www bzfxw com BRITISH STANDARD BS EN 724 1995 Guidance on the Application of EN 29001 and EN 46001 and of EN 29002 and EN 46002 for non active medical devices The European Standard EN 724 1994 has the[.]
BRITISH STANDARD Guidance on the Application of EN 29001 and EN 46001 and of EN 29002 and EN 46002 for non-active medical devices The European Standard EN 724:1994 has the status of a British Standard BS EN 724:1995 BS EN 724:1995 Committees responsible for this British Standard The preparation of this British Standard was entrusted to Technical Committee HCC/66, Quality systems for the manufacture of medical devices, upon which the following bodies were represented: Association of British Certification Bodies Association of British Health-care Industries Association of Contact Lens Manufacturers Association of X-ray Equipment Manufacturers (BEAMA Ltd.) British Anaesthetic and Respiratory Equipment Manufacturers’ Association British In Vitro Diagnostics Association British Orthopaedic Association British Surgical Trades Association Dental Laboratories Association Limited Department of Health Electro Medical Trade Association Limited GAMBICA (BEAMA Ltd.) Guild of Hospital Pharmacists Institute of Physical Sciences in Medicine (ISPM) Institute of Quality Assurance Medical Sterile Products Association Surgical Dressings Manufacturers’ Association This British Standard, having been prepared under the direction of the Health and Environment Sector Board, was published under the authority of the Standards Board and comes into effect on 15 April 1995 © BSI 11-1998 The following BSI references relate to the work on this standard: Committee reference HCC/66 Draft for comment 92/52898 DC ISBN 580 23762 Amendments issued since publication Amd No Date Comments BS EN 724:1995 Contents Committees responsible National foreword Foreword Text of EN 724 © BSI 11-1998 Page Inside front cover ii i BS EN 724:1995 National foreword This British Standard has been prepared by Technical Committee HCC/66 and is the English language version of EN 724:1994 Guidance on the application of EN 29001 and EN 46001 and of EN 29002 and EN 46002 for non-active medical devices, published by the European Committee for Standardization (CEN) BS EN 724 provides guidance on the operation of quality management systems used in the manufacture of non-active medical devices A similar standard, BS EN 501031), covers guidance for the manufacture of active medical devices including active implantable medical devices In addition another standard, BS EN 928, which will provide guidance on quality management systems used in the manufacture of in vitro diagnostic devices, is in preparation Cross-references Publication referred to Corresponding British Standard BS 5750 Quality systems EN 29001:1987 2) EN 29002:19872) Part 1:1987 Specification for design/development, production, installation and servicing Part 2:1987 Specification for production and installation EN 29004:19872) Part 0: Principal concepts and applications Section 0.2:1987 Guide to quality management and quality system elements EN 46001:1993 BS EN 46001:1994 Specification for application of EN 29001 (BS 5750-1) to the manufacture of medical devices EN 46002:1993 BS EN 46002:1994 Specification for application of EN 29002 (BS 5750-2) to the manufacture of medical devices A British Standard does not purport to include all the necessary provisions of a contract Users of British Standards are responsible for their correct application Compliance with a British Standard does not of itself confer immunity from legal obligations Summary of pages This document comprises a front cover, an inside front cover, pages i and ii, the EN title page, pages to 21 and a back cover This standard has been updated (see copyright date) and may have had amendments incorporated This will be indicated in the amendment table on the inside front cover 1) In preparation 2) For information, since the ratification of this European Standard, EN 29001:1987, EN 29002:1987 and EN 29004:1987 have been superseded by EN ISO 9001:1994, EN ISO 9002:1994 and EN ISO 9004-1:1994 The corresponding British Standards are BS EN ISO 9001:1994, BS EN ISO 9002:1994 and BS EN ISO 9004-1:1994 ii © BSI 11-1998 EUROPEAN STANDARD EN 724 NORME EUROPÉENNE EUROPÄISCHE NORM October 1994 ICS 11.020; 11.040.30 Descriptors: Medical equipment, design, manufacturing, quality, quality assurance, quality control, specifications, maintenance English version Guidance on the application of EN 29001 and EN 46001 and of EN 29002 and EN 46002 for non-active medical devices Guide d’application des EN 29001 et EN 46001 et des EN 29002 et EN 46002 pour les dispositifs médicaux non actifs Anleitung zur Anwendung von EN 29001 und EN 46001 und von EN 29002 und EN 46002 für nicht-aktive Medizinprodukte ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ This European Standard was approved by CEN on 1994-10-27 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 Central Secretariat 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 