ISO/TS 13004:2013
(Main)Sterilization of health care products — Radiation — Substantiation of selected sterilization dose: Method VDmaxSD
Sterilization of health care products — Radiation — Substantiation of selected sterilization dose: Method VDmaxSD
ISO/TS 13004:2013 describes a method for substantiating a selected sterilization dose of 17,5, 20, 22,5, 27,5, 30, 32,5 or 35 kGy that achieves a sterility assurance level (SAL) of 10−6 or less for radiation sterilization of health care products. ISO/TS 13004:2013 also specifies a method of sterilization dose audit used to demonstrate the continued effectiveness of the substantiated sterilization dose.
Stérilisation des produits de santé — Irradiation — Justification de la dose de stérilisation choisie: méthode VDmaxSD
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Standards Content (Sample)
TECHNICAL ISO/TS
SPECIFICATION 13004
First edition
2013-05-01
Sterilization of health care products —
Radiation — Substantiation of selected
SD
sterilization dose: Method VD
max
Stérilisation des produits de santé — Irradiation — Justification de la
SD
dose de stérilisation choisie: méthode VD
max
Reference number
ISO/TS 13004:2013(E)
©
ISO 2013
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ISO/TS 13004:2013(E)
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ii © ISO 2013 – All rights reserved
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ISO/TS 13004:2013(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
1.1 Inclusions . 1
1.2 Exclusions . 1
1.3 Application . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Definition and maintenance of product families for sterilization dose substantiation and
sterilization dose auditing . 5
4.1 General . 5
4.2 Defining product families . 5
4.3 Designation of product to represent a product family . 6
4.4 Maintaining product families . 7
4.5 Consequence of failure of sterilization dose substantiation or sterilization dose audit . 8
5 Selection and testing of product for substantiating and auditing a selected
sterilization dose. 8
5.1 Nature of product . 8
5.2 Sample item portion (SIP) . 9
5.3 Manner of sampling .10
5.4 Microbiological testing .11
5.5 Irradiation .11
SD
6 Method VD — Substantiation of a selected sterilization dose of 17,5, 20, 22,5, 27,5,
max
30, 32,5, or 35 kGy .11
6.1 Rationale.11
SD
6.2 Procedure for Method VD for multiple production batches .12
max
SD
6.3 Procedure for Method VD for a single production batch .17
max
7 Maintaining process effectiveness .21
7.1 General .21
7.2 Determination of bioburden .22
7.3 Sterilization dose audit .22
SD
8 Tables of values for SIP equal to 1,0 VD , SIP dose reduction factor and augmentation
max
dose corresponding to applicable values of average bioburden for selected sterilization
doses of 17,5, 20, 22,5, 27,5, 30, 32,5 and 35 kGy .27
9 Worked examples .53
9.1 Substantiation of a selected sterilization dose of 17,5 kGy (SIP less than 1,0) .53
9.2 Substantiation of a selected sterilization dose of 30 kGy (SIP equal to 1,0) .54
22,5
9.3 Sterilization dose audit for a sterilization dose substantiated using Method VD , the
max
findings from which necessitated augmentation of the sterilization dose .55
Bibliography .57
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ISO/TS 13004:2013(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.
In other circumstances, particularly when there is an urgent market requirement for such documents, a
technical committee may decide to publish other types of normative document:
— an ISO Publicly Available Specification (ISO/PAS) represents an agreement between technical
experts in an ISO working group and is accepted for publication if it is approved by more than 50 %
of the members of the parent committee casting a vote;
— an ISO Technical Specification (ISO/TS) represents an agreement between the members of a
technical committee and is accepted for publication if it is approved by 2/3 of the members of the
committee casting a vote.
An ISO/PAS or ISO/TS is reviewed after three years in order to decide whether it will be confirmed for
a further three years, revised to become an International Standard, or withdrawn. If the ISO/PAS or
ISO/TS is confirmed, it is reviewed again after a further three years, at which time it must either be
transformed into an International Standard or be withdrawn.
