EN ISO 13408-1:2011

SLOVENSKI STANDARD
01-oktober-2011
1DGRPHãþD
SIST EN 13824:2005
$VHSWLþQDSURL]YRGQMDL]GHONRY]D]GUDYVWYHQRQHJRGHO6SORãQH]DKWHYH,62

Aseptic processing of health care products - Part 1: General requirements (ISO 13408-
1:2008)
Aseptische Herstellung von Produkten für die Gesundheitsfürsorge - Teil 1: Allgemeine
Anforderungen (ISO 13408-1:2008)
Traitement aseptique des produits de santé - Partie 1: Exigences générales (ISO 13408-
1:2008)
Ta slovenski standard je istoveten z: EN ISO 13408-1:2011
ICS:
11.080.01 Sterilizacija in dezinfekcija na Sterilization and disinfection
splošno in general
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

EUROPEAN STANDARD
EN ISO 13408-1
NORME EUROPÉENNE
EUROPÄISCHE NORM
June 2011
ICS 11.080.01 Supersedes EN 13824:2004
English Version
Aseptic processing of health care products - Part 1: General
requirements (ISO 13408-1:2008)
Traitement aseptique des produits de santé - Partie 1: Aseptische Herstellung von Produkten für die
Exigences générales (ISO 13408-1:2008) Gesundheitsfürsorge - Teil 1: Allgemeine Anforderungen
(ISO 13408-1:2008)
This European Standard was approved by CEN on 10 June 2011.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European
Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national
standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN member.

This European Standard exists in three official versions (English, French, German). A version in any other language made by translation
under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management Centre has the same
status as the official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland,
Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.

EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION

EUROPÄISCHES KOMITEE FÜR NORMUNG

Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2011 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 13408-1:2011: E
worldwide for CEN national Members.

Contents Page
Foreword .3
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices .4
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on Medical Devices .5
Annex ZC (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 98/79/EC on in vitro diagnostic medical devices .6

Foreword
The text of ISO 13408-1:2008 has been prepared by Technical Committee ISO/TC 198 “Sterilization of health
care products” of the International Organization for Standardization (ISO) and has been taken over as
of which is held by BSI.
This European Standard shall be given the status of a national standard, either by publication of an identical
text or by endorsement, at the latest by December 2011, and conflicting national standards shall be withdrawn
at the latest by December 2011.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN 13824:2004.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EU Directives.
For relationship with EU Directives, see informative Annexes ZA, ZB, or ZC, which are integral parts of this
document.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following
countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech
Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,
Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain,
Sweden, Switzerland and the United Kingdom.
Endorsement notice
The text of ISO 13408-1:2008 has been approved by CEN as a EN ISO 13408-1:2011 without any
modification.
Annex ZA
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical
Devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 90/385/EEC on active implantable medical devices.

Once this standard is cited in the Official Journal of the European Union under that Directive and has been
implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in Table ZA.1 confers, within the limits of the scope of this standard, a presumption of
conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations.

Table ZA.1 — Correspondence between this European Standard and Directive 90/385/EEC
Clauses of this EN Essential Requirements (ERs) of Qualifying remarks/Notes
Directive 90/385/EEC
4,5,6,7,8,9,10,11,12 7 This relevant Essential Requirement is
only partly addressed in this European
Standard
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling
within the scope of this Standard.
Annex ZB
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on Medical Devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 93/42/EEC on medical devices.

Once this standard is cited in the Official Journal of the European Union under that Directive and has been
implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in Table ZB.1 confers, within the limits of the scope of this standard, a presumption of
conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations.

Table ZB.1 — Correspondence between this European Standard and Directive 93/42/EEC
Clauses of this EN Essential Requirements (ERs) of Qualifying remarks/Notes
Directive 93/42/EEC
4,5,6,7,8,9,10,11,12 8.3 This relevant Essential Requirement is
only partly addressed in this European
Standard
4,5,6,7,8,9,10,11,12 8.4
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling
within the scope of this Standard.
Annex ZC
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directive 98/79/EC on in vitro diagnostic medical
devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 98/79/EC on in vitro diagnostic medical devices.

