Sterilization of health care products—General requirement for characterization of a sterilization agent and the development, validation and routine control of a sterilization process for medical devices
This standard is developed in accordance with the rules given in GB/T 1.1-2009.
This standard replaces GB/T 19974-2005 Sterilization of health care products - General requirement for characterization of a sterilization agent and the development, validation and routine control of a sterilization process for medical devices. The following technical changes have been made with respect to GB/T 19974-2005:
——The definition of “process challenge device” has been added (see 3.18).
This standard, be means of translation, is identical to ISO 14937: 2009 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.
The Chinese documents consistent and corresponding with the normative international documents in this standard are as follows:
——GB 4793.4-2001 Safety requirements for electrical equipment for measurement, control and laboratory use - Particular requirements for autoclaves using steam for the treatment of medical materials and for laboratory process (odt IEC 61010-2-041: 1995)
——GB/T 16886.1-2011 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1:2009, IDT)
——GB/T 16886.17-2005 Biological evaluation of medical devices-Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17: 2002, IDT)
——GB 18282.1-2015 Sterilization of health care products - Chemical indicator - Part 1: General requirements (ISO 11140-1: 2005, IDT)
——GB/T 19022-2003 Measurement management systems - Requirements for measurement processes and measuring equipment (ISO 10012: 2003, IDT);
——GB/T 19973.1-2015 Sterilization of medical devices - Microbiological methods - Part 1: Determination of a population of microorganisms on products (ISO 11737-1: 2006, IDT)
——GB/T 19973.2-2018 Sterilization of medical devices - Microbiological methods - Part 2: Tests of sterility performed in the definition, validation and maintenance of a sterilization process (ISO 11737-2: 2009, IDT)
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. The issuing body of this document shall not be held responsible for identifying any or all such patent rights.
This standard was proposed by the China Food and Drug Administration.
This standard is under the jurisdiction of SAC/TC 200 National Technical Committee on Sterilization Techniques and Equipments of Standardization Administration of China.
The previous edition of this standard is as follows:
——GB/T 19974-2005.
Introduction
A sterile medical device is one that is free of viable microorganisms. The standards that specify requirements for validation and routine control of sterilization processes require, when it is necessary to supply a sterile medical device, that adventitious microbiological contamination of a medical device prior to sterilization be minimized. Even so, medical devices produced under standard manufacturing conditions in accordance with the requirements for quality management systems (see, for example, YY/T 0287-2003) could, prior to sterilization, have microorganisms on them, albeit in low numbers. Such medical devices are non-sterile. The purpose of sterilization is to inactivate the microbiological contaminants and thereby transform the non-sterile medical devices into sterile ones.
The kinetics of inactivation of a pure culture of microorganisms by physical and/or chemical agents used to sterilize medical devices generally can best be described by an exponential relationship between the number of microorganisms surviving and the extent of treatment with the sterilizing agent; inevitably this means that there is always a finite probability that a microorganism might survive regardless of the extent of treatment applied. For a given treatment, the probability of survival is determined by the number and resistance of microorganisms and by the environment in which the organisms exist during treatment. It follows that the sterility of any one medical device in a population subjected to sterilization processing cannot be guaranteed and the sterility of a processed population is defined in terms of the probability of there being a viable microorganism present on a medical device.
This standard describes requirements that, if met, will provide a sterilization process with appropriate microbicidal activity intended to sterilize medical devices. Furthermore, compliance with the requirements ensures that the sterilization process is both reliable and reproducible so that predictions can be made, with reasonable confidence, that there is a low level of probability of there being a viable microorganism present on a medical device after sterilization. Specification of this probability is a matter for regulatory authorities (see, for example, EN 556-1 and ANSI/AAMI ST67).
Generic requirements of the quality management system for design and development, production, installation and servicing are given in ISO 9001 and particular requirements for quality management systems for medical device production are given in YY/T 0287. The standards for quality management systems recognise that, for certain processes used in manufacturing, the effectiveness of the process cannot be fully verified by subsequent inspection and testing of the product. Sterilization is an example of such a process. For this reason, sterilization processes are validated for use, the performance of the sterilization process is monitored routinely and the equipment is maintained.
