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1、A Reference number ISO 13408-1:1998(E) INTERNATIONAL STANDARD ISO 13408-1 First edition 1998-08-01 Aseptic processing of health care products Part 1: General requirements Traitement aseptique des produits de sant Partie 1: Exigences gnrales Copyright International Organization for Standardization Pr
2、ovided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/12/2007 19:42:22 MDTNo reproduction or networking permitted without license from IHS -,-,- ISO 13408-1:1998(E) ISO 1998 All rights reserved. Unless otherwise specified, no part of this publication
3、may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from the publisher. International Organization for Standardization Case postale 56 CH-1211 Genve 20 Switzerland Internetisoiso.ch Printed in Switze
4、rland ii ContentsPage 1 Scope.1 2 Definitions.1 3 Quality management systems.5 4 Personnel.5 5 Facility design7 6 Aseptic Processing Area (APA).8 7 Support areas outside the APA9 8 Environmental air systems and controls9 9 Gowning.10 10 Cleaning and disinfection of the APA.11 11 Qualification of equ
5、ipment and utilities, and process validation.12 12 Materials and equipment delivered to aseptic areas12 13 Processing time .13 14 Environmental monitoring programmes.13 15 Alert and action levels15 16 Investigations and reports15 17 Media fills (process simulation tests).16 18 Finished-product steri
6、lity testing 23 19 Steam-in-place.23 20 Process filtration 24 21 Freeze-drying.25 Annex A (informative) Derivation of contamination-rate calculations for a given number of media-filled units29 Annex B (informative) Bibliography.31 Copyright International Organization for Standardization Provided by
7、IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/12/2007 19:42:22 MDTNo reproduction or networking permitted without license from IHS -,-,- ISOISO 13408-1:1998(E) iii Foreword ISO (the International Organization for Standardization) is a worldwide federati
8、on 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
9、. 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. Draft International Standards adopted by the techn
10、ical 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. International Standard ISO 13408-1 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products. I
11、SO 13408 consists of the following parts, under the general title, Aseptic processing of health care products: Part 1: General requirements Part 2: Filtration1) Part 3: Freeze-drying Part 4: Sterilization and cleaning in place1) Part 5: Aseptic processing of solid medical devices Part 6: Isolator/ba
12、rrier technology Annexes A and B of this part of ISO 13408 are for information only. 1) ISO 13408-1 includes normative and informative clauses on these subjects until such time that the more detailed additional parts of ISO 13408 are approved and published. Once such approved International Standards
13、 exist, it is intended that the related clauses included in ISO 13408-1 be deleted. Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/12/2007 19:42:22 MDTNo reproduction or networking perm
14、itted without license from IHS -,-,- ISO 13408-1:1998(E) ISO iv Introduction Health care products that are labeled “sterile“ have to be prepared using appropriate and validated methods. ISO/TC 198 has prepared standards for terminal sterilization of health care products by irradiation (ISO 11137), b
15、y moist heat (ISO 11134), by liquid chemical sterilants (ISO 14160) and by ethylene oxide (ISO 11135). When a health care product is intended to be sterile and cannot be terminally sterilized, aseptic processing provides an alternative. There are two distinct situations in which aseptic processing i
16、s applied: a)the aseptic preparation and filling of solutions; b)the aseptic handling, transfer and packaging of solid products which cannot be terminally sterilized in their final containers. Aseptic processing requires the presterilization of all product parts or components that are in direct cont
17、act with the aseptically filled product. The product is processed in a controlled environment in which microbial and particulate levels are maintained at defined levels and where human intervention is minimized. Aseptic processing is an exacting and demanding discipline. Manufacturers use validated
18、systems, adequately trained personnel, controlled environ- ments and well-documented systematic processes to assure a sterile finished product. While terminal sterilization involves the use of a process of known lethality, the assurance of sterility associated with aseptic processing can only be inf
19、erred as facilities, equipment and people are all factors associated with the process. Product development data should also exist to support the maintenance of sterility by the container and/or closure system following aseptic production. The major elements to be considered in aseptic processing inc
20、lude: a)training of personnel; b)layout and specifications for buildings, equipment and facilities; c)particulate and microbial environmental monitoring programmes; d)systems for water, steam, air and other process gases; e)descriptions of and procedures for manufacturing operations including people
21、, materials, material flow, solution preparation and associated acceptance criteria; f)use and validation of sterilization processes, including disinfection practices; g)validation methods and data requirements for media fills and container/closure systems; h)operating practices for acceptance crite
22、ria, investigation reviews and release/reject decisions. Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/12/2007 19:42:22 MDTNo reproduction or networking permitted without license from
23、IHS -,-,- INTERNATIONAL STANDARD ISOISO 13408-1:1998(E) 1 Aseptic processing of health care products Part 1: General requirements 1 Scope This part of ISO 13408 specifies the general requirements for, and offers guidance on, processes, programmes and procedures for the validation and control of asep
24、tically processed health care products. This part of ISO 13408 includes requirements and guidance relative to the overall topic of aseptic processing. NOTE Future parts of ISO 13408 will address specialty topics related to aseptic processing, including detailed descriptive information concerning var
25、ious specialized processes and methods related to filtration, freeze-drying, sterilization in place, cleaning in place, isolator technology, and solid medical devices. This part of ISO 13408 does not supersede or replace national regulatory requirements, such as Good Manufacturing Practices (GMPs) a