Once this standard is cited in the Official Journal of the European Union under that Directive and has been
implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in Table ZC.1 confers, within the limits of the scope of this standard, a presumption of
conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations.

Table ZC.1 — Correspondence between this European Standard and Directive 98/79/EC
Clauses of this EN Essential Requirements (ERs) of Qualifying remarks/Notes
Directive 98/79/EC
4,5,6,7,8,9,10,11,12 B.2.3 This relevant Essential Requirement is
only partly addressed in this European
Standard
4,5,6,7,8,9,10,11,12 B.2.4
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling
within the scope of this Standard.

INTERNATIONAL ISO
STANDARD 13408-1
Second edition
2008-06-15
Aseptic processing of health care
products —
Part 1:
General requirements
Traitement aseptique des produits de santé —
Partie 1: Exigences générales
Reference number
ISO 13408-1:2008(E)
©
ISO 2008
ISO 13408-1:2008(E)
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ii © ISO 2008 – All rights reserved

ISO 13408-1:2008(E)
Contents Page
Foreword. v
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions. 2
4 Quality system elements. 7
4.1 General. 7
4.2 Assignment of responsibilities . 7
4.3 Calibration . 7
5 Aseptic process definition. 8
5.1 General. 8
5.2 Risk management . 8
6 Manufacturing environment . 10
6.1 General. 10
6.2 Manufacturing environment design. 11
6.3 Layout . 12
6.4 Material and personnel flow . 14
6.5 HVAC system . 15
6.6 Cleanroom qualification. 17
6.7 Utility services and ancillary equipment . 17
6.8 Environmental and personnel monitoring programmes . 17
7 Equipment . 21
7.1 Qualification . 21
7.2 Maintenance of equipment . 23
8 Personnel. 23
8.1 General. 23
8.2 Training for APA qualification . 24
8.3 Gowning procedures. 25
8.4 General employee health . 26
9 Manufacture of the product . 27
9.1 Attainment and maintenance of sterility . 27
9.2 Duration of the manufacturing process .27
9.3 Aseptic manufacturing procedures . 28
9.4 Cleaning and disinfection of facilities . 28
9.5 Cleaning, disinfection and sterilization of equipment . 30
10 Process simulation. 31
10.1 General. 31
10.2 Media selection and growth support . 32
10.3 Simulation procedures. 32
10.4 Incubation and inspection of media filled units . 33
10.5 Initial performance qualification . 33
10.6 Periodic performance requalification . 34
10.7 Repeat of initial performance qualification. 35
10.8 Documentation of process simulations . 35
10.9 Disposition of filled product . 36
11 Test for sterility. 37
ISO 13408-1:2008(E)
11.1 General . 37
11.2 Investigation of positive units from tests for sterility . 37
Annex A (informative) Example of a flow chart . 38
Annex B (informative) Typical elements of an aseptic process definition . 39
Annex C (informative) Examples of specific risks . 40
Annex D (informative) Comparison of classification of cleanrooms . 41
Annex E (informative) Specification for water used in the process. 42
Annex F (informative) Aseptic processing area . 44
Bibliography . 45

