ISO/PRF TS 21387

TECHNICAL ISO/TS
SPECIFICATION 21387
First edition
Sterilization of medical devices —
Guidance on the requirements for the
validation and routine processing of
ethylene oxide sterilization processes
using parametric release
Stérilisation des dispositifs médicaux — Lignes directrices concernant
les exigences de validation et de traitement de routine des processus
de stérilisation à l’oxyde d’éthylène par libération paramétrique
PROOF/ÉPREUVE
Reference number
ISO/TS 21387:2020(E)
ISO 2020
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ISO/TS 21387:2020(E)
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© ISO 2020

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Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Quality management systems ................................................................................................................................................................. 2

5 Sterilization agent characterization ................................................................................................................................................ 2

6 Process and equipment characterization ................................................................................................................................... 2

6.1 General ........................................................................................................................................................................................................... 2

6.2 Process characterization ................................................................................................................................................................ 2

6.3 Equipment characterization ........................................................................................................................................................ 2

7 Product definition ............................................................................................................................................................................................... 4

7.1 General ........................................................................................................................................................................................................... 4

7.2 Product safety, quality and performance ......................................................................................................................... 4

7.3 Microbiological quality .................................................................................................................................................................... 4

8 Process definition ................................................................................................................................................................................................ 4

9 Validation ..................................................................................................................................................................................................................... 5

9.1 General ........................................................................................................................................................................................................... 5

9.2 Installation qualification ................................................................................................................................................................ 5

9.2.1 Equipment ............................................................................................................................................................................. 5

9.2.2 Installation qualification ........................................................................................................................................... 6

9.3 Operational qualification ............................................................................................................................................................... 7

9.4 Performance qualification ............................................................................................................................................................. 8

9.4.1 General...................................................................................................................................................................................... 8

9.4.2 Performance qualification — Microbiological ....................................................................................... 9

9.4.3 Performance qualification — Physical .......................................................................................................... 9

9.5 R eview and approval of validation ........................................................................................................................................ 9

10 Routine monitoring and control .......................................................................................................................................................10

11 Product release from sterilization ..................................................................................................................................................10

12 Maintaining process effectiveness ..................................................................................................................................................11

12.1 General ........................................................................................................................................................................................................11

12.2 Maintenance of equipment ........................................................................................................................................................12

12.3 Requalification .....................................................................................................................................................................................12

12.4 Assessment of change ....................................................................................................................................................................12

12.5 Assessment of equi valence ........................................................................................................................................................13

13 ISO 11135:2014, Annex A .........................................................................................................................................................................13

14 ISO 11135:2014, Annex B .........................................................................................................................................................................13

Annex A (informative) Establishing specifications for parametric release based on routine

processing data ...................................................................................................................................................................................................14

Bibliography .............................................................................................................................................................................................................................17

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This document was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.

Any feedback or questions on this document should be directed to the user’s national standards body. A

ISO 11135 includes requirements for development, validation and routine control of ethylene oxide (EO)

sterilization processes. This document is intended to be used in conjunction with ISO 11135.

ISO 11135:2014:11.1 refers to criteria for designating conformity of the sterilization process used for a

a) confirmation that the data recorded during routine processing meet the sterilization process

b) confirmation of no growth of the test organism for any biological indicator (BI) (if used).

Parametric release is the declaration of adequacy of routine processing for a validated sterilization

process based solely on measurement and documentation of physical process parameters rather than

The term BI release is used when the declaration of adequacy of the validated sterilization cycle includes

The guidance in this document is informative and is not intended as a checklist for auditors. The

guidance in this document provides examples of methods considered to be suitable as a means for

NOTE Sterilization in health care facilities differs from industrial sterilization, for example, the design of

processing areas, control of product bioburden, access to relevant expertise in EO sterilization and sterilization

equipment that might not be equipped to enable consideration of parametric release.

This guidance is intended for people who have knowledge of the principles of EO sterilization. Methods

other than those given in the guidance can be used if they are effective in achieving conformity with the

This document provides guidance on the requirements of ISO 11135 that apply when parametric release

is used to release the product after exposure to the sterilization process. It provides a path for transition

of existing cycles, as well as a path for the development and implementation of a parametric release

specification for a new cycle. Additionally, it highlights the importance and interrelationship of other

process factors, i.e. load configuration and equipment performance, which influence reproducibility of

NOTE For ease of reference, the numbering of clauses in this document corresponds to that in the normative

No additional guidance is offered for processes where the declaration of adequacy of the validated

sterilization cycle includes a requirement for no growth in biological indicators (BIs) exposed to that

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements 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 11135:2014, Sterilization of health-care products — Ethylene oxide — Requirements for the

development, validation and routine control of a sterilization process for medical devices

For the purposes of this document, the terms and definitions given in ISO 11135:2014 and the

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

Note 1 to entry: It is expressed as grams of moisture per cubic metre of air (g/m ).

Note 1 to entry: Humidity is usually expressed as absolute humidity (3.1) (i.e. vapour pressure density), relative

d) The equipment used for the measurement of temperature, EO and humidity should be specified.

In addition to the requirements specified in ISO 11135:2014, Clause 10, equipment should monitor

— chamber EO concentration by direct measurement, at intervals throughout EO exposure;

— data from a minimum of two independent temperature sensors placed in different locations.

The monitoring and recording systems should be defined, characterized and documented for each

The location(s) of temperature, humidity and EO sensors or measuring devices should represent

Humidity can be measured as either RH or AH. RH sensors typically use capacitive thin film

technology and measure vapour pressure density at a given temperature. AH is a measure of the

water concentration in a given volume of air and can be measured using spectroscopic technology. It

can be measured with either a fixed sensor, via a sampling port in the chamber or with a data logger.

