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In order to promote public education and public safety, equal justice for all, a better informed citizenry, the rule of law, world trade and world peace, this legal document is hereby made available on a noncommercial basis, as it is the right of all humans to know and speak the laws that govern them. Republic of Ireland ≠ EDICT OF GOVERNMENT ± I.S. EN ISO 13408-1 (2011) (English): Aseptic processing of health care products - Part 1: General requirements [Authority: The European Union Per Directive 90/385/EEC] @ NSAI · I rish Standard 1.5. EN ISO 13408-1:2011 Standards Aseptic processing of health care products - Part 1: General requirements (ISO 13408-1:2008) © NSAI 2011 No copying without NSAI permission except as permitted by copyright law. 1.5. EN ISO 13408-1:2011 Incorporating amendments/corrigenda/National Annexes issued since publication: The National Standards Authority of Ireland (NSAI) produces the following categories of forma.l documents: I.S. xxx: Irish Standard - national specification based on the consensus of an expert panel and subject to public consultation. S.R. xxx: Standard Recommendation - recommendation based on the consenslJs of an expert panel and subject to public consultation. SWiFT xxx: A rapidly developed recommendatory document based on the consensus of the participants of an I\JSAI workshop. This document replaces: EN 13824:2004 This document is based on: Published: EN ISO 13408-1:2011 5 July, 2011 EN 13824:2004 24 November, 2004 This document was published ICS number: under the authority of the NSAI 11.080.01 and comes into effect on: 5 July, 2011 NSAI T +353 1807 3800 Sales: 1 Swift Sq uare, F +353 1 807 3838 T +3531 857 6730 Northwood, Santry E standards@nsai.ie F +35318576729 Dublin 9 W standards.ie W NSALie Udaras um Chaighdeain Naisiunta na hEireann loS. EN ISO 13408-1 :2011 EUROPEAN STANDARD NORME EUROPEENNE EN ISO 13408-1 EUROpAISCHE NORM June 2011 ICS 11 .080.01 Supersedes EN 13824:2004 English Version Aseptic processing of health care products - Part 1: General requirements (ISO 13408-1 :2008) Traitement aseptique des produits de sante - Partie 1: Exigences generales (ISO 13408-1 :2008) Aseptische Herstellung von Produkten fUr die GesundheitsfUrsorge - Teil 1: Allgemeine Anforderungen (ISO 13408-1 :2008) This European Standard was approved by CEN on 10 June 2011 . CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN member. This European Standard exists in three official versions (English, French, German). A version in any other language made by translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management Centre has the same status as the official versions. CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom. EUROPEAN COMMITIEE FOR STANDARDIZATION C OMlTE EUROPEEN DE N ORMALISA n ON EUROPAISCHES KOMITEE FOR NORMUNG Management Centre: Avenue Marnix 17, B-1000 Brussels © 2011 CEN All rights of exploitation in any form and by any means reserved worldwide for CEN national Members. Ref. No. EN ISO 13408-1 :2011: E 1.5. EN ISO 13408-1 :2011 EN ISO 13408-1 :2011 (E) Contents Page Foreword .............................................................................................................................................................. 3 Annex ZA (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices ..................... .4 Annex ZB (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 93/42/EEC on Medical Devices ......................................................... 5 Annex ZC (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 98/79JEC on in vitro diagnostic medical devices ............................ 6 I.S. EN ISO 13408-1 :2011 EN ISO 13408-1 :2011 (E) Foreword The text of ISO 13408-1 :2008 has been prepared by Technical Committee ISO/TC 198 "Sterilization of health care products" of the International Organization for Standardization (ISO) and has been taken over as EN ISO 13408-1 :2011 by Technical Committee CENITC 204 "Sterilization of medical devices" the secretariat of which is held by BS!. This European Standard shall be given the status of a national standard, either by publication of an identical text or by endorsement, at the latest by December 2011, and conflicting national standards shall be withdrawn at the latest by December 2011. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent rights. This document supersedes EN 13824:2004. This document has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association, and supports essential requirements of EU Directives. For relationship with EU Directives, see informative Annexes lA, lB, or lC, which are integral parts of this document. According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of ISO 13408-1 :2008 has been approved by CEN as a EN ISO 13408-1 :2011 without any modification. EN ISO 13408-1 :2011 (E) I.S. EN ISO 13408-1 :2011 AnnexZA (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 90/385/EEC on active implantable medical devices. Once this standard is cited in the Official Journal of the European Union under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in Table ZA 1 confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZA.1 - Correspondence between this European Standard and Directive 90/385/EEC Clauses of this EN Essential Requirements (ERs) of Qualifying remarks/Notes Directive 90/385/EEC 4,5,6,7,8,9,10,11,12 This relevant Essential Requirement is only partly addressed in this European Standard WARNING - Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this Standard. 1.5. EN ISO 13408-1 :2011 EN ISO 13408-1 :2011 (E) Annex ZB (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 93/42/EEC on Medical Devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 93/42/EEC on medical devices. Once this standard is cited in the Official Journal of the European Union under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in Table ZB.1 confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZB.1 - Correspondence between this European Standard and Directive 93/42/EEC Clauses of this EN Essential Requirements (ERs) of Qualifying remarks/Notes Directive 93/42/EEC 4,5,6,7,8,9,10,11,12
only partly addressed in this European Standard 4,5,6,7,8,9,10,11,12
Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this Standard. EN ISO 13408-1: 2011 (E) 1.5. EN ISO 13408~1 :2011 Annex ZC (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 98/79/EC on in vitro diagnostic medical devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 98/79/EC on in vitro diagnostic medical devices. Once this standard is cited in the Official Journal of the European Union under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in Table lC.1 confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZC.1 - Correspondence between this European Standard and Directive 98/79/EC Cia uses of this EN Essential Requirements (ERs) of Qualifying remarks/Notes Directive 98/79/EC 4,5,6,7,8,9,10,11,12 B.2.3 This relevant Essential Requirement is only partly addressed in this European Standard 4,5,6,7,8,9,10,11,12 B.2.4 WARNING Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this Standard. 1.5. EN ISO 13408-1 :2011 INTERNATIONAL STANDARD ISO 13408-1 Second edition 2008-06-15 Aseptic processing of health care products - Part 1: General requirements Traitement aseptique des produits de sante - Partie 1: Exigences generales Reference number ISO 13408-1 :2008(E) © ISO 2008 I.s. EN ISO 13408-1:2011 ISO 13408-1 :2008(E) PDF disclaimer This PDF file may contain embedded typefaces. In accordance with Adobe's licensing policy, this file may be printed or viewed but shall not be edited unless the typefaces which are embedded are licensed to and installed on the computer performing the editing. In downloading this file, parties accept therein the responsibility of not infringing Adobe's licensing policy. The ISO Central Secretariat accepts no liability in this area. Adobe is a trademark of Adobe Systems Incorporated. Details of the software products used to create this PDF file can be found in the General Info relative to the file; the PDF-creation parameters were optimized for printing. Every care has been taken to ensure that the file is suitable for use by ISO member bodies. In the unlikely event that a problem relating to it is found, please inform the Central Secretariat at the address given below. COPYRIGHT PROTECTED DOCUMENT © ISO 2008 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO's member body in the country of the requester. ISO copyright office Case postale 56. CH-1211 Geneva 20 Tel. + 41227490111 Fax + 41 227490947 E-mail copyright@iso.org Web www.iso.org Published in Switzerland © ISO 2008 - All rights reserved 1.5. EN ISO 13408·1:2011 ISO 13408-1 :2008(E) Contents Page Foreword ............................................................................................................................................................. v Introduction ....................................................................................................................................................... vi Scope ..................................................................................................................................................... 1 I\lormative references ........................................................................................................................... 1 Terms and definitions ........................................................................................................................... 2 Quality system elements ...................................................................................................................... 7 4.1 General ................................................................................................................................................... 7 4.2 Assignment of responsibilities ........................................................................................................... 7 4.3 Calibration ............................................................................................................................................. 7 Aseptic process definition ................................................................................................................... 8 5.1 General ................................................................................................................................................... 8 5.2 Risk management ................................................................................................................................. 8 Manufacturing environment .............................................................................................................. 10 6.1 General ................................................................................................................................................. 10 6.2 Manufacturing environment design .................................................................................................. 11 6.3 Layout .................................................................................................................................................. 12 6.4 Material and personnel flow .............................................................................................................. 14 6.5 HVAC system ...................................................................................................................................... 15 6.6 Cleanroom qualification ..................................................................................................................... 17 6.7 Utility services and ancillary equipment .......................................................................................... 17 6.8 Environmental and personnel monitoring programmes ................................................................ 17 Equipment ........................................................................................................................................... 21 7.1 Qualification ........................................................................................................................................ 21 7.2 Maintenance of equipment ................................................................................................................ 23 Personnel ............................................................................................................................................. 23 8.1 General ................................................................................................................................................. 23 8.2 Training for APA qualification ........................................................................................................... 24 8.3 Gowning procedures .......................................................................................................................... 25 8.4 General employee health ................................................................................................................... 26 Manufacture of the product ............................................................................................................... 27 9.1 Attainment and maintenance of sterility .......................................................................................... 27 9.2 Duration of the manufacturing process ........................................................................................... 27 9.3 Aseptic manufacturing procedures .................................................................................................. 28 9.4 Cleaning and disinfection of facilities .............................................................................................. 28 9.5 Cleaning, disinfection and sterilization of equipment .................................................................... 30 Process simulation ............................................................................................................................. 31 10.1 General ................................................................................................................................................. 31 10.2 Media selection and growth support ................................................................................................ 32 10.3 Simulation procedures ....................................................................................................................... 32 10.4 Incubation and inspection of media 'filled units .............................................................................. 33 10.5 Initial performance qualification ....................................................................................................... 33 10.6 Periodic performance requalification ............................................................................................... 34 10.7 Repeat of initial performance qualification ...................................................................................... 35 10.8 Documentation of process simulations ........................................................................................... 35 10.9 Disposition of filled product .............................................................................................................. 36 Test for sterility ................................................................................................................................... 37 © ISO 2008 - All rights reserved iii loS. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 11.1 General ................................................................................................................................................. 37 11.2 Investigation of positive units from tests for sterility ..................................................................... 37 Annex A (informative) Example of a flow chart ............................................................................................. 38 Annex B (informative) Typical elements of an aseptic process definition ................................................. 39 Annex C (informative) Examples of specific risks ........................................................................................ 40 Annex D (informative) Comparison of classification of cleanrooms .......................................................... 41 Annex E (informative) Specification for water used in the process ............................................................ 42 Annex F (informative) Aseptic processing area ............................................................................................ 44 Bibliography ..................................................................................................................................................... 45 iv © ISO 2008 - All rights reserved I.S. EN ISO 13408-1:2011 ISO 13408-1 :2008(E) Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. International Standards are drafted in accordance with the rules given in the ISOIIEC 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 13408-1 was prepared by Technical Committee ISOITC 198, Sterilization of health care products. This second edition cancels and replaces the first edition (ISO 13408-1 :1998), which has been technically revised. Any normative and informative clauses on subjects which have meanwhile been addressed in Part 2 to Part 6 of ISO 13408 have been removed from this part. ISO 13408 consists of the following parts, under the general title Aseptic processing of health care products: Part 1: General requirements Part 2: Filtration Part 3: Lyophilization Part 4: Clean-in-place technologies Part 5: Sterilization in place Part 6: Isolator systems © ISO 2008 - All rights reserved v I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) Introduction Health care products that are labelled "sterile" are prepared using appropriate and validated methods under stringent control as part of a quality management system. For pharmaceuticals and medical devices there might be various requirements including compliance with ISO standards, GIVIP regulations and pharmacopoeial requirements. Wherever possible, healthcare products intended to be sterile should be sterilized in their final sealed container (terminal sterilization). ISOITC 198 has prepared standards for terminal sterilization of health care products by irradiation (series ISO 11137), by moist heat (ISO 17665-1), by dry heat (ISO 20857, in preparation) and by ethylene oxide (ISO 11135-1). When a health care product is intended to be sterile and cannot be terminally sterilized, aseptic processing provides an alternative. Presterilization of product, product parts and/or components and all equipment coming into direct contact with the aseptically-processed product is required. Aseptic processing intends to maintain the sterility of the pre-sterilized components and products during assembling. The resulting product is required to be sterile in its final container. Aseptic processing can also be used to prevent contamination of biological product or biological systems (e.g. tissues, vaccines). While terminal sterilization involves the control of a well-defined process of known lethality delivered to the product and a sterility assurance level (SAL) can be extrapolated from sterilization data, this is not applicable to aseptic processing. Examples of applications in which aseptic processing are used include: aseptic handling and filling of solutions, suspensions, semisolids and powders; aseptic handling, transfer and packaging of solid products including solid medical devices; aseptic handling, transfer and packaging of combination products; aseptic handling of tissues or biological production systems. Sterilization procedures which render components and/or parts sterile as a prerequisite for further aseptic processing can be treated as separate procedures. They have to be evaluated and validated separately and it is important that their risk of failure is minimal. The aseptic process definition encompasses all production steps following the sterilization of product and components until the final container or package is sealed. To keep the aseptic process definition clear and workable, this part of ISO 13408 is focused on the risks to the maintenance of sterility. It is important to control all possible sources of contamination in order to maintain the sterility of each and every component. To achieve this, a risk-based aseptic process definition is established encompassing each product and applied in a comprehensive way considering product, package deSign, environment and manufacturing process deSigns. The product is processed in a controlled environment where microbial and particulate levels are maintained at defined minimal levels and where human intervention is minimized. Validated systems, adequately trained personnel, controlled environments and well-documented systematic processes are applied to assure a sterile finished product. The aseptic process is divided into unit operations (e.g. sterilization of product or components including sterile filtration, assembly of components, handling and storage of sterilized product) and it is necessary that potential sources of contamination from materials, components, product, personnel, facility, equipment and utilities such as water systems be considered and minimized. Only if all risks of contamination have been recognised, wherever possible minimized, eliminated or controlled and finally have been evaluated as vi © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) acceptable, can the controls on the aseptic process be considered to be acceptable. Appropriate validation of the specified elements of the aseptic process is needed, of which process simulation studies are an essential. This revision of ISO 13408-1 :1998 is intended to adopt this International Standard to the actual state of technology in the field. © ISO 2008 - All rights reserved vii 1.5. EN ISO 13408-1 :2011 1.5. EN ISO 13408-1 :2011 I(\ITERNATIONAL STANDARD ISO 13408-1 :2008(E) Aseptic processing of health care products - Part 1: General requirements Scope
programmes and procedures for development, validation and routine control of the manufacturing process for aseptically-processed health care products.
processing. Specific requirements and guidance on various specialized processes and methods related to filtration, lyophilization, clean-in place (CIP) technologies, sterilization in place (SIP) and isolator systems are given in other parts of ISO 13408. NOTE This part of ISO 13408 does not supersede or replace national regulatory requirements, such as Good Manufacturing Practices (GMPs) and/or pharmacopoeial requirements that pertain in particular national or regional jurisdictions. Normative references Tile 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 9001, Quality management systems - Requirements ISO 11135-1, Sterilization of health care products - Ethylene oxide - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices ISO 11137-1, Sterilization of health care products - Radiation - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices ISO 11137-2, Sterilization of health care products - Radiation - Part 2: Establishing the sterilization dose ISO 13408-2, Aseptic processing of health care products - Part 2: Filtration ISO 13408-3, Aseptic processing of health care products - Part 3: Lyophilization ISO 13408-4, Aseptic processing of health care products - Part 4: Clean-in-place technologies ISO 13408-5, Aseptic processing of health care products - Part 5: Sterilization in place ISO 13408-6, Aseptic processing of health care products - Part 6: Isolator systems ISO 13485, Medical devices - Quality management systems - Requirements for regulatory purposes ISO 14160, Sterilization of single-use medical devices incorporating materials of animal origin - Validation and routine control of sterilization by liquid chemical sterilants © ISO 2008 - All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1:2008(E) ISO 14644-1:1999, Cleanrooms and associated controlled environments - Part 1: Classification of air cleanliness ISO 14644-2, Clean rooms and associated controlled environments Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1 ISO 14644-3, Cleanrooms and associated controlled environments Part 3: Test methods ISO 14644-4, Clean rooms and associated controlled environments - Part 4: Design, construction and start- up ISO 14644-5, Cleanrooms and associated controlled environments Part 5: Operations ISO 14644-7, Cleanrooms and associated controlled environments - Part 7: Separative devices (clean air hoods, gloveboxes, isolators and mini-environments) ISO 14698-1, Cleanrooms and associated controlled environments General principles and methods Biocontamination control Part 1: ISO 14698-2, Cleanrooms and associated controlled environments - Biocontamination control - Part 2: Evaluation and interpretation of biocontamination data ISO 14937, 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 ISO 14971, Medical devices - Application of risk management to medical devices I SO 17665-1, Sterilization of health care products - Moist heat Part 1.' Requirements for the development, validation and routine control of a sterilization process for medical devices ISO 208571), Sterilization of health care products - Dry heat - Requirements for the development, validation and routine control of a sterilization process for medical devices ICH Guidance for Industry Q9 Quality Risk Management 2) 3 Terms and definitions For the purposes of this document, the following terms and definitions apply: 3.1 action level established microbial or particulate monitoring results requiring immediate follow-up and corrective action 3.2 airlock room with interlocked doors designed to maintain pressure control between adjacent rooms of different cleanliness class 3.3 alert level established microbial or particulate monitoring results giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which could require follow-up investigation
Available at: http://www,ich.org © ISO 2008 - All rights reserved !.S. EN ISO 13408-1 :2011 ISO 13408-1:2008(E) 3.4 aseptic processing handling of sterile product, containers and/or devices in a controlled environment, in which the air supply, materials, equipment and personnel are regulated to maintain sterility NOTE This includes sterilization by membrane filtration which cannot be separated from the subsequent aseptic process. 3.5 aseptic processing area APA facilities for aseptic processing (3.4), consisting of several zones 3.6 bioburden population of viable microorganisms on or in product and/or sterile barrier system [ISO/TS 11139:2006, definition 2.2] NOTE For the purposes of aseptic processing, the bioburden of concern is that on or in the product including all factors affecting it such as raw material, intermediates, other components and equipment. 3.7 bio-decontamination removal of microbiological contamination or its reduction to an acceptable level [ISO 13408-6:2005, definition 3.1] 3.8 cleaning removal of contamination from an item to the extent necessary for further processing or for intended use [ISO/TS 11139:2006, definition 2.7] 3.9 combination product product comprised of drug/device, biologic/device, drug/biologic or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity 3.10 correction action to eliminate a detected nonconformity NOTE A correction can be made in conjunction with a corrective action. [ISO 9000:2005; definition 3.6.6] 3.11 corrective action action to eliminate the cause of a detected nonconformity or other undesirable situation [ISO 9000:2005, definition 3.6.5] NOTE 1 There can be more than one cause for a nonconformity. NOTE 2 Corrective action is taken to prevent recurrence whereas preventive action (3.29) is taken to prevent occurrence. NOTE 3 There is a distinction between correction and corrective action. NOTE 4 Corrective actions might be subject to change control. © ISO 2008 All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 3.12 critical processing zone location within the aseptic processing area in which product and critical surfaces are exposed to the environment 3.13 critical surface surface that may come into contact with or directly affect a product or its containers or closures 3.14 depyrogentatio n validated process designed to remove or deactivate endotoxins 3.15 design qualification verification that the proposed specification for the facility, equipment or system is suitable for the intended use [ISO/TS 11139:2006, definition 2.12] 3.16 direct support zone protective area directly surrounding a critical processing zone 3.17 disinfectant chemical agent that is able to reduce the number of viable microorganisms 3.18 disinfection removal, destruction or de-activation of microorganisms on objects or surfaces [ISO 14644-5:2004;definition 3.1.4] 3.19 endotoxin lipopolysaccharide component of the cell wall of Gram-negative bacteria which is heat stable and elicits a variety of inflammatory responses in animals and humans 3.20 environmental isolates microorganisms present in and/or isolated from processing or manufacturing environments 3.21 gowning procedure defined steps to reduce the risk of contamination while putting on the protective garments needed to enter the APA (3.5) 3.22 health care product medical device(s), including in vitro diagnostic medical device(s), or medicinal product(s), including biopharmaceutical( s) [ISOITS 11139:2006, definition 2.20] 3.23 high efficiency particulate air filter HEPA filter retentive matrix having a minimum particle-collection efficiency of 99,97 % (that is, a maximum particle penetration of 0,03 % for 0,3 IJm particles) © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 3.24 indirect support zone location within the aseptic processing area which protects the direct support zone NOTE The required grade of cleanliness of the indirect support zone depends on the aseptic processing activities performed in the indirect processing lone. 3.25 installation qualification 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} 3.26 isolator enclosure capable of preventing ingress of contaminants by means of physical interior/exterior separation, and capable of being subject to reproducible interior bio-decontamination NOTE An isolator can range in size from a small box to a large room. 3.27 operational qualification process of obtaining and documenting evidence that installed equipment operates within predetermined limits when used in accordance with its operational procedures [ISOITS 11139:2006, definition 2.27J 3.28 performance qualification PO 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 its specification [ISO/TS 11139:2006, definition 2.30J 3.29 preventive action action to eliminate the cause of a potential nonconformity or other undesirable potential situation [ISO 9000:2005, definition 3.6.4J NOTE 1 There can be more than one cause for a potential nonconformity. NOTE 2 Preventive action is taken to prevent occurrence whereas corrective action (3.11) is taken to prevent recurrence. 3.30 qualification documented process used by the health care product manufacturer to assure the reliability and capability of equipment and/or processes before approval for use in manufacturing NOTE Qualification of eqUipment and/or processes generally includes instal/ation qualification (3.25), operational qualification (3.27) and performance qualification (3.28). © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 3.31 risk control process in which decisions are made and measures implemented by which risks are reduced to, or maintained within, specified levels [ISO 14971:2007, definition 2.19] 3.32 separative device equipment utilizing constructional and dynamic means to create assured levels of separation between the inside and outside of a defined volume NOTE Some industry-specific examples of separative devices are clean air hoods, containment enclosures, gloveboxes, isolators and mini-environments. [ISO 14644-7:2004, definition 3.17] 3.33 shift scheduled period of work or production staffed by a single defined group of workers NOTE This is usually not more than 12 h in length. 3.34 sterile free from viable microorganisms [ISO/TS 11139:2006, definition 2.43] NOTE In practice, no such absolute statement regarding the absence of microorganisms can be proven, see sterilization (3.35). 3.35 sterilization validated process used to render a product free from viable microorganisms [ISO/TS 11139:2006, definition 2.47] 3.36 terminal sterilization process whereby product is sterilized within its sterile barrier system [ISO/TS 11139:2006, definition 2.52] 3.37 ultra low penetration air filter ULPA filter matrix with minimum 0,3 Ilm particle retaining efficiency of 99,999 % 3.38 unidirectional airflow air stream which has a defined direction 3.39 unit operation defined chemical or physical step in a manufacturing process NOTE See example of a flowchart in Annex A. © ISO 2008 - All rights reserved 3.40 validation 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 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] 3.41 worst case set of conditions that represent the greatest challenge to product integrity and safety which will be accepted during routine production Quality system elements
assure control over all activities affecting aseptic processing. Unless a superseding national, regional, or International Good Manufacturing Practice (e.g. the World Health Organization GMPs) is employed, the quality management system shall be in conformance with the requirements of ISO 9001 andlor ISO 13485. NOTE Guidance on selecting a suitable model is given in ISO 9004 and ISO/TR 14969.
control of the aseptic process shall be prepared and implemented.
personnel.
evidence of conformity to the requirements of this part of ISO 13408.
described in this part of ISO 13408 shall be assigned to qualified personnel as specified in ISO 13485.
employees to perform required work and that supervision is provided. Management shall periodically review the performance of the quality management system to assess any areas needing improvement.
independent quality management systems, the responsibilities and authority of each party shall be specified.
measuring systems.
measured. © ISO 2008 - All rights reserved 1.8. EN 180 13408-1 :2011 ISO 13408-1:2008(E) 5 Aseptic process definition
combined to maintain sterility. The purpose of the aseptic process definition is to obtain a comprehensive understanding of the integration of the different elements required. Typical elements are given in Annex B. 5.1.2 A justification for the use of aseptic processing shall be documented. NOTE The preferred option is terminal sterilization in the final container.
conducted. Methods and procedures to control these risks shall be described and implemented (see 5.2). Residual risks shall be justified. 5.1.4 The aseptic process definition shall be reviewed after stated intervals or whenever a change occurred that might impact the product or following a significant event (e.g. batch non-sterility).
how each element involved in processing contributes to the attainment and maintenance of a sterile product. NOTE For requirements for aseptically manufactured medical devices to be designated "sterile", see also ISO 15223 and national or regional requirements given in, for example, EN 556-2 or ANSI/AAMI ST67:2003.
5.2.1.1 A risk management process shall be carried out, applying ISO 14971 and/or ICH 09. Risks associated with the aseptic process shall be identified, assessed and controlled in order to establish acceptance criteria for all elements of the aseptic process definition. Compliance with the requirements as defined in Clause 6 et seq. and/or regulatory documents can be used to demonstrate acceptability of the implemented risk control. NOTE While this part of ISO 13408 is primarily concerned with microbiological contamination issues, there are other contamination risks that are relevant (e.g. endotoxin, particulate and chemical contamination).
clinical use. Microbiological risk management should follow the following four stages: a) identification of contamination risks; b) assessment of contamination risks; c) monitoring and detection of contamination; d) prevention of contamination. The measures taken to control the risks shall be proportionate to perceived risks. Specific risks shall be taken into account and the aseptic process shall be designed with due consideration of all identified factors (see Table C.1 for guidance). © ISO 2008 All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
Each unit operation shall be assessed for risks that might compromise the quality of the product. Factors to be considered shall include: a) origins of contamination:
inappropriate aseptic technique;
ability of microorganisms to cross a segregation barrier;
microorganisms being transported across a processing zone; c) proliferation of contamination:
conditions conducive to microbial proliferation; d) contamination detection and removal:
detection of microbial contamination;
adequate microbial removal. NOTE Examples of high risk procedures include handling by personnel, of sterile product or equipment and exposure of product or critical surfaces to the environment. The extent of the risk depends on the level of segregation between personnel and the item and the degree of control over the microbiological quality of the environment.
Any identified contamination risks shall be assessed regarding the potential effect on product quality. This assessment should include the evaluation of relevant process or monitoring data. Measures to minimize risks shall be prioritized based on the risk assessment. NOTE Established procedures such as Failure Mode and Effect Analysis (FMEA) or Hazard Analysis of Critical Control Points (HACep) can be applied in order to identify risks.
5.2.4.1 There shall be procedures for monitoring aseptic processing. 5.2.4.2 The procedures for monitoring the process shall not be limited to the isolation and identification of microbial contamination. Monitoring of processes shall also include particulates and endotoxins where relevant claims are made. Other contamination risks not specifically associated with aseptic processing are not addressed in this part of ISO 13408. NOTE Particle monitoring allows real-time detection of potential process deviations.
relevant for the product with regard to the nature of the material and its potential for microbiological contamination. Alert and action levels shall be set with regard to the risk of microbial proliferation and with due consideration of the control methods applied in the process. © ISO 2008 All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
microbiological quality. Monitoring shall address: a) microbiological quality of the product at defined stages during the manufacturing process (see 6.8); b) microbiological quality of the manufacturing environment including air and surfaces of rooms (see 6.8.3.1), equipment surfaces (see 6.8.3.1) and tools (see 6.8.1.7); c) microbiological status of the gloves and gowns of personnel at defined intervals (see 6.8). NOTE 1 Observation of activities is also useful for the purposes of identification of potential sources for the introduction of contaminants. NOTE 2 Monitoring of bioburden against established limits is a requirement in certain jurisdictions. 5.2.4.5 The rationale of the monitoring methods employed shall be documented. NOTE Pharmacopoeial procedures such as "Microbiological examination of non-sterile products: Microbial enumeration tests" shown in the Ph.Eur., JP and USP might be applicable.
methods with respect to recognition of risks shall be assessed. NOTE In general, the available microbiological monitoring methods are not sufficiently sensitive to detect all microbial contaminants.
response to a monitoring result should be correlated to the identified risk as determined in the risk management process.
eliminate these risks. NOTE Such measures can include design changes, additional training or procedural modifications.
preventive measures. Manufacturing environment
6.1.1 The manufacturing environment shall be designed and built in accordance with ISO 14644-4. 6.1.2 The objective(s) of the control programme for the manufacturing environment shall be defined. NOTE Aseptic processing is aimed at preventing product contamination. Where highly potent or cytotoxic health care products are to be processed, protection of personnel and the environment is considered an ancillary element of aseptic processing deSign.
a) APA layout and design including:
segregation for all cleanliness zones; © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) b) APA heating, venting and air conditioning (HVAC) system including:
airFlow velocities, number of air changes per hour and differential pressures;
airflow pattern for critical processing (and direct support zones where required);
temperature and relative humidity; c) appropriate monitoring parameters and set control levels for particulates and microorganisms; d) introduction and exhaust of utilities; e) introduction and removal of materials, components, product and waste; f) cleaning and disinfection procedures; g) provisions and procedures including gowning practices for entering and leaving of personnel; h) access for service and maintenance; i) behaviour and activities of personnel in the APA; j) provisions for corrective measures within the APA; k) personnel flow; I) pest control.
ISO 14644-7. 6.2.1.2 The facility design shall be compatible with processes or product types processed therein.
design is in compliance with the aseptic process definition or equivalent. Records of design reviews shall be retained (see 4.1.4).
assessment shall be undertaken.