iv © ISO 2008 – All rights reserved

ISO 13408-1:2008(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
(ISO member bodies). The work of preparing International Standards is normally carried out through ISO
technical committees. Each member body interested in a subject for which a technical committee has been
established has the right to be represented on that committee. International organizations, governmental and
non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the
International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 13408-1 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
This second edition cancels and replaces the first edition (ISO 13408-1:1998), which has been technically
revised. Any normative and informative clauses on subjects which have meanwhile been addressed in Part 2 to
Part 6 of ISO 13408 have been removed from this part.
ISO 13408 consists of the following parts, under the general title Aseptic processing of health care products:
⎯ Part 1: General requirements
⎯ Part 2: Filtration
⎯ Part 3: Lyophilization
⎯ Part 4: Clean-in-place technologies
⎯ Part 5: Sterilization in place
⎯ Part 6: Isolator systems
ISO 13408-1:2008(E)
Introduction
Health care products that are labelled “sterile” are prepared using appropriate and validated methods under
stringent control as part of a quality management system. For pharmaceuticals and medical devices there
might be various requirements including compliance with ISO standards, GMP regulations and
pharmacopoeial requirements.
Wherever possible, healthcare products intended to be sterile should be sterilized in their final sealed
container (terminal sterilization). ISO/TC 198 has prepared standards for terminal sterilization of health care
products by irradiation (series ISO 11137), by moist heat (ISO 17665-1), by dry heat (ISO 20857, in
preparation) and by ethylene oxide (ISO 11135-1).
When a health care product is intended to be sterile and cannot be terminally sterilized, aseptic processing
provides an alternative. Presterilization of product, product parts and/or components and all equipment
coming into direct contact with the aseptically-processed product is required. Aseptic processing intends to
maintain the sterility of the pre-sterilized components and products during assembling. The resulting product is
required to be sterile in its final container. Aseptic processing can also be used to prevent contamination of
biological product or biological systems (e.g. tissues, vaccines).
While terminal sterilization involves the control of a well-defined process of known lethality delivered to the
product and a sterility assurance level (SAL) can be extrapolated from sterilization data, this is not applicable
to aseptic processing.
Examples of applications in which aseptic processing are used include:
⎯ aseptic handling and filling of solutions, suspensions, semisolids and powders;
⎯ aseptic handling, transfer and packaging of solid products including solid medical devices;
⎯ aseptic handling, transfer and packaging of combination products;
⎯ aseptic handling of tissues or biological production systems.
Sterilization procedures which render components and/or parts sterile as a prerequisite for further aseptic
processing can be treated as separate procedures. They have to be evaluated and validated separately and it
is important that their risk of failure is minimal. The aseptic process definition encompasses all production
steps following the sterilization of product and components until the final container or package is sealed. To
keep the aseptic process definition clear and workable, this part of ISO 13408 is focused on the risks to the
maintenance of sterility.
It is important to control all possible sources of contamination in order to maintain the sterility of each and
every component. To achieve this, a risk-based aseptic process definition is established encompassing each
product and applied in a comprehensive way considering product, package design, environment and
manufacturing process designs. The product is processed in a controlled environment where microbial and
particulate levels are maintained at defined minimal levels and where human intervention is minimized.
Validated systems, adequately trained personnel, controlled environments and well-documented systematic
processes are applied to assure a sterile finished product.
The aseptic process is divided into unit operations (e.g. sterilization of product or components including sterile
filtration, assembly of components, handling and storage of sterilized product) and it is necessary that
potential sources of contamination from materials, components, product, personnel, facility, equipment and
utilities such as water systems be considered and minimized. Only if all risks of contamination have been
recognised, wherever possible minimized, eliminated or controlled and finally have been evaluated as
vi © ISO 2008 – All rights reserved

ISO 13408-1:2008(E)
acceptable, can the controls on the aseptic process be considered to be acceptable. Appropriate validation of
the specified elements of the aseptic process is needed, of which process simulation studies are an essential.
This revision of ISO 13408-1:1998 is intended to adopt this International Standard to the actual state of
technology in the field.
INTERNATIONAL STANDARD ISO 13408-1:2008(E)

