标准编号:	GB/T 19974-2018
中文名称:	医疗保健产品灭菌 灭菌因子的特性及医疗器械灭菌过程的开发、确认和常规控制的通用要求
英文名称:	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
中标分类:	C47    公共医疗设备
行业分类:	GB    国家标准
ICS分类:	11.080.01 11.080.01    消毒和灭菌综合 11.080.01
发布机构:	国家市场监督管理总局、中国国家标准化管理委员会
发布日期:	2018-05-14
实施日期:	2019-6-1
标准状态:	现行
替代旧标准:	GB/T 19974-2005 医疗保健产品灭菌 灭菌因子的特性及医疗器械灭菌工艺的设定、确认和常规控制的通用要求
翻译语言:	英文
文件格式:	PDF
中文字符数:	33000 字
翻译价格(元):	2310.00 元
交付时间:	付款后 1 个工作日

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
Bibliography

医疗保健产品灭菌 灭菌因子的特性及医疗器械灭菌过程的开发、确认和常规控制的通用要求
1 范围
1.1 适用范围
1.1.1本标准规定了灭菌因子的特性及医疗器械灭菌过程的开发、确认和常规控制的通用要求。
注：虽然本标准的范围只限于医疗器械，此标准规定的要求同样能适用于其他医疗保健产品。
1.1.2本标准适用于通过物理或化学方法灭活微生物的灭菌过程。
1.1.3本标准将被过程开发者、灭菌设备制造商、生产待灭菌的医疗器械的制造商和对医疗器械的灭菌负有职责的组织使用。
1.1.4本标准规定了保证适当特性的灭菌因子、开发、确认、常规监测和灭菌过程控制所应的质量管理体系要素。
注：本标准不要求有一个完整的质量管理体系。必要元素在正文中适当的地方规范性引用(详见第4章)。需要引起注意的是控制医疗器械生产或加工所有阶段的质量管理体系标准(见YY/T 0287)。有关医疗器械供应的国家和/或地区法规可能要求应执行一个完整的质量管理体系并且由第三方来实施对该体系的评价。
1.2不适用范围
1.2.1 本标准不适用于单纯依赖物理方法去除细菌(如过滤)的过程。
1.2.2本标准不规定微生物灭活评价的具体检验步骤。
1.2.3本标准不规定灭菌因子特性和海绵状脑病病原体灭活过程的开发、确认和常规控制要求，例如：羊痒病，牛海绵状脑病、克雅氏病。特别是有些国家对受这类因子潜在污染材料的处理已建议采用特别的方法。
注：见ISO 22442-1、ISO 22442-2和ISO 22442-3。
1.2.4本标准不取代或修改已出版的特殊灭菌过程的标准。
2规范性引用文件
下列文件对于本文件的应用是必不可少的。凡是注日期的引用文件，仅注日期的版本适用于本文件。凡是不注日期的引用文件，其最新版本(包括所有的修改单)适用于本文件。
GB 18281.1—2015 医疗保健产品灭菌 生物指示物 第1部分：通则(ISO 11138-1：2006，IDT)
YY/T 0287—2003 医疗器械 质量管理体系 用于法规的要求(ISO 13485：2003，IDT)
ISO 10012测量管理系统 测量方法和测量设备的要求(Measurement management systems—Requirements for measurement processes and measuring equipment)
ISO 10993-1医疗器械生物学评价 第1部分：风险管理过程中的评价与试验(Biological evaluation of medical devices—Part 1：Evaluation and testing within a risk management process)
ISO 10993-17 医疗器械生物学评价 第17部分：可沥滤物允许限量的建立(Biological evaluation of medical devices—Pan 17：Establishment of allowable limits for leachable substances)