6.2.2.1 Ceilings, walls, wall systems and floors shall be designed and constructed in a way that facilitates cleaning and disinfection and minimizes the shedding or accumulation of particles or microorganisms. Materials shall be chosen which are resistant to the repeated application of cleaning agents and to the disinfectants used. The edges of the floors of clean rooms shall be covered and sealed at the junction to the walls. 6.2.2.2 Ceilings shall be sealed to prevent ingress of particles from the space above. Filters, filter frames and housings, diffusers, lamps or any other penetration points shall be sealed and fitted flush with the ceiling. False ceilings and wall elements shall be sealed to prevent contamination from the surrounding areas.
operations from the outside of the cleanroom in order to minimize the need for access to the clean zones for any reason other than direct participation in the aseptic operations. Where glass is inserted in walls and doors it shall be non-opening with flush mounting on surfaces in the APA. © ISO 2008 - All rights reserved loS. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 6.2.2.4 cleaning. Where communication systems are provided in the APA they shall be designed to facilitate
cleaning agents and disinfectants used.
adequate cleaning and disinfection of ceilings, floors, walls and other surfaces.
openings or surfaces which are difficult to clean. Pipes, tubing and cables shall be routed in external service areas or ducts wherever possible. Power take-off points, switchboards, taps and connections shall be designed and installed to facilitate regular cleaning and to avoid the build-up of contamination in or behind blanking covers. Where protective housings or covers cannot be avoided (for example in switchboards of equipment), these shall be sealed in a way to prevent contamination of APA and shall only be opened when the APA is not is use.
support zones (see 6.3.3). Where drains are fitted to process equipment, appropriate backflow prevention shall be used. In other areas, sinks and drains shall be suitable for disinfection. and air breaks shall be fitted between the machine or sink and the drains to prevent back contamination. Floor drains in indirect support zones (see 6.3.4) shall be suitable for disinfection, fitted with traps or water seals and sealed when not in use.
component preparation, product preparation and filling shall be carried out in separate areas within the APA. NOTE Segregation (or separation) within the APA is achieved by the sweeping action of the air (airflows), pressure differentials, physical barriers or a combination thereof; see ISO 14644-4. Appropriate layouts shall be applied when sensitizing agents, cytotoxic or other hazardous materials are processed within the APA.
while eliminating or minimizing exposure of open containers or product to the environment. NOTE Wherever possible, utility systems and equipment are laid out to allow maintenance activities to be performed from outside the APA.
operational state.
Class 5 conditions are maintained under normal operational conditions. NOTE 1 This part of ISO 13408 refers to the classification according to ISO 14644-1. For other regional classification systems, see Annex D. NOTE 2 Examples of activities usually performed in a critical processing zone include: a) aseptic assembly of filling equipment; b) aseptic connections; © ISO 2008 All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) c) aseptic compounding and mixing; d) filling of product, containers and stoppers; e) staging and conveying of sterilized primary packaging materials; f) aseptic filling, stoppering, transfer of open or partially stoppered vials, including interventions; g) environmental monitoring. 6.3.2.2 Where isolators or similar separative devices are used for segregation of critical processing zones, ISO 13408-6 and ISO 14644-7 shall apply.
For a critical processing zone, a direct support zone with at least an ISO 14644-1 1999, Class 7 environment shall be provided to prevent contamination of the critical processing zone. In the case of an isolator or similar separative device, a risk assessment shall determine the necessary surrounding environmental class. Typically an ISO Class 8, in accordance with ISO 14644-1 :1999 or better, is used, based on the application of the isolator system. Special considerations for the room (surrounding environment) apply for negative pressure isolators (see ISO 13408-6). NOTE Examples of activities usually performed in the direct support zones include: a) transport and preparation of packaged materials for introduction into the critical processing zone; b) removal of closed product from the critical processing zone; c) preparation of operators for interventions in the critical processing zone (e.g. disinfection of gloves, staging of tools).
Indirect support zones within the APA shall be segregated and shall protect direct support clean zones. The required grade of cleanliness depends on the separation mechanism chosen. NOTE 1 A clean zone corresponding to ISO 14644-1 :1999, Class 8 is usually provided. NOTE 2 Examples of activities usually performed in an indirect support zone include: a) preparation of product solutions to be filtered; b) assembly of cleaned equipment to be sterilized; c) cleaning of equipment.
crowding, and shall be equipped with interlocking doors to prevent simUltaneous opening.
separation in time or by separate material airlocks with appropriate cleaning or decontamination in between.
classification to which it connects.
the cleanliness or segregation of the critical processing zone. © ISO 2008 All rights reserved loS. EN ISO 13408·1:2011 ISO 13408-1 :2008(E)
6.3.6.1 Personnel and materials shall enter through separate airlocks.
cleanroom and a less clean side accessible from the lower classification environment. The clean side shall be the same classification at rest as the area into which it leads. NOTE A swing-over bench is usually supplied as a minimum to separate clean and less clean parts of the airlock and to facilitate the gowning procedure. Separation of the personnel entering the direct support zone from those leaving should be achieved either by separation in time or by providing separate entry and exit routes as determined by risk assessment. Personnel airlocks should be fitted with interlocking doors to prevent doors to the clean and less-clean areas opening at the same time. Where interlocking is not implemented, doors shall be equipped with audio-visual indicators and recorder systems. Emergency exits shall be provided with a means to show that they have been opened.
cleanroom garment without contamination.
washing and hand disinfection. Hand washing facilities should only be provided in ISO 14644-1: 1999, Class 8 areas or other areas of lower control. The proper gowning practice shall be visually displayed. Gowning areas with access to the direct support zone shall be equipped with a mirror to allow the operator to confirm that the gowning has been completed properly.
Ancillary areas (such as cleaning, service and utilities), and toilet and refreshment areas shall be separated from the APA to avoid any compromise to segregation.
personnel and handling and processing of materials, components and equipment delivered to the APA in order to: a) maintain the integrity of critical processing zones; b) minimize the entry of contamination 'from outside the APA, and retain any such contamination so that it does not reach the critical processing zone; c) prevent cross contamination within the APA, ensure segregation of clean and dirty items, and ensure segregation of sterilized and non-sterilized components.
Clause 8) who are properly gowned (as described in 8.3.2). © ISO 2008 - All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
controlled to maintain segregation of the cleanroom under all specified operational conditions. 6.4.2.2 Contiguous conveyors shall not go between different classification zones.
sterilization is not possible (e.g. particle counter), the materials and/or equipment shall be biodecontaminated. Such material might be included in the monitoring programme. Where possible, dedicated equipment should be left in the APA to minimize the risk of introducing contamination.
shall be validated in accordance with ISO 11135-1, ISO 11137-1, ISO 11137-2, ISO 14160, ISO 14937, ISO 17665-1 or ISO 20857.
the APA, free of microorganisms, shall be validated.
be sterilized and introduced into the APA shall be determined at a defined and justified frequency based on the risk assessment.
potential increase in microbiological levels and possibly endotoxins that can occur up to the time that the bulk solutions are sterile filtered. Solutions shall be compounded in adequately protected tanks. A maximum allowable holding time for the solutions prior to filtration should be established.
Cleanrooms in the APA shall be ventilated and segregated to allow the specified cleanliness conditions to be maintained under operational conditions. Air entering cleanrooms shall be passed through HEPA filters to achieve the specified grade of cleanliness (see 6.2).
surrounding areas of lower grade under all operational conditions. For the critical processing zone, a unidirectional airflow of sufficient velocity to provide adequate protection shall operate other than in isolators. See 5.4 of ISO 13408-6:2005.
position, shall be defined. The specified parameters shall be controlled and recorded to demonstrate the maintenance of the specified conditions during the process.
6.5.3.1 Within the critical processing zone and direct support zone, an effectively flushing airflow pattern shall be specified. Effectiveness shall be demonstrated, verified and documented as demonstrated by air visualization studies for specified operational conditions to ensure that airflows do not present a contamination risk (e.g. distribute particles from a particle-generating person, operation or machine to a zone of higher product risk). © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1:2008(E)
adequate means at a predetermined interval for each HEPA filter and airflow patterns shall be re-established whenever a configuration change has been introduced. NOTE Significant reductions in velocity can increase the possibility of contamination and changes in velocity can affect the unidirectional pattern of the airflow.
with the sweeping action of the air.
the personnel working therein and compatible to the properties of the product being manufactured. These requirements shall be met in the presence of a full complement of operational personnel and with all equipment in operation.
where necessary.
Filters shall be tested in accordance with I SO 14644-3.
a defined aerosol challenge test within the 'filter manufacturer's facility. 6.5.5.2.2 Receipt of HEPA filters shall be accompanied by a supplier's certificate that indicates the filter has an efficiency of not less than 99,97 % for the retention of 0,3 IJm or larger particles.
method (e.g. aerosol challenge test).
confirmed. NOTE Generally, this is performed every six months.
documented procedures for the testing of the filters.
potential cause of the failure and any remedial action that has been taken shall be documented. A documented management review of investigation reports shall be conducted in accordance with defined procedures. 6.5.5.4.3 The percentage of the filter surface face area that can be repaired shall be specified. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
Cleanrooms shall be qualified to demonstrate that they meet the requirements specified in ISO 14644-1, ISO 14644-2, ISO 14644-3, ISO 14644-4, ISO 14644-5 and ISO 14644-7 and applicable regulatory guidelines and shall be compatible with the manufacturing environmental contamination control programme at rest and under operational conditions. This shall be demonstrated in a formal qualification programme.
cleanroom is not compromised by contamination from such services. 6.7.1.2 Manufacturing, storage and distribution systems for process related utilities such as purified water, water for injection(s), compressed air (and/or other gases), clean steam, and cleaning-in-place/sterilization-in- place shall be validated.
6.7.2.1 No water taps, basins or sinks shall be provided in ISO 14644-1:1999, Class 7 or better areas. Where water is needed for functioning of equipment (e.g. cooling water) this shall be contained in a closed system so that contamination of the APA is prevented. The integrity of the closed water cooling system shall be confirmed at a defined frequency. 6.7.2.2 Water used in the process in ancillary areas (e.g. for washing of primary packaging material) shall be of suitable quality to prevent contamination being introduced to the process. The water used in the process shall comply with the requirements given in Annex E.
All compressed gases (excluding combustible gases) that enter the aseptic facility shall be dry and oil-free. Those that come into direct contact with sterile products, container/closures or critical surfaces shall be filter sterilized. Integrity of the sterilizing filters shall be assured before use of the filter and at regular defined intervals, preferably by in-line testing.
6.7.4.1 If portable vacuum cleaning equipment is used it shall be fitted with an exhaust filter of at least the same efficacy as that filtering the air used for venting the area. 6.7.4.2 If a fixed vacuum source is used it shall be designed to prevent backflow.
documented programme that describes the routine particulate and microbiological monitoring of processing and manufacturing areas, and that includes a corrective action plan when specified action levels are exceeded. NOTE See Annex F for information on different zones and areas.
ISO 14644-1, ISO 14698-1 and ISO 14698-2 and/or relevant GMP requirements and shall take into account the risk assessment and the results of validation studies. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
a) sites monitored; b) frequency of monitoring; c) conditions for monitoring (at rest and/or in operation); d) method of monitoring; e) time and duration of sampling; f) alert and action levels. 6.8.1.4 The frequency of monitoring for the different zones shall be specified. a) For new facilities, the 'frequency shall be based on risk assessment. b) In other cases, the frequency shall be based on historical environmental monitoring data and with consideration of regulatory requirements. 6.8.1.5 The critical processing zone shall be monitored during each operational shift. Monitoring approaches shall not compromise the sterility of a product. NOTE Surface sampling is typically done at the end of the operation.
zone. The frequency of monitoring for such zones shall be specified. The frequency should be sufficient for the recognition of trends.
proVision for periodic surveillance monitoring at additional sites during and/or after operations. NOTE An example of such an additional sampling site is the surface of tools used for intervention in the critical processing zone. Sites selected typically relate to activities that present possible contamination risks to the product. 6.8.1.8 Additional monitoring shall be performed following initial start-up of operations or following periods of extended shutdown or modifications to the facility.
The particulate monitoring programme for areas or equipment in the aseptic processing facility where product quality or testing accuracy can be affected by particulates shall be in accordance with ISO 14644-2. NOTE 1 It is accepted that it might not always be possible to demonstrate conformity with particulate standards at the point of product exposure when aseptic processing is underway due to the generation of particles or droplets from the process itself. NOTE 2 In certain jurisdictions continuous or frequent sampling of particles is required for the critical processing zone and is recommended for the direct support zone.
designation of sites monitored by active and passive air monitoring and sites for surface monitoring, including equipment surfaces. © ISO 2008 - All rights reserved I.S. EN ISO 13408-1:2011 ISO 13408-1:2008(E)
particular aseptic processing operation. Sites shall be derived from, and be consistent with those used during validation activities and shall represent the highest microbiological risk to the product. Rationale for sites chosen shall be documented.
completion of the filling operation to prevent the risk of contamination of the product.
monitoring programme. Monitoring data shall be used to identify trends and evaluate the need for retraining. Gloved fingerprints of personnel present in the direct support zone and/or critical processing zone shall be monitored daily. At defined intervals samples from the gowns shall also be taken (e.g. both forearms, chest, hood). After a garment has been tested for microbial contamination it shall not be worn in the APA until is has been cleaned and sterilized. NOTE The frequency of sampling of gowns and gloves is based on the nature of the activities performed.
removed from work in the APA. Procedures shall be established for retraining and requalification.
air sampling methods, Semi-quantitative sampling methods should be used in addition, e.g. settle plates, swabs and contact plates, as appropriate. For active sampling, calibrated eqUipment shall be used. The rationale for the choice of sampling methodology shall be documented.
in the manufacturing environment and/or in product. The justification for the media selected and the microorganisms used to establish their growth-promoting capacity shall be documented. NOTE Qualified media, e.g. the pharmacopoeial media shown in "Microbiological examination of non-sterile products: Microbial enumeration tests" can be used.
recovered microorganisms (isolates) to facilitate a continued assessment of the risk to the product. NOTE All isolates from the critical processing zone are identified to the species level where feasible. The depth of routine characterization or identification of isolates from other zones will depend on the location of the sampling site within the APA. Differentiation of microbiological isolates shall be part of failure investigation in case of exceeded action levels,
Alert and action levels shall be developed for all sampling sites in the APA. For the critical processing zone, each microorganism detected shall be investigated. Alert levels and action levels shall be reviewed at defined, regular intervals. Alert levels in the APA shall be derived from and be consistent with results obtained from data trend analysis. NOTE 1 Action levels in support zones are typically based on regulatory guidance. NOTE 2 For new facilities, microbiological monitoring data from historical databases, process simulations, clean room qualification, and sanitization studies are frequently used in developing monitoring levels. © ISO 2008 - All rights reserved 1.5. EN 150 13408-1 :2011 ISO 13408-1 :2008(E} Appropriate investigation followed by corrective and preventive action shall be taken when action levels are exceeded. Repeated alert level results may be treated as being equivalent to an exceeded action level.
zone during the period of manufacture shall be reviewed against the alert and action levels established for the APA prior to batch release. The impact of any excursions on the product's quality shall be assessed. NOTE Averaging of results without due consideration of individual high values can mask unacceptable localized conditions.
on a routine basis. A trend report giving an overview of all environmental observations and trends shall be issued in fixed intervals. Trend reports should include data generated by location, shift, room, operator or other parameters. When indicated by individual excursions and/or trend data, an investigation shall be initiated. NOTE 1 It is important not to ignore correlations between sampling sites as single site trends may not provide a complete representation of the environment being monitored. NOTE 2 Examples of trends leading to an investigation include: a) a trend towards higher numbers of microorganisms at a sampling site; b) repeated occurrence of microorganisms not often encountered.
indicate a possible loss of environmental control such as: a) excursions above action levels; b) excursions above alert levels indicating a possible adverse trend; c) increased incidence of microbial counts below the action level and above historical levels; d) the occurrence or persistence of unusual circumstances (e.g. extended mechanical breakdowns); e) audit observations indicating a possible increase in contamination risk; f) a documented adverse trend. NOTE 1 Elements for consideration in course of the investigation include, e.g.:
data to be collected (e.g. surveillance monitoring at additional positions);
extent of review of environmental control data;
potential impact on product (e.g. need for quarantine of product);
follow-up testing;
notification of affected responsible personnel. NOTE 2 Additional testing can be required for, e.g.: the identification of source(s) of the contamination; the determination of possible impact of a deviation on product quality; a demonstration that any corrective actions were successful and the area is once again under control. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1:2008(E)
qualified personnel and distributed to the responsible key personnel.
disposition of product. 7 Equipment
Equipment used in the aseptic processing or associated testing, such as component washers, sterilizers, filter assemblies, sterilization filters, closure placement equipment, sealing machinery and Iyophilizers shall be qualified to assure its suitability for the intended purpose. NOTE This part of ISO 13408 deals only with features specific to aseptic processing. Equipment qualification is a wider concept and additional considerations are needed for technical qualification.
A user requirements document shall be generated defining the required equipment functionality and performance. It shall be reviewed and approved by the user. Considerations (in addition to other technical or safety questions) shall include, where appropriate: a) surface finish quality; b) specification for capability of being cleaned; c) specification for capability of being sterilized; d) ease of access for aseptic assembly; e) avoidance of recesses in or underneath the equipment; f) suitable arrangement of utility piping, tubing, or cables for aseptic operation; g) ease of access of internal workings without putting the APA at risk, including ability to service the equipment from outside, wherever possible; h) ease of mechanical and electrical adjustments from outside the critical processing zone wherever possible, or ease of access with minimal disturbance of the critical processing zone; i) compatibility of equipment handling with operation in an isolator, where applicable; j) prevention of contamination from computers and keyboards; k) fitting of equipment with an exhaust with filters such that the exhaust is of at least the same air quality grade as that of the area into which it is discharged; I) cleaning-in-place or sterilization-in-place of equipment.
safety requirements relevant for its intended use. © ISO 2008 - All rights reserved 1.5. EN ISO 13408·1:2011 ISO 13408-1 :2008(E)
intended product or process.
shall cross-reference appropriate equipment and "as installed" specifications. Documented evidence shall be collected to verify that the eqUipment is supplied and installed suitably for operation in the APA. Instruments shall also be calibrated before operational qualification. 7.1.4.2 Operating instructions shall be available.
or concurrent with the equipment qualification.
Documented evidence shall be collected to demonstrate that the equipment can be operated in the APA so that specified cleanroom conditions are maintained. For equipment operated in the critical processing zone, ISO 14644-1:1999, Class 5 conditions or better shall be maintained under all routinely-encountered operating conditions. Operational qualification shall demonstrate that the installed equipment is capable of delivering the specified process within the defined operating range. NOTE Specific items that are typically addressed during operational qualification for equipment used in aseptic processing include, e.g.: a} integrity of barriers; b} verification of airflow pattern and air quality; c) verification of alarm systems.
7.1.6.1 Data generated during installation qualification and operational qualification shall be reviewed for compliance with 7.1.4 and 7.1.5.
include a demonstration that the equipment operates to consistently yield sterile product.
conditions within specified tolerances throughout the process.
consistent segregation and function with minimal intervention when operated under worst case challenge conditions.
equipment shall be performed at defined intervals or as required as a result of investigations of deviations or complaints.
criteria in accordance with documented procedures. Records shall be retained of reviews of revalidation data, and of corrective action taken in the event of the specified acceptance criteria not being met © ISO 2008 - All rights reserved loS. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 7.1.7.3 The extent to which requalification is carried out shall be justified. 7.1.7.4 Requalification report(s) shall be documented and retained.
7.2.1.1 Utilities, services and equipment shall be part of the preventive maintenance programme.
documented in accordance with documented procedures.
a) of suitable design; b) capable of being cleaned; c) capable of being disinfected or sterilized; d) appropriately stored to prevent contamination.
requirements.
of service and shall not be re-used until it has been subjected to a defined cleaning and disinfection procedure before the area has been requalified.
support zone shall be performed using aseptic techniques and only to the extent that it has been simulated during process simulation. If the unplanned maintenance has not been qualified, the process shall be stopped and any exposed units of product shall be removed from the process and disposed of appropriately.
of service and not be re-used until it has been subjected to a defined cleaning and disinfection procedure before the area has been requalified.
that the specified process conditions have been re-established. Personnel
established and implemented. Management shall be responsible for defining criteria to assess personnel performance. These criteria shall include, at a minimum, process simulation participation, gowning qualification and compliance with procedures.
environmental conditions. The effectiveness of the documented procedures shall be evaluated at intervals defined by the manufacturer. © ISO 2008 - All rights reserved I.S. EN ISO 13408·1 :2011 ISO 13408-1 :2008(E)
personnel (including supervisors, quality assurance staff and maintenance staff) are appropriately qualified before entering or being assigned work in the APA, as defined in 8.2.
based on successful completion of defined training. Training in the various disciplines and activities should be in proportion to the individual's duties and directed at the appropriate level of knowledge.
a) fundamentals of microbiology related to aseptic processing; b) design and necessary functionality of the facility contamination control concept including awareness of segregation, barriers, monitors and alarms; c) microbiological risk assessment and risk prevention; d) personal hygiene (e.g. hand washing and disinfection procedures, and the requirement to report any adverse health conditions); e) rules concerning the wearing of cosmetics, wristwatches and jewellery; f) manufacture of sterile products within the APA; g) aseptic technique; h) gowning procedures; i) clean room practices; j) emergency procedures to protect product quality (e.g. failure of HVAC system, loss of power, etc). NOTE General issues of good manufacturing practice and health and safety aspects are not within the scope of this part of ISO 13408.
manufacturing process. Specifically, this training ensures operators have the requisite knowledge in good aseptic technique and practices necessary to avoid: a) any contact with critical surfaces including sterilized materials and components; b) unnecessary contact with walls, floors and cleaned surfaces; c) unnecessary and/or rapid movements which can generate particles or create turbulence; d) unnecessary talking; e) reaching across open containers and exposed product and components; f) blocking airflow over critical surfaces.
monitoring shall include multiple locations on the gown. Verification of results shall be documented and communicated to the personnel and management.
nature of the operations performed. The rationale shall be documented. © ISO 2008 - All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
shall be accompanied at all times by a person who has been qualified. Requirements shall be specified for access to the APA for persons who have a legal or contractual right of access (e.g. competent authorities, notified bod ies, contractors). Other visitors shall not have access to the critical processing zone and direct support zone.
equipment, filling or manufacture of sterile products or maintenance work in the critical processing zones shall take part in a process simulation that meets the requirements of this part of ISO 13408. 8.2.8 New personnel who will work in the critical processing zone shall take part in at least one successful process simulation or justified equivalent aseptic operation, which may be performed in a training environment, before they are permitted to participate in processes carried out in critical processing zones.
and relevant quality systems elements at a defined frequency and if there is an indication of necessity. 8.2.10 Training shall be documented and its effectiveness shall be assessed as appropriate (e.g. by oral or written tests, successful partiCipation in practical exercises or in process simulation). Records of training and evaluation shall be maintained.
contamination control assessment and the segregation requirements for the APA. Gowns to be used in the APA shall have a documented specification.
a) removal of personal outer clothing; b) donning factory uniform; c) donning indirect support zone clothing; d) donning critical processing zone and direct support zone clothing. NOTE It is possible to go from b) to d) using a dedicated changing room. Personnel shall not wear direct or indirect support clothing outside the APA. 8.3.1.3 defined. The maximum number of people that can be in the gowning airlock simultaneously shall be
aseptic processing environment. The procedures shall address: a) removal of outside garments, wristwatches, jewellery, cosmetics and shoes; b) hand washing and/or hand disinfection; c) specification of the complete set of cleanroom garments; © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1: 2008( E) d) stepping over barriers in compliance with the segregation concept; e) sequence of putting on the cleanroom garments; f) techniques of gowning and de-gowning; g) washing and validated sterilization procedures for gowns. The permissible number of washing/cleaning and sterilization cycles for the gowns shall be defined and a tracking system implemented to confirm the permissible number of washing/cleaning and sterilization cycles. Criteria shall be established for acceptability of gown integrity.
suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. These should not shed fibres. 8.3.2.3 Sterilized garments for critical processing zone and direct support zone shall fully cover the body. There shall be no exposed areas of the face. The garments shall retain particles while allowing passage of moisture vapour for wearing comfort. The fabric shall minimize particle shedding. Fresh garments shall be worn each time a person enters these zones. NOTE 1 Sterile garments for critical processing zone and direct support zone are frequently composed of a one-piece suit, hood, overboots, gloves, face-mask and goggles. NOTE 2 Some cleanroom operations use arm covers, extra high boots and double gloves to minimize the likelihood of gaps or tears occurring during movement. NOTE 3 Typically, cleanroom gowns are washed in a dedicated facility, individually packed in sterilizable bags and sterilized by steam or irradiation. 8.3.2.4 Garments worn in the APA shall fit the individual operator. NOTE For example, a large gown on a small individual could create a bellows-like effect and, in the process of normal operations, the gown could bellow outwardly emitting microorganisms and particulates into the room. Conversely, a small gown might not provide adequate coverage of hair and skin. 8.3.2.5 Employees shall wear gloves in critical processing and direct support zones. NOTE Two pairs of gloves are frequently used; the first pair of gloves can be used as gowning gloves.
verified by at least looking in a mirror.
wrist and neck) no gaps or exposed skin are apparent.
deSigned to minimize particulate generation, but these garments normally need not be sterile prior to use.
such as fever, skin lesions, common cold, diarrhoea, etc. 8.4.2 Personnel with reported or observed health conditions affecting aseptic work shall not be permitted to enter the APA but may be assigned work in other areas. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) Manufacture of the product
have been sterilized. 9.1.1.2 Suitable protection after sterilization shall be provided to prevent recontamination.
endotoxins shall comply with a limit test for endotoxins defined and justified by the manufacturer. This applies to raw materials (including water), intermediate products (such as bulk solutions or suspensions) and other components (such as container components) used as part of the product The levels of endotoxin shall be determined by pharmacopoeial procedures unless it is necessary, taking into account the nature of the product, for the manufacturer to define and document an alternative or modified test procedure. NOTE Examples of pharmacopoeias include Ph.Eur., JP and USP.
components prior to treatment in a depyrogenation process.
the process will remove a greater quantity of endotoxin than might have been originally present in the component or product. Typically, a reduction by a dry heat depyrogenation of at least three orders of magnitude of spiked endotoxin process is required. NOTE Plastic medical devices, closures and/or containers can be depyrogenated by rinse processes, and/or high temperature moulding and/or extrusion processes prior to filling. Rubber compound stoppers can be rendered pyrogen- free by multiple cycles of washing and rinsing prior to final steam sterilization.
manufacture (including raw materials incorporated directly in the product, bulk suspensions prepared in advance and container components) shall be sterilized where possible using validated methods of sterilization appropriate to the specific material. The chosen method of sterilization shall be justified.
requirements of ISO 13408-2 shall apply. 9.1.3.3 Where it is not possible to sterilize some materials (e g. live tissues or some live vaccines, the procedures to achieve product of the required quality shall be specified).
The total time for each unit operation of an aseptic process shall be minimized and limited to a defined maximum. Examples include: a) holding time for formulated bulk prior to filtration, where applicable; b) holding time for sterilized components prior to and during filling/assembly; © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1:2011 ISO 13408-1 :2008(E) c) filling or aseptic assembly; d) holding sterile product prior to filling; e) component washing and sterilization; f) maximum exposure time of sterilized containers and closures in the critical processing zone (including filling) prior to closure.
9.3.1 Procedures shall be in place describing the operation of all critical equipment. 9.3.2 Aseptic manufacturing procedures shall be described in detail in documented operating procedures. The procedures shall specify the sequence of steps to be performed, their execution, their time course and any permitted interventions.
9.4.1.1 A cleaning and disinfection programme for the APA shall be specified.
and disinfectants. Cleaning agents and disinfectants used on the same surface shall be mutually compatible. 9.4.1.3 retained. The application of cleaning and disinfection procedures shall be documented and records 9.4.1.4 The removal of disinfectant and cleaning agent residues from critical surfaces shall be validated. NOTE Residuals from cleaning agents might need to be removed prior to disinfection.
appropriate environmental control based on the evaluation of environmental data trends and the assessment of product contamination due to the frequency and nature of aseptic processing.
shall be reserved exclusively for this area.
agents and disinfectants unless alternative procedures are justified.
disinfection procedures.
shall be sterile.
The documented cleaning plan shall address at least: a) approved agents for cleaning, their working dilution, approved storage time and methods for sterilization, where applicable; b) procedures for cleaning; © ISO 2008 - All rights reserved 1.5. EN 150 13408-1:2011 ISO 13408-1:2008(E) c) cleaning aids used, their maintenance and, where applicable, sterilization and storage; d) time and frequency of cleaning; e) responsibilities.
a) approved agents for disinfection, their working dilution, approved storage time and conditions, methods for sterilization for ISO 14644-1: 1999, Class 5 and Class 7 APAs; a sporicidal agent shall be used if environmental monitoring indicates the necessity; b) procedures for disinfection, disinfectant application, required time of action and employee safety precautions; c) disinfection aids used, their maintenance and, where applicable, sterilization and storage; d) post-disinfection cleaning where required; e) time and frequency of disinfection; f) responsibilities. 9.4.3.2 Disinfectant containers shall be labelled with an expiration date.
use for critical processing zone and direct support zone. The use of these containers shall be restricted to one working day. 9.4.3.4 Interchanging or rotating disinfectants should be considered. NOTE When variations in species or species ratio of microorganisms are observed, interchanging or rotating disinfectants can be considered in order to avoid the development of microbial resistance to the disinfectants.
use. Equipment in ISO 14644-1:1999, Class 7 or better shall be sterilized before use.
appropriate evaluation shall be performed. The following characteristics shall be considered for APA use: a) particle generation (both wet and dry); b) sterilization compatibility; c) packaging to ensure sterile transfer into the APA area.
The continued effectiveness of cleaning and disinfection shall be assessed and documented (see 6.8.6).
determined. © ISO 2008 - All rights reserved 1.5. EN 150 13408-1 :2011 ISO 13408-1 :2008(E) NOTE Validation of disinfectant effectiveness is usually done in laboratory studies demonstrating the capacity of the agents to inactivate inoculated test microorganisms in suspension and in simulated use conditions. Manufacturer's validation reports, if suitably verified, or validation reports of independent testing institutions, can be accepted if it is confirmed to be relevant to the individual manufacturer situation.
microorganisms recovered from surfaces before and after cleaning.
9.5.1.1 A cleaning, disinfection and sterilization programme for the equipment shall be established. 9.5.1.2 Cleaning, disinfection and sterilization shall be documented and records retained. 9.5.1.3 Levels of residuals of cleaning agents shall be controlled at defined and justified maximum levels.
shall ensure removal of residues to defined levels. NOTE Residues can interfere with subsequent disinfection and sterilization.
a) location where cleaning is to be performed; b) procedures for disassembly, cleaning and reassembly; c) approved cleaning agent(s) used including their concentration, volume applied, cleanliness grade or specification, pre-treatment (e.g. sterilization) and approved storage time and conditions; d) tools to be used (e. g. wipes) including their cleanliness grade or specification, pre-treatment (e. g. sterilization) and storage conditions; e) measures to protect cleaned equipment or parts thereof from recontamination; f) specification of cleanliness (e.g. permitted residue limits) to be reached; g) control measures taken to assure that cleanliness specifications are met. 9.5.2.3 Where cleaning-in-place is used, ISO 13408-4 shall apply.