Aseptic processing of health care products —
Part 1:
General requirements
1 Scope
1.1 This part of ISO 13408 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.
1.2 This part of ISO 13408 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.
NOTE This part of ISO 13408 does not supersede or replace national regulatory requirements, such as Good
Manufacturing Practices (GMPs) and/or pharmacopoeial requirements that pertain in particular national or regional
jurisdictions.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 9001, Quality management systems — Requirements
ISO 11135-1, Sterilization of health care products — Ethylene oxide — Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices
ISO 11137-1, Sterilization of health care products — Radiation — Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices
ISO 11137-2, Sterilization of health care products — Radiation — Part 2: Establishing the sterilization dose
ISO 13408-2, Aseptic processing of health care products — Part 2: Filtration
ISO 13408-3, Aseptic processing of health care products — Part 3: Lyophilization
ISO 13408-4, Aseptic processing of health care products — Part 4: Clean-in-place technologies
ISO 13408-5, Aseptic processing of health care products — Part 5: Sterilization in place
ISO 13408-6, Aseptic processing of health care products — Part 6: Isolator systems
ISO 13485, Medical devices — Quality management systems — Requirements for regulatory purposes
ISO 14160, Sterilization of single-use medical devices incorporating materials of animal origin — Validation
and routine control of sterilization by liquid chemical sterilants
ISO 13408-1:2008(E)
ISO 14644-1:1999, Cleanrooms and associated controlled environments — Part 1: Classification of air
cleanliness
ISO 14644-2, Cleanrooms and associated controlled environments — Part 2: Specifications for testing and
monitoring to prove continued compliance with ISO 14644-1
ISO 14644-3, Cleanrooms and associated controlled environments — Part 3: Test methods
ISO 14644-4, Cleanrooms and associated controlled environments — Part 4: Design, construction and start-
up
ISO 14644-5, Cleanrooms and associated controlled environments — Part 5: Operations
ISO 14644-7, Cleanrooms and associated controlled environments — Part 7: Separative devices (clean air
hoods, gloveboxes, isolators and mini-environments)
ISO 14698-1, Cleanrooms and associated controlled environments — Biocontamination control — Part 1:
General principles and methods
ISO 14698-2, Cleanrooms and associated controlled environments — Biocontamination control — Part 2:
Evaluation and interpretation of biocontamination data
ISO 14937, Sterilization of health care products — General requirements for characterization of a sterilizing
agent and the development, validation and routine control of a sterilization process for medical devices
ISO 14971, Medical devices — Application of risk management to medical devices
ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development,
validation and routine control of a sterilization process for medical devices
1)
ISO 20857 , Sterilization of health care products — Dry heat — Requirements for the development, validation
and routine control of a sterilization process for medical devices
2)
ICH Guidance for Industry — Q9 Quality Risk Management
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply:
3.1
action level
established microbial or particulate monitoring results requiring immediate follow-up and corrective action
3.2
airlock
room with interlocked doors designed to maintain pressure control between adjacent rooms of different
cleanliness class
3.3
alert level
established microbial or particulate monitoring results giving early warning of potential drift from normal
operating conditions which are not necessarily grounds for definitive corrective action but which could require
follow-up investigation
1) To be published.
2) Available at: http://www.ich.org
2 © ISO 2008 – All rights reserved

ISO 13408-1:2008(E)
3.4
aseptic processing
handling of sterile product, containers and/or devices in a controlled environment, in which the air supply,
materials, equipment and personnel are regulated to maintain sterility
NOTE This includes sterilization by membrane filtration which cannot be separated from the subsequent aseptic
process.
3.5
aseptic processing area
APA
facilities for aseptic processing (3.4), consisting of several zones
3.6
bioburden
population of viable microorganisms on or in product and/or sterile barrier system
[ISO/TS 11139:2006, definition 2.2]
NOTE For the purposes of aseptic processing, the bioburden of concern is that on or in the product including all
factors affecting it such as raw material, intermediates, other components and equipment.
3.7
bio-decontamination
removal of microbiological contamination or its reduction to an acceptable level
[ISO 13408-6:2005, definition 3.1]
3.8
cleaning
removal of contamination from an item to the extent necessary for further processing or for intended use
[ISO/TS 11139:2006, definition 2.7]
3.9
combination product
product comprised of drug/device, biologic/device, drug/biologic or drug/device/biologic, that are physically,
chemically, or otherwise combined or mixed and produced as a single entity
3.10
correction
action to eliminate a detected nonconformity
NOTE A correction can be made in conjunction with a corrective action.
[ISO 9000:2005; definition 3.6.6]
3.11
corrective action
action to eliminate the cause of a detected nonconformity or other undesirable situation
[ISO 9000:2005, definition 3.6.5]
NOTE 1 There can be more than one cause for a nonconformity.
NOTE 2 Corrective action is taken to prevent recurrence whereas preventive action (3.29) is taken to prevent
occurrence.
NOTE 3 There is a distinction between correction and corrective action.
NOTE 4 Corrective actions might be subject to change control.
ISO 13408-1:2008(E)
3.12
critical processing zone
location within the aseptic processing area in which product and critical surfaces are exposed to the
environment
3.13
critical surface
surface that may come into contact with or directly affect a product or its containers or closures
3.14
depyrogentation
validated process designed to remove or deactivate endotoxins
3.15
design qualification
verification that the proposed specification for the facility, equipment or system is suitable for the intended use
[ISO/TS 11139:2006, definition 2.12]
3.16
direct support zone
protective area directly surrounding a critical processing zone
3.17
disinfectant
chemical agent that is able to reduce the number of viable microorganisms
3.18
disinfection
removal, destruction or de-activation of microorganisms on objects or surfaces
[ISO 14644-5:2004;definition 3.1.4]
3.19
endotoxin
lipopolysaccharide component of the cell wall of Gram-negative bacteria which is heat stable and elicits a
variety of inflammatory responses in animals and humans
3.20
environmental isolates
microorganisms present in and/or isolated from processing or manufacturing environments
3.21
gowning procedure
defined steps to reduce the risk of contamination while putting on the protective garments needed to enter the
APA (3.5)
3.22
health care product
medical device(s), including in vitro diagnostic medical device(s), or medicinal product(s), including
biopharmaceutical(s)
[ISO/TS 11139:2006, definition 2.20]
3.23
high efficiency particulate air filter
HEPA filter
retentive matrix having a minimum particle-collection efficiency of 99,97 % (that is, a maximum particle
penetration of 0,03 % for 0,3 µm particles)
4 © ISO 2008 – All rights reserved

