ISO INTERNATIONAL STANDARD

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1 INTERNATIONAL STANDARD ISO Second edition 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 Stérilisation des produits de santé Exigences générales pour la caractérisation d'un agent stérilisant et pour la mise au point, la validation et la vérification de routine d'un processus de stérilisation pour dispositifs médicaux Reference number ISO 14937:2009(E) ISO 2009

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3 Contents Page Foreword...v Introduction...vi 1 Scope Inclusions Exclusions Normative references Terms and definitions Quality management system elements Documentation Management responsibility Product realization Measurement, analysis and improvement Control of non-conforming product Sterilizing agent characterization General Sterilizing agent Microbicidal effectiveness Effects on materials Safety and the environment Process and equipment characterization General Process characterization Equipment characterization Product definition Process definition Validation General Installation qualification Operational qualification Performance qualification Review and approval of validation Routine monitoring and control Product release from sterilization Maintaining process effectiveness General Recalibration Maintenance of equipment Requalification Assessment of change...15 Annex A (normative) Factors to be considered in selection of microorganisms for demonstrating microbicidal effectiveness...16 Annex B (normative) Approach 1 Process definition based on inactivation of the microbial population in its natural state...18 Annex C (normative) Approach 2 Process definition based on inactivation of reference microorganisms and knowledge of bioburden...19 ISO 2009 All rights reserved iii

4 Annex D (normative) Approach 3 Conservative process definition based on inactivation of reference microorganisms...20 Annex E (informative) Guidance on application of this International Standard...22 Bibliography...36 iv ISO 2009 All rights reserved

5 Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2. The main task of technical committees is to prepare International Standards. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO was prepared by Technical Committee ISO/TC 198, Sterilization of health care products. This second edition cancels and replaces the first edition (ISO 14937:2000) and ISO 14937:2000/Cor.1:2003 which have been technically revised. ISO 2009 All rights reserved v

6 Introduction A sterile medical device is one that is free of viable microorganisms. International 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, ISO 13485) 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 nonsterile 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 International 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 and can vary from country to country (see, for example, EN 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 ISO 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. vi ISO 2009 All rights reserved

7 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 International 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 International 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 International Standard have been grouped together and are presented in a particular order, this International 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 International Standard will vary from case to case. This International 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 International 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 International Standard does not exist; for manufacturers and users of sterilization processes in health care settings for which a specific International Standard does not exist; as a framework for the preparation or revision of standards for specific sterilization processes. ISO 2009 All rights reserved vii

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9 INTERNATIONAL STANDARD ISO 14937:2009(E) 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 1 Scope 1.1 Inclusions This International 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 International Standard is limited to medical devices, the requirements specified herein can also be applied to sterilization processes for other health care products This International Standard applies to sterilization processes in which microorganisms are inactivated by physical and/or chemical means This International 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 This International 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 International 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 ISO 13485) 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 This International Standard does not apply to sterilization processes that rely solely on physical removal of microorganisms (for example, filtration) This International Standard does not describe detailed procedures for assessing microbial inactivation This International 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 , ISO and ISO This International Standard does not supersede or modify published International Standards for particular sterilization processes. ISO 2009 All rights reserved 1

10 2 Normative references The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 10012, Measurement management systems Requirements for measurement processes and measuring equipment ISO , Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management process ISO , Biological evaluation of medical devices Part 17: Establishment of allowable limits for leachable substances ISO :2006, Sterilization of health care products Biological indicators Part 1: General requirements ISO , Sterilization of health care products Chemical indicators Part 1: General requirements ISO , Sterilization of medical devices Microbiological methods Part 1: Determination of a population of microorganisms on products ISO , Sterilization of medical devices Microbiological methods Part 2: Tests of sterility performed in the definition, validation and maintenance of a sterilization process ISO 13485:2003, Medical devices Quality management systems Requirements for regulatory purposes IEC , Safety requirements for electrical equipment for measurement, control and laboratory use Part 2-040: Particular requirements for sterilizers and washer-disinfectors used to treat medical materials 3 Terms and definitions For the purposes of this International Standard, the following terms and definitions apply. 3.1 bioburden population of viable microorganisms on or in product and/or sterile barrier system [ISO/TS 11139:2006, definition 2.2] 3.2 biological indicator test system containing viable microorganisms providing a defined resistance to a specified sterilization process [ISO/TS 11139:2006, definition 2.3] 3.3 change control assessment and determination of the appropriateness of a proposed alteration to product or procedure [ISO/TS 11139:2006, definition 2.5] 2 ISO 2009 All rights reserved

