Aseptic processing of health care products – Part 1: General requirements (ISO 13408-1:2008)

Abstract

ISO 13408-1:2008 specifies the general requirements for, and offers guidance on, processes, programmes and procedures for development, validation and routine control of the manufacturing process for aseptically-processed health care products.

ISO 13408-1:2008 includes requirements and guidance relative to the overall topic of aseptic processing. Specific requirements and guidance on various specialized processes and methods related to filtration, lyophilization, clean-in place (CIP) technologies, sterilization in place (SIP) and isolator systems are given in other parts of ISO 13408.

DIN EN ISO 13408-1:2013-08 (E)
Aseptic processing of health care products – Part 1: General requirements (ISO
13408-1:2008 + Amd 1:2013 ) (includes Amendment A1:2013)
Contents Page
Introduction …………………………………………………………………………………………………………………………………… 6
1 Scope …………………………………………………………………………………………………………………………….. 8
2 Normative references …………………………………………………………………………………………………….. 8
3 Terms and definitions …………………………………………………………………………………………………….. 9
4 Quality system elements ………………………………………………………………………………………………. 14
4.1 General ………………………………………………………………………………………………………………………… 14
4.2 Assignment of responsibilities ……………………………………………………………………………………… 14
4.3 Calibration ……………………………………………………………………………………………………………………. 14
5 Aseptic process definition ……………………………………………………………………………………………. 15
5.1 General ………………………………………………………………………………………………………………………… 15
5.2 Risk management …………………………………………………………………………………………………………. 15
6 Manufacturing environment ………………………………………………………………………………………….. 17
6.1 General ………………………………………………………………………………………………………………………… 17
6.2 Manufacturing environment design ………………………………………………………………………………. 18
6.3 Layout ………………………………………………………………………………………………………………………….. 19
6.4 Material and personnel flow ………………………………………………………………………………………….. 21
6.5 HVAC system ……………………………………………………………………………………………………………….. 22
6.6 Cleanroom qualification ……………………………………………………………………………………………….. 24
6.7 Utility services and ancillary equipment ……………………………………………………………………….. 24
6.8 Environmental and personnel monitoring programmes …………………………………………………. 24
7 Equipment ……………………………………………………………………………………………………………………. 28
7.1 Qualification …………………………………………………………………………………………………………………. 28
7.2 Maintenance of equipment ……………………………………………………………………………………………. 30
8 Personnel …………………………………………………………………………………………………………………….. 30
8.1 General ………………………………………………………………………………………………………………………… 30
8.2 Training for APA qualification ………………………………………………………………………………………. 31
8.3 Gowning procedures ……………………………………………………………………………………………………. 32
8.4 General employee health ………………………………………………………………………………………………. 33
9 Manufacture of the product …………………………………………………………………………………………… 34
9.1 Attainment and maintenance of sterility ………………………………………………………………………… 34
9.2 Duration of the manufacturing process …………………………………………………………………………. 34
9.3 Aseptic manufacturing procedures ……………………………………………………………………………….. 35
9.4 Cleaning and disinfection of facilities ……………………………………………………………………………. 35
9.5 Cleaning, disinfection and sterilization of equipment …………………………………………………….. 37
10 Process simulation ………………………………………………………………………………………………………. 38
10.1 General ………………………………………………………………………………………………………………………… 38
10.2 Media selection and growth support ……………………………………………………………………………… 39
10.3 Simulation procedures …………………………………………………………………………………………………. 39
10.4 Incubation and inspection of media filled units ……………………………………………………………… 40
10.5 Initial performance qualification ……………………………………………………………………………………. 40
10.6 Periodic performance requalification …………………………………………………………………………….. 41

10.7 Repeat of initial performance qualification ……………………………………………………………………. 42
10.8 Documentation of process simulations ………………………………………………………………………… 42
10.9 Disposition of filled product …………………………………………………………………………………………. 43
11 Test for sterility ……………………………………………………………………………………………………………. 44
11.1 General ……………………………………………………………………………………………………………………….. 44
11.2 Investigation of positive units from tests for sterility …………………………………………………….. 44
Annex A (informative) Example of a flow chart …………………………………………………………………………….. 45
Annex B (informative) Typical elements of an aseptic process definition ……………………………………… 46
Annex C (informative) Examples of specific risks ………………………………………………………………………… 47
Annex D (informative) Comparison of classification of cleanrooms ……………………………………………… 48
Annex E (informative) Specification for water used in the process ……………………………………………….. 49
Annex F (informative) Aseptic processing area ……………………………………………………………………………. 51
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices ………… 52
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on Medical Devices ……………………………………….. 53
Annex ZC (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 98/79/EC on in vitro diagnostic medical devices …………….. 54
Bibliography ……………………………………………………………………………………………………………………………….. 55

Aseptic processing of health care products – Part 2: Filtration (ISO 13408-2:2003)

Abstract

ISO 13408-2:2003 specifies requirements for sterilizing filtration as part of aseptic processing of health care products. It also offers guidance to filter users concerning general requirements for set-up, validation and routine operation of a sterilizing filtration process, to be used for aseptic processing of health care products.