ISO 13408-1:2008(E)
3.24
indirect support zone
location within the aseptic processing area which protects the direct support zone
NOTE The required grade of cleanliness of the indirect support zone depends on the aseptic processing activities
performed in the indirect processing zone.
3.25
installation qualification
IQ
process of obtaining and documenting evidence that equipment has been provided and installed in
accordance with its specification
[ISO/TS 11139:2006, definition 2.22]
3.26
isolator
enclosure capable of preventing ingress of contaminants by means of physical interior/exterior separation, and
capable of being subject to reproducible interior bio-decontamination
NOTE An isolator can range in size from a small box to a large room.
3.27
operational qualification
OQ
process of obtaining and documenting evidence that installed equipment operates within predetermined limits
when used in accordance with its operational procedures
[ISO/TS 11139:2006, definition 2.27]
3.28
performance qualification
PQ
process of obtaining and documenting evidence that the equipment, as installed and operated in accordance
with operational procedures, consistently performs in accordance with predetermined criteria and thereby
yields product meeting its specification
[ISO/TS 11139:2006, definition 2.30]
3.29
preventive action
action to eliminate the cause of a potential nonconformity or other undesirable potential situation
[ISO 9000:2005, definition 3.6.4]
NOTE 1 There can be more than one cause for a potential nonconformity.
NOTE 2 Preventive action is taken to prevent occurrence whereas corrective action (3.11) is taken to prevent
recurrence.
3.30
qualification
documented process used by the health care product manufacturer to assure the reliability and capability of
equipment and/or processes before approval for use in manufacturing
NOTE Qualification of equipment and/or processes generally includes installation qualification (3.25), operational
qualification (3.27) and performance qualification (3.28).
ISO 13408-1:2008(E)
3.31
risk control
process in which decisions are made and measures implemented by which risks are reduced to, or
maintained within, specified levels
[ISO 14971:2007, definition 2.19]
3.32
separative device
equipment utilizing constructional and dynamic means to create assured levels of separation between the
inside and outside of a defined volume
NOTE Some industry-specific examples of separative devices are clean air hoods, containment enclosures,
gloveboxes, isolators and mini-environments.
[ISO 14644-7:2004, definition 3.17]
3.33
shift
scheduled period of work or production staffed by a single defined group of workers
NOTE This is usually not more than 12 h in length.
3.34
sterile
free from viable microorganisms
[ISO/TS 11139:2006, definition 2.43]
NOTE In practice, no such absolute statement regarding the absence of microorganisms can be proven,
see sterilization (3.35).
3.35
sterilization
validated process used to render a product free from viable microorganisms
[ISO/TS 11139:2006, definition 2.47]
3.36
terminal sterilization
process whereby product is sterilized within its sterile barrier system
[ISO/TS 11139:2006, definition 2.52]
3.37
ultra low penetration air filter
ULPA filter
matrix with minimum 0,3 µm particle retaining efficiency of 99,999 %
3.38
unidirectional airflow
air stream which has a defined direction
3.39
unit operation
defined chemical or physical step in a manufacturing process
NOTE See example of a flowchart in Annex A.
6 © ISO 2008 – All rights reserved