ISO 11140-1 医疗保健产品灭菌 化学指示物 第1部分：通则(Sterilization of health care products—Chemical indicators—Part 1：General requirements)
ISO 11737-1 医疗器械的灭菌 微生物学方法 第1部分：产品上微生物总数的测定(Sterilization of medical devices—Microbiological methods—Part 1：Determination of a population of microorganisms On products)
ISO 11737-2 医疗器械的灭菌 微生物学方法 第2部分：用于灭菌过程的定义、确认和维护的无菌试验(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测量、控制和实验室用电气设备的安全要求 第4部分：用于处理医用材料的灭菌器和清洗消毒器的特殊要求(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术语和定义
下列术语和定义适用于本文件。
3.1
生物负载bioburden
产品和(或)无菌屏障系统表面或内部存活微生物的总数。
[见GB/T 19971—2015，定义2.2]
3.2
生物指示物 biological indicator
对规定的灭菌过程有特定的抗力，含有活微生物的测试系统。
[见GB/T 19971—2015，定义2.3]
3.3
变更控制 change control
对产品或程序所建议的变更进行适当性的评估和决定。
[见GB/T 19971—2015，定义2.5]
3.4
化学指示物chemical indicator
非生物指示物 non-biological indicator
根据暴露于某一灭菌过程所产生的化学或物理变化，显现一个或多个预定过程变量变化的测试系统。
[见GB/T 19971—2015，定义2.6]
3.5
纠正措施 corrective action
为消除已发现的不合格或其他不期望情况的原因所采取的措施。
注1：一个不合格可能有若干个原因。
注2：采取纠正措施是为了防止再发生，而采取预防措施(3.17)是为了防止发生。
注3：纠正(3.6)和纠正措施是有区别的。
[见GB/T 19000—2008，定义3.6.5]
3.6
纠正 corrective
为消除已发现的不合格所采取的措施。
注：纠正能连同纠正措施(3.5)一起实施。
[见GB/T 19000—2008，定义3.6.6]
3.7
开发development
详细制定规范的活动。
[见GB/T 19971—2015，定义2.13]
3.8
建立establish
通过理论评估确定，并经试验证实。
[见GB/T 19971—2015，定义2.17]
3.9
故障fault
一个或多个过程参数超出了规定允差范围。
[见GB/T 19971—2015，定义2.19]
3.10
医疗保健产品health care product(s)
医疗器械(包括体外诊断医疗器械)或医药产品(包括生物制药产品)。
[见GB/T 19971—2015，定义2.20]
3.11
安装鉴定installation qualification；IQ
证明设备已按规范要求提供和安装，获得并形成文件化证据的过程。
[见GB/T 19971—2015，定义2.22]
3.12
物质安全技术说明书material safety data sheet；MSDS
详细说明材料特性及其对人及环境潜在的危害作用、安全使用及处置物品的必要预防措施的文件。
[见GB/T 19971—2015，定义2.23]
3.13
医疗器械medical device
制造商的预期用途是为下列一个或多个特定目的用于人类的，不论单独使用或组合使用的仪器、设备、器具、机器、用具、植入物、体外试剂或校准物、软件、材料或者其他相似或相关物品。这些目的是：
——疾病的诊断、预防、监护、治疗或者缓解；
——损伤的诊断、监护、治疗、缓解或者补偿；
——解剖或生理过程的研究、替代、调节或者支持；
——支持或维持生命；
——妊娠控制；
——医疗器械的消毒；
——通过对取自人体的样本进行体外检查的方式来提供医疗信息。