9.5.3.1 The effectiveness of the disinfection procedures shall be determined.
a) procedures for disinfection, disinfectant application, required contact time, post-disinfection cleaning (if required) and employee safety precautions; b) approved agents for disinfection, concentration (working dilution), methods for sterilization of the agents, where applicable, approved storage time (expiry dating) and applicable storage conditions; c) schedule and responsibility for disinfection. © ISO 2008 - All rights reserved 1.5. EN ISO 13408·1 :2011 ISO 13408-1 :2008(E)
9.5.4.1 Critical surfaces of equipment shall be sterile. NOTE SIP is preferred over disassembly, sterilization and aseptic reassembly. 9.5.4.2 Sterilization procedures shall be validated.
a) detailed procedure for disassembly, pre-treatment, sterilization and reassembly, where applicable; b) type of sterilization process and sterilization conditions to be reached; c) documented control measures taken to assure that process specifications are met throughout the equipment and all critical surfaces are reached; d) procedures to protect sterilized equipment or parts thereof from recontamination; e) storage time and conditions of sterilized components where applicable; f) procedure and frequency of revalidation measures for the sterilization process. 9.5.4.4 Where sterilization-in-place is used, ISO 13408-5 shall apply.
endotoxin level for a particular product or product component.
validated to demonstrate a defined reduction in endotoxin level.
endotoxin level. 10 Process simulation
is possible to divide the process into unit operations but all parts of the process shall be simulated. Filter bacterial retentive capacity shall be validated in accordance with ISO 13408-2. NOTE Process simulation is not intended to validate product sterilization (e.g. the capacity of the sterilizing filter).
product as the principal method available to assure that the aseptic process is functioning as intended. For sterile aseptically produced semi-solids, powders, solid materials (including medical devices), microspheres, liposomes and other formulations, evaluation by use of traditional liquid media filling may not be possible. In such cases surrogate procedures that represent the operations as closely as possible shall be developed and justified. These procedures may include processing of a sterile surrogate as normal with subsequent immersion in sterile media or some other means of simulation. Sterility of the surrogate shall be determined after it has been subjected to the total aseptic process. © ISO 2008 - All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
designated group of reference microorganisms and supporting microbiological recovery of low numbers of these microorganisms. NOTE Process simulation is usually conducted with soybean casein digest medium. Media fills with anaerobic media can be required if obligate anaerobic organisms are isolated from environmental or product samples.
material shall not inhibit the growth of the reference microorganisms.
incubation of the filled units and shall use an appropriate number of units from the run. Growth promotion tests shall be conducted with the organisms and methods specified in tile applicable pharmacopoeias. The growth promotion inoculum shall be less than 100 cfu (colony forming units) per filled unit. NOTE 1 Examples of pharmacopoeias include Ph.Eur, JP and USP. NOTE 2 For complex process simulations, it can be necessary to ascertain that the samples of media taken for growth promotion testing are representative of the entire process to ensure that no parts of the process alter the growth-promoting properties of the media.
procedures and shall, as far as is reasonably practicable, include permissible worst case conditions. Simulations shall include: a) maximum permitted holding times and interventions representative of the routine process at the maximum accepted frequency per number of filled units (e.g. weight adjustments, container/closure or product re- supply, sampling or environmental monitoring); b) frequently occurring unscheduled interventions in representative number and with the highest degree of intrusion acceptable (e.g. corrections for container breakage or tip-over, corrections for leakage of fluid, corrections for stopper jams, correction of line stoppage). A list of permitted interventions shall be prepared and retained.
may be used for initial validation (i.e. bracketing). NOTE 1 Following initial validation each configuration can be used in a process simulation at a defined frequency. NOTE 2 Containers with the widest diameter openings and operation at the lowest line speed can represent a worst case due to longest exposure, whereas small containers can represent a worst case due to lack of container stability in the line operations and the need for increased manual intervention.
programme.
inverted, and provide sufficient head space to ensure capability of microbial growth and to ensure that turbidity can be detected at examination.
not possible the examination shall be by transfer of the entire contents to a transparent vessel. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
air in the process simulation unless anaerobic simulation is intended.
otherwise to assist in the investigation should one become necessary. For lyophilized products process simulation, ISO 13408-3 applies.
possible, simulation runs shall be of sufficient duration to cover representative manipulations, interventions and shift changes performed in actual processing. Where the actual aseptic process is interrupted (e.g. during the night and continued the next day) such breaks should also be simUlated. Environmental monitoring shall be conducted to ensure that there has been no deterioration of the filling environment.
media with all interior surfaces in the container.
being rejected during routine documented visual inspection procedures shall be recorded and removed. Cosmetic defects, non-destructive weight checks and all other units shall be identified and incubated with the other units. If documentation clearly describes the disposition of containers exposed during interventions and these are normally discarded, then there is no need to incubate such containers produced during process simulation tests.
be within the range of 20°C to 35 °C. The use of a specific temperature or temperature range shall be justified and documented. NOTE If two temperatures are used for incubation, the units are typically incubated for at least 7 days at each temperature (starting with the lower temperature).
presence of microbial growth using a defined procedure. NOTE Inspection of the units at an earlier time period can be useful to gain a preliminary indication of the results.
required to assist in the determination of the likely source of the contaminant. NOTE Genotypic identification methods can be of use in aSSisting in determining the likely sources of contaminants if applied to test and environmental isolates.
Initial performance qualification shall be conducted for each aseptic processing operation for each line and for each unique product configuration that has not been represented in a previous performance qualification. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
10.5.2.1 A sufficient number of units shall be processed (filled) to simulate effectively all activities that are representative of the manufacturing process.
in Table 1. NOTE It might be necessary to fill more than the minimum number of containers per media fill run in order to accommodate process variables and interventions routinely encountered during production.
10.5.3.1 The aim of any process simulation shall be to achieve zero contaminated units. NOTE As the aim is to fill sterile product and not to fill product with a low number of contaminated units, the filling of a larger number of vials does not result in a higher number of contaminated units that can be accepted. 10.5.3.2 Any contaminated unit shall result in an investigation to determine the cause (if possible). For acceptance criteria, see Table 1.
every six months) for each aseptic process and filling line. A single filling configuration shall be chosen for each requalification run. The line qualification shall include the activities and interventions representative of each shift and shift changeover.
months shall be requalified with an acceptable process simulation test before production is resumed.
performed when investigation identifies the need, e.g. in case of major changes in personnel, anomalies in environmental monitoring results or finished product sterility test results. NOTE Change control might require requalification.
The minimum number of runs and the number of units filled per simulation are summarized in Table 2. NOTE It can be necessary to fill more than the minimum number of units per media fill run in order to accommodate process variables and interventions routinely encountered during production.
10.6.3.1 The aim of the process simUlation shall be zero contaminated units. 10.6.3.2 Each process simulation resulting in contaminated units shall be investigated. 10.6.3.3 Acceptance criteria are shown in Table 2.
qualification is restarted. © ISO 2008 - All rights reserved I.S. EN ISO 13408-1 :2011 ISO 1340S-1 :200S(E)
An aseptic process or filling line shall be subject to a repeat of the initial qualification studies when: a) requalification of the line has failed; b) production lines have not been in operation for an extended period of time, e.g. one year; c) there has been a change that has potential to affect the aseptic process. 10.S Documentation of process simulations
processed. I nformation included with, or cross referenced in, the records for each process simulation run should be, e.g.: a) date and time of process simulation; b) identification of processing area or room used; c) container/closure type and size; d) volume filled per container; e) processing speed; f) type of media filled; g) number of units filled; h) number of units rejected at inspection and the reason for the rejection; i) nurnber of units incubated; j) nurnber of units positive; k) incubation time(s) and temperature(s); I) procedures used to simulate any steps of a normal production fill, which might include, for example, mock lyophilization or substitution of vial headspace gas; m) microbiological monitoring data obtained during the media fill set-up and run; n) list of personnel per shift who participated in the process simulation; 0) growth promotion results; p) identification of the microorganisms from any positive units; q) management review; r) product(s) covered by the process simulation; s) investigation of runs with a positive unit or failed runs.
implemented. The effectiveness of the corrective measures should be investigated, where possible, and verified separately before conducting additional runs. © ISO 2008 - All rights reserved loS. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E)
quarantined until a successful resolution of the process simulation has occurred,
to aseptic production since the last successful process simulation. The outcome of the review shall include justification for the disposition of batches of product affected, Table 1 - Media fills - Initial performance qualification Number of Contaminated Simulation runs Minimum number units filled per units in any of affected by Action of simulations the three simulation simulations contaminated units Investigation, < 5 000 ~ 1 corrective measures, restart validation I Investigation, consideration of repeat of one media fill 5 000 to 10 000 Investigation,
1 1 corrective measures, restart validation Investigation 10 000 Investigation, corrective measures, restart validation Table 2 - Media fills - Periodic performance requalification Minimum number of Number of units Contaminated simulations filled per units Action simulation 5 000 Investigation, revalidation Investigation, consideration of repeat 5 000 to 10 000 media fill Two per year<> Investigation, 1 corrective measures, revalidation Investigation 10000 Investigation, corrective measures, revalidation a The simulations shall cover all line configurations and all shifts. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) 11 Test for sterility
Where sterility testing is required for aseptically-filled products, this testing shall be conducted for each batch. The pharmacopoeial sterility tests are used when the method is applicable. Where there is no specific method in the pharmacopoeia that is applicable to a particular product the manufacturer shall specify the method to be used. NOTE 1 Examples of pharmacopoeias include Ph.Eur., JP and USP. NOTE 2 In certain jurisdictions approval of non-pharmacopoeial sterility tests is required by the relevant competent authorities.
determine the source of contamination, including whether the growth occurred due to contamination during the test.
manufacturing environment and the sterility testing room and those isolated from positive units using tests for sterility. NOTE Further guidance on the investigation of organisms isolated from positive units using tests for sterility can be found in the pharmacopoeias. © ISO 2008 - All rights reserved ISO 13408-1 :2008(E) Key indirect support zone 1.5. EN ISO 13408-1 :2011 Annex A (informative) Example of a flow chart direct support zone outside APA critical processing zone direct support zone Figure A.1 - Example of an aseptic process divided into unit operations © ISO 2008 All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008{E) Annex B (informative) Typical elements of an aseptic process definition The following list contains typical elements that should be compiled to establish and document an aseptic process definition: a) justification (for not using terminal sterilization); b) applicable regulatory requirements and guidance; c) applicable quality management systems; d) facilities design; e) equipment design; f) product and delivery system; g) processes and technologies implemented;
product, component and equipment sterilization/depyrogenation;
aseptic process containment, i.e., RABS (restricted access barrier system), isolators or cleanrooms;
personnel protection systems'/methods' effect on aseptic processing;
product manufacturing methods;
closure/packaging integrity assurance; h) environmental control and monitoring programme; i) master validation plan (e.g., process simulations, validation of unit operations); j) change control process; k) product release process. In preparing an aseptic process definition, products might be grouped together based on their characteristics and presentation. NOTE It is useful to organize the aseptic process by unit operations, see example of a flow chart in Annex A. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1:2008(E) Annex C (i nformative) Examples of specific risks Table C.1 is given for guidance only. It includes examples of spedFic risks that might be of relevance in the risk management strategy. Table C.1 - Examples of specific risks including examples of control measures Aspect Examples Examples of specific Examples of control measuress microbiological risks Ingredients • Biological origin · High numbers of yeast, · Choice of approved suppliers · Natural product mould and bacteria • Supplier audits · Synthetic origin · Mycoplasma • Supplier certificates • Ingredient with biocidal • Viruses • Control of incoming materials activity • Endotoxin level • Control of pre-filtration bioburden • Prions (yeasts, moulds and bacteria) • Ultrafiltration (endotoxins) Nature of the · Solution · Ability to support • Perform growth studies on product product (preserved or microbial growth (if water based, non unpreserved) • Bioburden increase preserved) • Suspension · Endotoxin • Single dose formulation · Crystallized powder contamination · Water activity determination • Lyophilized powder • Contamination during • Holding time limitations of non • Cream or ointment manufacture sterile bulk • Solid device • Refrigeration of non sterile bulk • Combination product • In process bioburden monitoring Formulations with biocidal activity Product • Ampoules • Contamination during • 100 % leak test presentation! • Vials manufacture • Container closure integrity test design • Pre-filled syringes • Use of RABS or isolators • Form-fill-seal • Dual filters,final filter close to • Multi-dose containers pOint of fill • Environmental programme including continuous particle monitoring Technical · Multi-stage manufacturing • Contamination during • Use of RABS or isolators complexity of • Manual assembly steps manufacture • Pressurize sterile bulk tanks the • Complicated delivery during holding time manufacturing device • CIP!SIP of all sterile product process contact parts • Robotic assembly versus manual • Automatic transport and loading/unloading of freeze dried products Intended • Topical use • Potential impact of • Patient convenience devices clinical use of • Parenteral use product • Nurse convenience devices the product • Eye care (e.g. for reconstitution of vials) · Single dose/Multiple use • In-use time studies • Implantable • New preservative systems • Multidose preservative free presentations a These are examples only; alternative measures may be available and may be more effective for a specific application. © ISO 2008 - All rights reserved 1.5. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) Annex D (informative) Comparison of classification of cleanrooms In this part of ISO 13408 reference has been made to ISO 14644-1 classification only. This annex gives information on other regional and/or national classification systems. Table 0.1 - Classification systems Classification according to ISO 14644-1 ISO 13408-1 Traditionala EU GMP Guide EU GMP Guide Annex 1b Annex 1b (particles> 0,5 f-lm/m3) (particles ~ 0,5 f-lm/ft3) (in operation) (at rest) 5 (3 520) Critical processing zone Grade A Grade A and B 6 (35200) l\Iot defined 1 000 Not defined Not defined 7 (352 000) rect support zone 10 000 Grad", LJ Grade C 8 (3 520 000) Indirect support zonec 100 OOOc Grade C Grade D Grade D undefined a FDA Guidance for aseptic processing, September 2004. b EU GMP Guide, Annex 1 :2003 (drafted revision 2005) refers to ISO 14644 but limits for non-viable particles are defined differently. C Activities performed in these zones are split in the EU GMP Guide, Annex 1 into Grade C and D. © ISO 2008 - All rights reserved loS. EN ISO 13408·1:2011 ISO 13408-1 :2008(E) Annex E (i nformative) Specification for water used in the process E.1 Source water E.1.1 Potable water or water brougllt to potable water specification shall be the source water for the manufacture of purified water qualities used in aseptic manufacturing. Other use of source water shall be restricted to cleaning purposes outside of the APA, and for washing of hands in gowning rooms. E.1.2 A specification shall be established and documented for source water. Due account shall be taken of local legislation relating to the quality of source water in setting this specification. E.2 Treated source water E.2.1 If source water is given additional treatment to reduce further the bioburden, then strict separation shall be maintained between such water and untreated source water. NOTE 1 Suitable additional treatments can include ozonation or chlorination as an initial step. NOTE 2 Treated source water can also be used in certain circumstances such as spray coolant in such autoclaves where the coolant cannot be sterilized (e.g. by recirculating throughout the autoclave). E.2.2 Treated source water for spray cooling during autoclave cycles shall be monitored frequently for microbial content and for activity of added substance(s). E.3 Purified water E.3.1 Purified water can be used in initial rinsing of components, equipment, closures, etc. Purified water can be used as an ingredient in certain non-parenteral products, e.g. contact lens solutions. NOTE Purified water might be defined in national and regional pharmacopoeias. E.3.2 The microbial content shall be monitored and controlled to a limit appropriate to the intended use of the water as may be required by applicable regulatory or pharmacopoeia speCifications. NOTE Suitable test methods can be found in the pharmacopeias. E.3.3 Purified water distributed in fixed systems shall be circulated or kept in motion to minimize the formation of biofilm inside pipes and tanks. The system shall be sanitized according to a specified and documented frequency. E.3.4 The water distribution system shall be designed to avoid areas where water does not flow freely and shall not allow water to stagnate. E.3.5 If bacteria-retentive filters are used in the system they shall be sterilized, integrity tested, and shall be changed according to a defined frequency and procedure. Filters of other porosities, e.g. particulate retentive filters, if used, shall be changed at a defined frequency. E.3.6 Tanks and distribution systems for purified water should be constructed from suitable materials for the intended use. © ISO 2008 All rights reserved I.S. EN ISO 13408-1 :2011 ISO 13408-1 :2008(E) E.4 Water for injections E.4.1 Water for injection (WFI) shall be used for formulation of injectable products and other health care products as required by national regulations and in final rinsing of components, equipment, closures, etc. for the manufacture of such products. E.4.2 The feed-water to the WFI equipment shall be pretreated appropriately. Attention should be paid to bioburden and/or endotoxin levels in the feedwater. The composition of the incoming source water should determine the choice of subsequent pretreatment steps. If chlorine is present, the use of a carbon bed should be considered. If colloids, organic substances or silicates in the source can penetrate the ion exchangers, additional steps like single or double pass reverse osmosis units can be employed as additional steps. It is recommended that the feed water be circulated in order to minimize the formation of biofilm. E.4.3 WFI in distribution systems shall be maintained at > 70 °e and circulated within a loop. Where temperatures are < 70 °e a validated periodic sanitization cycle shall be used. The system shall be designed to avoid areas where water does not flow freely, and shall not allow water to stagnate. The temperature should minimally be monitored and recorded at the end of the return loop. E.4.4 The WFI distribution system shall be made of stainless steel suitable for the intended use. Its suitability shall be documented in the design qualification. Guidelines, e.g. ISPE Baseline, may be consulted for design aspects of finish, welding, slope, etc. E.4.5 Frequent monitoring of conductivity, TOe, bioburden and endotoxins shall be undertaken. Specified and documented monitoring shall be performed on all use points where water can be drawn from the system. NOTE Suitable test methods can be found in the pharmacopeias. E.4.S Disinfection or sanitization of the WFI system shall be undertaken according to a defined procedure and frequency, and after a system breach or after a system integrity failure. If chemicals are used in the cleaning/disinfection/sanitization process their removal from the system shall be validated and confirmed. WFI systems recirculating continuously at > 70 °e may not require periodic disinfection unless a system breach or integrity failure has occurred. However, provisions are recommended for heating up to, e.g., 95°C under certain circumstances. © ISO 2008 - All rights reserved ISO 13408-1 :2008(E) 1.5. EN 150 13408~1 :2011 Annex F (informative) Aseptic processing area Figure F.1 illustrates an example of an aseptic processing area. 3 4 10 1-.....:::l;·,"''''r-...c Key -
===== Part1_Amd =====
© ISO 2013
Aseptic processing of health care
products —
Part 1:
General requirements
AMENDMENT 1
Traitement aseptique des produits de santé —
Partie 1: Exigences générales
AMENDEMENT 1
INTERNATIONAL
STANDARD
ISO
13408-1
Second edition
2008-06-15
Reference number
ISO 13408-1:2008/Amd.1:2013(E)
AMENDMENT 1
2013-05-01
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ISO 13408-1:2008/Amd.1:2013(E)
Foreword
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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.
Amendment 1 to ISO 13408-1:2008 was prepared by Technical Committee ISO/TC 198, Sterilization of
health care products.
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Aseptic processing of health care products —
Part 1:
General requirements
AMENDMENT 1
Page vi, Introduction
In the second paragraph, replace the second sentence with the following:
ISO/TC 198 has prepared standards for terminal sterilization of health care products by irradiation
(ISO 11137 series), by moist heat (ISO 17665 series), by dry heat (ISO 20857), by ethylene oxide
(ISO 11135) and by liquid chemical sterilants (ISO 14160).
Page vii, Introduction
At the end of the last sentence of the penultimate paragraph, add the word “component” so that it reads:
“... of which process simulation studies are an essential component.”
Page 1, Normative references
Delete the following reference:
ISO 9001, Quality management systems — Requirements
Page 2, Normative references
Delete footnote 1 and renumber footnote 2 accordingly.
Page 3, 3.7
Delete the following:
[ISO 13408-6:2005, definition 3.1]
Page 4, 3.14
Correct the spelling of the term to read “depyrogenation”.
Page 5, 3.24
Replace the note with the following:
ISO 13408-1:2008/Amd.1:2013(E)
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ISO 13408-1:2008/Amd.1:2013(E)
NOTE
The required grade of cleanliness of the indirect support zone depends on the aseptic processing
technologies and activities performed.
Page 7, 4.1.1
In the first sentence, replace “over all activities affecting aseptic processing” with “over all activities
affecting aseptic processing (e.g. ISO 9001 and/or ISO 13485)”.
Delete the second sentence.
Page 7, 4.3.2
Replace the text with the following:
The accuracy and tolerance of all measuring instruments shall be adequate for the parameters
to be measured.
Page 8, 5.2.1.2
At the end of the subclause, insert the following note:
NOTE
Assessment of risk to condone poor or improper practice during aseptic processing is not appropriate.
Page 10, 5.2.4.4
Replace item a) with the following:
a) microbiological quality of the product at defined stages during the manufacturing process, alert
and action levels shall be established;
Page 10, 6.1.2
Replace the second sentence of the note with the following:
Where highly potent, cytotoxic or radioactive health care products are to be processed, protection of
personnel and the environment is considered an ancillary element of aseptic processing design.
Page 36, Table 1, fifth column
In the first, third and fifth rows, replace “restart validation” with “repeat initial performance
qualification” to be in line with the title of Table 1.
Page 36, Table 2, fourth column
In the first, third and fifth rows, replace “revalidation” with “repeat initial performance qualification” to
be in line with the title of Table 1.
2
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ISO 13408-1:2008/Amd.1:2013(E)
Page 37, 11.1
Replace the text of 11.1 (excluding the notes) with the following:
Where a test for sterility is required for aseptically-filled products, then this testing shall be
conducted for each batch of product. The pharmacopoeia test for sterility is used when the method is
applicable. Where there is no specific method in the pharmacopoeia that is applicable to a particular
product, then the manufacturer of the product shall specify the method to be used.
Replace NOTE 2 with the following:
NOTE 2
In certain jurisdictions approval of a non-pharmacopoeia test for sterility is required by the
relevant competent authorities.
Page 37, 11.2.2
Replace “from positive units using tests for sterility” with “from positive units during tests for sterility”.
In the note, replace “from positive units using tests for sterility can be found in the pharmacopoeias”
with “from positive units during tests for sterility can be found in the pharmacopoeias”.
Page 38, Figure A.1
Replace Figure A.1 with the following:
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ISO 13408-1:2008/Amd.1:2013(E)
Key
indirect support zone
direct support zone outside APA
critical processing zone
direct support zone
indirect support zone + grade A air flushing
Figure A.1 — Example of an aseptic process divided into unit operations
Page 41, Table D.1
In footnote b, replace “EU GMP Guide, Annex 1:2003 (drafted revision 2005)” with “EU GMP Guide,
Annex 1:2009”.
4
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Page 45, Bibliography
Insert the following new reference:
[2] ISO 9001, Quality management systems — Requirements
Renumber subsequent references accordingly.
Replace Reference [16] with the following:
[16] EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary
Use (GMP), Volume 4 — Annex 1:2009 Manufacture of Sterile Medicinal Products
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ISO 13408-1:2008/Amd.1:2013(E)
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ICS 11.080.01
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===== Part2 =====
© ISO 2018
Aseptic processing of health care
products —
Part 2:
Sterilizing filtration
Traitement aseptique des produits de santé —
Partie 2: Filtration stérilisante
INTERNATIONAL
STANDARD
ISO
13408-2
Second edition
2018-01
Reference number
ISO 13408-2:2018(E)
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ISO 13408-2:2018(E)
ii
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COPYRIGHT PROTECTED DOCUMENT
© ISO 2018
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
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ISO 13408-2:2018(E)
Foreword...........................................................................................................................................................................................................................................v
Introduction................................................................................................................................................................................................................................vi
Scope..................................................................................................................................................................................................................................1
Normative references.......................................................................................................................................................................................1
Terms and definitions......................................................................................................................................................................................2
Quality system elements...............................................................................................................................................................................3
4.1
General........................................................................................................................................................................................................... 3
4.2
Management responsibility.......................................................................................................................................................... 3
4.3
Procurement of filters....................................................................................................................................................................... 3
Sterilizing filter characterization........................................................................................................................................................3
5.1
General........................................................................................................................................................................................................... 3
5.2
Microbial removal effectiveness............................................................................................................................................... 4
5.3
Material effects........................................................................................................................................................................................ 4
5.4
Environmental considerations.................................................................................................................................................. 5
Process and equipment characterization...................................................................................................................................5
6.1
General........................................................................................................................................................................................................... 5
6.2
Risk management.................................................................................................................................................................................. 5
6.3
Process characterization................................................................................................................................................................. 6
6.4
Equipment characterization........................................................................................................................................................ 6
Fluid definition.......................................................................................................................................................................................................7
7.1
General........................................................................................................................................................................................................... 7
7.2
Microbiological quality..................................................................................................................................................................... 8
Process definition................................................................................................................................................................................................8
8.1
General........................................................................................................................................................................................................... 8
8.2
Filter definition and characterization.................................................................................................................................. 9
8.2.1
General...................................................................................................................................................................................... 9
8.2.2
Compatibility between the filter and fluid.................................................................................................9
8.2.3
Filter use...............................................................................................................................................................................10
8.3
Filtration process definition.....................................................................................................................................................10
8.4
Integrity testing process definition....................................................................................................................................11
Validation...................................................................................................................................................................................................................12
9.1
General........................................................................................................................................................................................................12
9.2
Validation of fluid-specific microbial retention by sterilizing filters for liquids..........................12
9.2.1
General...................................................................................................................................................................................12
9.2.2
Test organism...................................................................................................................................................................13
9.3
Validation of the integrity test for sterilizing filters for liquids.................................................................14
9.4
Validation of filter interactions with the process fluid......................................................................................15
9.5
Validation of the sterilization of filter system...........................................................................................................15
9.6
Validation of fluid-specific microbial retention by sterilizing filters for gases.............................15
9.6.1
General...................................................................................................................................................................................15
9.6.2
Aerosol retention..........................................................................................................................................................15
9.6.3
Validation of physical integrity testing.......................................................................................................15
9.6.4
Compatibility and service life.............................................................................................................................16
9.6.5
Validation of the sterilization of the filter system for gases.....................................................16
Routine monitoring and control........................................................................................................................................................16
Product release from sterilizing filtration..............................................................................................................................16
Maintaining process effectiveness...................................................................................................................................................17
12.1
General........................................................................................................................................................................................................17
12.2
Recalibration..........................................................................................................................................................................................17
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Contents
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ISO 13408-2:2018(E)
12.3
Maintenance of equipment........................................................................................................................................................17
12.4
Requalification......................................................................................................................................................................................17
12.5
Assessment of change....................................................................................................................................................................18
Annex A (informative) Guidance on the application of this document..........................................................................19
Bibliography..............................................................................................................................................................................................................................34
iv
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ISO 13408-2:2018(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
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. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following
URL: www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
This second edition cancels and replaces the first edition (ISO 13408-2:2003), which has been
technically revised.
A list of all parts in the ISO 13408 series can be found on the ISO website.
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ISO 13408-2:2018(E)
Introduction
ISO 13408-1 covers general aspects of aseptic processing. Several processes including sterilizing
filtration, lyophilization, clean and sterilization in place, isolator systems, and alternative processes for
medical devices and combination products were found to be in need of supplementary information,
which was too extensive to be included in the corresponding annexes to ISO 13408-1. This information
is presented in ISO 13408-2 to ISO 13408-7.
Sterilizing filtration is a critical step in an aseptic manufacturing process. Validation of sterilizing
filtration processes can be complex and is generally conducted in both a process and product specific
manner. This document describes requirements that, if met, will provide a sterilizing filtration process
that consistently removes microorganisms from a fluid (liquid or gas) without negatively affecting
the quality of the filtrate. Furthermore, conformity with the requirements ensures that a sterilizing
filtration process is both reliable and reproducible so that a determination can be made, with reasonable
confidence, that the sterilizing grade filter/s will provide a sterile filtrate under specified operational
conditions. This (the reliability and reproducibility of the filtration process) is essential, as unlike a
micro-biocidal sterilization process where process variables can be monitored continuously, microbial
retention and physical integrity of a sterilising grade filter cannot be monitored on a continuous basis
throughout a filtration process.
Where validation establishes a reproducible relationship between the product-specific bacterial
retention capability of a sterilizing grade filter and the physical integrity of that filter, then suitable
non-destructive pre-use and post-use filter integrity tests are used to determine whether a full-scale
sterilizing filtration process has been conducted successfully. During terminal sterilization the kinetics
of inactivation follows a mathematical order and allow calculation of a sterility assurance level (SAL).
Removal of organisms from a fluid by filtration does not follow such mathematical order and so the use
of the term “sterility assurance level” is not appropriate for product sterilized by filtration.
There has been a significant increase in the development and availability of biopharmaceuticals,
biologic-based medical devices and cell-based health care products since publication of the initial 2003
edition of this document. This second edition emphasizes the importance of a thorough understanding
of the nature of the indigenous bioburden of a fluid that is to be sterilized by filtration, including
its relationship to the test microorganism used to determine microbial retention capability of the
sterilizing grade filter. For example, Mycoplasma can cause serious contamination problems during the
manufacturing of biopharmaceutical, biotechnological and cell-based health care products. A thorough
understanding of the indigenous bioburden enables suitable safeguards to be implemented during
development, validation and control of a sterilizing filtration process to ensure the safety and quality of
the filtered fluid.
While the activities required by this document have been grouped together and are presented in a
particular order, this document 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 may be iterative. It is possible that performing these different activities will involve a
number of separate individuals and/or organizations, each of whom undertake one or more of these
activities. This document does not specify the particular individuals or organizations to carry out the
activities.
Guidance on the application of this document is given in Annex A.
vi
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Aseptic processing of health care products —
Part 2:
Sterilizing filtration
1 Scope
This document specifies requirements for sterilizing filtration as part of aseptic processing of health
care products conducted in accordance with ISO 13408-1. It also offers guidance to filter users
concerning general requirements for set-up, validation and routine operation of a sterilizing filtration
process.
This document is not applicable to removal of viruses.
Sterilizing filtration is not applicable to fluids that intentionally contain particles larger than the pore
size of the filter (e.g. bacterial whole-cell vaccines).
This document is not applicable to high efficiency particulate air (HEPA) filters.