Exposure to a properly validated, accurately controlled sterilization process is not the only factor associated with the provision of reliable assurance that a processed medical device is sterile and, in this regard, suitable for its intended use. Attention is also given to a number of factors including:
a) the microbiological status of incoming raw materials and/or components;
b) the validation and routine control of any cleaning and disinfection procedures used on the medical device;
c) the control of the environment in which the medical device is manufactured, assembled and packaged;
d) the control of equipment and processes;
e) the control of personnel and their hygiene;
f) the manner and materials in which the medical device is packaged;
g) the conditions under which the medical device is stored.
The type of contamination on a medical device to be sterilized varies, and this influences the effectiveness of a sterilization process. Medical devices that have been used in a health care setting and that are being presented for resterilization in accordance with the manufacturer's instructions (see ISO 17664) should be regarded as special cases. There is the potential for such medical devices to possess a wide range of contaminating microorganisms and residual inorganic and/or organic contamination in spite of the application of a cleaning process. Hence, particular attention has to be given to the validation and control of the cleaning and disinfection processes used during reprocessing.
The requirements are the normative parts of this standard with which compliance is claimed. The guidance given in Annex E is not normative and is not provided as a checklist for auditors. The guidance provides explanations and methods that are regarded as being a suitable means for complying with the requirements. Methods other than those given in the guidance can be used if they are effective in achieving compliance with the requirements of this standard.
The development, validation and routine control of a sterilization process comprise a number of discrete but interrelated activities, for example, calibration, maintenance, product definition, process definition, installation qualification, operational qualification and performance qualification. While the activities required by this standard have been grouped together and are presented in a particular order, this standard does not require that the activities be performed in the order that they are presented. The activities required are not necessarily sequential, as the programme of development and validation can be iterative. The responsibility for carrying out the activities required by this standard will vary from case to case. This standard requires that the responsibilities of the various parties be defined (see 4.2) but does not specify to whom the responsibilities are allocated. Annex E provides guidance on allocation of responsibility.
This standard has three distinct applications:
——for manufacturers of health care products who wish to apply to their products a sterilization process for which a specific standard does not exist;
——for manufacturers and users of sterilization processes in health care settings for which a specific standard does not exist;
——as a framework for the preparation or revision of standards for specific sterilization processes.
Sterilization of health care products -
General requirement for characterization of a sterilization agent and the development, validation and routine control of a sterilization process for medical devices
1 Scope
1.1 Inclusions
1.1.1 This standard specifies general requirements for the characterization of a sterilizing agent and for the development, validation and routine monitoring and control of a sterilization process for medical devices.
Note: Although the scope of this standard is limited to medical devices, the requirements specified herein can also be applied to sterilization processes for other health care products.
1.1.2 This standard applies to sterilization processes in which microorganisms are inactivated by physical and/or chemical means.
1.1.3 This standard is intended to be applied by process developers, manufacturers of sterilization equipment, manufacturers of medical devices to be sterilized, and organizations responsible for sterilizing medical devices.
1.1.4 This standard specifies the elements of a Quality Management System which are necessary to assure the appropriate characterization of the sterilizing agent, development, validation and routine monitoring and control of a sterilization process.
Note: It is not a requirement of this standard to have a full quality management system. The necessary elements are normatively referenced at appropriate places in the text (see, in particular, Clause 4). Attention is drawn to the standards for quality management systems (see YY/T 0287) that control all stages of production or reprocessing of medical devices. National and/or regional regulations for the provision of medical devices might require the implementation of a full quality management system and the assessment of that system by a third party.
1.2 Exclusions
1.2.1 This standard does not apply to sterilization processes that rely solely on physical removal of microorganisms (for example, filtration).