其作用于人体体表或体内的主要设计作用不是用药理学、免疫学或代谢的手段获得，但可能有这些手段参与并起一定辅助作用。
[见YY/T 0287—2003，定义3.7]
注：YY/T 0287—2003中本定义由全球协调工作组(GHTF 2002)制定。
3.14
运行鉴定operational qualification；OQ
证明已安装的设备按运行程序使用时能在预定限值内运行，获得并形成文件化证据的过程。
[见GB/T 19971—2015，定义2.27]
3.15
参数放行parametric release
根据能证明过程参数在规定允差范围内的记录，声明该产品无菌。
[见GB/T 19971—2015，定义2.29]
3.16
性能鉴定performance qualification；PQ
证明已按操作程序安装和运行的设备，可持续地按预定规范生产出符合规格的产品，获得并形成文件化证据的过程。
[见GB/T 19971—2015，定义2.30]
3.17
预防措施preventive action
为消除潜在不合格或其他潜在不期望情况的原因所采取的措施。
注1：一个潜在不合格可能有若千个原因。
注2：采取预防措施是为了防止发生，而采取纠正措施是为了防止再发生。
[见GB/T 19000—2008，定义3.6.4]
3.18
过程挑战装置process challenge device；PCD
对某一灭菌过程构成特定抗力的装置，用于评价该灭菌过程的性能。
[见GB/T 19971—2015，定义2.33]
3.19
过程参数process parameter
过程变量的规定值。
注：灭菌过程规范包括过程参数及其允差。
[见GB/T 19971—2015，定义2.34]
3.20
过程变量process variable
灭菌过程的条件，其变化可影响杀灭微生物效果。
示例：时间、温度、压力、浓度、湿度、波长。
[见GB/T 19971—2015，定义2.35]
3.21
公认的菌种保存库recognised culture collection
根据“国际公认微生物菌种保存专利与法规”布达佩斯(Budapest)公约建立的国际菌种保存机构。
[见GB/T 19971—2015，定义2.38]
3.22
参考微生物reference microorganism
从公认的菌种保存库获得的菌株。
[见GB/T 19971—2015，定义2.39]
3.23
再鉴定 requalification
为证实某一规定过程持续合格而重新进行的部分确认活动。
[见GB/T 19971—2015，定义2.40]
3.24
供给服务 services
设备运行所必需的各种外源供给。
示例：电力、水、压缩空气、排水系统。
[见GB/T 19971—2015，定义2.41]
3.25
规定 specify
在批准的文件内详细闸明。
[见GB/T 19971—2015，定义2.42]
3.26
无菌的sterile
无存活微生物的。
[见GB/T 19971—2015，定义2.43]
3.27
无菌 sterility
无微生物存活的状态。
注：实践中无法证实没有微生物存在的这种绝对说法[见“灭菌”一词的说明(3.28)]。
[见GB/T 19971—2015，定义2.45]
3.28
灭菌 sterilization
经确认的使产品无存活微生物的过程。
[见GB/T 19971—2015，定义2.47]
注：在灭菌过程中，微生物的灭活特性用指数函数表示。因此，任何单件产品上活微生物的存在能用概率表示。概率能减少到很低，但不可能降到零。(见GB/T 19971中“无菌保证水平”)
3.29
灭菌负载 sterilization load
采用给定灭菌过程，同放在一起待灭菌或已灭菌的物品。
[见GB/T 19971—2015，定义2.48]
3.30
灭菌过程 sterilization process
达到无菌规定要求所需的一系列动作和操作。
注：这一系列操作包括产品预处理(如果需要)、在规定的条件下暴露于相应灭菌因子和需要的后处理，灭菌过程不包括灭菌前的消洗、消毒或包装等过程。
[见GB/T 19971—2015，定义2.49]
3.31
灭菌因子sterilization agent