Electronic sensors (e.g. capacitive thin film sensors) for measuring and recording (RH) can be

NOTE It is common to report humidity as RH which can be determined by direct measurement or

RH sensors can be readily verified as being within their calibrated tolerances by comparing with a

Exposure to EO can impact the accuracy of some humidity sensors, resulting in them falling outside

their calibrated tolerance. This may require more frequent calibration or verification of these

sensors. Alternatively, they may be treated between uses or isolated during EO exposure to avoid

For EO concentration measurement systems, the accuracy and precision should be known and

There are two commonly used technologies employed for measurement of EO concentration:

Spectroscopic technology measures the EO concentration by infrared (IR) light absorption of the

EO molecule. Gas chromatographic technology measures the EO concentration against a standard

Measurement can be carried out either internally or externally. However, where the measurement

of the EO concentration is being carried out external to the chamber the following additional

— compatibility of pipework to EO, for example appropriate grade of stainless steel;

— heat tracing of pipework to minimize risk of condensation of EO or water vapour;

The type of equipment used for temperature monitoring is the same for both parametric or BI

release, but two separate monitoring locations are required for parametric release. If the data

from the sensors are averaged, then these sensors should be of the same type (e.g. thermocouple,

Product, packaging materials, load density and configuration can impact EO concentration, humidity

8.1 Specifications for humidity and EO concentration can be established based on the analysis of the

The minimum specifications for humidity and EO concentration can be established based on data

gathered during the microbiological performance qualification (MPQ) and physical performance

The maximum EO concentration specification should be established to ensure that product safety,

quality and performance is not compromised (see ISO 11135:2014, 7.2 and ISO 10993-7).

Additional PQ may be needed to establish the appropriateness of the process parameters and their

tolerances for parametric release. After PQ, the process specification includes the process parameters

NOTE The specification for other parameters including, but not limited to, temperature, pressure and time,

can be established in the same manner for both parametric and BI release processes.

9.1.4 Additional PQ cycles can be performed to demonstrate the physical and microbiological

performance reproducibility. This might involve designing cycles to deliver the process parameters for

humidity, temperature and EO concentration at the established lower specification limit to confirm

achievement of the required SAL and at the established upper specification to assess product or

The requirement to measure temperature within the sterilizer from a minimum of two locations is

established to ensure that an undetected fault in a temperature sensor does not lead to the inadvertent

release of an improperly processed load. If there is a difference in the two temperature data points, the

acceptable temperature difference should be defined within the processing specification.

Direct analysis of the head space for RH can be performed using electronic sensors, GC, IR or other

spectroscopic methods currently available to indicate water vapour concentration. The benefit of these

Electronic sensors require periodic calibration to offset the effect of exposure to the EO gas and can

require replacement, heat treatment of the electronic sensors or more frequent calibration after

repeated exposures to EO due to irreversible deterioration of materials currently utilized as sensing

The frequency of analysis required to demonstrate that the EO concentration process parameters

and their tolerances are maintained throughout exposure time should be established during the PQ

studies. Monitoring throughout the exposure time period should also be done as part of the validation,

to determine how the EO concentration changes over time. The results of this analysis are specific to

the product and load configuration being analysed. The analysis performed during the PQ study will

result in documented specifications for how often direct analysis should be performed during routine

As required in ISO 11135:2014, 9.5.5, the number of defined intervals for EO concentration sampling

should be sufficient so that there is verification that the EO concentration will be within specification

throughout EO exposure. This could be as few as two samples, with one taken after the end of gas

injection or defined equilibration period and a second prior to sterilant removal. Typically, the number

of samples is greater, for example when gas make-ups are used. Where an inert gas addition is included

after EO injection, the ability to capture EO concentration data at the end of injection should be

To ensure that the readings are representative of conditions within the chamber, it is important to

— Location: it is important to ensure that the sensor(s) or the sampling location(s) for EO concentration,

humidity and temperature measurement are representative of the environment in the chamber. If

the sensors or sampling points are located within the recirculation system (if used), they should be

— Water condensation: sensors or sampling point should be oriented in a manner to avoid any risk of

— Pressure influence: the measurement instrument should compensate for the impact of changing

— Temperature uniformity: sensors, sampling points or sample piping for EO concentration and

humidity might need to be either at or above the specified process temperature to give accurate

readings. To achieve this, the sensor, piping or both might require heating. Measuring equipment

should be located such that the maximum values of temperature and humidity specified for them

are not exceeded. The instructions provided by the measurement equipment manufacturer should

9.3.1 RH in the sterilizer chamber can be verified using a calibrated electronic sensor located at

the analytical instrument sampling point of the sterilizer chamber. Analytical instruments such as gas

chromatographs (GC), IR or other spectroscopic methods are less common and are more complex than

the electronic sensor. Such analytical instruments can be calibrated by instrument manufacturers and

the calibration should be verified after installation prior to operational qualification (OQ).

Confirmation of EO sensor calibration can be conducted in one of several ways. Some analytical

instrument suppliers can provide an instruction that can be placed in the system to confirm

maintenance of calibration. An alternative method is to calibrate or verify the EO sensor against known

EO concentrations in a fixed volume of chamber or sample cell. There are three methods of determining

Method 1: use of the ideal gas law, which is based upon pressure change and temperature of EO.

Method 2: use of the fixed volume of chamber (inclusive of relevant piping and recirculation system) or

Method 3: comparison of measured concentration with a commercially available standard

d) accurate measurement of chamber temperature at the sampling location, weight of EO added and

Confirmation of EO concentration using either the ideal gas law and weight/volume calculations i