ISO 13408-1:2008(E)
3.40
validation
documented procedure for obtaining, recording and interpreting the results required to establish that a process
will consistently yield product complying with predetermined specifications
[ISO/TS 11139:2006, definition 2.55]
3.41
worst case
set of conditions that represent the greatest challenge to product integrity and safety which will be accepted
during routine production
4 Quality system elements
4.1 General
4.1.1 A quality management system, appropriate to the nature of the operations, shall be implemented to
assure control over all activities affecting aseptic processing. Unless a superseding national, regional, or
International Good Manufacturing Practice (e.g. the World Health Organization GMPs) is employed, the
quality management system shall be in conformance with the requirements of ISO 9001 and/or ISO 13485.
NOTE Guidance on selecting a suitable model is given in ISO 9004 and ISO/TR 14969.
4.1.2 Documented procedures for each phase of the development, validation, routine monitoring and
control of the aseptic process shall be prepared and implemented.
4.1.3 Documents required by this part of ISO 13408 shall be reviewed and approved by designated
personnel.
4.1.4 Records of development, validation, routine control and monitoring shall be maintained to provide
evidence of conformity to the requirements of this part of ISO 13408.
4.2 Assignment of responsibilities
4.2.1 The responsibilities and authority for implementing, performing and monitoring the procedures
described in this part of ISO 13408 shall be assigned to qualified personnel as specified in ISO 13485.
4.2.2 Management shall be responsible for ensuring that there is an adequate number of qualified
employees to perform required work and that supervision is provided. Management shall periodically review
the performance of the quality management system to assess any areas needing improvement.
4.2.3 If the requirements of this part of ISO 13408 are undertaken by separate organizations with
independent quality management systems, the responsibilities and authority of each party shall be specified.
4.3 Calibration
4.3.1 A documented procedure shall be specified for the calibration of all measuring instruments or
measuring systems.
4.3.2 The accuracy and tolerance of all measuring instruments shall be adequate for the process to be
measured.
ISO 13408-1:2008(E)
5 Aseptic process definition
5.1 General
5.1.1 Aseptic processing is an activity composed of many unit operations that need to be effectively
combined to maintain sterility.
The purpose of the aseptic process definition is to obtain a comprehensive understanding of the integration of
the different elements required. Typical elements are given in Annex B.
5.1.2 A justification for the use of aseptic processing shall be documented.
NOTE The preferred option is terminal sterilization in the final container.
5.1.3 Based on the aseptic processing definition an assessment of aseptic processing risks shall be
conducted. Methods and procedures to control these risks shall be described and implemented (see 5.2).
Residual risks shall be justified.
5.1.4 The aseptic process definition shall be reviewed after stated intervals or whenever a change occurred
that might impact the product or following a significant event (e.g. batch non-sterility).
5.1.5 The aseptic process definition shall consider the complete process and give a rationale describing
how each element involved in processing contributes to the attainment and maintenance of a sterile product.
NOTE For requirements for aseptically manufactured medical devices to be designated “sterile”, see also ISO 15223
and national or regional requirements given in, for example, EN 556-2 or ANSI/AAMI ST67:2003.
5.2 Risk management
5.2.1 General
5.2.1.1 A risk management process shall be carried out, applying ISO 14971 and/or ICH Q9.
Risks associated with the aseptic process shall be identified, assessed and controlled in order to establish
acceptance criteria for all elements of the aseptic process definition.
Compliance with the requirements as defined in Clause 6 et seq. and/or regulatory documents can be used to
demonstrate acceptability of the implemented risk control.
NOTE While this part of ISO 13408 is primarily concerned with microbiological contamination issues, there are other
contamination risks that are relevant (e.g. endotoxin, particulate and chemical contamination).
5.2.1.2 The risk management strategy shall take into account the nature of the product and its intended
clinical use. Microbiological risk management should follow the following four stages:
a) identification of contamination risks;
b) assessment of contamination risks;
c) monitoring and detection of contamination;
d) prevention of contamination.
The meas
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