1.2.2 This standard does not describe detailed procedures for assessing microbial inactivation.
1.2.3 This standard does not specify requirements for characterization of an agent or for development, validation and routine control of a process for inactivating the causative agents of spongiform encephalopathies such as scrapie, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. Specific recommendations have been produced in particular countries for the processing of materials potentially contaminated with these agents.
Note: See also ISO 22442-1, ISO 22442-2 and ISO 22442-3.
1.2.4 This standard does not supersede or modify published standards for particular sterilization processes.
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.
GB 18281.1-2015 Sterilization of health care products-Biological indicators-Part 1:General requirements (ISO 11138-1: 2006, IDT)
YY/T 0287-2003 Medical devices - Quality management systems - Requirements for regulatory purposes (ISO 13485: 2003, IDT)
ISO 10012 Measurement management systems - Requirements for measurement processes and measuring equipment
ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
ISO 10993-17 Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances
ISO 11140-1 Sterilization of health care products - Chemical indicators - Part 1: General requirements
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 per-formed in the definition，validation and maintenance of a sterilization process
IEC 61010-2-040 Safety requirements for electrical equipment for measurement，control and laboratory use - Part 2-040: Particular requirements for sterilizers and washer-disinfcetors used to treat medical materials
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1
bioburden
population of viable microorganisms on or in product and/or sterile barrier system
[GB/T 19971-2015, definition 2.2]
3.2
biological indicator
test system containing viable microorganisms providing a defined resistance to a specified sterilization process
[GB/T 19971-2015, definition 2.3]
3.3
change control
assessment and determination of the appropriateness of a proposed alteration to product or procedure
[GB/T 19971-2015, definition 2.5]
3.4
chemical indicator
non-biological indicator
test system that reveals change in one or more pre-defined process variables based on a chemical or physical change resulting from exposure to a process
[GB/T 19971-2015, definition 2.6]
3.5
corrective action
action to eliminate the cause of a detected non-conformity or other undesirable situation
Note:
1 There can be more than one cause for a non-conformity.
2 Corrective action is taken to prevent recurrence whereas preventive action (3.17) is taken to prevent occurrence.
3 There is a distinction between correction (3.6) and corrective action.
[GB/T 19000-2008, definition 3.6.5]
3.6
correction
action to eliminate a detected non-conformity
Note: A correction can be made in conjunction with a corrective action (3.5).
[GB/T 19000-2008, definition 3.6.6]
3.7
development
act of elaborating a specification
[GB/T 19971-2015, definition 2.13]
3.8
establish
determine by theoretical evaluation and confirm by experimentation
[GB/T 19971-2015, definition 2.17]
3.9
fault
one or more of the process parameters lying outside of its/their specified tolerance(s)
[GB/T 19971-2015, definition 2.19]
3.10
health care product(s)
medical device(s), including in vitro diagnostic medical device(s), or medicinal product(s), including biopharmaceutical(s)
[GB/T 19971-2015, definition 2.20]
3.11
installation qualification; IQ
process of obtaining and documenting evidence that equipment has been provided and installed in accordance with its specification
[GB/T 19971-2015, definition 2.22]
3.12
material safety data sheet; MSDS
document specifying the properties of a substance, its potential hazardous effects for humans and the environment, and the precautions necessary to handle and dispose of the substance safely
[GB/T 19971-2015, definition 2.23]
3.13
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
[YY/T 0287-2003, definition 3.7]
Note: This definition from YY/T 0287-2003 has been developed by the Global Harmonization Task Force (GHTF 2002).
3.14
operational qualification; OQ
process of obtaining and documenting evidence that installed equipment operates within predetermined limits when used in accordance with its operational procedures
[GB/T 19971-2015, definition 2.27]
3.15
parametric release
declaration that a product is sterile, based on records demonstrating that the process parameters were delivered within specified tolerances
[GB/T 19971-2015, definition 2.29]
3.16
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 specifications
[GB/T 19971-2015, definition 2.30]
3.17
preventive action
action to eliminate the cause of a potential non-conformity or other undesirable potential situation
Note:
1 There can be more than one cause for a potential non-conformity.
2 Preventive action is taken to prevent occurrence, whereas corrective action is taken to prevent recurrence.
[GB/T 19000-2008, definition 3.6.4]
3.18
process challenge device; PCD
item designed to constitute a defined resistance to a sterilization process and used to assess performance of the process
[GB/T 19971-2015, definition 2.33]
3.19
process parameter
specified value for a process variable
Note: The specification for a sterilization process includes the process parameters and their tolerances.