在规定的条件下，具有充分的杀灭活力以达到无菌的物理或化学物质，或其组合。
[见GB/T 19971—2015，定义2.50]
3.32
存活曲线 survivor curve
显示在规定条件下随暴露于灭活因子的递增而变化的微生物总数的灭活情况的图表。
[见GB/T 19971—2015，定义2.51]
3.33
无菌检验test for sterility
产品经过灭菌处理后，按药典上的规定对产品进行技术操作。
3.34
无菌检查lest of sterility
为确定单元产品或其部分上有或没有活微生物而进行的技术操作，是开发、确认或再鉴定的一部分。
[见GB/T 19971—2015，定义2.54]
3.35
确认 validation
为确定某一过程可持续生产出符合预定规格产品所需结果的获取、记录和解释的文件化程序。
[见GB/T 19971—2015，定义2.55]
4质量管理体系要素
4.1 文件
4.1.1 应规定灭菌因子的特性、灭菌过程的开发、确认和常规控制及灭菌后产品放行的程序。
4.1.2 本标准要求的文件和记录应由指定的人员来评审和批准(见4.2.1)。文件和记录应符合YY/T 0287的要求。
4.2管理职责
4.2.1 应规定执行和满足本标准中所述要求的职责和权限。按照YY/T 0287，这种职责和权限应授予有能力胜任的人。
4.2.2如果本标准要求由多个具有单独的质量管理体系的团体承担实施，则应规定每一方的职责和权限。
4.3产品实现
4.3.1 应规定采购程序。这些程序应符合YY/T 0287的适用章条。
4.3.2应规定产品标识和可追溯性程序。这些程序应符合YY/T 0287的要求。
4.3.3 应规定符合YY/T 0287或ISO 10012相应章条的要求，用于满足本标准要求的、包括用于测试目的的仪器仪表的所有设备的校准程序。
4.4测量、分析与改进——不合格品的控制
应规定不合格产品的控制和纠正、纠正措施及预防措施的程序。这些程序应符合YY/T 0287的要求。
5灭菌因子特性
5.1 总则
本章的目的是定义灭菌因子，证明其杀灭微生物效果，确定影响杀灭微生物效果的因素，评估暴露灭菌因子对材料的影响，同时确定人员安全和环境保护的要求。这些工作可在检验或模拟系统中进行。在这种情况下，最终的设备规定(见6.3)应与测试或模拟设备的试验研究结果有关。
5.2灭菌因子
应规定灭菌因子。若适合，规定应包括保持灭菌因子在规定的货架寿命的期限内符合规定的灭菌因子贮存条件。
5.3微生物杀灭效果
5.3.1 杀灭微生物效果的研究应：
a)说明(证明)灭菌因子对根据附录A选择的一系列具有代表性的微生物的杀灭效果；
b)建立一个定义对特定抗性微生物灭活力的经验数学关系式，以预测微生物暴露在特定灭菌过程的存活概率；
c)确定对此灭菌因子具有高抗性的参考微生物；
d)确定影响灭菌因子杀灭力的过程变量及与杀灭力相关的这些过程变量的相互作用；
e)评估基于物理和/或化学相互作用而对灭菌因子的效果产生不利影响的因素；
示例：与由生产、清洁和/或消毒产生的材料和残留物的相互作用。
f)评价对灭菌因子的传递和/或分布产生不利影响的因素；
示例：生产、清洁和/或消毒的环境、材料和残留物。
g)若适用，确定终止灭菌因子作用的方式。
5.3.2测试方法、接受条件、测试结果及测试微生物选择的判定应形成文件。应记录测试结果(见4.1.2)。
5.4对材料的影响
5.4.1 应评估暴露灭菌因子对材料的物理和/或化学特性以及它们的生物安全性的影响。
5.4.2应采用可能对材料影响最大的过程参数组合来研究重复暴露于灭菌因子对材料特性的影响。
5.4.3应记录被测试的材料和检验的结果，以及暴露于灭菌因子前后材料特性的评价标准。
5.5安全和环境
5.5.1 应规定灭菌因子、灭菌因子的前体(若有)及它的副产品的材料安全数据和类似的安全信息。这个信息可由化学剂的供应商提供或通过对灭菌因子进行试验性研究获得。
5.5.2应评估在灭菌因子使用中或使用后，可能的任何已知或意外释放的物质对环境的潜在影响并应建立相应的物质控制措施。应记录包括潜在的影响(若有)及控制措施(若确定)的评估(见4.1.2)。
6过程和设备特性
6.1 总则
本章目的是定义整个灭菌过程和确保灭菌设备能够安全可重复地实现灭菌过程。
