Foreword
1 Introduction
2 Scope
3 Normative references
4 Definitions
5 Quality management systems
6 Personnel
6.1 Personnel management
6.2 Training and APA qualification
6.3 General employee health
6.4 Monitoring of personnel
6.5 Gowning training
6.6 Gowning requirements
6.7 Control of gowned personnel
7 Premises: conventional cleanrooms
7.1 Facility design features
7.2 Facility design review
7.3 Material flow
7.4 Aseptic processing area (APA)
7.5 Critical processing zones
7.6 Other processing zones
7.7 Support areas outside the APA
7.8 Environmental air systems and controls
7.9 Clean room design
7.10 Preparation areas
8 Premises: isolator technology
9 Process-related media
9.1 Water
9.2 Other media
10 Qualification of equipment and utilities, and process validation
10.1 General
10.2 Qualification and validation of processing equipment
10.3 Validation of sterilization of equipment product
contact surfaces
10.4 Qualification and validation of process related utilities
10.5 Qualification and requalification; validation and
revalidation
11 Processes
11.1 Cleaning and disinfection of the APA
11.2 Bioburden
11.3 Depyrogenation
11.4 Sterilization, assembly and use of filling equipment
and utensils
11.5 Clean in place (CIP)
11.6 Steam in place (SIP)
11.7 Feeding sterilized container components and product
to the filling line
11.8 Sterile filtration
11.9 Aseptically-produced suspensions
11.10 Filling process: interventions, rejects
11.11 Freeze drying
11.12 Sealing and final packaging
12 Environmental monitoring and controls
12.1 Particulate monitoring programme
12.2 Microbiological monitoring programme
12.3 Environmental monitoring trend analysis
12.4 Investigation and reports
13 Media fills (process simulation tests)
14 Finished product sterility testing
14.1 General
14.2 Investigation of sterility test positives
14.3 Sampling plans
15 Product release
Annex A (Normative) Isolator technology
A.1 Types of isolator
A.2 Transfer systems
A.3 Surrounding premises
A.4 Gloves, gauntlets, suits and half-suits
A.5 Pressure differentials
A.6 Cleaning of isolators
A.7 Sterilization of internal atmosphere by filtration
A.8 Pressure differential
A.9 Air change rate
A.10 Sterilization of Isolator internal surfaces by
microbicidal gas
A.11 Qualification
A.12 Monitoring
A.13 Alarms
A.14 Maintenance and requalification
A.15 Product release
Annex B (Informative) Aseptically-prepared suspensions
B.1 General
B.2 Media fill considerations
Annex C (Normative) Freeze drying
C.1 General
C.2 Validation
C.3 Freeze drying process control parameters
C.4 Process routing
C.5 Open containers and stoppers
C.6 Transport to freeze dryer
C.7 Unloading and transport to sealing equipment
C.8 Cleaning and disinfection of freeze dryer
C.9 Frequency
C.10 Vent filter system
C.11 Environmental monitoring and controls
C.12 Special media fill concerns for freeze drying
C.13 Maintenance
Annex D (Normative) Media fills (process simulation tests)
D.1 Initial performance qualification
D.2 Periodic performance requalification
D.3 Repeat of initial performance qualification
D.4 Media fill procedures
D.5 Media selection and growth support
D.6 Incubation and inspection of filled media units
D.7 Acceptance criteria
D.8 Contamination with media
D.9 Data required for media fills
D.10 Media fill runs exceeding action levels
Annex E (Informative) Derivation of contamination rate
calculations for a given number of media filled units
Annex F (Informative) Bibliography
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