[GB/T 19971-2015, definition 2.34]
3.20
process variable
condition within a sterilization process, changes in which alter microbicidal effectiveness
Examples: Time, temperature, pressure, concentration, humidity, wavelength.
[GB/T 19971-2015, definition 2.35]
3.21
recognised culture collection
depository authority under the Budapest Treaty on The International Recognition of the Deposit of Microorganisms for the Purpose of Patent and Regulation
[GB/T 19971-2015, definition 2.38]
3.22
reference microorganism
microbial strain obtained from a recognised culture collection
[GB/T 19971-2015, definition 2.39]
3.23
requalification
repetition of part of validation for the purpose of confirming the continued acceptability of a specified process
[GB/T 19971-2015, definition 2.40]
3.24
services
supplies from an external source, needed for the function of equipment
Examples: Electricity, water, compressed air, drainage.
[GB/T 19971-2015, definition 2.41]
3.25
specify
stipulate in detail within an approved document
[GB/T 19971-2015, definition 2.42]
3.26
sterile
free from viable microorganisms
[GB/T 19971-2015, definition 2.43]
3.27
sterility
state of being free from viable microorganisms
Note: In practice, no such absolute statement regarding the absence of microorganisms can be proven [see sterilization (3.28)].
[GB/T 19971-2015, definition 2.45]
3.28
sterilization
validated process used to render a product free from viable microorganisms
[GB/T 19971-2015, definition 2.47]
Note: In a sterilization process, the nature of microbial inactivation is exponential, and the survival of a microorganism on an individual item can thus 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 in GB/T 19971.)
3.29
sterilization load
product to be, or that has been, sterilized using a given sterilization process
[GB/T 19971-2015, definition 2.48]
3.30
sterilization process
series of actions or operations needed to achieve the specified requirements for sterility
Note: This series of actions or operations includes pre-treatment (if necessary), exposure under defined conditions to the sterilizing agent and any necessary post-treatment. It does not include any cleaning, disinfection or packaging operations that precede the sterilization process.
[GB/T 19971-2015, definition 2.49]
3.31
sterilization agent
physical or chemical entity, or combination of entities, that have sufficient microbicidal activity to achieve sterility under defined conditions
[GB/T 19971-2015, definition 2.50]
3.32
survivor curve
graphical representation of the inactivation of a population of microorganisms with increasing exposure to a microbicidal agent under stated conditions
[GB/T 19971-2015, definition 2.51]
3.33
test for sterility
technical operation, defined in a Pharmacopoeia, performed on product following exposure to a sterilization process
3.34
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 portions thereof
[GB/T 19971-2015, definition 2.54]
3.35
validation
documented procedure for obtaining, recording and interpreting the results required to establish that a process will consistently yield product complying with predetermined specifications
[GB/T 19971-2015, definition 2.55]
4 Quality management system elements
4.1 Documentation
4.1.1 Procedures for characterization of a sterilizing agent, development, validation, and routine control of a sterilization process and product release from sterilization shall be specified.
4.1.2 Documents and records required by this standard shall be reviewed and approved by designated personnel (see 4.2.1). Documents and records shall be controlled in accordance with the applicable clauses of YY/T 0287.
4.2 Management responsibility
4.2.1 The responsibility and authority for implementing and meeting the requirements described in this standard shall be specified. Responsibility shall be assigned to competent personnel in accordance with the applicable clauses of YY/T 0287.
4.2.2 If the requirements of this standard are undertaken by organizations with separate quality management systems, the responsibilities and authority of each party shall be specified.
4.3 Product realization
4.3.1 Procedures for purchasing shall be specified. These procedures shall comply with the applicable clauses of YY/T 0287.