11 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 [ISO/TS 11139:2006, 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. NOTE 2 Corrective action is taken to prevent recurrence whereas preventive action (3.17) is taken to prevent occurrence. NOTE 3 There is a distinction between correction (3.6) and corrective action. [ISO 9000:2005, 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). [ISO 9000:2005, definition 3.6.6] 3.7 development act of elaborating a specification [ISO/TS 11139:2006, definition 2.13] 3.8 establish determine by theoretical evaluation and confirm by experimentation [ISO/TS 11139:2006, definition 2.17] 3.9 fault one or more of the process parameters lying outside of its/their specified tolerance(s) [ISO/TS 11139:2006, 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) [ISO/TS 11139:2006, definition 2.20] ISO 2009 All rights reserved 3

12 3.11 installation qualification IQ process of obtaining and documenting evidence that equipment has been provided and installed in accordance with its specification [ISO/TS 11139:2006, definition 2.22] 3.12 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 [ISO/TS 11139:2006, 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 [ISO 13485:2003, definition 3.7] NOTE This definition from ISO 13485:2003 has been developed by the Global Harmonization Task Force (GHTF 2002) operational qualification OQ process of obtaining and documenting evidence that installed equipment operates within predetermined limits when used in accordance with its operational procedures [ISO/TS 11139:2006, definition 2.27] 3.15 parametric release declaration that a product is sterile, based on records demonstrating that the process parameters were delivered within specified tolerances [ISO/TS 11139:2006, definition 2.29] 4 ISO 2009 All rights reserved

13 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 [ISO/TS 11139:2006, 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. NOTE 2 Preventive action is taken to prevent occurrence, whereas corrective action (3.5) is taken to prevent recurrence. [ISO 9000:2005, 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 [ISO/TS 11139:2006, 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. [ISO/TS 11139:2006, 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. [ISO/TS 11139:2006, 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 [ISO/TS 11139:2006, definition 2.38] 3.22 reference microorganism microbial strain obtained from a recognised culture collection [ISO/TS 11139:2006, definition 2.39] ISO 2009 All rights reserved 5

14 3.23 requalification repetition of part of validation for the purpose of confirming the continued acceptability of a specified process [ISO/TS 11139:2006, definition 2.40] 3.24 services supplies from an external source, needed for the function of equipment EXAMPLES Electricity, water, compressed air, drainage. [ISO/TS 11139:2006, definition 2.41] 3.25 specify stipulate in detail within an approved document [ISO/TS 11139:2006, definition 2.42] 3.26 sterile free from viable microorganisms [ISO/TS 11139:2006, 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)]. [ISO/TS 11139:2006, definition 2.45] 3.28 sterilization validated process used to render a product free from viable microorganisms [ISO/TS 11139:2006, 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 ISO/TS ) 3.29 sterilization load product to be, or that has been, sterilized using a given sterilization process [ISO/TS 11139:2006, 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. [ISO/TS 11139:2006, definition 2.49] 6 ISO 2009 All rights reserved

15 3.31 sterilizing agent physical or chemical entity, or combination of entities, that have sufficient microbicidal activity to achieve sterility under defined conditions [ISO/TS 11139:2006, 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 [ISO/TS 11139:2006, definition 2.51] 3.33 test for sterility technical operation, defined in a Pharmacopoeia, performed on product following exposure to a sterilization process or following an aseptic manufacturing 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 [ISO/TS 11139:2006, 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 [ISO/TS 11139:2006, definition 2.55] 4 Quality management system elements 4.1 Documentation Procedures for characterization of a sterilizing agent, development, validation, and routine control of a sterilization process and product release from sterilization shall be specified Documents and records required by this International 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 ISO Management responsibility The responsibility and authority for implementing and meeting the requirements described in this International Standard shall be specified. Responsibility shall be assigned to competent personnel in accordance with the applicable clauses of ISO If the requirements of this International Standard are undertaken by organizations with separate quality management systems, the responsibilities and authority of each party shall be specified. ISO 2009 All rights reserved 7