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/TS 13004 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
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ISO/TS 13004:2013(E)
Introduction
This Technical Specification is intended to be used in conjunction with 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. One of the activities encompassed within process definition in ISO 11137-1 is
the option to select and substantiate a sterilization dose to be applied to health care products.
ISO 11137-2 includes Method VD for the substantiation of 25 kGy as a sterilization dose (termed
max
25 15
Method VD ) for product with an average bioburden less than or equal to 1 000 and Method VD
max max
for the substantiation of 15 kGy as a sterilization dose for product with an average bioburden less than
or equal to 1,5.
This Technical Specification extends the methods of selection and substantiation of a sterilization dose
specified in ISO 11137-2. It provides a methodology for the substantiation of selected sterilization doses
of 17,5, 20, 22,5, 27,5, 30, 32,5 and 35 kGy, each of which is valid only for a specified upper limit of
average bioburden.
NOTE Selected sterilization doses of 25 kGy and 15 kGy are not included in this Technical Specification. The
seven methods in this Technical Specification follow the same technical steps as the methods given in ISO 11137-2
for selection and substantiation of sterilization doses of 25 kGy and 15 kGy. However, the descriptive text in this
Technical Specification has been modified to better communicate the methods and hence the text occasionally
differs from that in ISO 11137-2.
The method described in this Technical Specification is for substantiation of a selected sterilization dose
−6 20
to achieve a sterility assurance level (SAL) of 10 or less at that dose, (e.g. Method VD for a selected
max
sterilization dose of 20 kGy). The application of the method is not limited by production batch size or
production frequency, and the number of product items irradiated in the verification dose experiment
remains constant. The method is founded on and embodies the following three principles:
— existence of a direct link between the outcome of the verification dose experiment and the attainment
−6
of an SAL of 10 at the selected sterilization dose;
— possession of a level of conservativeness at least equal to that of the standard distribution of
resistances (SDR);
— for a given bioburden, use of a maximal verification dose (VD ) corresponding to substantiation
max
of a selected sterilization dose.
[6]
This approach to sterilization dose substantiation was first outlined by Kowalski and Tallentire and,
[7]
from subsequent evaluations involving computational techniques (Kowalski, Aoshuang and Tallentire )
[8]
and field evaluations (Kowalski et al ), it was concluded that the method is soundly based. An overview
[9][10]
of the method and aspects of putting it into practice are provided in Kowalski and Tallentire.
Application of the Method VD approach to doses other than 25 kGy is discussed in Kowalski and
max
[11][12]
Tallentire.
SD
The method described here and designated Method VD procedurally comprises elements that
max
closely parallel those of dose setting Method 1 described in ISO 11137-2. One key area of difference is the
number of product items used in the verification dose experiment. In the computer evaluations referred
to above, changing the verification SAL value had little effect on the substantiation outcome and this
finding led to a sample size of 10 product items being chosen for subsequent field evaluations and,
ultimately, for inclusion in this document.
Manufacturers of health care products who intend to use this specification are reminded that the
requirements contained in ISO 11137 apply to the manufacture and control of production batches
destined for radiation sterilization. In particular, one requirement states that products have to be
manufactured in circumstances such that the bioburden is controlled. Compliance with the requirements
for controlling the quality of raw materials, the manufacturing environment, the health, hygiene and
attire of personnel and for establishing the basic properties of packaging material is essential.
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TECHNICAL SPECIFICATION ISO/TS 13004:2013(E)
Sterilization of health care products — Radiation —
Substantiation of selected sterilization dose: Method
SD
VD
max
1 Scope
1.1 Inclusions
This Technical Specification describes a method for substantiating a selected sterilization dose of 17,5,
−6
20, 22,5, 27,5, 30, 32,5 or 35 kGy that achieves a sterility assurance level (SAL) of 10 or less for radiation
sterilization of health care products. This Technical Specification also specifies a method of sterilization
dose audit used to demonstrate the continued effectiveness of the substantiated sterilization dose.