4.3.2 Procedures for identification and traceability of product shall be specified. These procedures shall comply with the applicable clauses of YY/T 0287.
4.3.3 A system complying with the applicable clause(s) of YY/T 0287 or ISO 10012 shall be specified for the calibration of all equipment, including instrumentation for test purposes, used in meeting the requirements of this standard.
4.4 Measurement, analysis and improvement - Control of non-conforming product
Procedures for control of product designated as non-conforming and for correction, corrective action and preventive action shall be specified. These procedures shall comply with the applicable clauses of YY/T 0287.
5 Sterilizing agent characterization
5.1 General
The purpose of this activity is to define the sterilizing agent, demonstrate its microbicidal effectiveness, identify the factors that influence microbicidal effectiveness, assess the effects that exposure to the sterilizing agent has on materials, and identify requirements for safety of personnel and protection of the environment. This activity may be undertaken in a test or prototype system. Where this occurs, the final equipment specification (see 6.3) shall be relatable to the results of experimental studies undertaken in the test or prototype equipment.
5.2 Sterilizing agent
The sterilizing agent shall be specified. The specification shall include, if appropriate, conditions of storage of the sterilizing agent to maintain the sterilizing agent within its specification for the duration of the stated shelf life.
5.3 Microbicidal effectiveness
5.3.1 Microbicidal effectiveness studies shall
a) demonstrate the lethal action of the sterilizing agent against a range of representative microorganisms selected in accordance with Annex A;
b) establish an empirical mathematical relationship defining the microbial inactivation kinetics of identified resistant microorganisms so that the probability of a microorganism surviving exposure to a defined treatment can be predicted;
c) identify reference microorganism(s) that has (have) known high resistance to the sterilizing agent;
d) identify the process variables that affect the lethal action of the sterilizing agent and the interactions of these process variables in relation to this lethal action;
e) assess those factors that can adversely influence the effectiveness of the sterilizing agent based upon physical and/or chemical interactions;
Examples: Interactions with materials and residues from manufacturing, cleaning and/or disinfection.
f) assess those factors that can adversely affect the delivery and/or distribution of the sterilizing agent;
Examples: The environment, materials and residues from manufacturing, cleaning and/or disinfection.
g) identify a means for terminating the activity of the sterilizing agent, if applicable.
5.3.2 The test method(s), acceptance criteria, test results and justification for the choice of test microorganisms shall be documented. Test results shall be recorded (see 4.1.2).
5.4 Effects on materials
5.4.1 The effects of exposure to the sterilizing agent on the physical and/or chemical properties of materials and on their biological safety shall be assessed.
5.4.2 The effects of repeated exposure to the sterilizing agent on the properties of materials shall be studied using the combination of process parameters likely to maximize effects on materials.
5.4.3 The materials tested and the outcomes of tests shall be recorded, together with the criteria against which the properties of materials were assessed before and after exposure to the sterilizing agent.
5.5 Safety and the environment
5.5.1 Either a material safety data sheet or analogous safety information shall be specified for the sterilizing agent, its precursors (if any) and any by-products of the sterilizing agent. This information may be provided by a supplier for a chemical agent or be prepared through the experimental studies on the sterilizing agent.
5.5.2 The potential effect on the environment of any substance which could be released, either deliberately or accidentally, during or following use of the sterilizing agent, shall be assessed and measured for the control of the substance(s) established. This assessment, including the potential effect (if any) and the measures for control (if identified), shall be recorded (see 4.1.2).
6 Process and equipment characterization
6.1 General
The purpose of this activity is to define the entire sterilization process and ensure the equipment can deliver the sterilization process safely and reproducibly.
6.2 Process characterization
6.2.1 The process parameters, together with their tolerances, shall be specified. These tolerances shall be based upon knowledge of the combination of process parameters yielding minimal acceptable microbicidal effectiveness. Processing at such process parameters shall routinely yield safe and functional product.