This document does not specify requirements for the development, validation and routine control of a
process for removing 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.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 11135, Sterilization of health-care products — Ethylene oxide — Requirements for the development,
validation and routine control of a sterilization process for medical devices
ISO 11137-1, Sterilization of health care products — Radiation — Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices
ISO 11139,1)Sterilization of health care products — Vocabulary — Terms used in sterilization and related
equipment and process standards
ISO 13408-1:2008, Aseptic processing of health care products — Part 1: General requirements
ISO 13408-1:2008/Amd. 1:2013, Aseptic processing of health care products — Part 1: General requirements
— Amendment 1
ISO 13408-5, Aseptic processing of health care products — Part 5: Sterilization in place
ISO 13485, Medical devices — Quality management systems — Requirements for regulatory purposes
ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development,
validation and routine control of a sterilization process for medical devices
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ISO 13408-2:2018(E)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 11139 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at https://www.electropedia.org/
— ISO Online browsing platform: available at https://www.iso.org/obp
3.1
bacterial challenge test
technical operation performed to evaluate the capability of a filter (3.5) to retain organisms from liquid
bacterial suspension under defined conditions
3.2
bioburden
population of viable microorganisms (3.9) on or in product and/or sterile barrier system
Note 1 to entry: For the purposes of this document, the definition of bioburden is the population of viable
microorganisms in a fluid (3.6) prior to sterilizing filtration (3.11).
3.3
chemical compatibilityA quality management system as defined in ISO 13408-1:2008, Clause 4, and ISO 13408-1:2008/Amd. 1:2013 shall be implemented to ensure control over all activities affecting sterilizing filtration. Additionally the requirements in 4.2 and 4.3 shall apply.
Operator training specific to filtration activities shall be implemented and documented for the following: a) filtration procedures, modes of failure and needed precautions; b) integrity test theory and practice; c) failure investigation procedures and measures taken in case of integrity test deviations; d) filter assembly procedure (including aseptic technique if required); e) filter installation, cleaning and sterilization procedures.
shall conform with the applicable clauses of ISO 13485 or equivalent quality system.
filter manufacturer will notify the filter user of any changes in the filter manufacturing conditions with potential to affect the defined fluid and process parameters. 4.3.3 Procedures for identification and traceability of filters shall be specified. These procedures shall conform with the applicable clauses of ISO 13485 or equivalent quality system. 5 Sterilizing filter characterization
Sterilizing filter characterization is the process of determining which filters might be suitable for use
as a sterilizing filter in a sterilizing filtration process for a given fluid. This is usually carried out by the
filter user considering information available from the filter manufacturer.
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ISO 13408-2:2018(E)
Sterilizing filter formats include, but are not limited to the following:
a) membrane filter discs for the user to assemble into filter holders/housings;
b) cartridge filters for the user to assemble into filter holders/housings;
c)
units supplied pre-assembled by the filter manufacturer (capsules).
The specification for the filters used in production shall be justified against the specification of those
used in the product and process validation.
filter and fluid type. This is usually by demonstration of retention of a a) product specific microbial challenge for liquid filtration, and b) generic aerosol challenge for gas filtration.
variables in relation to this effectiveness shall be identified. Such variables include, but are not limited to the following: a) filter membrane characteristics, such as the pore size distribution, surface chemistry, structure and polymer type of the membrane (see 8.2.1); b) filtration equipment characteristics (see 6.4); c) fluid characteristics, such as the effects of surfactants or additives; including the absorptive influence of the fluid on microorganisms, pH, viscosity, osmolarity, surface tension and ionic strength (see 7.1.2); d) fluid bioburden; number, type and cell size of organisms present in the fluid and process conditions or formulations which might affect cell size (see 7.1.2); e) process conditions, such as batch size, temperature, differential pressure, flow rate, hold times and processing times (see 8.3.1); f) the effect of the sterilization process for the filter on the filter performance. For the sterilization of gases by filtration, some of the above may not be applicable.
evaluated (see 8.2.2.2 and 8.2.2.3).
evaluated (see 8.2.2.4). 5.3.3 Filters shall not be fibre-releasing. NOTE A fibre is generally considered to be a particle having an aspect (length-to-width) ratio of 10 or more.
flushing and sterilization shall be justified. The effects of these processes on microbial removal
effectiveness and filter materials shall be evaluated (for further details see 8.2.3.2).
4
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ISO 13408-2:2018(E)
Procedures for the disposal of used filter material shall take into consideration the materials filtered and shall ensure safe disposal. NOTE Local waste disposal requirements can apply. 6 Process and equipment characterization
The purpose of this activity is to define the entire sterilizing filtration process so that it is both safe and reproducible.
1:2008/Amd. 1:2013 concerning risk management apply. 6.2.2 A risk assessment shall be performed during the selection of the filter and filtration equipment. The risk assessment shall include, but is not limited to the following: a) effects of variables identified in 5.2.2; b) the design of the sterilizing filtration system in terms of the incorporation of, and location within the system of particulate reduction or bioburden reduction filters, single or sterilizing filters in series, redundant sterilizing grade filters or parallel sterilizing grade filters; c) the risk to the sterility of the filtration system when pre-use post-sterilization integrity testing (PUPSIT) is carried out; d) the risks associated with filter reuse for the sterilizing filtration process for a given fluid.
outsourcing of sterilization of critical sterile components, for example, where filters are purchased sterile. For single use filtration systems this shall include an evaluation of the following: a) the supplier’s assembly design (including the filter user’s need for single, serial, redundant or parallel filter design), materials of construction, manufacturing and sterilization processes; b) filter location, i.e. inside or outside of an isolator; c) the ability to conduct a pre-use post-sterilization integrity test (if required); d) how the assembly performs in the filtration process for the fluid, including requirements for filter flushing or wetting; e) maintenance of downstream sterility; f) integrity testing of closed systems; g) how the assembly impacts the filtered fluid.
mitigation procedures shall be determined. Methods might include microbiological and particulate
monitoring of the fluid.
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ISO 13408-2:2018(E)
validation study.
if the sterilizing filtration process changes during development and validation.
upon knowledge of the combination of process parameters yielding minimal acceptable microbial removal effectiveness. Processing within such process parameters shall routinely yield safe and functional sterile filtrate. The establishment of tolerances for process parameters shall be based upon analyses of process variables (see Clause 8). 6.3.2 Means of controlling and monitoring the process variables shall be determined.
effectiveness of the sterilizing filtration process shall be specified (for example, the use of a bioburden reduction filter). 6.3.4 Following sterilizing filtration subsequent aseptic handling of sterile filtrate shall be as specified in ISO 13408-1.
process variables shall be specified.
necessary ancillary items, including materials of construction.
within the filtration system shall be documented and justified.
The filtration system components shall not impart impurities to or otherwise alter the quality of the
fluid. Such components can include the following:
a) piping systems and connections;
b) valves;
c)
gauges and/or other instruments;
d) gaskets, O-rings and/or packings;
e) filter materials.
6.4.4
In gas filtration, unintended wetting of the filter or accumulation of liquid in the filter equipment
shall be avoided.
6.4.5
The filtration system shall be designed in accordance with the following requirements.
a) To allow operation within validated process parameters.
6
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b) To
maintain
the
sterility
of
the
filtrate
(see
ISO
13408-1:2008,
Clause
6,
and
ISO 13408-1:2008/Amd. 1:2013).
c)
To ensure that sterilizing filter placement is based on risk assessment.
To minimize the risk of recontamination post-filtration, simple downstream systems containing
minimal joints and gaskets are preferred. Locating the sterilizing filter as close as possible to the
filling equipment or delivery system might also reduce recontamination risk.
d) To ensure that the sterilizing filtration process does not present an unacceptable risk of
contamination of the surrounding environment.
e) To allow cleaning procedures to be conducted as necessary.
f)
To allow sterilization of the filter material and all components or surfaces that contact fluid post
filtration.
NOTE
Approaches to sterilization can include
1) sterilization of the filtration system in place,
2) sterilization of the filtration assembly by the filter user followed by aseptic assembly of the
filtration system, or
3) purchase of sterilized components from approved suppliers.
g) To permit in-place integrity testing as a closed system post sterilization and prior to fluid filtration
where pre-use–post-sterilization integrity test (PUPSIT) is indicated.
h) To describe the instrumentation for monitoring and controlling the filtration process, including
sensor characteristics and locations, and indicating and recording instruments.
i)
To describe faults recognized by the filtration equipment.
j)
To list safety features, including those for personnel and environmental protection.
a quality management system that provides documented evidence that the software meets its design intention. NOTE Attention is drawn to ISO/IEC 90003. 7 Fluid definition
7.1.1 The purpose of this activity is to define the fluid to be sterilized. This activity should be considered as part of the product risk assessment (see ISO 13408-1). NOTE The term “fluid” is used here in place of the term “product”. Product is generally considered to be the filtrate post-sterilization or the finished product post aseptic processing. Thus, the definition describes the characteristics of the fluid to be sterilized which either affect the filtration process or which need to be retained in the filtrate.
defined limits where applicable:
a) formulation;
b) pH;
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c)
osmolarity;
d) ionic strength;
e) viscosity;
f)
density;
g) surface tension;
h) bioburden;
i)
particulates.
NOTE
The intention is that the pre-sterilizing filtration bioburden is controlled and maintained at a level
substantially below the validated retention performance of the filtration system.
including extractables, leachables, particulates and endotoxin shall be evaluated. 7.1.4 The potential for the formulation of the fluid or the nature of the filter to affect the cell size of microorganisms that might allow passage of bioburden microorganisms through the sterilizing grade filter shall be considered.
performance following the application of the defined sterilizing filtration process at the most challenging process parameters for the fluid.
evaluated.
sterilized is controlled and does not compromise the effectiveness of the sterilizing filtration process [see 5.2.2 d), 7.1.2 h), 7.1.4, 7.2.2, 8.2.3.1, 8.2.3.2].
and documented. NOTE Some guidance can be found in ISO 11737-1 and Pharmacopoeia procedures such as “Microbiological examination of non-sterile products: Microbial enumeration tests” shown in the European Pharmacopoeia (Ph. Eur.), Japanese Pharmacopoeia (JP) and United States Pharmacopoeia (USP). 8 Process definition
process to be applied to a defined product (see Clause 7). This shall be achieved by the following:
a) selecting the most appropriate filter (see Clause 5);
b) selecting the process parameters which consistently achieve a sterile filtrate without compromising
the safety, quality and performance of the product (see 5.2.2);
c)
selection of a sterilization method for the filtration system [see 6.4.5 f)].
8
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8.1.2
The routine process for filtration shall be defined and documented in a written procedure.
The filter user shall document a justification for the size and type of filters used in the filtration system that takes into account the fluid to be filtered and the process used for filtration. This shall include the following: a) effective filter surface area required for desired flow rate; b) filter pore size rating; c) thermal compatibility of filter materials with process and/or sterilization temperatures; d) hydraulic strength to withstand process differential pressure; e) filter configuration (plate vs cartridge), redundant filters, serial filters, parallel filters; f) filter longevity; g) fluid bioburden [see 5.2.2 d)].
studies shall include a) the effects of the formulation and process conditions on the chemical and physical attributes and performance of the filter, and b) the effects of the filter and process conditions on the relevant biological, chemical and physical attributes of the fluid. Evaluation shall include extractables and leachables, particulates and adsorption.
determined using the process fluid and the same filter type as that used for production. Where it is not possible to use the process fluid a surrogate may be used. Fluids with similar properties may be grouped and a worst case representative selected for testing. Where a surrogate fluid or grouping approach is used, the rationale shall be documented. NOTE Flushing filters prior to use can reduce the levels of potential leachables.
from substances extractable from the filter. NOTE Extractables data and chemical compatibility tables are generally available from the filter manufacturer and are commonly used as a starting point to determine whether further testing is required.
fluid composition and concentration shall be evaluated.
NOTE
Adsorption is a mechanism of process fluid components binding to the filter material that might affect
the composition of the filtrate. Flow rate, concentration of components, contact time, temperature and pH are
some factors that can affect adsorption.
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8.2.3.1 If reduction of bioburden is necessary prior to sterilizing filtration, use of a pre-filter prior to the sterilizing filter shall be considered. NOTE The criteria in 8.2.2.1 to 8.2.2.3, as applicable, can also be applied to pre-filters in view of their intended use. 8.2.3.2 A sterilizing grade filter that is to be reused shall be subject to the requirements as specified in 8.2, 8.3 and Clause 9. Where a sterilizing grade filter is to be reused, the filter user shall: a) assess and document the risks associated with filter reuse for the sterilizing filtration process for a given fluid [see 6.2.1 d)]; b) conduct and document effective validation and qualification studies to demonstrate that filter reuse for a given sterilizing filtration process and for a given fluid does not compromise performance of the sterilizing filter or filtrate quality (see Clause 9); c) document the maximum number of reuse cycles validated and permitted for the filter and implement controls to ensure that filters are not reused beyond the validated maximum number of cycles; records of these controls shall be maintained; d) implement controls to ensure that filters contaminated with fluid or cleaning agent residues, or considered defective in any other way, shall not be used to process subsequent batches; records of these controls shall be maintained.
a) monitoring of variables such as temperature, pressure, flowrate, total volume and duration to ensure that process parameters remain within specified tolerances; b) sterilization procedures for the filter assembly, filtration system and fluid path, including the permissible limit for cumulative sterilization time and/or number of cycles at applicable sterilization conditions in case of multiple sterilizations and re-use (see 8.2.3.2); c) filter configuration and set-up; d) filtration process conditions and their tolerances:
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ISO 13408-2:2018(E)
NOTE 1
Information from the filter manufacturer can be useful in designing and validating a flushing
procedure.
NOTE 2
Total organic carbon (TOC) test or protein specific assays can be useful in determining minimum
flush volumes.a) inspection of filtration system components; b) assembly of the filtration system; c) cleaning, sterilization and/or flushing; d) time between cleaning and sterilization (if applicable); e) time between sterilization and use; f) control testing including integrity testing; g) monitoring of parameters for temperature, differential pressure, flowrate; h) time between fluid filtration and cleaning, etc.
of failure investigation and conditions under which the filter integrity test can be repeated (see 8.4).
thus minimizing the challenge to the sterilizing filter.
integrity test post use and without removal of the filter from its housing. Test results shall correlate to the microbial retention capability of the filter established during validation. 8.4.2 The integrity of the filtration system prior to use is critical to ensure product sterility. Damage to filters, for example in transit or during sterilization, or inadequate fitting of filter cartridges to housings, if undetected would result in product rejection in the event of post use integrity test failure. Therefore consideration should be given to carrying out integrity testing pre- and post-filtration. The decision to omit the pre-use test, shall be based on the result of a risk assessment and documented. The following points shall be considered for integrity testing of the sterile filter before use: a) integrity testing shall not compromise the sterility of the sterilized filter or the downstream process; b) compatibility of the integrity test fluid with the process fluid. 8.4.3 If the process has been validated as a serial or parallel filtration system to achieve the sterility for a given fluid, the filtration system is considered to be a single sterilizing unit and all sterilizing grade filters within the system shall satisfactorily pass integrity testing after use.
acceptability of performance of a post-use integrity test on the secondary filter in the event of failure
of the post-use integrity test on the primary filter. This shall be carried out as part of the integrity test
process definition and not following an integrity test failure. In a redundant filtration system, if the post-
use integrity test of the primary sterilizing filter passes, then the post-use integrity test on the secondary
(redundant) filter is not necessary.
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be carried out pre- and post-use. Duration of use shall be specified depending on hold time, use time (duration), number of processes (sterilization), flow of fluid (volume, rate), etc.
of failure investigation and conditions under which the filter integrity test can be repeated. 9 Validation
The purpose of validation is to demonstrate that the filtration process established in the process definition (see 8.3) can be delivered effectively and reproducibly to achieve a sterile filtrate. Validation consists of a number of identified stages. For the validation of sterilization of liquids by filtration (see 9.2 to 9.5): a) fluid specific microbial retention (i.e. sterilization capability of filter medium); b) determination of fluid specific integrity test parameters related to 9.1 a); c) filter medium interactions; d) sterilization of the filtration system. For the validation of the sterilization of gases (see 9.6): e) demonstration of retention of a standard aerosol challenge under specified conditions; f) determination of integrity test parameters; g) sterilization of the filtration system.
appropriate bacterial challenge test using at least one filter from each of not less than three lots of filters with three consecutive successful outcomes. All failures shall be investigated. NOTE 1 This testing is usually performed in a scaled-down model system (which can include a different cartridge or disc size incorporating the same filter medium) in a laboratory environment to avoid jeopardizing the quality of the manufacturing environment. NOTE 2 Information from the filter manufacturer can be useful in designing and validating integrity test procedure(s). NOTE 3 Typically, filter manufacturers publish test methods and results used to qualify filters for sterilizing filtration applications. This documentation supports, but does not replace performance qualification studies of liquid filtration undertaken by the filter user.
in the bacterial challenge test shall have a pre-use physical integrity test value that is either at or near the filter manufacturer’s acceptance specification.
take into account the attributes described in 8.3.1 d).
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bacteria retention studies. Justification for grouping fluids and selection of worst case representatives shall be documented. 9.2.1.5 The testing fluid for the bacterial challenge test shall be the fluid to be filtered. The viability of the challenge organism in the fluid over the worst case test time shall be assessed. If the fluid to be filtered cannot be used due to antimicrobial or other properties, a simulation fluid or a change in simulation conditions shall be used. In determining the simulation conditions, the following shall be considered: a) modifying the fluid to be filtered e.g. reducing or eliminating the antimicrobial compound and/or adjusting pH; b) the simulation fluid shall mimic as closely as possible the fluid formulation and the following characteristics: pH, viscosity, ionic strength, osmolarity, surface activity/tension, density, and the effects of the fluid on the challenge organisms; c) reducing fluid-organism exposure time; d) reducing the fluid temperature during the challenge after exposing the filter to the fluid at process temperature; e) using a diminutive organism that is resistant to the antimicrobial properties of the fluid or process; f) exposing the filter to the fluid with the process fluid contact time, followed by a challenge in a modification of fluid as in 9.2.1.5 a) or b).
9.2.2.1 Indigenous bioburden of the fluid to be filter sterilized shall be determined (see also 7.2).
organism for an 0,2 µm sterilizing filter shall be Brevundimonas diminuta (i.e. ATCC 19146).
smaller than Brevundimonas diminuta, or small enough to challenge the retention capability of the sterilizing grade filter, then a suitable challenge microorganism (other than B. diminuta) shall be selected for use. The cultivation conditions shall be qualified to yield cells of small size. The effect of the fluid on the cell size shall be evaluated. NOTE Factors of potential concern can include the following: a) presence of material with the potential to affect the passage of microorganism through the filter membrane (e.g. liposome); b) presence of microorganisms known to penetrate filters; c) presence of pleomorphic organisms (e.g. L forms in penicillin solution, Mycoplasmas, Leptospiras).
potential to penetrate the filter have not been identified, the user shall justify the choice of alternative challenge microorganism. Where alternative microorganisms are cultivated as challenge organisms, cultivation conditions shall be chosen appropriately to yield cells of a small size.
(CFU/cm2) of effective filter surface area.
organisms smaller than Brevundimonas diminuta the challenge organism may be Acholeplasma laidlawii
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(ATCC 23206) or similar[9]. The minimum challenge level shall be 1 × 107 colony-forming units per
square centimetre (CFU/cm2) of effective filter surface area.
If the 0,1 µm sterilizing filter is used only to remove organisms which are equal to or bigger than
Brevundimonas diminuta refer to 9.2.2.2 to 9.2.2.5.
a) the challenge organisms are dispersed in a volume of the fluid where the total filtered volume is representative of the production batch size and effective filtration area, unless antimicrobial properties require a different approach; NOTE 1 This might require recirculation of the fluid when the challenge test is carried out in a scaled down system. b) the viable count of the challenge suspension is determined on an appropriate number of samples taken throughout the test duration to demonstrate that the intended challenge is delivered and remains consistent and viable for the duration of the test; c) the validation challenge is conducted under conditions that simulate the worst case conditions permitted in routine processing; d) the test organism as prepared is of a diminutive size; NOTE 2 This can be achieved by the use of a positive control to demonstrate passage of the challenge organism, for example, passage of B. diminuta through a 0,45 µm rated membrane or passage of A. laidlawii through a 0,2 µm rated membrane. e) the test method is capable of recovering small numbers of the test organism.
challenge organism through the three test filters. In each test the positive control shall be valid.
test specifications for a production filter. NOTE 1 Where validation establishes a reproducible relationship between the fluid-specific bacterial retention capability of a sterilizing grade filter and the physical integrity of that filter, then suitable non-destructive pre- use and post-use filter integrity tests are used to determine whether a full-scale production filtration process has been conducted successfully (see 8.4). NOTE 2 These specifications are used to determine if a production filtration process has been carried out successfully as bacterial challenge testing is a destructive test that is not practical for production filters.
demonstrated to achieve a sterile filtrate during validation.
The wetting fluid for the filter integrity testing shall be selected based on either the filter manufacturer’s
recommended standard wetting fluids (such as water and isopropyl alcohol solutions) or fluid to be
filtered (such as drug product, intermediates and buffer solutions). When the latter is selected, an
appropriate test specification shall be determined and qualified.
The fluid to be filtered should be used for integrity testing where
a) residuals of the standard wetting fluid have an adverse effect on the fluid to be filtered or the
process,
b) use of standard wetting fluid might introduce a risk to the sterility of the filtration process, and
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c)
an extended flushing operation with standard wetting fluid is needed to replace the fluid in the filter.
The following shall be qualified: a) leachables (see 8.2.2.2); b) extractables (see 8.2.2.3); c) materials removed from the process stream by absorbtion (see 8.2.2.4).
a) the sterilization process is effective at minimal exposure conditions, and b) maximum exposure conditions do not adversely affect the filter system.
ISO 17665-1, ISO 11135 or ISO 11137-1. NOTE Typical sterilization processes used for filtration systems are steam-in-place (SIP) or steam autoclave sterilization by the user, and ethylene oxide or irradiation by the manufacturer where filters or filtration systems are supplied sterilized.
Sterilizing filtration of gases is typically validated by the use of aerosol challenges. There is little evidence of the influence of carrier gas on the sterile filtration process. For this reason, a process- and gas-specific bacterial retention test is generally not required. NOTE Typically, filter manufacturers publish test methods and results used to qualify filters for sterilizing filtration applications.
The filter manufacturer’s retention data shall be evaluated to ensure its applicability to the specified process.
process. 9.6.3.2 The physical integrity test shall be correlated to the retention capability of the filter. NOTE Integrity test data are published in the filter manufacturer’s validation guide.
filter membranes. The wetting fluid for the filter integrity test shall be selected based on the filter
manufacturer’s recommended standard wetting fluids (such as isopropyl or tertiary butyl alcohol
solutions). The wetting fluid and the gas used shall be specified and the test shall be performed at
temperatures recommended by the filter manufacturer. Alternatively a water intrusion test can be
appropriate. In certain applications, an aerosol integrity test might be used.
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Compatibility of the filter under actual use conditions shall be demonstrated by integrity testing the filter before and after exposure to the conditions of use. Data shall be generated to demonstrate that filter integrity is maintained for the duration of use. NOTE In most applications, filters are used continuously or reused multiple times after sterilization.
See 9.5. 10 Routine monitoring and control
sterilizing filtration process has been delivered to the fluid.
within the defined tolerances.
tolerances. 10.4 All records shall be retained in accordance with ISO 13485 or equivalent quality system.
consistently lies within acceptable limits.
unless all aspects of manufacture are well controlled and previous test results have shown particulate levels to consistently lie within acceptable limits.
disturbing the filter in its housing. 11 Product release from sterilizing filtration
define the criteria for designating the sterilizing filtration process as conforming to its specification.
shall become part of a batch record.
a) dates of fluid preparation and filtration;
b) name and batch number of the fluid;
c)
operator's name(s);
d) filter manufacturer, filter type and filter manufacturer's lot and/or serial number(s);
e) cleaning of filtration system;
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f)
sterilization conditions for the filtration system;
g) reference to sterilization cycles used for components employed in the filtration process;
h) number of reuse cycles;
i)
filtration process conditions (for example, differential pressure, upstream pressure, downstream
pressure, flowrate, operation temperature, time, etc.);
j)
filter integrity test result and assessment;
k) results of pre-sterilization bioburden testing;
l)
deviations to written procedures;
m) name of the person approving the sterilizing filtration process.
and handled in accordance with documented procedures (see ISO 13485). 12 Maintaining process effectiveness
The continued effectiveness of the system for ensuring the condition of fluid presented for sterilizing filtration shall be demonstrated.
The accuracy and reliability of the instrumentation used to control, indicate, or record the sterilizing filtration process shall be verified periodically in accordance with ISO 13408-1:2008, 4.3.2, and ISO 13408-1:2008/Amd. 1:2013.
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 in accordance with ISO 13408- 1:2008, 4.1.4, and ISO 13408-1:2008/Amd. 1:2013.
satisfactorily completed and recorded.
periodically by a designated person. The results of the review shall be recorded in accordance with ISO 13408-1:2008, 4.1.4, and ISO 13408-1:2008/Amd. 1:2013.
12.4.1 The extent to which requalification is carried out shall be justified.
necessary.
following maintenance.
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12.4.4 Requalification procedures shall be specified and records of requalification retained.
with documented procedures. Records shall be retained of reviews of requalification together with corrections made and corrective actions taken.
Any change shall be assessed for its impact on the effectiveness of the sterilizing filtration process.
Changes to be considered (if applicable) shall include the following:
a) replacement of a part of the filtration system which could cause a process parameter change;
b) any change to the formulation of the fluid being filtered;
c)
any change in the bioburden of the fluid being filtered;
d) any change to the sterilizing filter;
e) any change in filter manufacturing conditions as reported by the filter manufacturer shall be
evaluated with respect to their potential to affect the defined fluid and process parameters
(see 4.3.2);
f)
any change to the process parameters;
g) new or modified software or hardware.
The outcome of this assessment, including the rationale for the decisions reached and the extent of the
changes made to the sterilizing filtration process, or requalification requirements shall be documented.
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Annex A
(informative)
Guidance on the application of this document
NOTE
For ease of reference, the numbering of clauses in this annex corresponds to that in the main body of
this document.
A.1 General
The guidance given in this annex is not intended as a checklist for assessing conformity with this
document. This guidance is intended to assist in obtaining a uniform understanding and implementation
of this document by providing explanations and acceptable methods for achieving conformity with
specified requirements. It highlights important aspects and provides examples. Methods other than
those given in the guidance may be used, providing their performance conforms with this document.
A.2 Note on normative references
See Clause 2.
A.3 Note on terms and definitions
Figure A.1 is provided to demonstrate the common terminology for the elements of a sterilizing filter.
The filter material (1) is the membrane/matrix which removes the microorganisms from the process
fluid. This filter material can be manufactured onto a supporting unit (2) by the filter manufacturer to
produce a filter cartridge (4). The filter cartridge is then fitted into a filter housing (6) by the user and
sterilized. The cartridge in the housing is often referred to as a filter assembly (7).
Alternatively the filter material can be manufactured into a capsular supporting unit (3) to produce a
pre-assembled filter capsule (5) which can be supplied to the user sterile or non-sterile.
The filter assembly with its associated valves, gauges, etc., is referred to as the filtration system (8).
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Key
filter material
filter capsule
supporting unit for filter cartridge
filter housing
supporting unit for filter capsule
filter assembly
filter cartridge
filtration system
Figure A.1 — Pictorial aide to filter terminology
A.4 Quality system elements
A.4.1 General
No guidance is offered.
A.4.2 Management responsibility
No guidance is offered.
A.4.3 Procurement of filters
NOTE
The clause refers to the requirements for the purchasing of filters and filtration equipment to be used
for product realization. Purchasing controls for starting materials for products to be processed by sterilizing
filtration are covered in ISO 13408-1.
A.4.3.1 No guidance is offered.
A.4.3.2 Adherence to written agreements can be verified by the filter user through audits of the filter
manufacturer.
A.4.3.3 No guidance is offered.
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A.5 Sterilizing filter characterization
A.5.1 General
The following basic information is typically available from filter manufacturers:
a) materials of the filter assembly;
b) hydrophilic/hydrophobic characteristics;
c)
extractables in model solvents (e.g. water);
d) general chemical compatibility;
e) recommended sterilization procedure(s) (cumulative time, number of cycles and sterilization
conditions);
f)
thermal resistance;
g) particulate retentiveness;
h) maximum acceptable pressure differential;
i)
flow characteristics;
j)
particle and/or fibre shedding (filter media migration) characteristics in a model solvent (e.g. water);
k) microbial retentivity and correlation to integrity test data under stated test conditions;
l)
nominal pore-size rating;
m) recommended integrity test procedures;
n) biological safety data.
Lot-specific quality certificates for filter cartridges might include information on the following:
o) integrity test result;
p) endotoxin or pyrogen;
q) bacterial challenge testing results;
r)
oxidizable substances or total organic carbon;
s)
extractable substances;
t)
fibre- and particle-release characteristics;
u) biological safety data;
v) water flowrate;
w) hydraulic stress resistance;
x) thermal stress resistance.
NOTE 1
Items a), b), c) and d) are typically reported based on tests performed for each lot.
NOTE 2
The quality certificates are generally applied to filter cartridges, but can also be applied to filter discs
or filter sheets.
A.5.2 Microbial removal effectiveness
No guidance is offered.
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A.5.3 Material effects
A.5.3.1 Typically materials are extracted or leached from the filter into liquids. Effects on gases might
need to be considered under exceptional circumstances.
A.5.3.2 Typically materials are adsorbed onto the filter from liquids. Effects of adsorption of gases
might need to be considered under exceptional circumstances.
A.5.3.3 No guidance is offered.
A.5.3.4 No guidance is offered.
A.5.4 Environmental considerations
No guidance is offered.
A.6 Process and equipment characterization
A.6.1 General
No guidance is offered.
A.6.2 Risk management
A.6.2.1 No guidance is offered.
A.6.2.2 A guidance is offered to 6.2.2 b).
Aseptic processes with sterilizing filtration systems exist in many different configurations and can
include, for example, the following.
a) A process with only a single sterilizing filter typically 0,2 µm rated or less, see Figure A.2.
Key
bulk material (non-sterile)
sterile effluent
sterilizing filter
a
Filter integrity test required.
Figure A.2 — Process with a single sterilizing filter
b) A process with a particulate and/or bioburden reduction filter (typically 0,45 µm or 0,2 µm rated)
prior to the sterilizing filter, see Figure A.3. This process minimizes and controls the challenge to
the sterilizing filter. If the bioburden of the bulk material is more than 10 CFU/100 ml, this-filtration
system should be considered.
22
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Key
bulk material (non-sterile)
sterile effluent
bioburden reduction filter
a
Filter integrity test required.
sterilizing filter
Figure A.3 — Process with bioburden reduction step and single sterilizing filter
c)
A process with a particulate and/or bioburden reduction filter (typically 0,45 µm or 0,2 µm rated)
prior to an intermediate low bioburden hold before the sterilizing filter, see Figure A.4. This filter
system is generally used when it is required to hold solutions for limited periods of time during
filling. The sterility of the final filtrate is dependent on the integrity the sterilizing filter.