Central Secretariat has the same status as the official versions CEN members are the national standards bodies of Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom CEN European Committee for Standardization Comité Européen de Normalisation Europäisches Komitee für Normung Central Secretariat: rue de Stassart 36, B-1050 Brussels © 1994 Copyright reserved to CEN members Ref No EN 724:1994 E EN 724:1994 Foreword This European Standard was prepared by the Technical Committee CEN TC 205, Non-active medical devices, the Secretariat of which is held by BSI This European Standard has been prepared under a Mandate given to CEN by the European Commission and the Secretariat of the European Free Trade Association, and supports essential requirements of EC Directive(s) 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 April 1995, and conflicting national standards shall be withdrawn at the latest by April 1995 Annexes designated informative are given only for information In this standard annexes A, B and C are informative According to the CEN/CENELEC Internal Regulations, the following countries are bound to implement this European Standard: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom Contents Foreword Introduction Scope Normative references Definitions Guidance on quality system requirements 4.1 Management responsibility 4.2 Quality system 4.3 Contract review 4.4 Design control 4.5 Document control 4.6 Purchasing 4.7 Purchaser supplied product 4.8 Product identification and traceability 4.9 Process control 4.10 Inspection and testing 4.11 Inspection, measuring and test equipment 4.12 Inspection and test status 4.13 Control of nonconforming product 4.14 Corrective action 4.15 Handling, storage, packaging and delivery 4.16 Quality records 4.17 Internal quality audits 4.18 Training 4.19 Servicing 4.20 Statistical techniques Annex A (informative) Guidance on elements of quality systems relevant to sterile product manufacture Annex B (informative) Features of job descriptions of key individuals Annex C (informative) Bibliography Page 3 3 4 5 8 9 11 ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ 12 12 12 12 13 15 15 16 16 16 17 20 21 © BSI 11-1998 EN 724:1994 Introduction This European Standard has been written to give guidance to organizations providing a non-active medical device who wish to ensure that they will comply with EN 29001/EN 29002 and the particular requirements given in EN 46001/EN 46002 It is also intended to provide guidance for certifying and regulatory bodies The guidance in this standard for the fulfilment of requirements should always be in relation to the products being manufactured and interpreted accordingly This standard needs to be read in conjunction with the EN 29000 series of standards with which compliance is sought This standard is not intended as a replacement for EN 29004 which has its own very distinct relationship with the EN 29000 series of standards The combination of EN 29001/EN 46001 and EN 29002/EN 46002 embraces the principles of Good Manufacturing Practices (GMP) which have been in operation in the manufacture of non-active medical devices for a number of years This document seeks to assist in the transition from GMP to quality systems by presenting familiar concepts under the relevant paragraphs of EN 29001/EN 46001 and EN 29002/EN 46002 The references which have been made to EN 29004 are not necessarily exhaustive but seek to identify sections of EN 29004 with particular relevance to the guidance in this document Consideration of this document alone is not an alternative to understanding EN 29004 and it is therefore recommended that EN 29004 is first read and understood in its entirety For ease in the use of this standard, references to clauses in EN 29004 have been cited within the framework of EN 29001 and EN 29002 Annex A to this European Standard provides additional guidance on those elements of quality systems to which particular emphasis should be placed for medical devices which are supplied either sterile or to a defined standard of microbial or particulate cleanliness The guidance in annex A is intended to be considered in addition to that provided in the body of the standard This European Standard provides examples of how to meet the requirements, recognizing that other methods which achieve the same ends are equally acceptable; gives general advice on how to meet the requirements; and draws attention to aspects of requirements that may not be readily apparent to those unfamiliar with quality systems for non-active medical devices Annex A to this European Standard provides guidance on the elements of quality systems which are relevant to the manufacture of medical devices which are to be supplied either sterile or at a defined level of microbiological or particulate cleanliness The adoption of systems other than those described in this European Standard is not to be regarded as a non-compliance with EN 29001 and EN 29002 and/or the specific requirements in EN 46001 