16 4.3 Product realization Procedures for purchasing shall be specified. These procedures shall comply with the applicable clauses of ISO Procedures for identification and traceability of product shall be specified. These procedures shall comply with the applicable clauses of ISO A system complying with the applicable clause(s) of ISO or ISO shall be specified for the calibration of all equipment, including instrumentation for test purposes, used in meeting the requirements of this International 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 ISO 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 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. 8 ISO 2009 All rights reserved

17 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 The test method(s), acceptance criteria 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 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 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 The materials tested and the outcomes of tests shall be recorded (see 4.1.2), 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 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 as a prelude to experimental studies on the sterilizing agent 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 the equipment necessary to deliver the sterilization process safely and reproducibly. 6.2 Process characterization 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 d)], including those process variables that are excluded or minimized in ensuring the effectiveness of the sterilization process Means of monitoring and controlling the process variables shall be determined Any treatment of product that is required prior to exposure to the sterilizing agent to ensure effectiveness of the sterilization process shall be specified 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. ISO 2009 All rights reserved 9

18 6.3 Equipment characterization The equipment to deliver the process in a safe manner within the tolerances stipulated for the process parameters shall be specified The specification shall include, but is not limited to: a) physical description of the equipment and necessary ancillary items, including materials of construction; 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 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 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 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 For medical devices to be reprocessed, this demonstration shall include assessment of the effectiveness of the specified cleaning and, if applicable, disinfecting process. 10 ISO 2009 All rights reserved

19 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 ISO 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 International Standards for equipment to be used in cleaning and disinfecting medical devices (ISO 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 ISO and any subsequent parts of ISO 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 and any subsequent parts of ISO 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 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 A health-based risk assessment shall be conducted in accordance with ISO 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 It shall be demonstrated that product meets its specified requirements for safety, quality, and performance following application of the specified sterilization process The sterilization process shall be specified. ISO 2009 All rights reserved 11

20 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 Equipment Equipment to be used in the sterilization process, including any ancillary items, shall be specified Sterilization equipment shall comply with IEC 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 Installation 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) Instructions for installation shall be specified and shall include instructions pertinent to the health and safety of personnel If applicable, conditions for the safe storage of the sterilizing agent to ensure that its quality and composition remain within specification shall be specified 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) It shall be demonstrated that the equipment, any ancillary items and storage conditions, as installed, operate as intended. 12 ISO 2009 All rights reserved

21 9.3 Operational qualification 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) OQ shall demonstrate that the installed equipment is capable of delivering the specified process (see 8.11) within defined tolerances. 9.4 Performance qualification Calibration activities (see 4.3.3) shall be completed for instruments used in PQ The manner of presenting the product for sterilization, including the orientation of product, shall be specified Product used in PQ shall be packaged identically to that to be sterilized routinely Data shall be generated to demonstrate the attainment of the defined physical and/or 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 Microbiological performance qualification studies shall comprise delivery of the sterilizing agent under conditions so designed that the extent of treatment is reduced relative to that in the sterilization process. 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 Biological indicators employed during microbiological performance qualification shall comply with 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 If chemical indicators are used in PQ, they shall comply with If PCDs are used in PQ, they shall comply with 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. EXAMPLES The finding might be attributed, but not limited to, power failures, loss of services or failure of external monitoring equipment 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) 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. ISO 2009 All rights reserved 13

22 9.5 Review and approval of validation 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 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) 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 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) Data shall be recorded to demonstrate the attainment of process parameters within defined tolerances All records shall be retained in accordance with If biological indicators are used in routine monitoring, they shall comply with 8.3 a) and b) If chemical indicators are used in routine monitoring, they shall comply with If PCDs are used in routine monitoring and control, they shall comply with Product release from sterilization 11.1 A procedure for product release from sterilization shall be specified. This procedure shall define the criteria (see 9.5.3) for designating a sterilization process as conforming to its specification Parametric release shall only be used if all process parameters are specified, controlled and directly monitored. Records of process parameters shall be retained (see 4.1.2) If biological indicators or chemical indicators are used to monitor the sterilization process (see 10.5 and 10.6), the results from exposure to these indicators shall be included within the criteria for product release from sterilization If the criteria specified in 11.1 are not met, product shall be considered as non-conforming and handled in accordance with documented procedures (see 4.4). 14 ISO 2009 All rights reserved