Key
bulk material (non-sterile)
sterilizing filter
bioburden reduction filter
sterile effluent
low bioburden intermediate material hold
a
Filter integrity test required.
Figure A.4 — Process with a particulate and/or bioburden reduction filter
d) A process with two or more sterilizing filters in series, see Figure A.5. In this system, the fluid is
filtered through two or more filters of the same or decreasing pore size in series (one after the
other). In this situation, the filter system is considered to be a single sterilizing unit. Both filters are
required to be integral to effect the validated sterilizing process.
Key
bulk material (non-sterile)
sterile effluent
sterilizing filter
a
Filter integrity test required.
Figure A.5 — Process with two sterilizing filter in series
e) A process with an identical sterilizing filter that is used as a backup (this system is often referred
to as redundant filtration), see Figure A.6. In this system microbial retention is validated using only
one of the two filters. The backup filter is a redundant filter and need not be integrity tested after
use unless the integrity test on the primary filter fails. A redundant filter might be used to ensure
against filtrate loss in the event of post-use integrity test failure of the primary sterilizing filter.
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Key
bulk material (non-sterile)
sterile effluent
back-up sterilizing filter (redundant filter)
a
Filter integrity test required.
main sterilizing filter
b
Filter integrity test only in the event of failure of the
integrity test of the main filter.
Figure A.6 — Process with a redundant sterilizing filter
f)
A process with two or more sterilizing filters in series with an intermediate holding step. Product
is filtered through a sterilizing filter into sterilized holding vessel and then filtered through a
second sterilizing filter during delivery, see Figure A.7. This filter system is generally used when
it is required to hold solutions for extended periods of time during filling. The sterility of the
intermediate material hold and the final filtrate is dependent on the integrity of both filters.
Key
bulk material (non-sterile)
sterile effluent
sterilizing filter
a
Filter integrity test required.
sterile intermediate material hold
Figure A.7 — Process with serial filtration with a sterile intermediate product hold
g) A process with parallel sterilizing filters where the process stream splits and is filtered through
multiple filters equally, see Figure A.8. This filter system is generally used to increase the capacity
or flow rate of a filter system – all filters required to be integral.
24
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Key
bulk material (non-sterile)
sterile effluent
sterilizing filter
a
Filter integrity test required.
Figure A.8 — Process with parallel sterilizing filters
Examples of common filtration systems are shown in Figure A.9 and Figure A.10.
Key
non-sterile solution
0,22 µm sterilizing filter
0,45 µm bioburden reduction filter
sterile solution
bioburden controlled bulk solution
to filler
bioburden sampling port
Figure A.9 — Filtration of non-sterile fluid with a bioburden reduction filter followed by an
optional bioburden controlled hold tank, bioburden sampling port and then a sterilizing filter
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Key
non-sterile solution
sterile solution
bioburden sampling port
to filler
0,22 µm sterilizing filter
Figure A.10 — Multi-filter configuration in series for controlling bioburden and particulates
or redundant sterile filtration
A.6.2.3 No guidance is offered.
A.6.2.4 No guidance is offered.
A.6.2.5 No guidance is offered.
A.6.2.6 No guidance is offered.
A.6.3 Process characterization
No guidance is offered.
A.6.4 Equipment characterization
A.6.4.1 No guidance is offered.
A.6.4.2 No guidance is offered.
A.6.4.3 No guidance is offered.
A.6.4.4 No guidance is offered.
A.6.4.5 A guidance is offered to 6.4.5 b):
In a serial filtration system it is critical for sterility to be maintained between each sterilizing filter
during all processing steps, including pre-use integrity testing (if performed post-sterilization) and
filtration.
A.6.4.6 No guidance is offered.
A.7 Fluid definition
A.7.1 General
A.7.1.1 No guidance is offered.
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A.7.1.2 It is important that the fluid to be sterilized is consistent and reproducible from batch to batch
within defined limits. This assumption underpins filter validation for a given fluid. From this, suitable
flow rates, processing times etc., for routine production are set.
A.7.1.3 No guidance is offered.
A.7.1.4 No guidance is offered.
A.7.1.5 No guidance is offered.
A.7.1.6 No guidance is offered.
A.7.2 Microbiological quality
A.7.2.1 Bioburden data for raw materials and intermediates (where applicable) and the fluid to be
sterilized should be reviewed to determine the characteristics and level of bioburden typically present in
a fluid prior to sterilizing filtration. This review should include
a) an assessment as to whether microorganisms that comprise the bioburden of the fluid or the raw
materials are smaller than the standard test microorganism used to determine the microbial
retention capability of the sterilizing grade filter, and
b) where bioburden microorganisms are smaller than the standard test microorganism used to
determine microbial retention capability of the sterilizing grade filter, an assessment of the risk
of passage of bioburden microorganisms through one or more sterilizing grade filters under
controlled operational conditions.
The effectiveness of the system for bioburden control should be demonstrated.
A.7.2.2 No guidance is offered.
A.8 Process definition
A.8.1 General
No guidance is offered.
A.8.2 Filter definition and characterization
A.8.2.1 General
Filter manufacturers typically publish results of tests performed according to applicable compendial
methods to qualify the filter. Tests commonly performed by the filter manufacturer include the
following:
a) bacterial retention in water or saline lactose broth with integrity test correlation;
b) chemical capability and effect on filter integrity;
c)
extractables;
d) sterilization methods and effect on filter integrity;
e) integrity test in water or solvent;
f)
toxicity testing;
g) particulate matter;
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h) non-fibre release;
i)
TOC and conductivity.
A.8.2.2 Compatibility between the filter and fluid
Aseptic filtration is vulnerable to non-uniformity of the filter, chemical attack on the filter medium,
mechanical defects in configuration, overpressurization, non-sterility of the filtration equipment
and excessive bioburden loading. Filters are available in varying sizes, configurations and membrane
chemistries.
A.8.2.3 Filter use
A.8.2.3.1 No guidance is offered.
A.8.2.3.2 A general guidance to 8.2.3.2 is offered.
Hydrophobic sterilizing grade filters used for the sterile filtration of gas, or for venting purposes are
often reused multiple times after steam sterilization between batches or campaigns.
Sterilizing grade filters for liquids are generally intended for single batch use or for campaign use
(where the filter remains in place for more than one batch); however, some might be supplied for
multiple reuse (where the filter is cleaned and re-sterilized between batches). Filters should not be
reused for chemically different liquids unless after proper cleaning and sterilization the leachables and
uptake are validated.
The reuse of a sterilizing-grade filter is not generally recommended where that filter is used in the
final step of a sterilizing filtration process to produce a sterile liquid filtrate. The reuse of a sterilizing-
grade filter might be considered appropriate in circumstances when the challenge liquid is of low
bioburden and where
a) different batches of the same liquid are filtered, and
b) the total volume of liquid filtered does not compromise filter capacity.
NOTE 1
Regulatory agencies do not prohibit the reuse of sterilizing-grade filters for liquids; however, they do
not generally advocate the practice in aseptic processing because of the critical nature of the sterilizing filtration
process. The added complexity of reuse can present a compliance risk that might entail additional regulatory
scrutiny.
NOTE 2
A sterilizing grade filter can be used for in-process particulate or bioburden control prior to the
sterilizing filtration step. In this situation the filtrate from the bioburden control filter is not claimed to be sterile.
Caution should be exercised where filter packaging states for example, that a sterilizing-grade filter can
withstand 25 steam sterilization cycles at 121 °C for 20 min. This statement should not automatically
be interpreted to mean that the filter can be re-sterilized and reused up to 25 times to sterilize a liquid.
This statement might refer only to robustness of the filter in terms of the margin of safety regarding the
number of sterilization cycles the filter can safely withstand before polymer degradation is a concern.
This filter processing information is important to a product manufacturer when re-sterilization might be
required, however, it should not be simply extrapolated to repeated re-sterilization and reuse of the filter.
A guidance to 8.2.3.2 b) is offered as follows.
Validation and qualification studies to demonstrate that filter reuse during the filtration process for a
given liquid does not compromise performance of the sterilizing filter or filtrate quality should consider
the following but is not restricted to the following.
a) Any reuse effects on the filter from the filter user’s processes, for example exposure to multiple
filtration, flushing, cleaning, rinsing, drying and sterilization processes.
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b) Storage conditions for reused filters, including after immediate use and after sterilization prior
to reuse.
c)
Leaching of contaminants or cleaning agent residues from used filters. This should include the
potential for contamination with bacterial endotoxin as a result of lysis of bacterial cells from
carryover of bioburden from batch to batch.
Bacterial retention validation studies should be conducted on filters at the extent of reuse and which
have been exposed to actual production conditions (including worst-case processing conditions). These
studies are necessary as post-use integrity testing in the absence of bacterial retention studies is not
sufficient to determine if multiple reuse adversely affects the retention capabilities of a sterilizing filter.
A.8.3 Filtration process definition
No guidance is offered.
A.8.4 Integrity testing process definition
A.8.4.1 No guidance is offered.
A.8.4.2 Integrity testing prior to filtration may be omitted when
a) filtrate is automatically rejected in the event of a post use integrity test failure, or
b) process risk assessment permits re-filtration.
Figures A.11 and A.12 are examples of methods for post sterilization pre-use integrity testing designed
to maintain system sterility.
Key
product
0,2 µm product filter
wetting/flushing fluid
wetting and flushing biocontainer
pump
0,2 µm gas filter
0,2 µm gas filter
sterile connector
integrity test instrument
Figure A.11 — Typical equipment for pre-use integrity test on single 0,2 µm filter in a pre-
sterilized single-use system
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Key
product
0,2 µm product filter
wetting/flushing fluid
wetting and flushing biocontainer
pump
0,2 µm gas filter
0,2 µm gas filter
sterile connector
integrity test instrument
Figure A.12 — Typical equipment for pre-use integrity test on two single 0,2 µm filter in a pre-
sterilized single-use system
A.8.4.3 No guidance is offered.
A.8.4.4 No guidance is offered.
A.8.4.5 No guidance is offered.
A.8.4.6 No guidance is offered.
A.9 Validation
A.9.1 General
No guidance is offered.
A.9.2 Validation of fluid-specific microbial retention by sterilizing filters for liquids
A.9.2.1 General
A.9.2.1.1 No guidance is offered.
A.9.2.1.2 Previous versions of this document required that integrity test results for one of the filters
tested should lie within 10 % of the manufacturer’s limits for physical integrity test parameters. With
improvements in filter manufacture it may no longer be possible to source filters with integrity test
parameters >40 % from the middle of the specification in all cases.
A.9.2.1.3 No guidance is offered.
A.9.2.1.4 No guidance is offered.
A.9.2.1.5 No guidance is offered.
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A.9.2.2 Test organism
A.9.2.2.1 No guidance is offered.
A.9.2.2.2 No guidance is offered.
A.9.2.2.3 In culturing B. diminuta the culture conditions might contribute to reduced size and greater
filter penetration[8].
A review of environmental monitoring, raw material and pre-filtration bioburden isolates is usually
conducted to identify small organisms in the facility and raw materials. Where appropriate the isolates
are sized in the fluid to be filtered and compared with B. diminuta.
The use of water from systems that are not operated under self-sanitizing conditions might contribute
to the presence of diminutive organisms.
A.9.2.2.4 No guidance is offered.
A.9.2.2.5 No guidance is offered.
A.9.2.2.6 Growing A. laidlawii in TSB might result in an apparent increase in the percentage of very small
cells but these cells might be less penetrative than cells grown under other conditions. A growth medium
supplemented with 10 % horse serum might produce more penetrative cells (which are not necessarily
the smallest cells)[9].
A.9.2.2.7 No guidance is offered.
A.9.2.2.8 No guidance is offered.
A.9.2.2.9 No guidance is offered.
A.9.2.2.10 No guidance is offered.
A.9.3 Validation of the integrity test for sterilizing filters for liquids
No guidance is offered.
A.9.4 Qualification of filter interactions with the process fluid
No guidance is offered.
A.9.5 Validation of the sterilization of filter system
A.9.5.1 Consideration of the sterilization process for a sterilizing grade filter should include the
potential for the process to cause damage to the filter or filtration system. For example, steam sterilization
in place might be used to eliminate or to reduce aseptic connections; however, there might be a risk of
damage to a filter membrane due to dynamic flow through the filter at elevated temperature. There is
less risk of physical damage to a filter membrane from static processes such as irradiation sterilization
or moist heat sterilization in a steam sterilizer; however, the use of these processes might necessitate the
use of more aseptic connections.
A.9.5.2 No guidance is offered.
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A.9.6 Validation of fluid-specific microbial retention by sterilizing filters for gases
A.9.6.1 General
Gas filters are used in aseptic processing to vent breathing of aseptic processing tanks, vacuum breaks
for autoclaves and lyophilizers, nitrogen blanket for oxygen-sensitive products and blow-fill-seal
equipment.
A.9.6.2 Aerosol retention
Liquid or aerosol challenges can be used to qualify the retention capability of gas filters. Liquid bacterial
challenges represent a worst-case condition because the retention efficiency is much lower in liquids
than in gases. Conversely the enhanced efficiency in gases, bacterial aerosol challenge is less rigorous
than a liquid challenge even though it represents use conditions.
A.9.6.3 Validation of physical integrity testing
No guidance is offered.
A.9.6.4 Compatibility and service life
No guidance is offered.
A.9.6.5 Validation of the sterilization of the filter system for gases
No guidance is offered.
A.10 Routine monitoring and control
No guidance is offered.
A.11 Product release from sterilizing filtration
No guidance is offered.
A.12 Maintaining process effectiveness
A.12.1 General
No guidance is offered.
A.12.2 Recalibration
No guidance is offered.
A.12.3 Maintenance of equipment
No guidance is offered.
A.12.4 Requalification
No guidance is offered.
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A.12.5 Assessment of change
If there is a change in the fluid to be filtered (e.g. changes in raw materials, chemical composition,
concentrations, viscosity, changes to processing conditions), it is necessary to assess the change to see
if it could have an adverse effect on the performance of the sterilizing grade filter, or whether it might
invalidate the existing filter validation studies.
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Bibliography
[1]
ISO 10993-12:2012, Biological evaluation of medical devices — Part 12: Sample preparation and
reference materials
[2]
ISO 13408-3, Aseptic processing of health care products — Part 3: Lyophilization
[3]
ISO 13408-4, Aseptic processing of health care products — Part 4: Clean-in-place technologies
[4]
ISO 13408-6, Aseptic processing of health care products — Part 6: Isolator systems
[5]
ISO 13408-7, Aseptic processing of health care products — Part 7: Alternative processes for medical
devices and combination products
[6]
ISO 11737-1, Sterilization of medical devices - Microbiological methods - Part 1: Determination of a
population of microorganisms on products
[7]
ISO/IEC 90003, Software engineering — Guidelines for the application of ISO 9001:2008 to
computer software
[8]
Lee S-H, Lee S-S, Kim C-W Changes in the Cell Size of Brevundimonas diminuta Using Different
Growth Agitation Rates. PDA J. Pharm. Sci. Technol. 2002, 56 pp. 99–108
[9]
Parenteral Drug Association. PDA Technical Report No. 75 (TR 75) Consensus Method for
Rating 0.1µm Mycoplasma Reduction Filters, 2016
34
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ICS 11.080.01
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===== Part3 =====
Reference number ISO 13408-3:2006(E) © ISO 2006
INTERNATIONAL STANDARD ISO 13408-3 First edition 2006-09-15 Aseptic processing of health care products — Part 3: Lyophilization Traitement aseptique des produits de santé — Partie 3: Lyophilisation
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© ISO 2006 – All rights reserved
iii
Contents
Page
Foreword............................................................................................................................................................ iv
Introduction ........................................................................................................................................................ v
Scope ..................................................................................................................................................... 1
Normative references ........................................................................................................................... 1
Terms and definitions........................................................................................................................... 1
Quality system elements...................................................................................................................... 1
4.1
General................................................................................................................................................... 1
4.2
Management responsibility ................................................................................................................. 2
4.3
Design control....................................................................................................................................... 2
4.4
Measuring instruments and/or measuring systems ......................................................................... 2
Product definition ................................................................................................................................. 2
Process definitions............................................................................................................................... 2
User requirements ................................................................................................................................ 3
7.1
General................................................................................................................................................... 3
7.2
Equipment characterization................................................................................................................. 3
7.3
Product handling .................................................................................................................................. 4
7.4
Microbiological and particulate environmental monitoring ............................................................. 4
7.5
Cleaning and sterilization .................................................................................................................... 4
7.6
Vent filter system.................................................................................................................................. 5
7.7
Lyophilizer leak test.............................................................................................................................. 5
Validation............................................................................................................................................... 5
8.1
General................................................................................................................................................... 5
8.2
Design qualification.............................................................................................................................. 6
8.3
Installation qualification....................................................................................................................... 6
8.4
Operational qualification...................................................................................................................... 6
8.5
Performance qualification.................................................................................................................... 8
8.6
Process validation ................................................................................................................................ 8
8.7
Review and approval of validation...................................................................................................... 9
Routine monitoring and control.......................................................................................................... 9
9.1
General................................................................................................................................................... 9
9.2
Operator training................................................................................................................................... 9
9.3
Standard operating procedures .......................................................................................................... 9
9.4
Requalification .................................................................................................................................... 10
9.5
Maintenance of equipment ................................................................................................................ 10
9.6
Change control.................................................................................................................................... 10
Bibliography ..................................................................................................................................................... 11
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ISO 13408-3:2006(E)
iv
© ISO 2006 – All rights reserved
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 13408-3 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
ISO 13408 consists of the following parts, under the general title Aseptic processing of health care products:
⎯ Part 1: General requirements
⎯ Part 2: Filtration
⎯ Part 3: Lyophilization
⎯ Part 4: Clean-in-place technologies
⎯ Part 5: Sterilization in place
⎯ Part 6: Isolator systems
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ISO 13408-3:2006(E)
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v
Introduction
This part of ISO 13408 deals with lyophilization, which is a physical-chemical drying process designed to
remove solvents from both aqueous and non-aqueous systems, primarily to achieve product or material
stability. Lyophilization is synonymous to the term freeze-drying. Lyophilization involves freezing an aqueous
system and removing the solvent, first by sublimation (primary drying) and then by desorption (secondary
drying), to a level that no longer supports chemical reactions or biological growth. The result is a stable, well-
formed product meant to rapidly disperse or solubilize while retaining biological or other activity. Because it is
often the final step in an aseptic process with direct impact on the safety, quality, identity, potency and purity
of a product, lyophilization is a critical processing step.
Where the finished lyophilized product is intended to be sterile, the product to be dried is an aqueous system
that has already been sterilized. Therefore, all activities that can affect the sterility of the product or material
need to be regarded as extensions of the aseptic processing of that sterilized product or material. In general,
the predominant challenge in ensuring product or material sterility during lyophilization is to prevent
microbiological and particulate contamination between the filling operation and completion of the lyophilization
process. Of special, equipment-related concern is the protection of the product or material from
microbiological contamination within the chamber.
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INTERNATIONAL STANDARD
ISO 13408-3:2006(E)
© ISO 2006 – All rights reserved Aseptic processing of health care products — Part 3: Lyophilization Scope This part of ISO 13408 specifies requirements for, and offers guidance on, equipment, processes, programmes and procedures for the control and validation of lyophilization as an aseptic process. It does not address the physical/chemical objectives of a lyophilization process. 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 9001, Quality management systems — Requirements ISO 13408-1, Aseptic processing of health care products — Part 1: General requirements ISO 13408-4, Aseptic processing of health care products — Part 4: Clean-in-place technologies ISO 13408-5, Aseptic processing of health care products — Part 5: Sterilization in place Terms and definitions For the purposes of this document, the terms and definitions given in ISO 13408-1 and the following apply. 3.1 lyophilization physical-chemical drying process designed to remove solvents from both aqueous and non-aqueous systems, by sublimation and desorption 3.2 leak test physical test for the capability to provide a quantifiable leakage rate under repeatable test conditions Quality system elements
4.1.1 The requirements of ISO 13408-1 shall apply.
and maintenance of the lyophilizer shall be prepared and implemented.
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ISO 13408-3:2006(E)
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personnel.
evidence of conformity to the requirements of this part of ISO 13408.
4.2.1 The responsibility and authority for implementing and performing the procedures described in this part of ISO 13408 shall be specified.
management systems, the responsibilities and authority of each party shall be specified.
The design of the lyophilizer shall be undertaken in accordance with a documented plan. At defined stages, design reviews shall be planned, conducted and documented. Software used to control and/or to monitor shall be prepared in accordance with a quality system that provides documented evidence that the software meets its design specification.
measuring systems.
designated as non-conforming, and for corrective action. Product definition 5.1 The product to be lyophilized shall be defined and documented. The specification of the product shall include but not be limited to: a) its chemical, physical and pharmaceutical properties as appropriate; b) container and closure configuration. 5.2 Following application of the specified lyophilization process it shall be demonstrated that the product meets its specified requirements for safety, quality and performance. Process definitions 6.1 A specification for the lyophilization process shall be documented. 6.2 The lyophilization process applicable for a defined product shall be established. Process development shall be performed to determine critical process parameters.
shall include, but not be limited to:
a)
the range of temperatures and pressures;
b)
the rates of freezing;
c)
the time at a given temperature and pressure.
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ISO 13408-3:2006(E)
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6.4
During all processes the conditions achieved shall be monitored, maintained within specified tolerances,
and recorded.
6.5
Where conditioning of the product is required prior to the lyophilization process it shall be defined and
documented as part of the lyophilization process.
maximum hold or wait times: a) between the start of filling and the start of the lyophilization cycle; b) between the end of the lyophilization cycle and the start of unloading (where stoppers are not seated into the product containers within the equipment prior to the opening of the lyophilizer chamber); c) between sterilization of the lyophilizer and the start of the lyophilization cycle; d) between sterilization and use of utensils (such as trays, bags, placing devices, tweezers etc).
documented. ISO 13408-4 and ISO 13408-5 shall apply. User requirements
required but without regard as to how that functionality shall be designed or implemented. It shall be reviewed and approved by the user.
conditions/parameters, together with their tolerances, shall be defined so that the use of the lyophilizer and the ancillary equipment will produce a reliable and safe product.
7.2.1 Design specifications for equipment to deliver the required processes within defined tolerances shall be established and documented. 7.2.2 The equipment shall be designed, built and located so as to facilitate aseptic processing, cleaning, sterilization and lyophilization. For CIP and SIP, ISO 13408-4 and ISO 13408-5 shall apply.
the prior processing step through to loading and unloading, with special attention to the position of equipment, personnel and critical processing zones.
condenser.
7.2.5
Blocks, cassettes, frames, shelves, trays etc. required for the lyophilization process shall be defined
and documented as part of the process.
NOTE
Flat shelves are desirable for even product contact for both reasons of temperature uniformity and the
distribution of mechanical pressure (e.g. during stoppering in the case of vials with stoppers) and for the prevention of
condensate retention.
7.2.6
The maximum permitted leakage of air into the lyophilizer shall be specified.
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7.2.7 If compressed air, nitrogen or any other gas is admitted into the lyophilizer, its purity and rate of admission shall not impair the integrity of the product. 7.2.8 Equipment controls in the critical processing zone shall be minimized. 7.2.9 The specification for the location in which the equipment and its components are to be installed shall be established and documented and include (but not be limited to): a) the services that are required for the lyophilizer and for the area in which it is installed; b) the materials of construction for the parts that transport the utilities to and from the lyophilizer.
specified and documented. 7.3.1.2 Transport to the lyophilizer and loading of the filled product, utensils or other equipment into the lyophilizer shall take place in a critical processing zone. Where auxiliary equipment or containers are used for transport, the validated conditions maintained therein shall be equivalent to the critical processing zone.
unsealed containers are exposed shall maintain critical processing zone conditions. 7.3.1.4 Utensils used during transfer to, and loading of, the lyophilizer that could contaminate the product shall be subjected to a validated sterilization process.
7.3.2.1 A procedure for unloading the lyophilizer shall be specified and documented. NOTE Seating of the stoppers is normally performed within the lyophilizer chamber prior to unloading.
removed from the lyophilizer shall remain in a critical processing zone during subsequent handling.
disinfection and/or sterilization process.
A programme for microbiological and particulate monitoring of the environment during product transfer and lyophilization shall be defined and documented.
7.5.1 Cleaning-in-place (CIP) For CIP processes ISO 13408-4 shall apply.
adequate challenge that represents the worst-case conditions experienced during routine operation and
cleaning of the equipment.
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ISO 13408-3:2006(E)
© ISO 2006 – All rights reserved
or material during the lyophilization process, and to remove any residues that would otherwise create a barrier between the sterilizing agent and the equipment surfaces. NOTE An automated process is preferred in order to improve consistency, reliability and personal safety. 7.5.3 Sterilization in place (SIP) 7.5.3.1 For sterilization in place processes, ISO 13408-5 shall apply.
campaign. A limit to the number of dryer loads in a campaign should be specified and validated. 7.5.3.3 Conditions protecting the lyophilizer from contamination after sterilization shall be maintained, the efficacy of the protection shall be validated and the performance documented.
chamber should be addressed where applicable.
7.6.1 Bacteria retentive filters shall be used to maintain lyophilizer integrity when breaking the vacuum. Flow or pressure increase rate shall be specified, documented and justified.
the filter. NOTE In situ filter sterilization is preferred. 7.6.3 The frequency of the filter integrity testing shall be specified, justified and documented.
7.7.1 The lyophilizer shall comply with user-defined leak test procedures and limits.
the targeted vacuum conditions (depth and duration), the maximum permitted leakage of air into the lyophilizer chamber and condenser, as well as the alert limits and rationale behind possible corrective actions. Validation
Written protocol(s) shall be established and shall specify how validation is to be conducted. Protocol(s) shall
be reviewed and approved and shall specify critical parameters and acceptance criteria. Validation of
equipment design, installation, operation, performance and processes shall be performed by qualified
personnel in accordance with the approved protocol(s). Any deviation from the protocol(s) shall be
documented, investigated and resolved.
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Appropriateness of system design and design of the facilities, utilities, equipment and materials used shall be confirmed to meet the requirements for the intended use at the first stage of validation. Design qualification should be emphasised in validation activities as specified in ISO 9001. NOTE Design qualification is documented verification that the proposed design of the facilities, utilities, equipment and system is suitable for the intended use.
Installation qualification shall be carried out in accordance with a documented procedure that cross-references appropriate equipment and “as installed” specifications.
8.3.2.1 It shall be documented and verified that the equipment and its location conform to its specification.
installation instructions.
specification.
controlling, indicating or recording shall be verified.
is to be operated during operational qualification.
operational qualification.
Computerized control systems and associated software shall be qualified before starting operational tests on the equipment to demonstrate conformance to the specification.
The alarm system shall be qualified to demonstrate conformance with specifications and to demonstrate that the appropriate control system responses are observed and documented.
Operational qualification shall be performed in accordance with documented procedures to demonstrate that the installed equipment is capable of delivering the specified processes within defined tolerances.
A leak test shall be performed to demonstrate conformance with the specification. The leakage of air into the
lyophilizer chamber shall not exceed the specified limits.
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ISO 13408-3:2006(E)
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8.4.3 Thermal control system(s)
The system(s) that control temperatures shall be qualified to demonstrate that the rate of thermal control and
ultimate temperature capabilities of the system conform to the specification(s).
NOTE
Thermal control system(s) are used to control variables such as shelf temperature, condenser temperature,
and jacket temperature.
The vacuum system shall be qualified to demonstrate that the rate of evacuation and the ultimate capabilities of the vacuum system conform to the specification.
The refrigeration system capacity and cooling rate of change shall be qualified to demonstrate conformance with the specification. Operational qualification is the first check of the condenser capacity and may be done with a reference solvent such as water.
Where a defrost cycle is specified, the sequence of operations shall be performed to demonstrate conformance with the specification.
The sequence of operation of the lyophilization cycle shall be performed to demonstrate conformance with the specification.
Operational qualification shall be performed in accordance with documented procedures to demonstrate compliance with the requirements of ISO 13408-4.
Operational qualification shall be performed in accordance with documented procedures to demonstrate compliance with the requirements of ISO 13408-5. 8.4.10 Stoppering seating system(s) Stoppering seating system(s), where present, shall be qualified to demonstrate conformance to their specification.
variations and shall demonstrate conformance to the specification.
Ideally, these studies should be performed with the chamber at atmospheric pressure and include a range of
temperatures that take into account both the heating and cooling phases of the lyophilization cycle.
8.4.11.2
The number of temperature sensors used shall be specified.
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ISO 13408-3:2006(E)
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Data generated during installation qualification and operational qualification shall be reviewed before performance qualification is started to verify that the requirements of both performance qualification and process validation will be met. Usually, performance qualification is performed with actual product. However, where a well-characterized equivalent placebo is available, this may be used.
the intended product or process.
procedures, and processed to demonstrate conformance to the predetermined cycle parameters.
Performance qualification shall be performed, in accordance with documented procedures, to demonstrate compliance with the requirements of ISO 13408-5.
Process validation shall be performed to demonstrate that the lyophilization process leads to the intended product quality and characteristics. NOTE Subparts of process validation are process simulation, cleaning and product qualification simulating routine production.
Cleaning of the lyophilizer shall be validated. CIP processes shall be validated in accordance with the requirements of ISO 13408-4.
NOTE 1 Process simulations representing the aseptic processing of lyophilized products include extra difficulties associated with manipulative activities and human intervention. NOTE 2 Concerns related to the introduction of microbiological media into a lyophilizer are minimized by a combination of working, cleaning, disinfection and sterilization methods, which make the use of liquid broth solutions in lyophilizers acceptable.
processing chain, including filling, transport, loading, chamber dwell, unloading and sealing, under specified, documented and justified conditions representing worst case operating parameters.
freezing, as practical, including partial vacuum and duration as appropriate for the media. Boiling-over or
actual freezing of the solution shall be avoided.
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ISO 13408-3:2006(E)
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Factors to consider include, where applicable:
a)
use of air instead of nitrogen;
b)
maximum interval between sterilizations of the lyophilizer;
c)
maximum period of time between sterilization and lyophilization;
d)
quantitative aspects of worst-case situations.
NOTE
An example is the number of trays loaded and duration of loading (chamber open to environment).
specifications and that product requirements for safety, quality, identity and purity are met. Quality attributes to be tested for should include (but not be limited to) sterility, stability, residual solvent, reconstitution, appearance, potency and uniformity. 8.6.4.2 Testing shall be performed in accordance with an approved sampling plan.