and EN 46002 Normative references This European Standard incorporates, by dated or undated reference, provisions from other publications These normative references are cited at the appropriate places in the text and the publications are listed hereafter For dated references, subsequent amendments to or revisions of any of these publications apply to this European Standard only when incorporated in it by amendment or revision For undated references the latest edition of the publication referred to applies EN 29001:1987, Quality systems — Model for quality assurance in design/development, production, installation and servicing EN 29002:1987, Quality systems — Model for quality assurance in production and installation EN 29004:1987, Quality management and quality system elements — Guidelines EN 46001:1993, Quality systems — Medical devices — Particular requirements for the application of EN 29001 EN 46002:1993, Quality systems — Medical devices — Particular requirements for the application of EN 29002 ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ Scope This European Standard provides guidance on the establishment and maintenance of the quality systems specified in EN 29001/EN 46001 or EN 29002/EN 46002 for the manufacture of non-active medical devices It does not add to, or otherwise change, the requirements of those standards and is not intended to be used for the assessment of a manufacturer’s quality system © BSI 11-1998 Definitions For the purpose of this standard the definitions given in EN 46001 and EN 46002 apply, together with the following: 3.1 contract any agreement between the supplier and the purchaser concerning the supply of product NOTE both A contract may be in writing, verbal, or a combination of EN 724:1994 3.2 design 4.1.2 Organization process of developing a product from concept to manufacture Guidance for clauses 4.1.2.1 of EN 29001 and EN 46001 and for clauses 4.1.2.1 of EN 29002 and EN 46002 It is important that conformance with specified requirements is not compromised by considerations of increased production, economy or market pressure Therefore, within an organization, levels of responsibility, authority and inter-relationships are established and typically illustrated in an organization chart In particular, responsibilities for key elements of the quality system should be identified and be included in written job descriptions Responsibility for the effective operation of the quality system rests with the management representative (see 4.1.2.3) who should establish systems to ensure: a) product meets specified requirements; b) documented quality systems, standards and specifications are maintained; and c) regular internal quality audits are performed The responsibility for quality assurance and production should be assigned to separate individuals Annex B to this European Standard provides an example of the features of a job description for these individuals Particular guidance on responsibility and authority for the manufacture of sterile products, or other products for which the microbiological cleanliness is of significance, is provided in annex A Deputies for the key individuals identified above should be nominated and be capable of assuming the responsibilities when necessary For general guidance, see also 5.2.1, 5.2.2 and 5.2.3 of EN 29004 3.3 purchaser recipient of product and/or service delivered by the supplier 3.4 specified requirements any of the following apply: a) requirements prescribed by the purchaser and agreed by the supplier in a contract for product; b) requirements prescribed by the supplier which are perceived as satisfying a market need; or c) regulatory requirements 3.5 validation exercise of carrying out a programme designed and documented to demonstrate that a process, operating within specified limits, will consistently produce product or services complying with predetermined requirements NOTE Validation is considered as a total process which consists of: a) obtaining and documenting evidence that the installation of equipment follows design intentions and that the equipment as installed will perform consistently within predetermined limits (commissioning); and b) obtaining and documenting evidence that the equipment as installed and operated in accordance with process specifications will function reliably, produce acceptable product or services, and that key process variables are known (performance qualification) Guidance on quality system requirements 4.1 Management responsibility 4.1.1 Quality policy Guidance for clauses 4.1.1 of EN 29001 and EN 46001 and for clauses 4.1.1 of EN 29002 and EN 46002 When defining and documenting the supplier’s quality policy, commitment and objectives, the management should express the policy in language that the staff can understand The policy should be specific to the product supplied and to the staff employed Management should be seen to demonstrate commitment to their quality policy both actively and on a continuing basis For general guidance see 4.1, 4.2, 