NOTE Selection and substantiation of the sterilization dose is used to meet the requirements for establishing
the sterilization dose within process definition in ISO 11137-1.
1.2 Exclusions
This method is for the substantiation of a selected sterilization dose of 17,5, 20, 22,5, 27,5, 30, 32,5,
or 35 kGy only and is not used to substantiate other sterilization doses. The method is not used for
the substantiation of a selected sterilization dose if the average bioburden of the entire product item
exceeds the limit specified for the selected sterilization dose (see Table 3).
NOTE The methods for substantiation of selected sterilization doses of 25 kGy and 15 kGy are not included in
this Technical Specification; they are described in ISO 11137-2.
1.3 Application
If the decision is made to use this method of sterilization dose establishment, the method is to be followed
according to the requirements (shall) and guidance (should) stipulated herein.
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 11137-1:2006, Sterilization of health care products — Radiation — Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices
ISO 11737-1, Sterilization of medical devices — Microbiological methods — Part 1: Determination of a
population of microorganisms on products
ISO 11737-2, Sterilization of medical devices — Microbiological methods — Part 2: Tests of sterility
performed in the definition, validation and maintenance of a sterilization process
3 Terms and definitions
For the purposes of this document, the following abbreviations, terms and definitions apply.
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ISO/TS 13004:2013(E)
3.1
batch
defined quantity of product, intended or purported to be uniform in character and quality, that has been
produced during a defined cycle of manufacture
[SOURCE: ISO/TS 11139:2006, 2.1]
3.2
bioburden
population of viable microorganisms on or in product and/or sterile barrier system
[SOURCE: ISO/TS 11139:2006, 2.2]
3.3
correction
action to eliminate a detected nonconformity
Note 1 to entry: A correction can be made in conjunction with corrective action (3.4).
[SOURCE: ISO 9000:2005, 3.6.6, modified]
3.4
corrective action
action to eliminate the cause of a detected nonconformity or other undesirable situation
Note 1 to entry: There can be more than one cause for a nonconformity.
Note 2 to entry: Corrective action is taken to prevent recurrence whereas preventive action is taken to
prevent occurrence.
Note 3 to entry: There is a distinction between correction and corrective action.
[SOURCE: ISO 9000:2005, 3.6.5]
3.5
dose
absorbed dose
quantity of ionizing radiation energy imparted per unit mass of specified material
Note 1 to entry: The unit of absorbed dose is the gray (Gy), where 1 Gy is equivalent to the absorption of 1 J/kg.
Note 2 to entry: For the purposes of this document, the term dose is used to mean absorbed dose.
[SOURCE: ISO 11137-1:2006, 3.1, modified]
3.6
dose mapping
measurement of dose distribution and variability in material irradiated under defined conditions
[SOURCE: ISO 11137-1:2006, 3.10]
3.7
false positive
test result interpreted as growth arising from product, or portion thereof, tested when either growth
resulted from extraneous microbial contamination or turbidity occurred from interaction between the
product, or portion thereof, and the test medium
[SOURCE: ISO 11137-2:2012, 3.1.3]
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ISO/TS 13004:2013(E)
3.8
health care product(s)
medical device(s), including in vitro diagnostic medical device(s), or medicinal product(s), including
biopharmaceutical(s)
[SOURCE: ISO/TS 11139:2006, 2.20]
3.9
medical device
instrument, apparatus, implement, machine, appliance, implant, in vitro reagent or calibrator, software,
material, or other related article intended by the manufacturer to be used, alone or in combination, for
human beings for one or more of the specific purpose(s) of:
— diagnosis, prevention, monitoring, treatment, or alleviation of disease;
— diagnosis, monitoring, treatment, alleviation of or compensation for an injury;
— investigation, replacement, modification, or support of the anatomy or of a physiological process;
— supporting or sustaining life;
— control of conception;
— disinfection of medical devices;
— providing information for medical purposes by means of in vitro examination of specimens derived
from the human body;
and which does not achieve its primary intended action in or on the human body by pharmacological,
immunological or metabolic means, but which may be assisted in its function by such means
Note 1 to entry: This definition from ISO 13485 has been developed by the Global Harmonization Task Force
(GHTF 2002)
[SOURCE: ISO 13485:2003, 3.7, modified]
3.10
Method VD
max
procedure for sterilization dose substantiation that uses the maximal verification dose for a given
−6
bioburden, consistent with the attainment of a SAL of 10 at a selected sterilization dose
SD
Note 1 to entry: The substantiation method is generally referred to as Method VD , where SD takes the value
max
of the selected sterilization dose.
