolator technology
B.1 Types of isolator
B.1.1 General
B.1.2 Transfer devices used with isolators
B.2 Transfer devices
B.2.1 General
B.2.2 Classification system for transfer devices
B.3 Surrounding area
B.3.1 General
B.3.2 Siting of Isolators
B.4 Gloves, gauntlets, half suits and full suits
B.4.1 General
B.4.2 Use of gloves/gauntlets
B.4.3 Changing gloves/gauntlets
B.4.4 Use of half suits, full suits
B.5 Pressure differentials
B.6 Cleaning of isolators
B.7 Filtration of air in isolators
B.8 Pressure differential
B.9 Air change rate
B.10 Biodecontamination of isolator internal surfaces
by microbicidal gas
B.10.1 Gas contact
B.10.2 Biodecontaminant residuals
B.10.3 Isolator biodecontamination: Validation
B.11 Qualification
B.12 Monitoring
B.12.1 Particulate monitoring
B.12.2 Microbiological monitoring
B.12.3 HEPA filters
B.13 Alarms
B.14 Maintenance and requalification (see also Clause 10)
B.15 Product release
Annex C (informative) Aseptically-prepared suspensions
C.1 General
C.2 Media fill considerations
Annex D (normative) Freeze-drying
D.1 General
D.2 Validation
D.3 Gases used during the freeze-drying process
D.4 Process routing
D.5 Open containers and stoppers
D.6 Transport to freeze-dryer
D.7 Unloading and transport to sealing equipment
D.8 Cleaning and disinfection of freeze dryer
D.9 Biodecontamination of the freeze dryer
D.9.1 Frequency
D.9.2 Methods
D.10 Vent filter system
D.11 Environmental monitoring and controls
D.12 Media fills for freeze-drying
D.13 Maintenance
Annex E (normative) Media fills (process simulation tests)
E.1 Performance qualification
E.2 Performance requalification
E.3 Repeat of performance qualification
E.4 Media fill procedures
E.5 Media selection and growth support
E.6 Incubation and inspection of media filled units
E.7 Acceptance criteria
E.7.1 General
E.7.2 Acceptance criteria tables
E.8 Contamination with media
E.9 Data required for media fills
E.10 Media fill runs for which action levels
are exceeded
E.10.1 Investigation
E.10.2 Further actions
Annex F (informative) Contamination rate calculations for
a given number of media filled units
Annex ZA (informative) Clauses of this European Standard
addressing essential requirements or other provisions
of Council Directive 90/385/EEC relating to active
implantable medical devices
Annex ZB (informative) Clauses of this European Standard
addressing essential requirements or other provisions
of Council Directive 93/42/EEC relating to
medical devices
Bibliography