26、nd/or compendial requirements, that pertain in particular to national or regional jurisdictions. 2 Definitions For the purposes of this part of ISO 13408, the following definitions apply. 2.1 action level environmental monitoring hence the term “line“. 2.7 aseptic processing handling the aseptic fil
27、ling of product containers and/or devices in a controlled environment, in which the air supply, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels 2.8 aseptic processing area APA controlled environment for aseptic processing, cons
28、isting of several zones, in which the air supply, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels 2.9 batch manufacturing record process documentation that supports the manufacturing of a lot or batch of product consistent with
29、 defined product manufacturing and quality assurance specifications 2.10 bioburden population of viable microorganisms on or in a health care product or package prior to sterilization 2.11 bioburden population of viable microorganisms on materials and equipment introduced into the APA 2.12 biologica
30、l indicator microorganism, traceable to a recognized culture collection and of a known sterilization resistance, that is used to develop and/or validate a sterilization process NOTE The microorganisms are frequently used with a carrier, which is the supporting material on which test organisms are de
31、posited. 2.13 container configuration denotes the same container design independent of capacity NOTE Since all aseptically processed products may not be final-filled into a container, this part of ISO 13408 also uses the expression “product/container configuration.” 2.14 critical processing zone loc
32、ality of aseptic processing area in which product and product contact surfaces are exposed to the environment NOTE Aseptic manipulations performed in a critical processing zone can include aseptic connections, filling, stoppering and closing operations. Copyright International Organization for Stand
33、ardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/12/2007 19:42:22 MDTNo reproduction or networking permitted without license from IHS -,-,- ISO ISO 13408-1:1998(E) 3 2.15 critical surface surface in the critical processing zone withi
34、n close proximity to aseptic operations and which poses a potential risk to the product 2.16 differential air pressure difference in pressure between or within rooms or areas 2.17 disinfectant chemical or physical agent that inactivates vegetative microorganisms but not necessarily highly resistant
35、spores 2.18 environmental flora environmental isolates microorganisms present in and/or isolated from processing or manufacturing environments 2.19 gas filter porous material placed in compressed gas lines to remove nonviable and/or viable particulate matter from gas streams which come directly or i
36、ndirectly in contact with a product 2.20 health care product medical device, medicinal product (pharmaceuticals and biologicals) and in vitro diagnostics 2.21 high efficiency particulate air filter HEPA filter retentive matrix having a minimum particle-collection efficiency of 99,97% (that is, a max
37、imum particle penetration of 0,03%) for 0,3 m particles of thermally generated DOP or specified alternative aerosol 2.22 laminar air flow air flow which is comprised of uniform velocities of air flow along parallel flow lines NOTE Laminar air flow is frequently used in cabinets and hoods. cf. unidir
38、ectional air flow (2.33) 2.23 media fill method of evaluating an aseptic process using a microbial growth medium NOTE Media fills are understood to be synonymous to process simulation tests, simulated product fills, simulated filling operations, broth trials, broth fills, etc. 2.24 other processing
39、zone processing zone, other than critical processing zones, in which health care products are not exposed to the environment NOTE These zones include staging, transport and storage areas for sterilized components, containers and bulk products in protected vessels; autoclave-unloading areas; and proc
40、essing rooms from which critical areas are accessed. 2.25 product contact surface surface which comes into contact with sterilized product or containers/closures Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/997254
41、5001 Not for Resale, 04/12/2007 19:42:22 MDTNo reproduction or networking permitted without license from IHS -,-,- ISO 13408-1:1998(E) ISO 4 2.26 product sterilizing filter porous material with a nominal rating of less than or equal to 0,22 m, capable of retaining a defined number of microorganisms
42、using defined challenge tests and conditions 2.27 qualification documented scientific 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
43、generally includes installation qualification, operational qualification, and performance qualification. 2.27.1 installation qualification process which demonstrates that the unit or process under test is in compliance with all relevant design criteria and safety standards, and is calibrated 2.27.2
44、operational qualification testing which demonstrates that the equipment and/or process functions as intended, that procedures exist describing operation of the equipment, and that personnel have been trained to set up, operate and maintain the equipment 2.27.3 performance qualification testing which
45、 involves actual challenges to the system to substantiate its effectiveness and reproducibility 2.28 shift scheduled period of work or production, usually less than 12 h, staffed by a single defined group of workers 2.29 sterile state of being free from viable microorganisms NOTE In practice, no suc
46、h absolute statement regarding the absence of microorganisms can be proven. cf. sterilization (2.30) 2.30 sterilization validated process used to render a product free from viable microorganisms NOTE The number of microorganisms that survive a sterilization process can be expressed in terms of proba
47、bility. While the probability may be reduced to a very low number, it can never be reduced to zero. 2.31 support area outside the APA environmentally controlled area not within the aseptic processing area and not part of critical or other processing zones 2.32 terminal sterilization process whereby
48、a product is sterilized in its final container and which permits the measurement and evaluation of quantifiable microbial lethality 2.33 unidirectional air flow air flow which has a singular direction of flow and may or may not contain uniform velocities of air flow along parallel flow lines cf. laminar air flow (2.22) Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/12/2007 19:42:22 MDTNo reproduction or networking permitted without license from IH