6.2过程特性
6.2.1 应规定过程参数及其允差。此允差应基于达到最低的可接受的微生物杀灭效果的过程参数组合。按此过程参数处理应通常产生安全和有效的产品。
注：过程参数的建立遵循过程变量的定义[见5.3.1d)]，包括那些为确保灭菌过程效果被去除的或被最小化的过程变量。
6.2.2应确定监测和控制过程变量的手段。
6.2.3 应规定为保证灭菌过程效果对暴露于灭菌因子之前要求对产品处理的方法。
6.2.4暴露于灭菌因子后，为保证产品安全所要求的任何对产品的处理应定义为灭菌过程的一部分。
6.3设备特性
6.3.1 应规定在过程参数规定的公差范围内的一个安全的设备交付过程。
6.3.2规定应包括但不限于：
a)设备及其必需的辅助设施的物理描述，包括结构、材料；
b)灭菌因子的规定(见5.2)及其提供的方法，包括实施所需的基质和添加材料；
c)监测和控制灭菌过程的设备描述，包括感应器的特点和位置、显示和记录仪器；
d)灭菌设备识别的故障；
e)安全设施，包括用于人员及环境保护的；
f)安装要求，包括控制排放方面的(若适用)。
6.3.3用于控制和/或监测过程的软件应符合质量管理体系的要求，并提供文件化证据(见4.1.2)证明软件符合设计目的。
注：关注ISO 90003。
6.3.4应提供一种措施以确保控制功能出现故障时不会导致过程记录出错而使无效的过程显示有效。可通过使用独立的控制和监测系统，或通过反复核对识别差异和显示故障的控制和检测系统来实现。
7产品定义
7.1本章的目的是定义待灭菌的产品，包括灭菌前产品的微生物特性和产品的包装方式及灭菌方法。
7.2应规定待灭菌的产品，包括采用的包装材料以及产品置于灭菌过程中的方法。
符合本要求可能需要医疗器械和灭菌设备的制造商为从事灭菌过程的机构提供适当的信息。
注：示例见ISO 17664。
7.3应规定和维持一个体系以保证即将进行灭菌的产品，包括微生物、有机物和无机物污染水平的条件受到控制，而且不会损害灭菌过程的效果。
7.4应证明符合7.3定义体系的效果。对于一次性使用的医疗器械，此证明应包括按照ISO 11737-1要求对生物负载的估计。对于再处理的医疗器械，此证明应包括对规定的清洁、消毒过程(若适用)的效果评估。
为了使生物负载保持稳定而低的水平，应考虑灭菌前原材料、产品、生产和再处理过程的特点。这可通过贯穿医疗器械生产过程中实施符合YY/T 0287的质量管理体系，或采用灭菌前一个确定和受控的已证明有效的清洁过程和消毒过程(若规定)和防止医疗器械再污染来取得。
注：用于清洁和消毒医疗器械的设备的标准(ISO 15883系列)包括证明清浩和消毒过程效果的方法。
8 过程定义
8.1 本章的目的是在不损害产品的安全、质量与性能的情况下获得对指定产品(见第7章)实施的灭菌过程的详细规定。
8.2应建立适用于指定产品的灭菌过程，并应通过以下方法达到：
a)选择过程参数，若可能，通过测量以证明达到要求；
b)在表示为过程增量的条件与用于灭菌过程的附录B、附录C、附录D方法之一的条件相比，运送了更少的灭菌因子的杀灭力。
8.3若生物指示物作为建立灭菌过程的一部分，它们应：
a)符合GB 18281.1—2015和任何适用于灭菌过程的GB 18281的要求；
b)对灭菌因子的抗力与待灭菌产品的生物负载有关；
c)放在产品中认定灭菌条件最难达到的位置或者一个过程挑战装置(PCD)内。
8.4如果化学指示物被作为建立灭菌过程的一部分使用，它们应符合ISO 11140-1和任何适用于灭菌过程的ISO 11140的要求。化学指示物应被放置在产品中认定最难达到灭菌条件的位置或者一个PCD内(见8.6)。
8.5 如果无菌检查在建立灭菌过程期间进行，这些试验应符合ISO 11737-2的要求。
8.6 如果PCDs被作为建立灭菌过程的一部分使用，应确定它们的适当性。与产品中认定灭菌条件最难达到的位置相比，PCDs应具有相当的或更大的挑战。
8.7暴露于灭菌过程之后的产品生物安全性应按照ISO 10993-1的要求建立。
8.8基于健康的风险评估应按照ISO 10993-17进行，以识别和规定产品上/内过程残留限量。
8.9如必要，应建立降低产品上/内的过程残留水平的措施，使之低于8.8的规定。