ISO 13408-2:2003 is not applicable to removal of viruses. Sterilizing filtration is not applicable to fluids containing particles as effective ingredient larger than the pore size of a filter (e.g. bacterial whole-cell vaccines).

DIN EN ISO 13408-2:2011-09 (E)
Aseptic processing of health care products – Part 2: Filtration (ISO 13408-2:2003)
Contents Page
Foreword ……………………………………………………………………………………………………………………………………….3
Introduction ……………………………………………………………………………………………………………………………………4
1 Scope ……………………………………………………………………………………………………………………………..5
2 Normative references ……………………………………………………………………………………………………..5
3 Terms and definitions ……………………………………………………………………………………………………..5
4 General requirements ……………………………………………………………………………………………………..7
5 Selection of filters and filter assemblies based on filter manufacturer’s data ……………………7
6 Fluid-specific selection criteria based on filter user’s data ……………………………………………….7
7 Filtration process ……………………………………………………………………………………………………………8
7.1 Process parameters ………………………………………………………………………………………………………..8
7.2 Validation of fluid-specific microbial retention by filters …………………………………………………..9
8 Filtration system design ………………………………………………………………………………………………..11
9 Routine process ……………………………………………………………………………………………………………12
10 Process documentation ………………………………………………………………………………………………..12
11 Maintenance and change control …………………………………………………………………………………..13
12 Operator training …………………………………………………………………………………………………………..13
Annex A (informative) Basic information and quality certificates for filter cartridges ……………………..14
Bibliography …………………………………………………………………………………………………………………………………18

Aseptic processing of health care products – Part 3: Lyophilization (ISO 13408-3:2006)

Abstract

ISO 13408-3:2006 specifies requirements for, and offers guidance on, equipment, processes, programmes and procedures for the control and validation of lyophilization as an aseptic process. It does not address the physical/chemical objectives of a lyophilization process.

DIN EN ISO 13408-3:2011-09 (E)
Aseptic processing of health care products – Part 3: Lyophilization (ISO 13408-
3:2006)
Contents Page
Foreword ……………………………………………………………………………………………………………………………………….3
Introduction ……………………………………………………………………………………………………………………………………4
1 Scope ……………………………………………………………………………………………………………………………..5
2 Normative references ……………………………………………………………………………………………………..5
3 Terms and definitions ……………………………………………………………………………………………………..5
4 Quality system elements …………………………………………………………………………………………………5
4.1 General …………………………………………………………………………………………………………………………..5
4.2 Management responsibility ……………………………………………………………………………………………..6
4.3 Design control ………………………………………………………………………………………………………………..6
4.4 Measuring instruments and/or measuring systems ………………………………………………………….6
5 Product definition ……………………………………………………………………………………………………………6
6 Process definitions …………………………………………………………………………………………………………6
7 User requirements …………………………………………………………………………………………………………..7
7.1 General …………………………………………………………………………………………………………………………..7
7.2 Equipment characterization ………………………………………………………………………………………………
7.3 Product handling …………………………………………………………………………………………………………….8
7.4 Microbiological and particulate environmental monitoring ……………………………………………….8
7.5 Cleaning and sterilization ………………………………………………………………………………………………..8
7.6 Vent filter system ……………………………………………………………………………………………………………9
7.7 Lyophilizer leak test ………………………………………………………………………………………………………..9
8 Validation ……………………………………………………………………………………………………………………….9
8.1 General …………………………………………………………………………………………………………………………..9
8.2 Design qualification ………………………………………………………………………………………………………10
8.3 Installation qualification ………………………………………………………………………………………………..10
8.4 Operational qualification ……………………………………………………………………………………………….10
8.5 Performance qualification ……………………………………………………………………………………………..12
8.6 Process validation …………………………………………………………………………………………………………12
8.7 Review and approval of validation …………………………………………………………………………………13
9 Routine monitoring and control …………………………………………………………………………………….13
9.1 General …………………………………………………………………………………………………………………………13
9.2 Operator training …………………………………………………………………………………………………………..13
9.3 Standard operating procedures ……………………………………………………………………………………..13
9.4 Requalification ………………………………………………………………………………………………………………14
9.5 Maintenance of equipment …………………………………………………………………………………………….14
9.6 Change control ……………………………………………………………………………………………………………..14
Bibliography …………………………………………………………………………………………………………………………………18
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices ………….15

Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on Medical Devices ……………………………………….. 16
Annex ZC (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 98/79/EC on in vitro diagnostic medical devices …………….. 17

Aseptic processing of health care products – Part 6: Isolator systems (ISO 13408-6:2005)

Abstract

ISO 13408-6:2005 specifies the requirements for isolator systems used for aseptic processing and offers guidance on qualification, bio-decontamination, validation, operation and control of isolator systems used for aseptic processing of health care products.

ISO 13408-6:2005 is focused on the use of isolator systems to maintain aseptic conditions; this may include applications for hazardous materials.

ISO 13408-6:2005 does not supersede or replace national regulatory requirements, such as Good Manufacturing Practices (GMPs) and/or compendial requirements that pertain in particular to national or regional jurisdictions.

DIN EN ISO 13408-6:2013-07 (E)
Aseptic processing of health care products – Part 6: Isolator systems (ISO 13408-
6:2005 + Amd 1:2013) (includes Amendment A1:2013)
Contents Page
Introduction …………………………………………………………………………………………………………………………………… 5
1 Scope …………………………………………………………………………………………………………………………….. 6
2 Normative references …………………………………………………………………………………………………….. 6
3 Terms and definitions …………………………………………………………………………………………………….. 6
4 Quality system elements ………………………………………………………………………………………………… 7
4.1 General ………………………………………………………………………………………………………………………….. 7
4.2 Management responsibility …………………………………………………………………………………………….. 7
4.3 Design control ……………………………………………………………………………………………………………….. 8
4.4 Measuring instruments and measuring systems …………………………………………………………….. 8
5 Design of isolator systems …………………………………………………………………………………………….. 8
5.1 General ………………………………………………………………………………………………………………………….. 8
5.2 Types of isolators …………………………………………………………………………………………………………… 8
5.3 Materials of construction ……………………………………………………………………………………………….. 8
5.4 Air-handling system ……………………………………………………………………………………………………….. 9
5.5 Operator interface ………………………………………………………………………………………………………… 10
5.6 Ancillary equipment ……………………………………………………………………………………………………… 10
6 Facility requirements ……………………………………………………………………………………………………. 11
6.1 Surrounding room classification …………………………………………………………………………………… 11
6.2 Process utilities ……………………………………………………………………………………………………………. 11
7 User requirements ………………………………………………………………………………………………………… 11
7.1 Product/process application …………………………………………………………………………………………. 11
7.2 Ergonomics ………………………………………………………………………………………………………………….. 11
7.3 Cleaning ………………………………………………………………………………………………………………………. 12
7.4 Bio-decontamination …………………………………………………………………………………………………….. 12
8 Validation …………………………………………………………………………………………………………………….. 15
8.1 General ………………………………………………………………………………………………………………………… 15
8.2 Design qualification ……………………………………………………………………………………………………… 15
8.3 Installation qualification ……………………………………………………………………………………………….. 15
8.4 Operational qualification ………………………………………………………………………………………………. 16
8.5 Performance qualification …………………………………………………………………………………………….. 17
8.6 Review and approval of validation ………………………………………………………………………………… 18
8.7 Requalification ……………………………………………………………………………………………………………… 19
9 Routine monitoring and control ……………………………………………………………………………………. 19
9.1 Procedures …………………………………………………………………………………………………………………… 19
9.2 System integrity …………………………………………………………………………………………………………… 19
9.3 Bio-decontamination process monitoring ……………………………………………………………………… 19
9.4 Environmental monitoring ……………………………………………………………………………………………. 19
9.5 Change control …………………………………………………………………………………………………………….. 20
9.6 Maintenance and calibration …………………………………………………………………………………………. 20
10 Personnel training ………………………………………………………………………………………………………… 20

Bibliography ……………………………………………………………………………………………………………………………….. 21
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices ………… 22
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on Medical Devices ……………………………………….. 23
Annex ZC (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 98/79/EC on in vitro diagnostic medical devices …………….. 24