Information gathered or produced during design qualification, installation qualification, operational qualification, performance qualification and process validation shall be reviewed for conformity to the acceptance criteria specified for each element of the validation process. The results of this review shall be documented. Routine monitoring and control
The purpose of routine monitoring and control is to demonstrate that the validated and specified processes have been delivered.
9.2.1 Operators shall be trained according to established procedures. 9.2.2 Specific operator training shall be implemented in accordance with a documented programme. Training shall demonstrate the operator’s: a) understanding of the principles of the process, including operational and construction features; b) ability to perform the routine operation; c) understanding of the actions to be taken if a process or any part of the process fails; d) understanding of the safety aspects of the systems.
Established and documented operational procedures based on the validated parameters shall include, but not
be limited to:
a)
step-by-step operating instructions;
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ISO 13408-3:2006(E)
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b) acceptance criteria for the operating cycle parameters, and actions to be taken if those criteria have not been met; c) duties and responsibilities; d) housekeeping, calibration and maintenance instructions.
documented plan. 9.4.2 Records shall be retained of the reviews of requalification data and of any corrective actions taken when the specified acceptance criteria are not met.
Preventative maintenance shall be planned and performed in accordance with documented procedures.
assessed for its impact on the effectiveness of the processes. The magnitude of the change should be considered in determining the extent to which installation qualification, operational qualification, performance qualification and process validation are undertaken.
qualification that is necessary, shall be documented.
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Bibliography
[1]
ISO 9000, Quality management systems ― Fundamentals and vocabulary
[2]
ISO/TS 11139:2006, Sterilization of health care products — Vocabulary
[3]
ISO 13485, Medical devices — Quality management systems — Requirements for regulatory
purposes
[4]
U.S. Food and Drug Administration, 21 CFR Part 210 and Part 211, Current Good Manufacturing
Practices for Finished Pharmaceuticals
[5]
U.S. Food and Drug Administration, 21 CFR Part 11, Electronic records, electronic signature
[6]
U.S. Food and Drug Administration, Guideline on the General Principles of Process Validation,
May 1987
[7]
U.S. Food and Drug Administration, Guide to Inspections of Lyophilization of Parenterals, 15.02.01
[8]
EEC Guide to Good Manufacturing Practice for Medicinal Products, Annex 1, Manufacture of Sterile
Medicinal Products
[9]
ISPE, GAMP 4.0. Good Automated Manufacturing Practice Guide for Validation of Automated Systems
in Pharmaceutical Manufacture
[10]
FISCHER, T., Lyophilizer Qualification: Some Practical Advice, Drugs and the Pharmaceutical Sciences,
Vol. 137, Freeze–Drying/Lyophilization of Pharmaceutical and Biological Products, 2nd edition, 2004,
pp. 517–533, Marcel Dekker
[11]
PDA, Process Simulation Testing for Aseptically Filled Products, PDA Technical Report No. 22, 1996
[12]
JENNINGS, T.A., Validation of the Lyophilization Process, Validation of Aseptic Pharmaceutical
Processes, 1986, pp. 595-633, Marcel Dekker
[13]
CAMERON, P., Good Pharmaceutical Freeze-Drying Practice, 1999, Chapter 9, Interpharm Press,
[14]
JENNINGS, T.A., Lyophilization — Introduction and Basic Principles, 1999, Chapter 8, Interpharm Press,
[15]
AUTERHOFF, G., EG-Leitfaden einer Guten Herstellungspraxis für Arzneimittel, 5th edition, 1998,
ECV-Verlag, Aulendorf
[16]
OETJEN, G.-W., Gefriertrocknen, 1997, VCH Verlagsgesellschaft, Weinheim
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ICS 11.080.01
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===== Part4 =====
Reference number ISO 13408-4:2005(E) © ISO 2005
INTERNATIONAL STANDARD ISO 13408-4 First edition 2005-11-01 Aseptic processing of health care products — Part 4: Clean-in-place technologies Traitement aseptique des produits de santé — Partie 4: Technologies de nettoyage sur place
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ISO 13408-4:2005(E)
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iii
Contents
Page
Foreword............................................................................................................................................................ iv
Introduction ........................................................................................................................................................ v
Scope ..................................................................................................................................................... 1
Normative references ........................................................................................................................... 1
Terms and definitions........................................................................................................................... 1
Quality system elements...................................................................................................................... 2
4.1
General................................................................................................................................................... 2
4.2
Management responsibility ................................................................................................................. 2
4.3
Design control....................................................................................................................................... 2
4.4
Measuring instruments and measuring systems .............................................................................. 2
Process and equipment characterization .......................................................................................... 3
5.1
General concepts.................................................................................................................................. 3
5.2
Effectiveness of CIP ............................................................................................................................. 3
5.3
Equipment ............................................................................................................................................. 4
Cleaning agent characterization ......................................................................................................... 5
6.1
Selection of cleaning agent(s)............................................................................................................. 5
6.2
Quality of cleaning agent(s)................................................................................................................. 5
6.3
Safety and the environment................................................................................................................. 6
CIP process ........................................................................................................................................... 6
7.1
Process parameters.............................................................................................................................. 6
7.2
Process control..................................................................................................................................... 6
7.3
Residues of cleaning agent(s)............................................................................................................. 8
Validation............................................................................................................................................... 8
8.1
Validation protocol ............................................................................................................................... 8
8.2
Evaluation of the CIP process ............................................................................................................. 8
8.3
Design qualification.............................................................................................................................. 8
8.4
Installation qualification....................................................................................................................... 8
8.5
Operational qualification...................................................................................................................... 9
8.6
Performance qualification.................................................................................................................... 9
8.7
Review and approval of validation.................................................................................................... 10
8.8
Requalification .................................................................................................................................... 10
Routine monitoring and control........................................................................................................ 10
9.1
CIP process control............................................................................................................................ 10
9.2
Procedures .......................................................................................................................................... 10
9.3
CIP process records........................................................................................................................... 11
9.4
Change control.................................................................................................................................... 11
9.5
Maintenance and calibration ............................................................................................................. 11
Personnel training .............................................................................................................................. 11
Annex A (informative) Description of sampling methods............................................................................ 12
Annex B (informative) Calculation examples for acceptance criteria......................................................... 13
Bibliography ..................................................................................................................................................... 14
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ISO 13408-4:2005(E)
iv
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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 13408-4 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products. ISO 13408 consists of the following parts, under the general title Aseptic processing of health care products: Part 1: General requirements Part 2: Filtration Part 3: Lyophilization Part 4: Clean-in-place technologies Part 5: Sterilization in place Part 6: Isolator systems
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ISO 13408-4:2005(E)
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v
Introduction
During the process of preparing ISO 13408-1 several items, e.g. filtration, lyophilization drying and
sterilization-in-place technologies, were found to be in need of supplementary information that was too
voluminous to be given in corresponding annexes.
This part of ISO 13408 includes requirements and guidance that are to be observed during clean-in-place
processes. The purpose of this part of ISO 13408 is to achieve standardization in the field of validation and
routine control of clean-in-place processes used in the manufacture of health care products.
Clean-in-place processes allow parts of the equipment or an entire process system to be cleaned without
being dismantled, reducing the need for disassembling and connections under clean conditions. For example,
tanks, vessels, freeze-dryers piping and other processing equipment used for manufacture may be cleaned in
place.
The clean-in-place process is in most instances followed by sterilization-in-place process (described in
ISO 13408-5). While clean-in-place and sterilization-in-place methods differ considerably in technology, the
concept of in situ treatment is similar.
Design considerations of all systems are critical to ensure that clean-in-place technologies can be successfully
applied to clean manufacturing equipment to the desired level of cleanliness.
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INTERNATIONAL STANDARD
ISO 13408-4:2005(E)
© ISO 2005 – All rights reserved
Aseptic processing of health care products —
Part 4:
Clean-in-place technologies
Scope
This part of ISO 13408 specifies the general requirements for clean-in-place (CIP) processes applied to
product contact surfaces of equipment used in the manufacture of sterile health care products by aseptic
processing and offers guidance on qualification, validation, operation and control.
This part of ISO 13408 is applicable to processes where cleaning agents are delivered to the internal surfaces
of equipment designed to be compatible with CIP, which may come in contact with the product.
This part of ISO 13408 is not applicable to processes where equipment is dismantled and cleaned in a washer.
This part of ISO 13408 does not supersede or replace national regulatory requirements, such as Good
Manufacturing Practices (GMPs) and/or compendial requirements that pertain to particular national or regional
jurisdictions.
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 13408-1, Aseptic processing of health care products ― Part 1: General requirements
ISO/IEC 90003, Software engineering ― Guidelines for the application of ISO 9001:2000 to computer
software
Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 13408-1 and the following apply.
3.1
cleaning agent
organic or inorganic chemical including water, detergent or mixture thereof, used as an aid in the cleaning
process for cleaning equipment
3.2
clean-in-place
CIP
method of cleaning of the internal surfaces of parts of the equipment or an entire process system without or
with minimal disassembly
NOTE
CIP also includes the removal of remaining residual cleaning agent to an acceptable level which is defined
based on the nature of the product and the process tolerance.
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ISO 13408-4:2005(E)
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3.3 dead leg location which, by design, does not permit adequate accessibility of the cleaning agent 3.4 design qualification documented verification that the proposed design of the facilities, equipment, or system is suitable for the intended use 3.5 material safety data sheet document specifying the properties of a material, its potential hazardous effects for humans and the environment, and the precautions necessary to handle and dispose of the material safely 3.6 worst-to-clean most difficult conditions for cleaning EXAMPLES Materials to be removed, surface types to be cleaned, process parameters to be met or position(s) to be reached. Quality system elements
4.1.1 The requirements of ISO 13408-1 shall apply.
control of the CIP process shall be prepared and implemented.
personnel.
evidence of conformity to the requirements of this part of ISO 13408.
part of ISO 13408 shall be specified.
management systems, the responsibilities and authority of each party shall be specified.
Characterization of the cleaning agent(s), cleaning method, equipment to deliver CIP and the equipment subject to CIP, shall be undertaken in accordance with a documented plan. At defined stages, design reviews shall be planned, conducted and documented.
4.4.1 A documented system shall be specified for the calibration of all measuring instruments or measuring systems.
measured.
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ISO 13408-4:2005(E)
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Process and equipment characterization
a) physical and chemical properties of the material to be removed and the strength of its adherence to the surface from which it is to be removed; b) physical and chemical properties and mechanism of action of cleaning agent(s); c) compatibility of the equipment with the cleaning agents and processing conditions; d) pre-cleaning period and conditions prior to cleaning; e) the number of passes (single-pass cleaning, and/or multi-pass cleaning); f) filling and immersing period with cleaning agent(s); g) agitation or spraying of cleaning agent(s); h) cleaning agent(s) elimination; i) post-cleaning drying; j) post-cleaning protection of the cleanliness of the equipment; k) maximum post-cleaning hold period and conditions. 5.1.2 Cleaning agent(s) shall be reproducibly delivered in effective quantities and concentrations to all parts of the system. 5.1.3 In order to ensure effective CIP, all parameters necessary to control the cleaning conditions shall be established and documented. These conditions shall be maintained and monitored within specified limits.
should overlap to ensure that all portions of the system are adequately and effectively cleaned. NOTE Although the entire processing system can be cleaned as a single entity in CIP, it can be advantageous to divide the system into several parts in order to simplify the cleaning procedures. 5.1.5 Complex sequences of opening and shutting of valves in the pipes of a system could be required. Where this is controlled manually, detailed documentation of individual steps shall be established. Where automation is used, electronic automation systems should be carefully designed and validated.
5.2.1 The necessary level of cleanliness shall be established and documented. Justification of the process parameters and the permitted levels of residual substances shall be included in the documentation. There shall be no residue that poses a significant risk to patient safety. NOTE Residual substances can include previous product or decomposition products thereof and/or cleaning agents.
processed in the equipment to be cleaned taking into account potency, toxicity, biocompatibility,
carcinogenicity, mutagenicity, potential for tissue sensitization where equipment is not dedicated, etc. Where
removal of product is not possible with sufficient efficacy, it may be necessary to use dedicated equipment.
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ISO 13408-4:2005(E)
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account ease of cleaning with regard to the characteristics of the products to be processed. Worst-to-clean locations shall be minimized through the use of smooth, impervious, non-grooved, continuous and polished surfaces. NOTE Dead legs, locations with stagnant liquid in piping, shoulders of tanks, intricate irregular internal surfaces such as gasket interfaces and pump internal parts can usually be regarded as worst-to-clean locations.
a) smoothness of inner surface of equipment; b) distribution of the cleaning agent(s) to all relevant surfaces (e.g. valves, connections, filter assemblies); c) necessity to use special equipment such as spray devices, their number, location and coverage; d) absence of dead legs in piping systems; e) drainability of the system (e.g. slope of piping to ensure the complete removal of remaining liquid in the system); f) compatibility of materials of construction (e.g. pipes, tanks, valves, nozzles, filters, gaskets, sensors) with the cleaning agent(s) and process conditions selected; g) access to allow monitoring of cleaning conditions in appropriate locations; h) protection of the cleaned equipment from re-contamination.
a) physical description of the equipment, together with any necessary ancillary items, including materials of construction, (including as-built drawings); b) specifications of the cleaning agent and means by which it is provided, including any additives or precursors necessary for its delivery; c) description of instrumentation for monitoring and controlling the cleaning process, including sensor characteristics and their locations, indicating and recording instruments; d) description of safety features, including those for personnel and environmental protection; e) description of installation requirements, if applicable; f) documented evidence that the software used to control and/or monitor the process is prepared in accordance with a quality system and that the software meets its design intention; g) a process flow diagram which outlines the processing equipment layout to be cleaned, including valve sequencing.
equipment to be cleaned. Primary functions to be verified in qualification shall include but not be limited to:
a)
preparation and storage of cleaning agent(s);
b)
admittance of cleaning agent(s) into the equipment to be cleaned in a controlled and safe manner;
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ISO 13408-4:2005(E)
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c)
distribution of cleaning agent(s) within the equipment to be cleaned;
d)
maintenance of effective cleaning conditions throughout the equipment to be cleaned, (e.g. delivery
pressure and delivery temperature).
a) physical description of the equipment, together with any necessary ancillary items, including materials of construction, (including as-built drawings); b) specifications of the cleaning agent and means by which it is provided, including any additives or precursors necessary for its delivery; c) description of instrumentation for monitoring, controlling and recording the cleaning process, including sensor characteristics, and their locations, indicating and recording instruments; d) description of safety features, including those for personnel and environmental protection; e) description of installation requirements, if applicable; NOTE This can include, for example, the location and the environment in which the equipment is to be installed and the services that are required for the CIP and for the area in which the CIP system is installed. f) documented evidence that the software used to control and/or monitor the process is prepared in accordance with a quality system and that the software meets its design intention.
Means shall be provided to ensure that a failure in a control function does not lead to any failure in recording of process parameters such that an ineffective process appears effective. Cleaning agent characterization 6.1 Selection of cleaning agent(s) 6.1.1 Only cleaning agent(s) that have been shown to be suitable for their intended purpose shall be used. For selection of the most suitable cleaning agent(s) at least the following considerations shall be addressed: a) physical and chemical characteristics of residual substances to be removed; b) characteristics of potential cleaning agent(s); c) compatibility with the manufacturing equipment; d) ability to remove residual cleaning agent(s) including a method to detect residual cleaning agent(s).
cleaning agent(s), such as purified water or water for injection as appropriate.
NOTE
Examples of cleaning agent(s) include water, hot water, detergents, alkaline solution, hot alkaline solution,
organic solvents, or acids.
6.2 Quality of cleaning agent(s)
Quality specifications for the cleaning agents shall be established, justified and documented. In establishing a
specification, at least the following shall be considered:
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ISO 13408-4:2005(E)
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a) identity of the cleaning agent(s); b) chemical composition and bioburden; c) assurance of strength or concentration; d) shelf life.
available. 6.3.2 An assessment of the potential environmental impact of the cleaning agent(s) shall be available. CIP process
7.1.1 The cleaning method shall be determined by considering the construction features of the equipment to be cleaned, and by considering the physical and chemical characteristics of residual substances.
documented. Process parameters shall be adequate to ensure cleaning of equipment to the previously determined acceptable level. Such parameters shall include, as appropriate: a) flow rate and pressure; b) type and concentration of the cleaning agent(s); c) temperature of cleaning agent(s); d) time for priming the system, undertaking the CIP process, inactivation/rinsing and draining/drying the product contact surfaces; e) total time of cleaning including rinsing and drying as appropriate; f) agitator motion; g) volume of cleaning agent and rinse water.
manufactured using the same equipment. This assessment is intended to identify the most difficult to remove residual product as well as the most toxic residues to be removed. NOTE Indicator products are frequently used as worst case and the CIP validation can be based on these as an alternative to validating each single substance or product.
Means of monitoring and controlling the process parameters shall be defined and documented.
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ISO 13408-4:2005(E)
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7.2.2 Selection of sampling method(s)
The sampling method(s) shall be established with a rationale by considering the construction features of the
equipment, and also by considering the physical and chemical characteristics of the product. Sampling
methods are described in Annex A.
NOTE 1
Usually, a combination of visual inspection, swab method and rinse methods is used.
NOTE 2
Examples for analytical methods to determine the amount of residual substances are HPLC, TLC, TOC, UV
absorption method, pH, ion-strength, conductivity, osmotic pressure, colour, smell and/or visual inspection.
The specificity and sensitivity of analytical methods and the recovery using the sampling method shall be determined and validated. The method shall be valid in the presence of other materials (e.g. cleaning agents). Recovery efficiency results for any sampling method shall be factored into the test results.
Acceptance criteria shall be based upon a calculation of theoretical carryover into the next batch. A documented rationale shall be written which specifies the acceptance criteria for cleaning. When calculating carryover into next batch, potential distribution of residue in total rinse or first pass should be considered. NOTE Acceptance criteria can also be based on toxicity, analytical detectability and process capability of the CIP process.
Visual examination shall be performed using approved procedures and trained operators looking for visible contamination. Procedures shall include requirements for lighting or visual aids.
A method to determine chemical residuals shall be established. The effectiveness of the CIP procedure shall be determined. Chemical residuals shall be established, either: a) directly, by quantifying the amount of residual present on the surface of the equipment or in the rinse, or b) indirectly by measuring parameters correlated with the residual, e.g. conductivity or TOC. Acceptance criteria shall be evaluated against the products and specified in the validation protocol with proper justification. Examples for calculation are given in Annex B.
using surface swabbing or rinse samples. 7.2.7.2 Acceptance criteria shall be based upon efficacy of any subsequent processing (sterilization).
microbial proliferation.
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ISO 13408-4:2005(E)
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evaluated as part of CIP validation.
compendial requirements.
CIP shall remove all particles and foreign matter to specified levels consistent with the requirements of the product intended to be manufactured in the equipment. NOTE Visual inspection is the primary methodology for verifying the absence of bristles, fibres, etc. For smaller (sub-visible) contamination, rinse samples can be taken to validate the capability of the process to achieve acceptable and reproducible results. 7.3 Residues of cleaning agent(s) After the CIP process has been completed, any cleaning agent(s) shall be removed from the system. Permissible levels of residues shall be specified and justified. Validation
Written protocol(s) shall be established, and specify how qualification and validation are to be conducted. Protocol(s) shall be reviewed and approved and specify critical steps and acceptance criteria. Qualification of equipment design, installation, operation and performance shall be performed in accordance with the approved protocol(s). Any deviation(s) from the protocol(s) shall be documented, investigated and resolved.
Acceptance criteria for the validation of CIP shall be established based on the evaluation of cleanliness and ability to remove cleaning agent residue (see Clause 7).
The CIP system shall be designed for its intended use. Appropriateness of system design, process design, design of all facilities, equipment and materials used shall be confirmed at the first stage of validation to meet the requirement for the intended use.
Installation qualification shall be performed to demonstrate that the equipment used to perform CIP and deliver the cleaning agent, and the equipment to be subjected to CIP, and any ancillary items have been supplied and installed in accordance with their specifications.
a)
the location of the equipment conforms to its specification,
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b)
the equipment is installed in accordance with installation instructions,
c)
the services to the equipment conform to their specification(s).
8.4.2.2
The calibration of all measuring instruments critical to the process (including any test instruments)
used for monitoring, controlling, indicating or recording shall be confirmed.
NOTE
Alternatively, calibration can be confirmed at the commencement of operational qualification.
demonstrate conformance to ISO/IEC 90003 or other relevant guidelines for the manufacture of the product.
8.5.1 Operational qualification shall demonstrate that the installed equipment is capable of performing the specified CIP process throughout the equipment within defined parameters. 8.5.2 The operating procedures for the equipment shall be verified to meet established requirements. These operating procedures shall include but not be limited to: a) step-by-step operating instructions; b) the method by which a failure to attain the operating cycle parameters can be identified, and the actions to then be taken; c) housekeeping, calibration and maintenance instructions; d) the means by which an error in the result of a measurement for control, indication and recording can be identified; e) details of contacts for technical support.
(control, indication and recording) shall be determined at significant parts of the CIP system.
8.6.1 Data generated during installation qualification and operational qualification shall be approved before performance qualification is started.
achievement of defined acceptance criteria determined by visual, swab method and/or rinse methods. Data shall be collected to demonstrate that the CIP process achieves predetermined residual limits. 8.6.3 Performance qualification shall include a series of at least three consecutive and successful runs of the CIP process to demonstrate the reproducibility and effectiveness of the process. If failure can be attributed to factors not relevant to the effectiveness of the CIP process being validated, this test can be documented as unrelated to performance of the CIP process without requiring three further consecutive, successful runs. NOTE Examples of this type of failure include, but are not limited to, power failures, loss of services, or failure of external monitoring equipment.
favourable limit (ensuring "worst-to-clean" conditions and locations yielding acceptable CIP effectiveness).
The outcome of such studies shall predict that, on application of the CIP process, the specified requirements
for cleanliness will be met.
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8.6.5 CIP process qualification shall be performed at the maximum period after use before the equipment is cleaned.
evidence shall be provided to show that the number and locations used are sufficient to demonstrate that the requirements for cleanliness in the CIP system are met. Locations sampled shall address worst-to-clean locations.
8.7.1 Information gathered or produced during design qualification, installation qualification, operational qualification and performance qualification shall be documented and reviewed for acceptability. The results of this review shall be documented.
confirmed. This process specification shall also include the criteria for designating an individual CIP process as conforming or acceptance criteria.
responsible for preparing, reviewing and accepting this(these) report(s) against the acceptance criteria in the validation protocol(s).
calibration at the time of the performance qualification.
intervals and in response to CIP process failures.
with documented procedures. Records of reviews of revalidation data, and corrective actions taken in the event that the specified acceptance criteria are not met, shall be retained. 8.8.3 Requalification report(s) shall be documented and retained. Routine monitoring and control
Routine monitoring and control shall be performed on each CIP process. Data shall be recorded to demonstrate that the validated and specified CIP process parameters have been delivered to the system.
Written procedures shall be consistent with those of validation studies. These procedures shall include but not
be limited to:
a)
step-by-step operating instructions;
b)
duties and responsibilities;
c)
acceptance criteria for the operating cycle parameters and actions to be taken if those criteria have not
met;
d)
housekeeping, calibration and maintenance instructions;
e)
detailed description of the CIP process.
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a) date of operation; b) name of process and lot (batch) number that is produced before CIP; c) name of operator(s); d) CIP process parameters and their confirmation. Records can include equipment printout of contact time, temperature, pressure measured at predetermined positions, alarms or other parameters which influence cleaning efficacy, such as identification and concentrations of cleaning agents. 9.3.2 CIP process records shall be reviewed and accepted prior to the manufacturing of the next batch.
equipment shall be assessed for their potential impact on the effectiveness of the CIP process and the need for requalification.
qualification, operational qualification or performance qualification is undertaken.
qualification that is necessary shall be documented.
Preventive maintenance including calibration of instruments shall be planned, performed and documented in
accordance with documented procedures.
10 Personnel training
10.1 Personnel shall be trained according to established procedures.
10.2 A specific training programme for personnel shall be established, implemented and documented.
Training shall demonstrate the personnel's:
a)
understanding of the theory and operation of CIP process, including construction features;
b)
ability to perform the routine operation, maintenance or testing as appropriate;
c)
understanding of the actions to be taken if the process or any part of the process fails;
d)
understanding of the safety aspects of the cleaning agent(s) and CIP system.
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ISO 13408-4:2005(E)
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Annex A (informative)
Description of sampling methods
A.1 Swab samples
Swabs are used to recover residue from the surface of selected locations after cleaning. Simulated surfaces
(e.g. carriers, coupons) may be used to supplement surfaces to be sampled. Recovery of residue is
determined and factored into the test results. The level of contamination of all product contact surfaces is
based on the level of contamination from the residue swab sample. The assumption is made that the
contamination from the sample is equal to or worse than the total surface of the equipment.
A.2 Rinse samples
Sampling of the final rinse after cleaning to determine the quantity of any residue in the rinse can be used to
calculate the quantity of residue on the surface of the equipment that potentially could carryover into the next
batch. The recovery percentage of residue is determined and factored into the test results.
A.3 Placebo samples
The manufacturing of a placebo batch in the equipment after the process to be cleaned, using the same
operating parameters used for processing product, can allow sampling of the placebo batch for residual
contamination. Because of the difficulty in assuring the uniform distribution of any contaminate, this method
should only be used in conjunction with swab and/or rinse sampling.
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ISO 13408-4:2005(E)
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Annex B
(informative)
Calculation examples for acceptance criteria
B.1 Example 1 — 3-log reduction methodology
The acceptable limit calculates the minimum therapeutic dose (or pharmacologically significant concentration)
for each material selected to be cleaned, and verifies less than 1/1 000th of that material in the maximum daily
dose of the next batch. The calculation is as follows.
a)
Determine the maximum daily dose of the next possible product.
b)
Determine the minimum batch size of the next possible product.
c)
Calculate the maximum number of doses in the next batch.
d)
Determine the minimum therapeutic level of the active material to be cleaned, and divide that amount by
1 000.
e)
Calculate the amount of carryover permitted by multiplying the number of doses c) by 1/1 000th of the
minimum level of active d).
f)
This amount e) shall be factored by the sample method recovery value and calculated based on the
sampling method.
B.2 Example 2 — Analogue methodology
This approach is based on an analogy to allowable impurities of known toxicity, and uses compendial
specifications to set acceptance criteria. To apply this approach:
a)
Categorize all materials into classes of risk. For example:
low risk: non-active materials (e.g. inactive ingredients);
medium risk: low activity materials [e.g. over-the-counter (OTC) actives];
high risk: significant pharmacological activity (e.g. prescription drugs).
b)
For each category, select a poison/toxic analogue. For example:
low risk: heavy metals limit as specified in the pharmacopoeia;
medium risk: arsenic levels (for some products) as specified in the pharmacopoeia;
high risk: arsenic levels (for some products) as specified in the pharmacopoeia.
c)
Set residue limits for each class based upon compendial limits for the analogue material.
d)
Justify the inclusion of each material to be cleaned into one of the classes of risk.
e)
Adjust all analytical results based upon the recovery value determined for the method and material.
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Bibliography [1] ISO 9000, Quality management systems ― Fundamentals and vocabulary [2] ISO 14937, 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 [3] SEIBERLING, DALE A. Clean-In-Place and Sterilise-In-Place Applications in the Parenteral solutions Process. Pharmaceutical Engineering, 6 (6), Nov/Dec 1986, pp. 30-35 [4] MARGARETA HOEGGSTROEM. New Developments in Aseptic Design Relating to CIP and SIP. Biotech Forum Europe, Dr. Alfred Huthig Verlag GmbH, Heidelberg, 3/92, pp. 164-167 [5] DAVID M., MARKS, P.E. An Integration Approach to CIP/SIP Design for Bioprocess Equipment. Pharmaceutical Engineering, March/April 1999, pp. 34-45 [6] EEC Guide to Good Manufacturing Practice for Medicinal Products, Annex 11, EEC Commission Document III/2244/87 Rev [7] 21 CFR Part 11, Electronic records, electronic signature [8] MCCORMICK, P.Y. and CULLEN, L.F., in Pharmaceutical Process Validation, 2nd Ed., edited by I.R. Berry and R. A. Nash, 1993, pp. 319-349 [9] FDA, Guide to Inspection of Validation of Cleaning Processes (Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, July 1993)
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ISO 13408-4:2005(E)
ICS 11.080.01
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===== Part5 =====
INTERNATIONAL STANDARD ISO 13408-5 First edition 2006-11-15 Reference number ISO 13408-5:2006(E) © ISO 2006 Aseptic processing of health care products — Part 5: Sterilization in place Traitement aseptique des produits de santé — Partie 5: Stérilisation sur place
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ISO 13408-5:2006(E)
ii
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ISO 13408-5:2006(E)
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iii
Contents
Page
Scope ....................................................................................................................................................
Normative references ..........................................................................................................................
Terms and definitions ..........................................................................................................................
Quality system elements .....................................................................................................................
4.1
General .................................................................................................................................................
4.2
Management responsibility ................................................................................................................
4.3
Design control .....................................................................................................................................
4.4
Measuring instruments and measuring systems .............................................................................
Process and equipment characterization ..........................................................................................
5.1
General concepts ................................................................................................................................
5.2
Effectiveness of sterilization in place (SIP) ......................................................................................
5.3
Equipment ............................................................................................................................................
Sterilizing agent characterization ......................................................................................................
6.1
Selection of sterilizing agent(s) .........................................................................................................
6.2
Quality of sterilizing agent(s) .............................................................................................................
6.3
Safety and the environment ...............................................................................................................
SIP process ..........................................................................................................................................
7.1
Process parameters ............................................................................................................................
7.2
Cycle development ..............................................................................................................................
Validation ..............................................................................................................................................
8.1
Validation protocol ..............................................................................................................................
8.2
Design qualification ............................................................................................................................
8.3
Installation qualification .....................................................................................................................
8.4
Operational qualification ....................................................................................................................
8.5
Performance qualification ..................................................................................................................
8.6
Review and approval of validation ...................................................................................................
8.7
Requalification ...................................................................................................................................
Routine monitoring and control .......................................................................................................
9.1
SIP process control ...........................................................................................................................
9.2
Procedures .........................................................................................................................................
9.3
SIP process records ..........................................................................................................................
9.4
Change control ..................................................................................................................................
9.5
Maintenance of equipment ...............................................................................................................
Personnel training .............................................................................................................................
Annex A (informative) Steam sterilization in place .................................................................................
Bibliography ...............................................................................................................................................