8.10应证明在采用了规定的灭菌过程后，产品符合规定的安全、质量和性能要求。
8.11应规定灭菌过程。
9确认
9.1 总则
确认的目的是为了证明建立在过程定义(见第8章)基础上的灭菌过程能对灭菌负载进行有效的和可重复的灭菌。确认由几个确定的阶段组成：安装鉴定(IQ)、运行鉴定(OQ)和性能鉴定(PQ)。
IQ是为了证明灭菌设备和任何辅助项目都是按照它们的规范提供和安装的。
OQ是采用空载的设备或适当的测试材料证明设备达到了已定义灭菌过程的能力(见第8章)。
PQ是一个确认的阶段，它采用产品去证明设备根据预设的条件标准持续运行并且生产出无菌的并满足要求的产品。
9.2 安装鉴定
9.2.1 设备
9.2.1.1应规定用于灭菌过程的设备，包括任何辅助设施。
9.2.1.2灭菌设备应符合IEC 61010-2-040。
9.2.1.3应规定设备的操作程序。这些操作的程序应包括，但不限于：
a)操作规程；
b)显示故障状态的方式和应采取的措施；
c)维护和校准说明；
d)联系技术支持的详细资料。
9.2.2 安装
9.2.2.1应规定设备安装的位置，包括所有要求的服务。任何特别的警示和规定都应确定(如：安全设备)。
9.2.2.2应规定安装规范，并包括与人员健康和安全有关的要求。
9.2.2.3若适用，应规定灭菌因子的安全贮存条件，以保证其质量和组成成分符合规范要求。
9.2.2.4在IQ前，应确认所有用于监视、控制、显示或记录设备(包括任何检验仪器)的校准状况(见4.3.3)。
9.2.2.5应证明设备、任何辅助设施和储存条件已按预期安装和运行。
9.3运行鉴定
9.3.1 在OQ前，应确认所有用于监视、控制、显示或记录设备(包括任何测试仪器)的校准状况(见4.3.3)。
9.3.2 OQ应证明已安装的设备能够在规定的允差内实施规定的过程(见8.11)。
9.4性能鉴定
9.4.1 应完成PQ中使用仪器的校准(见4.3.3)。
9.4.2应规定产品进行灭菌的方式，包括产品的方向。
9.4.3用于PQ的产品包装应与常规灭菌产品的一致。
9.4.4应有数据证明在整个灭菌负载中能够获得规定允差范围内的已定义的物理和化学条件。应建立发生在用于日常监控灭菌过程的位置和发生在整个灭菌负载之间的条件之间的关系。以上关系通过整个灭菌负载中规定的条件在预设位置下的获得来开发。
9.4.5应包括在与灭菌过程相比较低的处理程度的情况下灭菌因子的递送。这些降低处理程度的结果的推断可用于预测在灭菌过程中规定的无菌要求的满足情况。在附录B、附录C和附录D中描述的过程定义的方法也可能用于微生物性能鉴定研究。
9.4.6 微生物性能鉴定期间采用的生物指示物应符合8.3。
9.4.7如果对产品按照9.4.5规定的条件进行无菌检查，这样的测试应按照ISO 11737-2进行。
9.4.8如果化学指示物用于PQ，它们应符合8.4。
9.4.9 如果PCDs用于PQ，它们应符合8.6。
9.4.10 PQ性能鉴定应包括在规定的允差内连续地至少三次成功将产品暴露于灭菌过程，以证明过程的可重复性。应评审超出规定允差的PQ结果，并在开始新的暴露前确定和实施纠正措施。
3次成功暴露系列应是连续执行，除非发现超出规定的允差范围结果的因数与过程的有效性无关。这类与灭菌过程的性能无关的发现应形成文件。
注：结果可能归因于，但不限于：供电故障、无法进行维修或外部监测设备的故障。
9.4.11应证明暴露于过程参数上限之后的过程残余水平低于基于健康的风险评估中规定的极限(见8.8)。
9.4.12应证明在采用了过程参数的上限实施规定的灭菌过程后，产品符合规定的安全、质量和性能要求。
注：按照8.9收集的信息能用于满足这一要求。
9.5确认的评审和批准
9.5.1 本章的目的是对确认的数据进行评审和形成文件，以确认灭菌过程合格并批准过程规范。
9.5.2应记录和评审在IQ、OQ和PQ时收集或产生的信息并评审是否合格(见4.1.2)。应记录评审的结果(见4.1.2)。
9.5.3应确认完整的过程规范，包括过程参数和它们的允差。此过程规范也应包括用于某个特定灭菌负载的灭菌过程的准则。
10 常规监测和控制
10.1 常规监测和控制的目的是说明已确认的和规定的灭菌过程已经在产品上实施。