Note: The establishment of the process parameters follows the definition of process variables [see 5.3.1 d)], including those process variables that are excluded or minimized in ensuring the effectiveness of the sterilization process.
6.2.2 Means of monitoring and controlling the process variables shall be determined.
6.2.3 Any treatment of product that is required prior to exposure to the sterilizing agent to ensure effectiveness of the sterilization process shall be specified.
6.2.4 Any treatment of product that is required following exposure to the sterilizing agent to ensure safety of product shall be specified as part of the sterilization processes.
6.3 Equipment characterization
6.3.1 The equipment to deliver the process in a safe manner within the tolerances stipulated for the process parameters shall be specified.
6.3.2 The specification shall include, but is not limited to:
a) physical description of the equipment and necessary ancillary items, including construction and materials;
b) specification of the sterilizing agent (see 5.2) and the means by which it is provided, including any additives or precursors necessary for its delivery;
c) description of instrumentation for monitoring and controlling the sterilization process, including sensor characteristics and locations, and indicating and recording instruments;
d) faults recognized by the sterilizing equipment;
e) safety features, including those for personnel and environmental protection;
f) installation requirements, including those for the control of emissions, if applicable.
6.3.3 Software used to control and/or monitor the process shall be prepared in accordance with a quality management system that provides documented evidence (see 4.1.2) that the software meets its design intention.
Note: Attention is drawn to ISO 90003.
6.3.4 Means shall be provided to ensure that a failure in a control function does not lead to a failure in recording of process parameters such that an ineffective process appears effective. This may be achieved either by the use of independent systems for control and monitoring, or by a cross-check between control and monitoring that identifies any discrepancies and indicates a fault.
7 Product definition
7.1 The purpose of this activity is to define the product to be sterilized, including the microbiological quality of the product prior to sterilization and the manner in which product is packaged and presented for sterilization.
7.2 Product to be sterilized, including the packaging materials to be used and the manner in which product is to be presented to the sterilization process, shall be specified.
Meeting this requirement could necessitate that appropriate information be provided to the organization undertaking the sterilization process by the manufacturer of the medical device and the manufacturer of the sterilization equipment.
Note: See, for example, ISO 17664.
7.3 A system shall be specified and maintained to ensure that the condition of the product presented for sterilization, including microbiological, organic and inorganic contamination levels, is controlled and does not compromise the effectiveness of the sterilization process.
7.4 The effectiveness of the system defined in accordance with 7.3 shall be demonstrated. For medical devices to be supplied for single use, this demonstration shall include estimation of bioburden in accordance with ISO 11737-1. For medical devices to be reprocessed, this demonstration shall include assessment of the effectiveness of the specified cleaning and, if applicable, disinfecting process.
The intention is that bioburden be stable and low, taking account of the nature of the raw materials, product and manufacturing or reprocessing procedures prior to sterilization. This can be achieved by employing a quality management system complying with YY/T 0287 throughout the manufacture of the medical device, or by employing a defined and controlled cleaning process of demonstrated effectiveness, together with a disinfection process (if specified) prior to sterilization, and thereafter preventing recontamination of the medical device.
Note: Standards for equipment to be used in cleaning and disinfecting medical devices (ISO 15883 series) include methods to demonstrate the effectiveness of a cleaning and disinfecting process.
8 Process definition
8.1 The purpose of this activity is to obtain a detailed specification for the sterilization process to be applied to defined product (see Clause 7), without compromising the safety, quality and performance of that product.
8.2 The sterilization process appropriate for defined product shall be established. This shall be achieved by:
a) selecting the process parameters and, if practicable, demonstrating their attainment by measurements;
b) delivering the sterilizing agent under conditions so designed to represent increments of treatment that deliver less lethality than the intended sterilization process using one of the approaches outlined in Annexes B, C or D.
8.3 If biological indicators are used as part of the establishment of the sterilization process, they shall:
a) comply with GB 18281.1-2015 and any subsequent parts of GB 18281 that are applicable to the sterilization process;
b) be shown to be resistant to the sterilizing agent relative to the bioburden of product to be sterilized;
c) be placed either at positions in product where it has been determined that sterilizing conditions are most difficult to achieve or within a process challenge device (PCD).