4.3 and 4.4.4 of EN 29004 4.1.2.1 Responsibility and authority ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ 4.1.2.2 Verification resources and personnel Guidance for clauses 4.1.2.2 of EN 29001 and EN 46001 and for clauses 4.1.2.2 of EN 29002 and EN 46002 The resources which need to be provided may include personnel trained in specific disciplines, for example materials science, microbiology or statistics For general guidance, see also 5.2.4 and 18.3 of EN 29004 © BSI 11-1998 EN 724:1994 4.1.2.3 Management representative 4.3 Contract review Guidance for clauses 4.1.2.3 of EN 29001 and EN 46001 and for clauses 4.1.2.3 of EN 29002 and EN 46002 If the management representative (see also 4.1.2.1) who has the responsibility for the quality system has other functions to perform, there should be no conflict of interest Guidance for clauses 4.3 of EN 29001 and EN 46001 and for clauses 4.3 of EN 29002 and EN 46002 It is important that the supplier obtains a thorough understanding of the purchaser’s needs This is established during contract review Contract review should cover factors such as: — product description, quantity and price; — delivery details; — any special packaging, storage and transport requirements; — service; — spare parts 4.1.3 Management review Guidance for clauses 4.1.3 of EN 29001 and EN 46001 and for clauses 4.1.3 of EN 29002 and EN 46002 For general guidance, see 5.5 of EN 29004 4.2 Quality system Guidance for clauses 4.2 of EN 29001 and EN 46001 and for clauses 4.2 of EN 29002 and EN 46002 The main document in the quality system is usually a quality manual This documents quality policy and describes the quality system The quality manual is usually supported by detailed procedures, work instructions and specifications for product and processes Such supporting documents themselves are generally not within the quality manual because of the frequency at which they may be subject to change EN 46001 and EN 46002 require that documentation supporting the quality manual is organized in a file for each product type Such files may be referred to as “Device Master File” or “Device Master Record” This can contain, or give reference to the location of, documentation relevant to the manufacture of that product Examples of such documentation may include: — specifications for raw materials, labelling, packaging materials, intermediate and finished products; — drawings; — work instructions, including equipment operation; — sterilization process details, if applicable; — inspection procedures and acceptance criteria Such files may also contain quality records (see 4.16) such as: — design verification records; — process validation records All this documentation forms part of the quality system and should be subject to document control procedures (see 4.5) For general guidance, see also 5.1.1, 5.1.2, 5.2.5, 5.3.2 and 5.3.3 of EN 29004 NOTE The relationship between the supplier and the sub-contractor is covered by 4.6 of EN 29001 and this standard 4.4 Design control 4.4.1 General Guidance for clauses 4.4.1 of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 The design phase takes a product from concept to production and is an important phase in the life cycle of a medical device The essential quality aspects of safety, performance and reliability of a device are established during this phase Therefore, adequate design controls should be established and implemented to ensure these aspects are met prior to production One of the major causes of quality problems leading to device recalls and failures is deficient design For general guidance see also 8.1 and clause 19 of EN 29004 ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ © BSI 11-1998 4.4.2 Design and development planning Guidance for clauses 4.4.2.1 of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 The planning, operation and management of the design phase may be documented in a design manual For general guidance, see also 8.2.1, 8.2.2 and 8.2.3 of EN 29004 4.4.2.1 Activity assignment Guidance for clauses 4.4.2.1 of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 For general guidance, see 8.2.1 and 8.2.2 of EN 29004 EN 724:1994 4.4.2.2 Organizational and technical interfaces 4.4.5 Design verification Guidance for clauses 4.4.2.2 of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 When input to the design is from a variety of sources, such as from personnel from different functions and/or disciplines within or external to the supplier’s organization or from individuals with specialist expertise, the inter-relationship or interfaces should be clearly understood and controlled For general guidance see also clause of EN 29004 Guidance for clauses 4.4.5 of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 Design verification should be a formal procedure A detailed, documented description of the design verification programme should be established, including organizational functions involved, procedures and methods to be used, documentation required, and variables to be