10.2应通过测量或在必要时通过生物指示物(见10.5)或化学指示物(见10.6)作为补充来证明灭菌过程是在定义的允差内实施的(见9.5.3)。
10.3应记录数据以证明达到了规定允差内的过程参数。
10.4所有的记录均应按4.1.2保留。
10.5 如果在常规监测中使用了生物指示物，它们应符合8.3a)和b)。
10.6如果在常规监测中使用了化学指示物，它们应符合8.4。
10.7 如果在常规监测和控制中使用了PCDs，它们应符合8.6。
11 灭菌后产品放行
11.1 应规定灭菌后产品放行的程序，此程序应定义规定的灭菌过程条件符合规范(见9.5.3)的条件。
11.2 参数放行只准许用于所有过程参数被规定、控制和直接监控时。应保存过程参数的记录(见4.1.2)。
11.3若生物指示物或化学指示物用于监控灭菌过程(见10.5和10.6)，这些指示物暴露的结果应包含在灭菌后产品放行的条件之内。
11.4 如果不满足11.1中规定的条件，产品应被判为不合格品并应按文件化程序处理(见4.4)。
12维持过程有效性
12.1 总则
应证明确保灭菌产品条件的系统(见7.3)的持续有效性(见7.4)。
12.2再校准
应定期对用于控制和监控灭菌过程的设备的准确性和可靠性进行验证(见4.3.3)。
12.3设备的维护
12.3.1 预防性维修应根据文件化的程序计划和进行。应规定每个计划的维修任务及开展这些计划频度的程序。应保留维修记录(见4.1.2)。
12.3.2除非规定的维修任务都已很圆满地完成并记录，否则设备不应用于加工产品。
12.3.3应由指定的人员定期评维护方案、维护程序和维护记录。应记录评审结果(见4.1.2)。
12.4再鉴定
12.4.1 对规定产品和设备的灭菌过程的再鉴定应在规定的间隔内进行应证明进行的再鉴定程度的合理性。
12.4.2应规定再鉴定程序和保留再鉴定记录(见4.1.2)。
12.4.3应根据书面程序中规定的接受准则评审再鉴定的数据应保留再鉴定的数据评审记录，以及如果不满足接受准则所采取的纠正和纠正措施的记录。
12.5变更评估
12.5.1 应评估可能影响灭菌过程处理的灭菌设备任何变化。如果判定灭菌过程的功效受影响，应重复进行部分或全部的IQ、OQ和PQ(见第9章)。应记录评估的结果，包括做出决定的理由(见4.1.2)。
12.5.2应评估产品、其包装或产品灭菌模式的任何变化对灭菌过程适合性的影响。基于变化的性质，应进行过程定义(见第8章)和/或PQ(见9.4)。应记录评估的结果，包括做出决定的理由(见4.1.2)。
附 录A
(规范性附录)
验证微生物杀灭效果的指示微生物的选择因素
A.1 总则
本附录介绍了选择用于验证灭菌因子微生物杀灭效果时考虑的因素。表A.1列举了能够包括在这些研究中的微生物的示例。对于新的灭菌过程，表A.1内容并不详尽，不宜假定表A.1中列举的微生物就具有最商的抗性。
A.2 参考微生物的识别
在灭菌因子特性、过程定义研究(若适用)时，应使用微生物杀灭效果获得的数据鉴别适合的参考微生物来作为高抗的代表微生物。
注：通常选择细菌芽孢。
A.3微生物的选择
选择用于证明灭菌因子对微生物杀灭能力的微生物时，应考虑下列几点：
a)已知的对灭菌因子高抗性的微生物或来源于科学文献知识的对灭菌因子的作用方式具有预期高抗性的微生物；
b)典型灭菌过程的已知抗性的微生物；
c)微生物的种类(需氧性和厌氧性的革兰氏阳性和阴性的细菌和芽孢、分枝杆菌、真菌包括孢子形式和酵母、寄生虫和病毒)；
d)产品结构材料中和产品生产环境里存在的微生物；
e)用于加工的典型产品上的生物负载预计培养期间可分离的微生物，若适用，可能存在于前一个病人使用可重复使用医疗器械的微生物。
应记录选定的微生物以及选择这些微生物的依据(见4.1.2)。这些微生物可由公认的菌种保存库参考指定或由其他可溯源的标识标注。
注1：A.3 b)中所给出的关于微生物的信息是提供了与其他灭菌过程的比较，以及确保典型微生物的研究被包括其中。
注2：含有动物源材料的灭菌产品在处理过程中，病毒和/或寄生虫的灭活[见A.3c)]是应特别加以考虑的因素(见ISO 22442-3)，重复使用医疗器械的处理也一样。
注3：在考虑A.3 e)中所给出的关于微生物的信息时，应注意从产品中分离出来、进行重新培养的微生物的抗力发生变化。