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ISO 13408-5:2006(E)
iv
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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 13408-5 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
ISO 13408 consists of the following parts, under the general title Aseptic processing of health care products:
— Part 1: General requirements
— Part 2: Filtration
— Part 3: Lyophilization
— Part 4: Clean-in-place technologies
— Part 5: Sterilization in place
— Part 6: Isolator systems
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ISO 13408-5:2006(E)
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v
Introduction
During the process of preparing ISO 13408-1, several items, e.g. filtration, freeze drying and sterilization in
place, were found to be in need of supplementary information which was too voluminous to be given in
corresponding annexes.
This part of ISO 13408 includes requirements and guidance that are to be observed during sterilization in place.
The purpose of this part of ISO 13408 is to achieve standardization in the field of validation and routine control
of sterilization in place processes used in the manufacture of health care products.
Sterilization in place is, in most instances, preceded by cleaning in place which is described in ISO 13408-4.
While methods of cleaning in place and sterilization in place differ considerably in technology, the concept of in
situ treatment is similar.
The most important issue to consider in establishing sterilization-in-place technology is the design of the
system(s) to ensure that they be able to successfully sterilize manufacturing equipment to the desired level of
sterility assurance.
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INTERNATIONAL STANDARD
ISO 13408-5:2006(E)
© ISO 2006 – All rights reserved
Aseptic processing of health care products —
Part 5:
Sterilization in place
Scope
1.1
This part of ISO 13408 specifies the general requirements for sterilization in place (SIP) applied to product
contact surfaces of the equipment used in the manufacture of sterile health care products by aseptic processing
and offers guidance on qualification, validation, operation and control.
NOTE
SIP can be achieved by using steam or other gaseous or liquid sterilizing agents. Specific guidance on steam
sterilization in place, which is the most common method used, is given in Annex A.
1.2
This part of ISO 13408 applies to processes where sterilizing agents are delivered to the internal surfaces
of equipment that can come in contact with the product.
sterilizer.
Manufacturing Practices (GMPs) and/or compendial requirements that pertain in particular national or regional
jurisdictions.
1.5
This part of ISO 13408 does not specify requirements 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.
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 11138 (all parts), Sterilization of health care products — Biological indicators
ISO 11140 (all parts), Sterilization of health care products — Chemical indicators
ISO 13408-1, Aseptic processing of health care products — Part 1: General requirements
ISO 13408-4, Aseptic processing of health care products — Part 4: Clean-in-place technologies
ISO 14161, Sterilization of health care products — Biological indicators — Guidance for the selection, use and
interpretation of results
ISO 14937, 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
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ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development,
validation and routine control of a sterilization process for medical devices
ISO/IEC 90003, Software engineering — Guidelines for the application of ISO 9001:2000 to computer software
Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 13408-1 and the following apply.
3.1
dead leg
location which, by design, does not permit adequate accessibility of the sterilizing agent
3.2
design qualification
verification that the proposed specification for the facility, equipment or system is suitable for the intended use
[ISO/TS 11139:2006, definition 2.12]
3.3
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]
3.4
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]
3.5
process variable
condition within a sterilization process, changes in which alter microbicidal effectiveness
EXAMPLE
Time, temperature, pressure, concentration, humidity, wavelength.
[ISO/TS 11139:2006, definition 2.35]
3.6
sterilization in place
SIP
method of sterilization of the internal surfaces of parts of the equipment or an entire process system in situ,
without disassembly, using appropriate sterilizing agents
NOTE
The term “Steam in place” is used in ISO 13408-1, Clause 19, and this term is sometimes abbreviated as SIP.
However, in this part of ISO 13408, “SIP” is used with a wider meaning and includes not only steam in place, but all kinds of
sterilization used for the sterilization “in place” or “in situ”. In this part of ISO 13408, “Steam sterilization in place” is referred
to as “Steam SIP”.
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3.7
sterility assurance level
SAL
probability of a single viable microorganism occurring on an item after sterilization
NOTE 1
The term SAL takes a quantitative value, generally
or
. When applying this quantitative value to
assurance of sterility, an SAL of
provides a greater assurance of sterility than an SAL of
.
[ISO/TS 11139:2006, definition 2.46]
NOTE 2
For the purposes of this part of ISO 13408, the product is considered to be product contact surfaces subject to SIP.
3.8
sterilization process
series of actions or operations needed to achieve the specified requirements for sterility
[ISO/TS 11139:2006, definition 2.49]
3.9
sterilizing agent
physical or chemical entity, or combination of entities, having sufficient microbicidal activity to achieve sterility
under defined conditions
[ISO/TS 11139:2006, definition 2.50]
Quality system elements
4.1.1 The requirements of ISO 13408-1 shall apply. 4.1.2 Documented procedures for each phase of the development, validation, routine monitoring and control of the SIP process shall be prepared and implemented. 4.1.3 Documents required by this part of ISO 13408 shall be reviewed and approved by designated personnel.
evidence of conformity to the requirements of this part of ISO 13408.
4.2.1 The responsibilities and authority for implementing and performing the procedures described in this part of ISO 13408 shall be specified.
management systems, the responsibilities and authority of each party shall be specified.
Characterization of the sterilizing agent, sterilization process, equipment to deliver SIP and equipment to be subject to SIP shall be undertaken in accordance with a documented plan. At defined stages, design reviews shall be planned, conducted and documented.
4.4.1
A documented system shall be specified for the calibration of all measuring instruments or measuring
systems.
10−6
10−3
10−6
10−3
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measured. Process and equipment characterization
a) compatibility of the equipment with the sterilizing agent(s) and processing conditions; b) pre-requisite cleaning procedure, where necessary; c) introduction, homogeneity, distribution and contact time with the sterilizing agent; d) physical and/or chemical characteristics of sterilizing agent(s); e) demonstration of the efficacy of the process; f) sterilizing agent residuals or degradation products; g) drying of product contact surfaces, where necessary; h) maintenance of sterility after the completion of the process; i) acceptable tolerances for any potential residues from the process in the product to be made in the equipment; j) physical integrity testing and establishing limits. 5.1.2 Process parameters and their tolerances shall be specified, documented and reviewed. 5.1.3 During production processes, the sterilizing conditions achieved shall be monitored, maintained within specified tolerances, and documented throughout the duration of the sterilization process. 5.1.4 Although the entire processing system can be sterilized as a single entity in SIP, it can be advantageous to divide the system into several parts in order to simplify the sterilization procedures. When a large system is sterilized by dividing it into several segments, the segments should overlap to ensure that all portions of the system are adequately and effectively sterilized. 5.1.5 Complex sequences of opening and shutting of valves in the pipes of a system could be required. Where this is controlled manually, detailed documentation of individual steps is required. Where automation is used, electronic automation systems should be carefully designed and validated. 5.2 Effectiveness of sterilization in place (SIP) The sterility assurance level of the process shall be established and documented. Justification of the process parameters shall be included in the documentation.
5.3.1.1
The equipment shall be designed and manufactured to facilitate SIP and to ensure that the sterilizing
agent(s) can enter all internal product contact parts of the equipment to be sterilized (such as filter housings,
pipe branches, and valves).
Design considerations shall include, but not be limited to:
a)
smoothness of inner surface of equipment;
b)
accessibility of the sterilizing agent to all relevant surfaces;
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c)
correct placement of ports to admit the sterilizing agent(s) and, where applicable, to allow bleeding to
facilitate sterilizing agent distribution;
d)
absence of dead legs in piping systems;
e)
drainability of the system (e.g. slope of piping to ensure the complete removal of remaining liquid in the
system);
f)
correct placement of ports to permit inclusion of process monitoring devices;
g)
where applicable, exhaust port for safe removal of gaseous sterilizing agent;
h)
where applicable, resistance of the equipment to pressure, vacuum and heat;
i)
compatibility of materials of construction (e.g. pipes, tanks, valves, nozzles, filters, gaskets, sensors) with
the sterilizing agent, over the anticipated number of sterilization cycles;
j)
provisions for maintenance of sterility during and after completion of SIP (e.g. by elevated pressure).
Materials made of resin, such as gaskets, require particular attention.
Inner corners or shoulders of the tank and/or vessel of the system should be designed so that they do not entrap
air and thereby cause incomplete sterilization in the resulting air pocket.
Valves, connections and other equipment (such as heat exchangers) should be designed and oriented to
reduce the inaccessible surfaces and entrapment of air.
a) physical description of the equipment, together with any necessary ancillary items (including materials of construction and “as-built” drawings); b) specifications of the sterilizing agent and 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 their locations, indicating instruments and recording instruments; NOTE Temperature monitoring will normally be at the slowest-to-heat locations. d) description of safety features, including those for personnel and environmental protection; e) description of installation requirements, if applicable; f) documented evidence that the software used to control and/or monitor the process is prepared in accordance with a quality system and that the software meets its design intention; g) a process flow diagram that outlines the processing equipment layout to be sterilized, including valve sequencing.
equipment to be sterilized. Its primary functions to be verified in qualification shall include but not be limited to:
a)
generation of the sterilizing agent, where applicable;
b)
admittance of the sterilizing agent into the equipment to be sterilized in a controlled and safe manner;
c)
distribution of the sterilizing agent within the equipment to be sterilized;
d)
maintenance of effective sterilization conditions throughout the equipment to be sterilized;
e)
controlling and monitoring of the sterilization conditions in the defined locations;
f)
safe removal of the sterilizing agent;
g)
maintenance of the sterility of the equipment.
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a) a physical description of the equipment, together with any necessary ancillary items, including materials of construction and “as-built” drawings; b) a specification of the sterilizing agent and means by which it is provided, including any additives or precursors necessary for its delivery; c) a description of instrumentation for monitoring, controlling and recording the sterilization process, including sensor characteristics, tolerances and locations; d) a description of safety features, including those for personnel and environmental protection; e) a description of installation requirements, if applicable; this should include the location and the environment in which the equipment is to be installed and the services that are required for SIP and for the area in which the SIP system is installed; f) documented evidence that the software used to control and/or monitor the process is prepared in accordance with a quality system and that the software meets its design intention.
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 can be achieved, either through the use of independent systems for control and monitoring, or through a crosscheck between control and monitoring, which identifies any discrepancies and indicates a fault. Sterilizing agent characterization 6.1 Selection of sterilizing agent(s) 6.1.1 The sterilizing agent used shall be compatible with the equipment, shall not leave objectionable residues and shall be capable of delivering the stated sterility assurance level within specified sterilization parameters. 6.1.2 In selecting sterilizing agents, due consideration should be given to the potential for interactions with product residue (see ISO 13408-4). 6.2 Quality of sterilizing agent(s) 6.2.1 Data shall be available to demonstrate the microbicidal effectiveness of the sterilizing agent. 6.2.2 A specification including purity for the sterilizing agent shall be established and documented.
6.3.1 A material safety data sheet or analogous safety information for the sterilizing agent shall be available. 6.3.2 An assessment of the potential environmental impact shall be available for any sterilizing agent other than steam. SIP process
7.1.1
Process parameters as justified in 5.2, including their minimum and maximum limits, shall be defined and
documented. Process parameters shall be adequate to ensure sterilization of the equipment being subjected to
SIP.
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a) number of evacuation cycles and their variables; b) concentration of sterilizing agent; c) humidity, temperature, pressure; d) time at sterilizing conditions; e) maintenance of sterilizing conditions (e.g. constant replacement of inactivated sterilizing agent, integrity testing of vent filters, positive pressure); f) type of sterile purging medium, and the time, flow rate and temperature required to purge and dry the system after assembly. 7.1.3 Means of monitoring and controlling the process variables shall be defined and documented.
7.2.1 Prerequisite information for the sterilization process, such as effectiveness on microbial challenge organisms and determination of lethality, shall be obtained. The SIP process shall be designed and developed based on this information. 7.2.2 Sterilization operational procedures shall be established and the process parameters required to meet validated sterilization conditions shall be defined. 7.2.3 All operational procedures shall be established as written procedures and shall be followed. 7.2.4 The most-difficult-to-sterilize locations within the equipment to be sterilized shall be determined and it shall be demonstrated that, at these locations, sterilization is effective to the pre-determined acceptable level. NOTE This can include occluded surfaces or spaces where sterilizing conditions are the most difficult to attain. Validation
Written protocol(s) shall be established specifying how qualification and validation are to be conducted. Protocol(s) specifying critical steps and acceptance criteria shall be reviewed and approved. Qualification of equipment design, installation, operation and performance shall be performed in accordance with the approved protocol(s). Any deviation(s) from the protocol(s) shall be documented, investigated and resolved.
The SIP system shall be designed for its intended use. The appropriateness of system design, process design, design of all facilities, equipment and materials used shall, at the first stage of validation, be confirmed to meet requirements for the intended use.
Installation qualification shall be performed to demonstrate that equipment used to perform SIP and deliver the
sterilizing agent, equipment to be subjected to SIP, and any ancillary items, have been supplied in accordance
with their specifications.
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a) the location of the equipment conforms to its specification; b) the equipment is installed in accordance with installation instructions; c) the services to the equipment conform to their specification. 8.3.2.2 The calibration of all measuring instruments critical to the process (including any test instruments) used for monitoring, controlling, indicating or recording shall be confirmed. Alternatively, calibration may be confirmed at the commencement of operational qualification.
demonstrate conformance to ISO/IEC 90003 or other relevant guidelines for the manufacture of the product.
8.4.1 Operational qualification shall demonstrate that the installed equipment is capable of performing the specified SIP process throughout the equipment within defined tolerances. 8.4.2 The operating procedures for the equipment shall be verified to meet established requirements. These operating procedures shall include, but not be limited to: a) step-by-step operating instructions; b) the method by which a failure to attain the operating cycle parameters can be identified, and the actions to be taken; c) housekeeping, calibration and maintenance instructions; d) the means by which an error in the result of a measurement for control, indication and recording can be identified; e) details of contacts for technical support. 8.4.3 The potential most-difficult-to-sterilize locations of the equipment shall be determined by taking into consideration the individual physical and/or chemical properties of the sterilizing agent and the inactivation characteristics of the sterilization process. NOTE Dead legs and shoulder of tanks can be regarded as potential worst case locations. 8.4.4 Data shall be generated to verify that the defined sterilizing conditions (e.g. time, pressure, temperature, concentration of sterilizing agent and its distribution) are attained within specified tolerances throughout the SIP system.
(control, indication and recording) shall be determined at significant parts of the SIP process. 8.4.6 The number and locations of sensors used for qualification, such as temperature and pressure, shall be specified. Documented evidence shall be provided to show that the number and locations used are sufficient to demonstrate that the requirements for SIP of the equipment have been met.
8.5.1.1
Data generated during installation qualification and operational qualification shall be approved before
performance qualification is started.
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ISO 13408-5:2006(E)
© ISO 2006 – All rights reserved
(see ISO 14937).
conditions, within the specified tolerances throughout processing. The appropriateness of any routine monitoring positions or devices shall be established. This is achieved by mapping the attainment of the specified condition(s) at representative points throughout processing. See ISO 14937.
in the SIP process to those provided at the time of the SIP system's design. The acceptability of any deviation from those specified at the time of design shall be confirmed by reference to existing data and tests.
performance qualification is sufficient to demonstrate compliance with the specification for SIP of the equipment. 8.5.1.6 Biological indicators or inoculated carriers shall be used during the performance qualification. They shall comply with ISO 11138-1 and any other appropriate part of ISO 11138, as applicable (see ISO 14937). The number and locations of biological indicators shall be specified. Documented evidence shall be provided to show that the number and locations of biological indicators are sufficient to demonstrate that the requirements for SIP of the equipment have been met at locations presenting the greatest sterilization challenge.
ISO 11140-1 and any other appropriate part of ISO 11140 as applicable (see ISO 14937). The number and locations of chemical indicators shall be specified. Documented evidence shall be provided to show that the number and locations of chemical indicators are sufficient to demonstrate that the requirements for SIP of the equipment have been met at locations presenting the greatest sterilization challenge. 8.5.1.8 Performance qualification shall include a series of at least three consecutive and successful runs of the SIP process to demonstrate the reproducibility and effectiveness of the process. The successful SIP runs shall be determined by measurement of physical parameters and inactivation of biological indicators or inoculated carriers which shall demonstrate the required microbicidal effectiveness. 8.5.1.9 If a failure of a run (see 8.5.1.8) can be attributed to factors not relevant to the effectiveness of the SIP process being validated, this test may be documented as unrelated to the performance of the SIP process without requiring three further consecutive, successful runs. NOTE Examples of this type of failure include, but are not limited to, power failures, loss of services or failure of external monitoring equipment (see ISO 14937).
Microbicidal effectiveness studies shall achieve the following.
a)
Demonstrate that the lethality of the sterilizing agent against resistant microbial challenge organisms is
sufficient to achieve a SAL of
.
NOTE 1
This can be demonstrated by showing total kill of an appropriate resistant biological indicator to the
sterilization condition in a fractional cycle.
One or more biological model systems may be used for the validation of the effectiveness of the cycle. The
selection of the microorganisms should be based on cycle characteristics and on worst case considerations.
Justification for the choice of test microorganisms should be documented.
b)
Establish that there is an empirical mathematical relationship defining the microbial inactivation kinetics of
identified resistant microorganisms, and confirm that the lethal action can be extrapolated to predict the
probability of a microorganism surviving when exposed to a defined treatment.
The characteristics of the organism used to demonstrate the microbicidal effectiveness of the process when
exposed to the sterilizing agent under specific conditions (such as
-value, population) should be
determined (either by testing or by vendor certification) and documented. The test method(s), acceptance
criteria, and test results should be documented (see ISO 14161).
10−6
D
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ISO 13408-5:2006(E)
© ISO 2006 – All rights reserved
c)
Identify the process variables that can adversely affect the lethal action of the sterilizing agent.
d)
Assess factors that can adversely affect the delivery and/or distribution of the sterilizing agent.
NOTE 2
Such factors can include, for example, interactions with materials and residues, degradation products or
inactivated product generated from the sterilizing agent, such as condensate water generated from steam, and
degradants resulting from manufacturing, cleaning and/or disinfection.
8.6.1 Information gathered or produced during design qualification, installation qualification, operational qualification and performance qualification shall be documented and reviewed for acceptability. The results of this review shall be documented.
confirmed. This process specification shall also include the criteria for designating an individual SIP process as conforming to acceptance criteria.
responsible for preparing, reviewing and accepting this (these) report(s) against the acceptance criteria provided in the validation protocol(s). 8.6.4 The validation report(s) shall include a verification that all gauges, recorders etc., were within calibration at the time of the performance qualification.
8.7.1 Requalification of processes carried out with specified equipment shall be performed at defined intervals and in response to SIP failures. 8.7.2 SIP process data shall be reviewed periodically against specified acceptance criteria in accordance with documented procedures. Records of reviews of revalidation data and corrective actions taken in the event that the specified acceptance criteria were not met shall be retained. 8.7.3 Requalification report(s) shall be documented and retained. Routine monitoring and control
Routine monitoring and control shall be performed on each SIP process. Data shall be recorded to demonstrate that the validated and specified SIP process parameters have been delivered to the system.
Written procedures shall be consistent with those of validation studies. These procedures shall include, but not
be limited to:
a)
step-by-step operating instructions;
b)
duties and responsibilities;
c)
acceptance criteria for the operating cycle parameters and actions to be taken if those criteria have not
been met;
d)
the means by which the error in the result of a measurement for control, indication and recording can be
identified;
e)
detailed description of the SIP process;
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ISO 13408-5:2006(E)
© ISO 2006 – All rights reserved
f)
housekeeping, calibration and maintenance instructions;
g)
details of contacts for technical support.
a) date of operation; b) identification and cycle number of SIP process; c) operator identification; d) SIP process parameters and their confirmation. NOTE Records can include, for example, an equipment printout of critical parameters (e.g. contact time, temperature, and pressure measured at predetermined positions). 9.3.2 Additional evidence may be supplied (by biological or chemical indicators) that the sterilization process was delivered within the defined tolerances. 9.3.3 SIP process records shall be reviewed and accepted prior to the manufacturing of the next batch.
equipment shall be assessed for the potential impact on the effectiveness of the SIP process and the need of requalification.
qualification, operational qualification or performance qualification is undertaken.
qualification that is necessary, shall be documented.
Preventative maintenance shall be planned and performed in accordance with documented procedures.
Personnel training
10.1
Personnel shall be trained according to the established procedures.
10.2
A specific training programme for personnel shall be established, implemented and documented.
Training shall demonstrate personnel's:
a)
understanding the principles of the process, including operational and construction features;
b)
ability to perform the routine operation, maintenance or testing, as appropriate;
c)
understanding of the actions to be taken if the process or any part of process fails;
d)
understanding of the safety aspects of the sterilizing agent(s) and SIP system.
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ISO 13408-5:2006(E)
© ISO 2006 – All rights reserved
Annex A
(informative)
Steam sterilization in place
A.1
Introduction
A.1.1
This annex includes specific guidelines on steam sterilization in place (steam SIP). It addresses
fundamental considerations that are unique to steam SIP, but are not intended to be exhaustive.
A.1.2
This guideline on design, construction and control of steam SIP has been prepared by taking into
consideration the actual practice of steam SIP. It is recommended that new developments be taken into
consideration when designing steam SIP processes.
A.1.3
Attention is drawn to the fact that this guideline should be considered together with the normative
sections of this part of ISO 13408 which include the requirements applicable to steam SIP.
A.2
Process and equipment characterization
A.2.1
Critical process parameters for steam SIP are time, temperature and steam pressure. Their minimum
and maximum limits should be specified and controlled throughout the sterilization cycle.
A.2.2
The design of the steam SIP system should permit:
a)
complete displacement and elimination of air;
b)
bleeding of steam at all low points to eliminate accumulation of condensate;
c)
maintenance of sterility after completion of the sterilization process.
A.2.3
The following factors should be considered when designing a steam SIP process.
— Steam should be introduced in such a way as to facilitate distribution into all parts of the system.
— The tank and/or vessel should be designed to avoid retention of air.
— Condensate drains should be installed at low points in the system.
— Valves, drains, dead legs, low points, gas filters and housings within the system are locations where air can
become entrapped and/or where condensate can accumulate. These are typically the most-difficult-to-
sterilize locations (also called “worst location” or “cold spot”) in a steam SIP system.
— Piping should be sloped to the drain, enabling the complete removal of condensate. Other parts that may
retain condensate should be constructed to facilitate complete drainage.
— The displacement of the air with steam shall be achieved by a well-designed system and strategically
placed bleeds. Gravity displacement is often used for the displacement of air with steam, though
pre-vacuums can also be used.
— A bleed location could require closing once air has been eliminated, unless it is also utilized for condensate
removal.
— After completion of the sterilization cycle, sterile gas (air or nitrogen) is usually introduced into the system
through a sterilizing grade filter while the total system is still under positive pressure. The gas is used to
purge the system of steam and condensate, and maintain it under a slight positive pressure until ready for
use. As the piping cools after sterilization, it could form a vacuum, so it is important to maintain positive
pressure with sterilized gas.
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ISO 13408-5:2006(E)
© ISO 2006 – All rights reserved
A.2.4
When using steam SIP to sterilize a filter, the following aspects should be taken into consideration.
— Condensate drainage should be equipped at the lowest part of both the sterile side and the non-sterile side
of each filter housing.
— Steam bleed(s) should be positioned, where necessary, in the part of housing that might cause air retention.
— The pressure differential across the filter element at the operating temperature should not exceed the
manufacturer's recommendations.
— Steam pressure and differential pressure should be monitored.
— Temperature should be measured downstream of the filter.
— Cartridge filters should be oriented so that condensate drainage from both sides of the filter surface is
enabled.
A.3
Quality of steam
A.3.1
Non-condensable gases in steam, liquid water, oils from compressors, and other contaminants should
be controlled according to the specifications of the steam.
A.3.2
Condensate of steam should meet the chemical requirements for “purified water”.
A.3.3
Steam condensate should correspond to the WFI (water for injection) specification if the system is used
for parenteral products (and for systems used for any other process applications that require WFI).
A.3.4
Steam used for the steam SIP should be dry, saturated and not superheated.
A.4
Microbicidal effectiveness
Usually, a highly resistant spore challenge is applied to demonstrate microbicidal effectiveness of the steam SIP,
such as a biological indicator with
of Geobacillus stearothermophilus, which is inactivated using a fractional
cycle.
See ISO 14161 and ISO 17665-1 (overkill approach).
A.5
Routine monitoring and control
Records should include a printout of the steam SIP to include, but (not be limited to) time, temperature and
pressure measured at predetermined locations.
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ISO 13408-5:2006(E)
© ISO 2006 – All rights reserved
Bibliography
[1]
ISO 9000, Quality management systems — Fundamentals and vocabulary
[2]
ISO/TS 11139:2006, Sterilization of health care products — Vocabulary
[3]
ISO 22442 (all parts), Medical devices utilizing animal tissues and their derivatives
[4]
21 CFR — Part 11 — Electronic records, electronic signature
[5]
EEC Guide to Good Manufacturing Practice for Medicinal Products, Annex 11, EEC Commission
Document III/2244/87 Rev.
[6]
AGALLOCO, J. Steam Sterilization-In-Place Technology, Journal of Parenteral Science and Technology, 44
No. 5, 1990, pp. 253-256
[7]
BERMAN, D., MYER, T. and CHRAI, S. Factors Involved in Cycle Development of a Steam-In-Place System,
Journal of Parenteral Science and Technology, 40, No. 4, 1986, pp. 119-1121
[8]
HAEGGSTROEM, M. New Developments in Aseptic Design Relating to CIP and SIP, Biotech Forum Europe
3/92, pp. 164-167, Dr. Alfred Huthig Verlag GmbH, Heidelberg
[9]
MARKS, D.M. and Kirsten, D.E. An Integration Approach to CIP/SIP Design for Bioprocess Equipment,
Pharmaceutical Engineering, March/April, 1999, pp. 34-45
[10]
MYER, T. and CHRAI, S. Design Considerations for Development of Steam-In-Place Sterilization
Processes, Journal of Parenteral Science and Technology, 35, No. 1, 1981, pp. 111-115
[11]
MYER, T. and CHRAI, S. Steam-In-Place Sterilization of Cartridge Filters In-line with a Receiving Tank,
Journal of Parenteral Science and Technology, 36, No. 3, 1982, pp. 108-112
[12]
PFLUG, I.J. and KIRSTEN, D.E. Carrying out biological qualification, the control operation of moist heat
(steam sterilization) processes for producing sterile pharmaceuticals and medical devices, PDA Journal of
Pharmaceutical Science and Technology, 54 (2), 2000
[13]
SEIBERLING, D.A. Clean-In-Place & Sterilise-In-Place Applications in the Parenteral solutions Process,
Pharmaceutical Engineering, Nov/Dec, 6, No. 6, 1986, pp. 30-35
[14]
YOUNG, J.H., FERKO, B.L. and GABER, R.P. Parameters Governing Steam Sterilization of Dead legs,
Journal of Parenteral Science and Technology, 46, No. 4, 1992, pp. 117-123
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.
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ISO 13408-5:2006(E)
ICS 11.080.01
Price based on 14 pages
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===== Part6_Amd =====
© ISO 2013
Aseptic processing of health care
products —
Part 6:
Isolator systems
AMENDMENT 1
Traitement aseptique des produits de santé —
Partie 6: Systèmes isolateurs
AMENDEMENT 1
INTERNATIONAL
STANDARD
ISO
13408-6
First edition
2005-06-15
Reference number
ISO 13408-6:2005/Amd.1:2013(E)
AMENDMENT 1
2013-03-15
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ISO 13408-6:2005/Amd.1:2013(E)
ii
© ISO 2013 – All rights reserved
COPYRIGHT PROTECTED DOCUMENT
©
ISO 2013
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ISO 13408-6:2005/Amd.1:2013(E)
Foreword
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$PHQGPHQWWR,62 ZDVSUHSDUHGE\7HFKQLFDO&RPPLWWHH,627& Sterilization of health
care products.
© ISO 2013 – All rights reserved
iii
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Aseptic processing of health care products —
Part 6:
Isolator systems
AMENDMENT 1
Foreword, last paragraph
Add the following to the list of parts:
— Part 7: Alternative processes for medical devices and combination products
Page 1, Clause 2
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Page 4, 5.1.2, Note 2
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ISO 13408-6:2005/Amd.1:2013(E)
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ISO 13408-6:2005/Amd.1:2013(E)
Page 6, 5.6.2.1
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Page 9, 7.4.3.2
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h) personnel exposure limits.
Page 10, 7.4.6.2
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Residues of the bio-decontaminating agent shall be removed to an acceptable level after bio-
decontamination.
NOTE
The acceptable level of residual bio-decontaminating agent should be based on risk assessment of the
effect residues would have on:
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Page 11, 8.2
In the second paragraph delete “(e.g. in ISO 9001:2001)”.
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ISO 13408-6:2005/Amd.1:2013(E)
Page 13, 8.5.1.3
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Other points that shall be addressed include but are not limited to:
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challenges and aeration.
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development, validation and routine control of a sterilization process for medical devices2)
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preparation as ISO/TS 17665-3.