considered and evaluated The extent of design verification required is a function of the safety, performance and the reliability requirements for the item under consideration, the complexity of the design, the existence of published technical standards, the state of the art and the similarity with previously proven designs Should the person(s) responsible for design verification decide that certain aspects or parameters related to safety, performance and reliability not need to be verified, the decision should be properly reasoned and recorded Upon completion of design verification activities, the final design configuration is documented and manufacturing specifications established prior to release to production For any subsequent design changes see 4.4.6 Design verification commonly consists of design reviews supported by other design control measures as described in a) to d) below a) Design reviews Design reviews involve critical analysis of the design activities and are carried out at the conclusion of each design phase Records of design review meetings are retained (see 4.16) and usually identify those present and decisions reached b) Qualification tests and demonstrations Once the design is translated into physical form, its safety, performance and reliability should be verified by testing under simulated use conditions Such verification may include in vitro and/or in vivo testing Clinical evaluation may be required as part of the design verification activities The general guidance presented here also embraces any clinical evaluations within the quality system The conduct of the clinical investigation of medical devices is the subject of a harmonized European Standard (EN 540) c) Alternative calculations The appropriateness of any alternative calculation method should be reviewed 4.4.3 Design input Guidance for clauses 4.4.3 of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 Design input is typically in the form of a performance specification and/or a product description Design input should be specified to the level of detail necessary to permit the design activity to be carried out effectively, and to provide a consistent basis for design decisions, design verification and design changes Design input data may include a product brief and performance requirements, together with requirements of regulations, harmonized European Standards and other published technical standards Design input data may also include advice from an appropriately qualified practitioner For example, consideration may need to be given to anatomical and physiological implications of the intended use of the product For general guidance, see also clauses 7, 8.2.4 and 8.2.5 of EN 29004 4.4.4 Design output Guidance for clauses 4.4.4 of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 The design output documents include typically: — product specifications and drawings; — manufacturing specifications and drawings They should: — be able to be related to the design input and permit design verification; — identify aspects which affect safety, performance and reliability; — be maintained as quality records (see also 4.16) ｗｗｗ．ｂｚｆｘｗ．ｃｏｍ © BSI 11-1998 EN 724:1994 4.6 Purchasing 4.6.1 General Guidance for clauses 4.6.1 of EN 29001 and EN 46001 and for clauses 4.5.1 of EN 29002 and EN 46002 A supplier may purchase, from a number of sources, products and services which may include: — raw materials; — components or sub-assemblies manufactured by others using equipment owned by, and/or materials provided by, the supplier; — components or sub-assemblies available as standard items from other sources; — components or sub-assemblies manufactured by others to the supplier’s specifications; — completed product bearing the mark and/or name of the supplier; this may be ready for sale or require some further processing such as packaging and/or sterilization; — services, e.g sterilization, calibration, testing, pest control, waste disposal, cleaning, environmental monitoring, laundry, transport, installation EN 29001 and EN 46001 use the term “sub-contractor” to include all providers of materials, components, sub-assemblies, finished products or services However, a broad division can be made between purchase of materials or services to the supplier’s specification and the purchase of standard commercially available items This can be useful in deciding on the type and extent of control to be applied to purchased materials or services For general guidance, see also 9.1, 9.5 and 9.6 of EN 29004 4.6.2 Assessment of sub-contractors Guidance for clauses 4.6.2 of EN 29001 and EN 46001 and for clauses 4.5.2 of EN 29002 and EN 46002 The selection of providers of products or services consists of establishing criteria, making an initial selection, and subsequent formal assessment of capability; sub-contractors should be subjected to an on-going surveillance and monitoring of performance All providers of products and services should be able to meet the needs of the supplier The criteria which form the