8.4 If chemical indicators are used as part of the establishment of the sterilization process, they shall comply with ISO 11140-1 and any subsequent parts of ISO 11140 that are applicable to the process. Chemical indicators shall be placed either at positions in product where it has been determined that sterilizing conditions are most difficult to achieve or within a PCD (see 8.6).
8.5 If tests of sterility are performed during the establishment of the sterilization process, such tests shall comply with ISO 11737-2.
8.6 If PCDs are used as part of the establishment of the sterilization process, their appropriateness shall be determined. PCDs shall present a challenge equivalent to or greater than that at the position in product where it has been determined that sterilizing conditions are most difficult to achieve.
8.7 The biological safety of product following exposure to the sterilization process shall be established in accordance with ISO 10993-1.
8.8 A health-based risk assessment shall be conducted in accordance with ISO 10993-17 to identify and specify limits for process residuals on/in product.
8.9 If necessary, means shall be established to reduce level(s) of process residual(s) on/in product below that (those) identified in accordance with 8.8.
8.10 It shall be demonstrated that product meets its specified requirements for safety, quality, and performance following application of the specified sterilization process.
8.11 The sterilization process shall be specified.
9 Validation
9.1 General
The purpose of validation is to demonstrate that the sterilization process established in the process definition (see Clause 8) can be delivered effectively and reproducibly to the sterilization load. Validation consists of a number of identified stages: installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ).
IQ is undertaken to demonstrate that the sterilization equipment and any ancillary items have been supplied and installed in accordance with their specification.
OQ is carried out either with unloaded equipment or using appropriate test materials to demonstrate the capability of the equipment to deliver the sterilization process that has been defined (see Clause 8).
PQ is the stage of validation that uses product to demonstrate that the equipment consistently operates in accordance with predetermined criteria and the process yields product that is sterile and meets the specified requirements.
9.2 Installation qualification
9.2.1 Equipment
9.2.1.1 Equipment to be used in the sterilization process, including any ancillary items, shall be specified.
9.2.1.2 Sterilization equipment shall comply with IEC 61010-2-040.
9.2.1.3 The operating procedures for the equipment shall be specified. These operating procedures shall include, but are not limited to:
a) step-by-step operating instructions;
b) fault conditions, the manner in which they are indicated, and actions to be taken;
c) instructions for maintenance and calibration;
d) details of contacts for technical support.
9.2.2 Installation
9.2.2.1 The location in which the equipment is to be installed, including any services required, shall be specified. Any special precautions and provisions shall be identified (for example, safety equipment).
9.2.2.2 Instructions for installation shall be specified and shall include instructions pertinent to the health and safety of personnel.
9.2.2.3 If applicable, conditions for the safe storage of the sterilizing agent to ensure that its quality and composition remain within specification shall be specified.
9.2.2.4 Prior to IQ, the calibration status of all instrumentation (including any test instruments) used for monitoring, controlling, indicating or recording shall be confirmed (see 4.3.3).
9.2.2.5 It shall be demonstrated that the equipment, any ancillary items and storage conditions, as installed, operate as intended.
9.3 Operational qualification
9.3.1 Prior to OQ, the calibration status of all instrumentation (including any test instruments) used for monitoring, controlling, indicating, or recording shall be confirmed (see 4.3.3).
9.3.2 OQ shall demonstrate that the installed equipment is capable of delivering the specified process (see 8.11) within defined tolerances.
9.4 Performance qualification
9.4.1 Calibration activities (see 4.3.3) shall be completed for instruments used in PQ.
9.4.2 The manner of presenting the product for sterilization, including the orientation of product, shall be specified.
9.4.3 Product used in PQ shall be packaged identically to that to be sterilized routinely.
9.4.4 Data shall be generated to demonstrate the attainment of the defined physical and chemical conditions, within specified tolerances, throughout the sterilization load. Relationship(s) between the conditions occurring at positions used routinely to monitor the sterilization process and those conditions occurring throughout the sterilization load shall be established. This is achieved by determining the attainment of the specified condition(s) at predetermined positions throughout the sterilization load.