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Add the following reference:
,&+4 Quality risk management
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ISO 13408-6:2005/Amd.1:2013(E)
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ICS 11.080.01
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===== Part7 =====
© ISO 2012
Aseptic processing of health care
products —
Part 7:
Alternative processes for medical devices
and combination products
Traitement aseptique des produits de santé —
Partie 7: Procédés alternatifs pour les dispositifs médicaux et les
produits de combinaison
INTERNATIONAL
STANDARD
ISO
13408-7
First edition
2012-08-01
Reference number
ISO 13408-7:2012(E)
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ISO 13408-7:2012(E)
ii
© ISO 2012 – All rights reserved
COPYRIGHT PROTECTED DOCUMENT
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ISO 13408-7:2012(E)
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iii
Contents
Page
Foreword ............................................................................................................................................................................iv
Introduction ........................................................................................................................................................................ v
Scope ...................................................................................................................................................................... 1
Normative references ......................................................................................................................................... 1
Terms and definitions ......................................................................................................................................... 1
Quality system elements ................................................................................................................................... 2
Aseptic process definition ................................................................................................................................ 2
5.1
General ................................................................................................................................................................... 2
5.2
Risk management ................................................................................................................................................ 2
Manufacturing environment ............................................................................................................................. 3
Equipment ............................................................................................................................................................. 3
Personnel ............................................................................................................................................................... 3
Manufacture of the product .............................................................................................................................. 3
Process simulation ............................................................................................................................................. 3
10.1
General ................................................................................................................................................................... 3
10.2
Media selection and growth support.............................................................................................................. 3
10.3
Simulation procedures ....................................................................................................................................... 3
10.4
Incubation and inspection of process simulation units ........................................................................... 6
10.5
Initial performance qualification ..................................................................................................................... 6
10.6
Periodic performance requalification ............................................................................................................ 6
10.7
Repeat of initial performance qualification .................................................................................................. 7
10.8
Documentation of process simulations ........................................................................................................ 7
10.9
Disposition of filled product ............................................................................................................................. 7
Test for sterility .................................................................................................................................................... 7
11.1
General ................................................................................................................................................................... 7
11.2
Investigation of positive units from tests for sterility ............................................................................... 7
Annex A (informative) Risk assessment for aseptic processing — Quality risk management method ...... 8
Annex B (informative) Selection of a sample for testing for microbial contamination ..................................15
Annex C (informative) Testing options for process simulation ...........................................................................16
Bibliography .....................................................................................................................................................................19
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ISO 13408-7:2012(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
(ISO member bodies). The work of preparing International Standards is normally carried out through ISO
technical committees. Each member body interested in a subject for which a technical committee has been
established has the right to be represented on that committee. International organizations, governmental and
non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International
Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
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 13408-7 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
ISO 13408 consists of the following parts, under the general title Aseptic processing of health care products:
— Part 1: General requirements
— Part 2: Filtration
— Part 3: Lyophilization
— Part 4: Clean-in-place technologies
— Part 5: Sterilization in place
— Part 6: Isolator systems
— Part 7: Alternative processes for medical devices and combination products
iv
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ISO 13408-7:2012(E)
Introduction
ISO 13408 is the International Standard, published in a series of parts, for aseptic processing of health care
products. Historically, sterile health care products that are aseptically produced have typically been liquids,
powders or suspensions that cannot be terminally sterilized. More recently, medical devices and health care
products have been developed that are combined with medicinal products, including biological and viable cells,
that cannot be terminally sterilized.
The application of ISO 13408-1 to these medical devices and combination products can require the development
of alternative approaches to process simulation. This part of ISO 13408 specifies requirements and provides
guidance for developing such alternative approaches for the qualification of aseptic processes through process
simulation of medical devices and combination products that meet the requirements of ISO 13408-1.
ISO 13408-1:2008, 10.1.2 permits the use of alternative process simulation approaches, based on particular medical
devices or combination products, where the substitution in full with sterile liquid media might not be possible.
Medical devices and combination products that typically require aseptic processing might include, for example,
the following.
a)
Medical devices that cannot be terminally sterilized and where the process simulation approach according
to ISO 13408-1 cannot be applied:
— bioprostheses (e.g. heart valves, vascular implants);
— biodegradable implants (e.g. hernia meshes);
— artificial and/or non-viable biologically based matrixes;
— extracorporeal processing devices (e.g. immuno-adsorbers);
— implantable osmotic pumps;
— hermetically sealed electromechanical devices and partially enclosed electronic devices (e.g. invasive
and non-invasive diagnostic devices).
b)
Combination products (including viable cell-based combination products):
— implants coated with drug and/or biologically derived substances (e.g. drug-coated stents, carrier
materials with protein, bone-graft material with growth factors, biodegradable drug-coated stents);
— wound dressings (e.g. dressings with haemostatic agents, tissue sealants, or biologics);
— transdermal or injectable delivery systems (e.g. drug-coated or biologics interstitial patches);
— kits containing a biological or drug component (e.g. demineralized bone matrices).
For such products, a risk management strategy and method(s) can be used for the identification, evaluation and
quantification (estimation) of contamination risks throughout the entire product/process life cycle. Environmental
monitoring and microbiological studies can be performed on individual steps of the process to evaluate the
effectiveness of contamination controls and risk mitigations. The design of the process simulation can then be
driven by the results of the risk analysis. If the results of the process simulation are acceptable, this provides
evidence that the aseptic process is in a state of contamination control (i.e. no extrinsic microbiological/microbial
contamination has been introduced during the aseptic process).
This part of ISO 13408 should be read in conjunction with ISO 13408-1.
Within this International Standard, text that supplements ISO 13408-1 by providing additional requirements or
guidance is identified by the prefix “Addition”.
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Aseptic processing of health care products —
Part 7:
Alternative processes for medical devices and combination
products
1 Scope
This part of ISO 13408 specifies requirements and provides guidance on alternative approaches to process
simulations for the qualification of the aseptic processing of medical devices and combination products that cannot
be terminally sterilized and where the process simulation approach according to ISO 13408-1 cannot be applied.
This part of ISO 13408 describes how risk assessment can be used during the development of an aseptic
process to design a process simulation study for medical devices and combination products in those cases
where a straightforward substitution of media for product during aseptic processing is not feasible or would not
simulate the actual aseptic process.
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 13408-1:2008, Aseptic processing of health care products — Part 1: General requirements
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 13408-1 and the following apply.
3.1
extrinsic contamination
ingress of material of external origin during the manufacturing process
NOTE
The focus of extrinsic contamination in this part of ISO 13408 is biological agents e.g. bacteria, mould, yeast.
3.2
process simulation
exercise that simulates the manufacturing process or portions of the process in order to demonstrate the
capability of the aseptic process to prevent biological contamination
3.3
risk management
systematic application of quality management policies, procedures and practices to the tasks of analysing,
evaluating, controlling and monitoring risk
[ISO 14971:2007, definition 2.22]
3.4
surrogate product
item designed to represent product in process simulations and which is comparable to the actual product
INTERNATIONAL STANDARD
ISO 13408-7:2012(E)
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ISO 13408-7:2012(E) 4 Quality system elements ISO 13408-1:2008, Clause 4 applies. 5 Aseptic process definition
ISO 13408-1:2008, 5.1 applies.
ISO 13408-1:2008, 5.2.1 applies with the following additional requirements. a) Risk assessment shall consider all steps of the aseptic process and determine whether the aseptic process is to be simulated in one continuous process or divided into sub-processes for the purposes of process simulation. Risk assessment shall not be used to justify the simulation of only some but not all of the processes of an aseptic process. NOTE 1 Successful process simulation provides evidence of the capability of the specified aseptic process to produce an acceptable overall residual risk of microbiological/microbial contamination. NOTE 2 The risk assessment method selected should be appropriate for the given stage of aseptic process development. b) A comprehensive risk assessment process may not be required for the design of the process simulation in instances where the approach is readily discernable. The rationale for the decisions reached shall be documented.
ISO 13408-1:2008, 5.2.2 applies.
ISO 13408-1:2008, 5.2.3 applies.
ISO 13408-1:2008, 5.2.4 applies.
ISO 13408-1:2008, 5.2.5 applies. The following additional requirements to ISO 13408-1:2008, 5.2, concerning risk management, apply:
prior to commercial production
during the development of the aseptic process. Risk control measures to prevent microbiological/microbial
contamination for each step in the aseptic process shall be identified.
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ISO 13408-7:2012(E) 5.2.6.2 The estimation of contamination risk by quantitative methods and the verification of effectiveness of risk mitigation procedures shall be determined. Methods such as microbiological and particulate monitoring of the product, personnel and environment may be used. NOTE Quantitative risk modelling can also be applied. 5.2.6.3 The outcome of the risk assessment shall be used in the design of the process simulation study.
the aseptic process develops and changes during development.
commercial production Risk assessment shall be used to design the process simulation for validation of the commercial aseptic process. Risk assessment shall identify those actions to be included in the process simulation and their appropriateness. NOTE Annex A provides a practical application of risk management in designing a process simulation for a combination drug/device. 6 Manufacturing environment ISO 13408-1:2008, Clause 6 applies. 7 Equipment ISO 13408-1:2008, Clause 7 applies. 8 Personnel ISO 13408-1:2008, Clause 8 applies. 9 Manufacture of the product ISO 13408-1:2008, Clause 9 applies. 10 Process simulation
ISO 13408-1:2008, 10.1 applies.
ISO 13408-1:2008, 10.2 applies.
ISO 13408-1:2008. 10.3.1 applies with the following additional requirements.
a)
General considerations
The process simulation approach for a given medical device or combination product is based on a detailed
knowledge of the entire aseptic process definition including discrete process steps and interventions as well as
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ISO 13408-7:2012(E) the use of risk assessment tools, as appropriate (see 5.2.6 and 5.2.7). The process simulation approach shall be included in the design/process review for the manufacturing of product. b) Development of a process simulation strategy
If the process simulation approach outlined in ISO 13408-1 is not practicable, a rationale shall be documented including evidence that consideration was given during product and process development to: — use of sterile liquid media as a substitute for product during process simulation, or — direct media contact at the end of the process, i.e. into the sterile barrier system prior to final closure.
The entire aseptic process definition shall be included in the process simulation strategy. If the aseptic process is divided into sub-processes for the purposes of process simulation, the process simulation for each sub-process in total shall include all steps in the aseptic process.
Risk assessment shall be part of the life cycle of the aseptic process and shall be used to determine the process simulation strategy throughout the product/process life cycle.
The simulation options shall be selected and the process simulation strategy for the entire process shall be documented. c) Process simulation throughout the product lifecycle
The initial process simulation approach shall be established during the development of the aseptic process and the first process simulation shall be performed in advance of the production of the first- in-human clinical products to verify acceptable aseptic processing conditions.
As the aseptic process is scaled-up and enhanced for later stages of clinical production, the process simulation approach shall be modified to address the changing aseptic process. NOTE The aseptic process used for early clinical production is often manual and/or not optimized or scaled up for commercial production.
For commercial production, a process simulation study shall be designed and performed as part of the process validation.
Any change to the aseptic process which could add risk shall generate additional risk assessment and mitigation and a re-evaluation of the process simulation strategy. This shall include a re-evaluation of the process risk assessment. d) Selection of sample(s) for testing for microbial contamination
Product: Whenever possible, product shall be tested for microbial contamination. Product testing can take several forms. See Annex B for information. If the product as designed cannot be tested, then prior to considering use of a surrogate product, the possibility of redesigning the product or process such that the actual product can be tested shall be assessed.
Surrogate product:
A surrogate product shall only represent the actual product if it constitutes an equivalent or greater
challenge to the maintenance of asepsis than that provided by the actual product. The reason why the
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ISO 13408-7:2012(E) actual product is unsuitable for testing shall be documented and the rationale for the selection of the surrogate product test sample described. Surrogate product may be used for microbiological testing where product attributes preclude the use of actual product for testing. Examples of product attributes may include those that: — are too large or irregularly shaped (e.g. osmotic pump); — have antimicrobial properties (e.g. antibiotic stent); — are rare and scarce (e.g. autologous chondrocyte); — cause physical interference with the test method (e.g. product that breaks down in the growth medium generating particles that may be confused with microbial growth). Selection and design of surrogate product shall reflect as much as possible the design of the actual product. Processing of surrogate product shall include all aseptic processing steps and interventions applied during manufacture of the actual product. See Annex B for guidance.
[Figure 1 — Flow diagram of risk assessment process]
e)
Test methods for process simulation
The risk of contamination due to human intervention exists with all tests for microbial contamination.
The selection of the test method shall consider both the sensitivity of the test as well as the number of
interventions or manipulations. The risk assessment performed in the course of the process simulation
study design (5.2.6.3) shall address the risks of introducing contamination during testing and define steps
for reducing the likelihood of extrinsic contamination.
The test method shall be designed or selected based on product to be tested (actual or surrogate product).
Test method development shall include consideration of suitable test options (see Annex C). The test
method shall be validated.
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ISO 13408-7:2012(E) ISO 13408-1:2008, 10.3.2 to 10.3.6 also apply.
ISO 13408-1:2008, 10.4 applies.
ISO 13408-1:2008, 10.5.1 applies.
ISO 13408-1:2008, 10.5.2.1 applies with the following additional requirements. a) For operations with production batch sizes of fewer than 5 000 units, the number of process simulation units manufactured shall at least equal the maximum batch size produced. b) All units manufactured for process simulation shall be tested for the presence of microbial contamination (see also ISO 13408-1:2008, 10.4.2). c) If the process simulation is divided into subsets, then the number of units tested in each subset shall be justified. At least three consecutive successful simulations shall be performed for each discrete subset of the aseptic process. All of the filled units from each subset shall be tested for the presence of microbial contamination. ISO 13408-1:2008, 10.5.2.2 also applies.
ISO 13408-1:2008, 10.5.3.1 applies. ISO 13408-1:2008, 10.5.3.2 applies with the following additional requirement: When the aseptic process simulation is divided into subsets, all subsets shall have zero contaminated units for the process simulation to be approved. If a single sub-process of the simulation fails, a documented investigation shall be performed to identify the root cause of the failure. If a root cause for the failure can be identified, then that root cause shall be corrected prior to requalification. In the event a definitive root cause cannot be identified, a review of the process and design of the process simulation shall be performed, and modifications made. Following corrective actions, three consecutive simulation tests of that subset shall be performed that have zero contaminated units for the simulation to be approved.
ISO 13408-1:2008, 10.6.1 applies.
ISO 13408-1:2008, 10.6.2 applies with the following additional requirement: For operations with production batch sizes of fewer than 5 000 units, the number of process simulation units manufactured shall at least equal the maximum batch size produced.
ISO 13408-1:2008, 10.6.3 applies.
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ISO 13408-7:2012(E)
ISO 13408-1:2008, 10.7 applies.
ISO 13408-1:2008, 10.8 applies.
ISO 13408-1:2008, 10.9 applies. 11 Test for sterility For products where a test for sterility according to the European, US and Japanese Pharmacopoeias cannot be applied, an alternative test regime shall be established and justified. Refer to Annex B for additional guidance.
ISO 13408-1:2008, 11.1 applies with the following additional requirement: Where a product containing viable cells is shown to interfere with the test for microbial contamination, then a suitable alternative test method for microbiological control of finished product shall be developed. This test method shall be shown to be at least equivalent to the test for microbial contamination in terms of its sensitivity and ability to detect a broader range of microorganisms. NOTE Alternative test methods can include rapid microbiological methods and non-growth-based test methods. Examples of Pharmacopoeias include Ph.Eur.[10], JP[11] and USP[12].
ISO 13408-1:2008,11.2 applies.
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ISO 13408-7:2012(E) Annex A (informative)
Risk assessment for aseptic processing — Quality risk management
method
A.1
General
This annex provides a practical application of the concepts presented in this part of ISO 13408. A Failure Mode
and Effects Analysis (FMEA) approach has been selected as the basis for the method because it is one of the
methods that works well with the assessment and decision-making needed for aseptic processing.
The following example uses an FMEA method [with risk priority number (RPN) scoring] that contains content
chosen to illustrate concepts previously introduced. This is a hypothetical situation. The risk ranking and RPN
scoring are presented as examples only. For further details see ISO 14971.
A.2
Background
This case study focuses on the conventional aseptic manufacture of a device coated with an antibiotic which
is then primary packaged. In the initial design of the process for product for clinical studies, operations were
performed manually, resulting in numerous intrusions into the cleanroom environment (see Figure A.1). The
larger the number of interventions, the greater the risk of potential sources of contamination.
With optimization of the aseptic manufacturing process for commercial production, the FMEA process was
revisited to verify that mitigations resulted in a reduced risk of contamination to an acceptable level (see
Figure A.2 and Table A.1).
A.3
Risk priority number determination
A semi-quantitative approach was used for assessing the risk of contamination by ranking the severity,
occurrence and detection on a numerical scale of 1 to 10. The RPN is calculated by multiplying
severity × occurrence × detection. The unwanted event is contamination of the product.
In this example severity has been assigned a value of 10. Occurrence is difficult to quantify for interventions.
However, this method requires data to justify the occurrence number (1 being a low likelihood of contamination,
and 10 being the highest likelihood of contamination). In this method the inability to detect microbial
contamination is high; detection is given a value of 8 to 10 (assumes environmental monitoring and extrinsic
microbial contamination testing provide some degree of detection).
A.4
Risk assessment
The initial assessment indicates that the use of a highly manual coating and packaging process requires many
human interventions and poses an inherently high risk of contamination (see Figure A.1).
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ISO 13408-7:2012(E) Key box indicates human and environmental interaction with product/components which can negatively impact product box indicates only environmental interaction with product/components which can negatively impact product box indicates steps which have little or no potential negative impact product
Figure A.1 — Initial process flow chart
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ISO 13408-7:2012(E)
Key
box indicates steps which are addressed in the FMEA
box indicates human and environmental interaction with product/components which can
negatively impact product
box indicates only environmental interaction with product/components which can
negatively impact product
box indicates steps which have little or no potential negative impact product
Figure A.2 — Process flow chart following process optimization
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ISO 13408-7:2012(E)
A.5
Risk acceptance
For the purposes of this assessment, an initial risk acceptance RPN of 100 was established as the target risk
acceptance value. An RPN value greater than 100 would trigger a preventive action (mitigation) to reduce the RPN
to 100 or lower. This acceptance value was reassessed periodically to further reduce microbiological/microbial
contamination risk in the aseptic process.
A.6
Risk reduction
Possible means of reducing risk (mitigations) were identified. This included automating the coating process,
locating the drying and primary packaging processes in a restricted access barrier system (RABS), etc.
NOTE
There are many options to address contamination. These options were chosen to illustrate the use of the
method for simplicity.
An assessment of the risks associated with the initial aseptic process (Figure A.1) and the optimized process
(Figure A.2) is presented in Table A.1. The impact of each mitigation in the optimized process was assessed through
microbiological monitoring and studies of contamination, which resulted in an acceptable RPN of 100 or less.
A.7
Verification of acceptability of overall residual risk
A process simulation study protocol was designed that incorporated each of the contamination risk factors
(potential causes of failure) described in the FMEA process (Table A.1) and the entire aseptic process to verify
that the overall residual risk was acceptable (absence of contaminated product).
A.8
Key process parameters
The following are key process parameters for this example of a combination medical device/drug product.
a)
The manufacturing process was designed to aseptically produce a maximum of 300 units of finished
product (30 trays of 10 devices and sufficient antibiotic solution to coat 300 units as per specifications).
Total processing time is between 3 hours and 4 hours (one shift).
b)
The environmental monitoring performed during the process simulation study was based in part on the
FMEA, i.e. all high-risk areas were monitored continuously during aseptic operations. Aseptic processing
operators perform environmental and personnel monitoring.
c)
A maximum of four aseptic processing operators are permitted in the aseptic processing area (APA) at one
time (typically, two operators are in the APA). One aseptic processing operator performs aseptic processing
steps 1 to 5, and a second aseptic processing operator performs steps 6 to 8 (following Figure A.2). A total
of four aseptic processing operators were qualified to perform all aseptic processing steps.
A.9
Process simulation design
A.9.1
Process simulation of the initial aseptic process (manual method)
A.9.1.1 The maximum production size for initial production for clinical studies was 20 units. Therefore the
initial process simulation was designed consisting of one run of 20 units of a surrogate product (rejected devices
and placebo antibiotic solution). The units were tested for microbial contamination using direct immersion into a
microbiological growth medium.
NOTE
A placebo antibiotic solution was used as a surrogate product so that a direct immersion microbial contamination
test of the final product could be used (see also B.2.3).
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ISO 13408-7:2012(E) Table A.1 — Project worksheet — Failure mode and effect analysis Process step (initial process) Failure mode SEV Potential cause(s)/ mechanism(s) of failure OCC Current process controls (optimized process) DET RPN Recommended action(s) Respons- ibility and completion date Action results and verification of effectiveness SEV OCC DET RPN Process steps from the initial (manual) process flow chart (see Figure A.1) In what ways might the process potentially fail to meet the process require- ments and/ or design intent? How severe is the effect to the cust- omer? How can the failure occur? Describe in terms of something that can be corrected or controlled. Be specific. Try to identify the causes that directly impact the failure mode, i.e. root causes. How often does the cause or failure mode occur? What are the existing controls and procedures (inspection and test) that either prevent failure mode from occurring or detect the failure should it occur? Should include an SOP number. How well can you detect cause or FM? SEV x OCC x DET What are the actions for reducing the occurrence, or improving detection, or for identifying the root cause if it is unknown? Should have actions only on high RPNs or easy fixes. Who is responsible for the recomm- ended action? List the completed actions that are included in the recalculated RPN. Include the implement- ation date for any changes. What is the new seve- rity? What is the new proc- ess capab- ility? Are the dete- ction limits impro- ved? Recom- pute RPN after actions are com- plete. Transfer materials into aseptic processing area Contami- nated product Operator or surface contamination
Grade A, triple wrap, training
Remove medical device one at a time from tray and place onto individual posts (10) Contami- nated product Operator contaminates one or more medical devices during removal of tray lid
Grade A environment and use of sterile forceps and tray handle to remove tray; training, EM data shows no contamination of tray surfaces or devices
Remove medical device one at a time from tray and place onto individual posts (10) Contami- nated product Operator contaminates one or more medical devices during transfer of 10 devices from tray to post Training and positioning fixtures in laminar flow hood Grade A environment and use of sterile forceps to transfer; training
Conduct microbiology simulation study to verify procedure does not result in contamination; qualify all operators Assemble coating apparatus and attach to antibiotic holding tank Contami- nated product Operator contaminates critical surfaces in coating area Training and positioning fixtures in laminar flow hood Grade A environment and use of sterile instruments and gloves; training
Conduct
microbiology
simulation
study to verify
procedure
does not
result in
contamination;
qualify all
operators
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ISO 13408-7:2012(E) Process step (initial process) Failure mode SEV Potential cause(s)/ mechanism(s) of failure OCC Current process controls (optimized process) DET RPN Recommended action(s) Respons- ibility and completion date Action results and verification of effectiveness SEV OCC DET RPN Assemble coating apparatus and attach to antibiotic holding tank Contami- nated product Operator contaminates critical surfaces on sterilized equipment Training and positioning fixtures in laminar flow hood Grade A environment and use of sterile instruments and gloves; training
Conduct microbiology simulation study to verify procedure does not result in contamination; qualify all operators Coat each device on post (automatic process using spray nozzle and rotating post) Contami- nated product Environmental contamination
Grade A environment; automated process
Transfer to adjacent drying/ primary packaging RBS unit using conveyer Contami- nated product Operator contaminates product
Transfer in Grade A environment, use of conveyor system into RABS unit
Allow 30 min air drying (RABS unit) Contami- nated product Environmental contamination
RABS unit
Using mechanical device, remove device from post and place into pre-sterilized pouch and seal (RBS unit) Contami- nated product Environmental contamination
RABS unit; robotic control
Total Risk Priority Number = 100-
”After” Risk Priority Number =
Table A.1 (continued)
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ISO 13408-7:2012(E)
A.9.1.2 Each of the processing steps and their interventions were implemented into this simulation. In this
example, the process simulation included all process intervention(s) as identified in the FMEA process.
A.9.2
Process simulation for the optimized aseptic process
A.9.2.1 The process simulation was designed consisting of three runs of 300 units of a surrogate product
(rejected devices and placebo antibiotic solution). Each of the processing steps and their interventions were
implemented into this simulation. In this example the process simulation included the following elements:
a)
four aseptic processing operators in the APA;
b)
one change of personnel at the midpoint in processing;
c)
4-hour process;
d)
all process intervention(s) as identified in the FMEA process.
A.9.2.2 The units were tested for microbial contamination using direct immersion into a microbiological
growth medium.
A.10 Acceptance criteria
The process simulation was considered acceptable as there were zero contaminated units from the test for
microbial contamination.
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ISO 13408-7:2012(E) Annex B (informative)
Selection of a sample for testing for microbial contamination
B.1
Actual product
Testing of actual product can take the following forms.
a)
Whole product: the entire product is tested for absence of microbiological/microbial contamination.
b)
A portion or sub-set of the product (sample item portion): if the product is too large or irregularly shaped,
it may be cut into pieces or disassembled for testing purposes.
c)
Fluid path: if only the fluid path is intended to be free of microbial contamination, then testing of the fluid
path is appropriate.
d)
Exterior surface: for hermetically sealed products, such as medical devices where the exposed surface of
the device is claimed to be sterile, testing of only the exterior surface is appropriate.
B.2
Surrogate product
B.2.1
A surrogate product can be, for example:
a)
one that is representative of the actual product in terms of materials and size;
b)
a component or combination of components from the actual product.
B.2.2
For products that are too large or irregularly shaped to be immersed, the product can be broken into
parts or disassembled. If the process of breaking or dissembling the product provides an unacceptable risk of
contamination, consider using a surrogate product. Alternatively, it may be possible to aseptically process the
surrogate product without fully connecting or sealing the parts together so that the unassembled product can be
tested without manipulation.
B.2.3
For products with antimicrobial properties, determine whether it is possible to overcome the antimicrobial
properties (e.g. neutralization, increased media to product ratio, filtration). If the antimicrobial properties cannot
be overcome, consider using a surrogate product that does not contain the antimicrobial agent (e.g. placebo or
inert material).
B.2.4
For products that interfere with the microbiological test, determine whether the test method can be
designed to overcome the interference. For example, if the product’s matrix renders the growth medium turbid,
subculturing can be performed (see pharmacopoeias or ISO 11737-2 for guidelines).
B.2.5
For products that contain viable cells which might interfere with the microbiological/microbial contamination
test, determine whether the viable cells can grow in the test medium. If the viable cells produce turbidity that
mimics microbial contamination, then a suitable surrogate product which does not contain viable cells can be
used. Examples of surrogate product include killed cells or tissue, or another entity which is processed in an
identical manner to the product that contains viable cells.
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ISO 13408-7:2012(E) Annex C (informative)
Testing options for process simulation
C.1
Testing option considerations
C.1.1
The risk of contamination due to human intervention exists with all tests for microbial contamination. The
selection of the test method should consider both the sensitivity of the test as well as the number of interventions
or manipulations required to perform the test. The most sensitive test with the fewest manipulations should be
selected, when possible.
C.1.2
Assess the risks of introducing microbial contamination during the test method used to evaluate the
process simulation. Since human intervention is a major source of contamination during test manipulations,
when possible perform testing in an isolator or restricted access barrier system (RABS). If an isolator or other
advanced barrier system is unavailable, testing should be performed in an environment as good as, or better
than, that used for manufacturing. Sources of microbiological/microbial contamination during a test may/can
include the following:
a)
inadequate cleaning and decontamination of the test environment, work surfaces and material placed into
the test area;
b)
inadequate sterilization of testing equipment, media and transfer instruments;
c)
inadequately gowned and gloved personnel;
d)
inadequately trained test personnel;
e)
contamination occurring during preparation for transport of samples to the test area due to the transportation
container or packing;
f)
contamination introduced during the opening of the transport packaging or container due to particle generation;
g)
contamination on media containers;
h)
poor aseptic technique during sample transfer, cutting or sectioning, or surface sampling;
i)
poor aseptic technique when completing connections when testing by flushing or in situ incubation.
C.1.3
The interval of time between collecting the samples and performing the tests should be as short as practicable.
C.1.4
If the product or surrogate product causes turbidity in the culture media, then a method for differentiating
this turbidity from turbidity produced as a result of microbial growth in the medium should be established. See
ISO 11737-2 for guidance on verifying microbial growth in a test for microbial contamination.
C.1.5
When the test sample has been defined and the test method has been determined, the test method
should be validated to confirm that it is suitable for the recovery of low numbers of microorganisms in the
presence of the product to be tested. See ISO 11737-2 and the pharmacopoeias for guidance on verifying the
suitability of a test method for recovery of microorganisms in the presence of product.
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ISO 13408-7:2012(E)
C.2
Test methods
C.2.1
Direct contact of media with product
C.2.1.1 General considerations
Immersion of the product or surrogate product is the preferred method of testing. This method allows for full
media contact with the product surfaces and also addresses contamination risks for all process steps and
interventions that are used to make the product.
C.2.1.2 Direct immersion method
If the product or surrogate product can fit into a vessel containing sterile liquid growth medium, then the
product should be completely immersed and incubated in this medium. Manipulation of the product or surrogate
product may be necessary to ensure that all surfaces are exposed to the growth medium for the duration
of the incubation period, e.g. cutting or disassembly of product. If the product size or configuration is such
that it cannot be immersed in sterile liquid growth medium, then the product may be broken into pieces or
disassembled for testing. If the product is made up of several components, then it may be possible to simulate
the aseptic process without actually connecting the component parts. This may reduce the risk of adventitious
contamination during testing.
C.2.1.3 In situ direct contact of media with patient contact surfaces
If the product claim is “sterile fluid path only”, liquid medium may be added into the fluid path of the product
and incubated in situ. In this method the product and media are in direct contact, with the product acting as the
media container.
An example of an in situ test would be the addition of sterile liquid growth medium to a product, e.g. cell culture
bag, sealing of the cell culture bag and incubation of the sealed bag. Following incubation the growth medium
is examined for evidence of microbial growth. If the container is not transparent it will be necessary to drain the
growth medium into a secondary sterile, transparent container for examination.
C.2.2
Elution/removal methods
For those products and parts for which direct immersion or in situ testing are not feasible, an elution/removal
method may be the only option.
Flush or rinse: if the product can only be flushed or rinsed, the eluate can be either collected in a container for
incubation or the eluate can be filtered followed by immersion and incubation of the filter. ISO 11737-2 includes
guidance on these approaches. The suitability of this method for removal and recovery of contaminating
microorganisms from the product should be determined.
Comparison of methods: the most suitable test method should be selected and the rationale for the choice
documented. The benefits and limitations of each of the methods are presented in Table C.1.
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ISO 13408-7:2012(E)
Table C.1 — Summary of testing options
Type
Method
Sensitivity
Benefits
Limitations
Direct media
contact
Liquid media
immersion of
actual product or
surrogate product
High
Excellent sensitivity
Compendial validation
method published
Regulatory
acceptability
Not practical for large items
Availability of suitably sized
medium container
In situ media
challenge
High
Excellent sensitivity
Compendial validation
method published
Regulatory
acceptability
Limited to fluid-path microbial
contamination claims
May require special connector
fabrication and assembly
For non-transparent products early
detection of positive test samples
may not be possible
Elution and
removal
methods
Flushing or rinsing
Variable
Eliminates media
container constraints
May be only viable
option
Requires validation of recovery
efficiency
Limited assurance of removing
microorganisms from all product
surfaces
If interior and exterior are claimed
sterile, the procedure and
validation can be very complex
Requires rationale for regulatory
acceptance
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ISO 13408-7:2012(E)
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ISO 11137-2, Sterilization of health care products — Radiation — Part 2: Establishing the sterilization dose
[2]
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[16]
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[17]
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[18]
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[19]
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Tidswell, edward C. and MCGarvey, Bernard, Quantitative risk modelling assists parenteral batch
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Tidswell, edward C. and MCGarvey, Bernard, Quantitative risk modelling in aseptic manufacture.
PDA Journal of Pharmaceutical Science and Technology, Vol. 60, No.5
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ISO 13408-7:2012(E)
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ICS 11.080.01
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