3.11
microorganism
entity of microscopic size, encompassing bacteria, fungi, protozoa and viruses
Note 1 to entry: A specific standard might not require demonstration of the effectiveness of the sterilization
process in inactivating all types of microorganisms, identified in the definition above, for validation and/or
routine control of the sterilization process.
[SOURCE: ISO/TS 11139:2006, 2.26]
3.12
packaging system
combination of the sterile barrier system and protective packaging
[SOURCE: ISO/TS 11139:2006, 2.28]
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ISO/TS 13004:2013(E)
3.13
positive test of sterility
test result for which there is detectable microbial growth from product, or portion thereof, subjected to
a test of sterility
[SOURCE: ISO 11137-2:2012, 3.1.8]
3.14
product
result of a process
Note 1 to entry: For the purposes of sterilization standards, product is tangible and can be raw material(s),
intermediate(s), sub-assembly(ies) or health care product(s)
[SOURCE: ISO 9000:2005, 3.4.2, modified]
3.15
sample item portion
SIP
defined portion of a health care product that is tested
[SOURCE: ISO 11137-2:2012, 3.1.9]
3.16
sterile barrier system
minimum package that prevents ingress of microorganisms and allows aseptic presentation of product
at the point of use
[SOURCE: ISO/TS 11139:2006, 2.44]
3.17
sterility
state of being free from viable microorganisms
Note 1 to entry: In practice, no such absolute statement regarding the absence of microorganisms can be proven
[see sterilization (3.19)].
[SOURCE: ISO/TS 11139:2006, 2.45]
3.18
sterility assurance level
SAL
probability of a single viable microorganism occurring on an item after sterilization
−6 −3
Note 1 to entry: The term SAL takes a quantitative value, generally 10 or 10 . When applying this quantitative
−6
value to assurance of sterility, an SAL of 10 has a lower value but provides a greater assurance of sterility than
−3
an SAL of 10 .
[SOURCE: ISO/TS 11139:2006, 2.46]
3.19
sterilization
validated process used to render product free from viable microorganisms
Note 1 to entry: In a sterilization process, the nature of microbial inactivation is exponential and thus the survival
of a microorganism on an individual item can be expressed in terms of probability. While this probability can be
reduced to a very low number it can never be reduced to zero [see sterility assurance level (3.18)].
[SOURCE: ISO/TS 11139:2006, 2.47]
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ISO/TS 13004:2013(E)
3.20
sterilization dose
SD
dose selected to achieve the specified requirements for sterility
[SOURCE: ISO 11137-1:2006, 3.40, modified]
3.21
sterilization dose audit
exercise undertaken to confirm the appropriateness of an established sterilization dose
[SOURCE: ISO 11137-2:2012, 3.2.12]
3.22
test of sterility
technical operation performed as part of development, validation or requalification to determine the
presence or absence of viable microorganisms on product or portion thereof
[SOURCE: ISO/TS 11139:2006, 2.54]
3.23
verification dose
−2
dose predicted to give a predetermined SAL greater than or equal to 10 used in establishing the
sterilization dose
−1
Note 1 to entry: For the purpose of this Technical Specification, this predetermined SAL is 10 .