23 12 Maintaining process effectiveness 12.1 General The continued effectiveness of the system for ensuring the condition of product presented for sterilization (see 7.3) shall be demonstrated (see 7.4) Recalibration The accuracy and reliability of the instrumentation used to control and monitor the sterilization process shall be verified periodically (see 4.3.3) Maintenance of equipment Preventative maintenance shall be planned and performed in accordance with documented procedures. The procedure for each planned maintenance task and the frequency at which it is to be carried out shall be specified. Records of maintenance shall be retained (see 4.1.2) Equipment shall not be used to process product until specified maintenance tasks have been satisfactorily completed and recorded The maintenance scheme, maintenance procedures and maintenance records shall be reviewed periodically by a designated person. The results of the review shall be recorded (see 4.1.2) Requalification Requalification of a sterilization process, carried out for defined product and specified equipment, shall be performed at defined intervals. The extent to which requalification is carried out shall be justified Requalification procedures shall be specified and records of requalification shall be retained (see 4.1.2) Requalification data shall be reviewed against specified acceptance criteria in accordance with documented procedures. Records shall be retained (see 4.1.2) of reviews of requalification data together with corrections made and corrective actions taken if specified acceptance criteria are not met (see 4.4) Assessment of change Any change in the sterilization equipment that could affect delivery of the sterilization process shall be assessed. If the effectiveness of the sterilization process is judged to be affected, a repeat of part or all of IQ, OQ or PQ shall be carried out (see Clause 9). The outcome of this assessment, including the rationale for decisions reached, shall be recorded (see 4.1.2) Any change in product, its package, or the presentation of product for sterilization shall be assessed for the effect on the appropriateness of the sterilization process. Based on the nature of the change, parts of process definition (see Clause 8) and/or PQ (see 9.4) shall be undertaken. The outcome of the assessment, including the rationale for the decisions reached, shall be recorded (see 4.1.2). ISO 2009 All rights reserved 15

24 Annex A (normative) Factors to be considered in selection of microorganisms for demonstrating microbicidal effectiveness A.1 General This annex presents the factors to be considered in selecting microorganisms used in demonstrating the microbicidal effectiveness of a sterilizing agent. Table A.1 gives examples of microorganisms that can be included in such studies. Table A.1 is not exhaustive and, for a new sterilization process, it should not be assumed that the microorganisms listed in Table A.1 will be the most resistant. A.2 Identification of reference microorganism The data obtained in the demonstration of microbicidal effectiveness shall identify a suitable reference microorganism to be employed as a representative model of high resistance during sterilizing agent characterization and, if applicable, process definition studies. NOTE Generally a bacterial spore is selected. A.3 Selection of microorganisms In selecting microorganisms to be used in demonstrating the microbicidal effectiveness of a sterilizing agent, the following shall be considered: a) microorganisms with known high resistance to the sterilizing agent or an expectation of a high resistance from information in the scientific literature or a knowledge of the mode of action of the sterilizing agent; b) microorganisms with known resistance to well-characterized sterilization processes; c) types of microorganisms (aerobic and anaerobic Gram positive and Gram negative bacteria, bacterial spores, mycobacteria, fungi including sporing forms, yeasts, parasites and viruses); d) microorganisms present on the materials of construction of the product and in the environment in which the product is manufactured; e) microorganisms that have been isolated during determinations of bioburden undertaken on typical product to be processed and, if applicable, microorganisms likely to be present on a re-usable medical device as a result of its prior use on a patient. The microorganisms selected and the rationale for their choice shall be recorded (see 4.1.2). These microorganisms may be designated by a recognised culture collection reference or other identifier that allows the source to be traced. NOTE 1 The information with respect to microorganisms given in A.3 b) is to provide a comparison with other sterilization processes and to ensure that well-characterized microorganisms are included in the studies. NOTE 2 Inactivation of viruses and/or parasites [see A.3 c)] is a particular consideration in processes used to sterilize products containing material of animal origin (see also ISO ), as well as when reprocessing medical devices in health care facilities. NOTE 3 In considering the information obtained with respect to microorganisms given in A.3 e), it should be noted that the resistance of microorganisms isolated from product can be modified by recultivation. 16 ISO 2009 All rights reserved