9.4.5 The delivery of the sterilizing agent under conditions so designed that the extent of treatment is reduced relative to that in the sterilization process shall be included. Extrapolation of the outcomes of such reduced treatment(s) shall be used to predict that, on application of the sterilization process, the specified requirements for sterility are met. The approaches to process definition described in Annexes B, C or D may also be employed in microbiological performance qualification studies.
9.4.6 Biological indicators employed during microbiological performance qualification shall comply with 8.3.
9.4.7 If tests of sterility are performed on product subjected to conditions as specified in 9.4.5, such tests shall be performed in accordance with ISO 11737-2.
9.4.8 If chemical indicators are used in PQ, they shall comply with 8.4.
9.4.9 If PCDs are used in PQ, they shall comply with 8.6.
9.4.10 PQ shall include a series of at least three successful exposures of product to the sterilization process, within defined tolerances, in order to demonstrate the reproducibility of the process. Results from PQ outside of defined tolerances shall be reviewed and corrective actions determined and instituted before initiating a new series of exposures.
The series of three successful exposures shall be performed consecutively, unless finding outside defined tolerances can be attributed to factors not relevant to the effectiveness of the process being validated. Such findings shall be documented as unrelated to performance of the sterilization process.
Note: The finding might be attributed, but not limited to, power failures, loss of services or failure of external monitoring equipment.
9.4.11 The levels of any process residues following exposure to the upper tolerances of the process parameters shall be demonstrated as being below the specified limits identified in the health-based risk assessment (see 8.8).
9.4.12 It shall be confirmed that the product meets its specified requirements for safety, quality and performance following application of the defined process at the upper tolerances of the process parameters.
Note: Information gathered in accordance with 8.9 can be used to meet this requirement.
9.5 Review and approval of validation
9.5.1 The purpose of this activity is to undertake and document a review of the validation data to confirm the acceptability of the sterilization process and to approve the process specification.
9.5.2 Information gathered or produced during IQ, OQ and PQ shall be recorded and reviewed for acceptability (see 4.1.2). The results of this review shall be recorded (see 4.1.2).
9.5.3 A complete process specification, including the process parameters and their tolerances, shall be confirmed. This process specification shall also include the criteria for designating an individual sterilization process used for a particular sterilization load as conforming.
10 Routine monitoring and control
10.1 The purpose of routine monitoring and control is to demonstrate that the validated and specified sterilization process has been delivered to the product.
10.2 There shall be evidence through measurements, supplemented as necessary by biological indicators (see 10.5) or chemical indicators (see 10.6), that the sterilization process was delivered within the defined tolerances (see also 9.5.3).
10.3 Data shall be recorded to demonstrate the attainment of process parameters within defined tolerances.
10.4 All records shall be retained in accordance with 4.1.2.
10.5 If biological indicators are used in routine monitoring, they shall comply with 8.3 a) and b).
10.6 If chemical indicators are used in routine monitoring, they shall comply with 8.4.
10.7 If PCDs are used in routine monitoring and control, they shall comply with 8.6.
Foreword i
Introduction iii
1 Scope
2 Normative references
3 Terms and definitions
4 Quality management system elements
5 Sterilizing agent characterization
6 Process and equipment characterization
7 Product definition
8 Process definition
9 Validation
10 Routine monitoring and control
11 Product release from sterilization
12 Maintaining process effectiveness
Annex A (Normative) Factors to be considered in selection of microorganisms for demonstrating microbicidal effectiveness
Annex B (Normative) Approach 1 - Process definition based on inactivation of the microbial population in its natural state
Annex C (Normative) Approach 2 - Process definition based on inactivation of reference microorganisms and knowledge of bioburden
Annex D (Normative) Approach 3 - Conservative process definition based on inactivation of reference microorganisms
Annex E (Informative) Guidance on application of this Standard
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