3.24
SD
VD
max
SD
maximal verification dose for a particular selected sterilization dose (SD) obtained in using Method VD
max
4 Definition and maintenance of product families for sterilization dose substan-
tiation and sterilization dose auditing
4.1 General
The establishment of a sterilization dose, for which sterilization dose selection and substantiation can
be undertaken, and the carrying out of sterilization dose audits are activities that are part of process
definition and maintaining process effectiveness (see ISO 11137-1). For these activities, product may
be grouped into families; definition of product families is based principally on the numbers and types
of microorganisms on or in product (the bioburden), the type being indicative of the microorganism’s
resistance to radiation (see ISO 11737-1). Variables such as density and product configuration within its
packaging system are not considered in the establishment of these product families because they are
not factors that influence bioburden.
In using product families for establishing the sterilization dose and for carrying out sterilization dose
audits, it is important to be aware of the reduction in the ability to detect an inadvertent change within
the manufacturing process that influences the effectiveness of sterilization. Furthermore, with the use
of a single product to represent the product family, changes that occur in other members of the product
family might not be detected. The effect of a reduction on ability to detect changes in other members
of the product family should be evaluated and a plan for maintaining product families developed and
implemented before proceeding.
4.2 Defining product families
4.2.1 The criteria for defining a product family shall be documented. Product shall be assessed against
these criteria and the similarities between potential product family members considered. Consideration
shall include all product-related variables that affect bioburden, including, but not limited to:
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ISO/TS 13004:2013(E)
a) nature and sources of raw materials, including the effect, if any, of raw materials that might be
sourced from more than one location;
b) components;
c) product design and size;
d) manufacturing processes;
e) manufacturing equipment;
f) manufacturing environment;
g) manufacturing location.
The outcome of the assessment and considerations shall be recorded (see 4.1.2 of ISO 11137-1:2006).
4.2.2 Product shall only be included in a product family if it is demonstrated that the product-related
variables (see 4.2.1) are similar and under control.
4.2.3 To include product within a product family, it shall be demonstrated that bioburden comprises
similar numbers and types of microorganisms.
4.2.4 Inclusion of product from more than one manufacturing location in a product family shall be
specifically justified and recorded (see 4.1.2 of ISO 11137-1:2006). Consideration shall be given to the
effect on bioburden of:
a) geographic and/or climatic differences between locations;
b) any differences in the control of the manufacturing processes or environment;
c) sources of raw materials and processing adjuvants (e.g. water).
4.3 Designation of product to represent a product family
4.3.1 Product to represent a product family
4.3.1.1 The number and types of microorganisms on or in product shall be used as the basis for selecting
product to represent a product family.
4.3.1.2 A product family shall be represented by:
a) a master product (see 4.3.2), or
b) an equivalent product (see 4.3.3), or
c) a simulated product (see 4.3.4).
4.3.1.3 A formal, documented assessment shall be undertaken to decide which of the three potential
representative products in 4.3.1.2 is appropriate. In this assessment, consideration shall be given to
the following:
a) number of microorganisms comprising the bioburden;
b) types of microorganisms comprising the bioburden;
c) environment in which the microorganisms occur;
d) size of product;
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ISO/TS 13004:2013(E)
e) number of components;
f) complexity of product;
g) degree of automation during manufacture;
h) manufacturing environment.
4.3.2 Master product
A member of a product family shall only be considered a master product if assessment (see 4.3.1.3)
indicates that the member presents a challenge to the sterilization process that is greater than that of
all other product family members. In some situations, there can be several products within the product
family, each of which could be considered as the master product. In such circumstances, any one of these
products may be selected as the master product to represent the family, either
a) at random, or
b) according to a documented procedure to include the different products each of which could be
considered as the master product.
4.3.3 Equivalent product
A group of product shall only be considered equivalent if assessment (see 4.3.1.3) indicates that group
members require the same sterilization dose. Selection of the equivalent product to represent the family
shall be either a) at random, or b) according to a documented procedure to include different members of
the product family. The manufacturing volume
...
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