basis for the assessment of potential candidates should be established The supplier should be able to demonstrate that the system provides for: — formal consideration of the extent of assessment required; — selection based on a sufficiently structured appraisal appropriate to the product or service procured; — periodic reassessment of performance; — due account of the results of surveillance when re-ordering Surveillance may consist of one or more of the following activities a) For a provider of standard, commercially available, products or services: — periodic inspection of products or services received; — monitoring of inspection results; — accepting certification of the sub-contractor’s quality system by third parties; — accepting certificates of conformance and/or of analysis from the sub-contractor b) For a provider of products or services to the specification of the supplier: — auditing of the quality system by the supplier, in addition to the items listed in a) above For general guidance, see also 9.3 of EN 29004 4.6.3 Purchasing data Guidance for clauses 4.6.3 of EN 29001 and EN 46001 and for clauses 4.5.3 of EN 29002 and EN 46002 For general guidance, see 9.2 and 9.4 of EN 29004 4.6.4 Verification of purchased product Guidance for clauses 4.6.4 of EN 29001 and EN 46001 and for clauses 4.5.4 of EN 29002 and EN 46002 This requirement of EN 29001 applies when the purchaser is the customer for the product which the supplier manufactures (see clause 3) 4.7 Purchaser supplied product Guidance for clauses 4.7 of EN 29001 and EN 46001 and for clauses 4.6 of EN 29002 and EN 46002 This subclause applies when the purchaser provides items to the supplier to be incorporated by the supplier into the completed product or service For example, the purchaser may provide items to the supplier for inclusion into a kit or set In such cases, the supplier should not knowingly incorporate nonconforming parts into the product or service supplied to the purchaser © BSI 11-1998 EN 724:1994 4.8 Product identification and traceability 4.9 Process control Guidance for clauses 4.8 of EN 29001 and EN 46001 and for clauses 4.7 of EN 29002 and EN 46002 a) Identification Identification of raw materials, components and finished products is important for a number of reasons, including: — control of material throughout manufacture; — demonstration of product source, status and safety requirements; — permitting traceability; — facilitating fault diagnosis in the event of quality problems It is usual for finished products to be identified by a batch/lot number or serial number The extent to which raw materials and components need to be identified and related to the finished product batch/lot or serial number will depend upon a number of factors including: — the material involved; — the type of finished product; — the effect of failure of finished product or materials used therein; — specified requirements; — traceability if necessary; — design input; — regulatory requirement For general guidance, see also 16.1.3 of EN 29004 b) Traceability Batch/lot or serial numbers on products permit traceability in two directions: forward to purchasers and backward to raw materials, components and processes used in manufacture The former is important if it is necessary to trace products to the user, e.g patients or hospitals, and the latter enables investigation of quality problems and feedback for the prevention of nonconforming product Where in-plant traceability of raw materials and components is important to quality, appropriate identification should be maintained throughout the production process to ensure traceability to original material identification and quality status The supplier should establish and maintain a forward traceability system up to the point when products leave the suppliers’ possession For general guidance, see also 11.2 of EN 29004 Guidance for clauses 4.9 of EN 29001 and EN 46001 and for clauses 4.8 of EN 29002 and EN 46002 © BSI 11-1998 4.9.1 General NOTE In order to group together related issues and to maintain readability, the subdivision of this clause does not correspond exactly to that of EN 46001 and EN 46002 Particular guidance on process control for the manufacture of sterile products, or other products for which the microbiological cleanliness is of significance, is provided in annex A For general guidance, see 10.1.1, 10.1.5, 10.2, 10.3, 11.3, 11.5, and 11.6 of EN 29004 a) Production processes Manufacture begins with the issue of raw materials and provision of equipment and continues through all subsequent stages of production until the finished product is released for sale A documented procedure should be agreed for each stage of manufacture This may include: — equipment and materials to be used; — precautions to be taken; — step by step instructions; — any in-process quality checks conducted by production personnel; — the procedure to be followed in the event of quality problems; — the disposition of accepted or rejected products Before and during the introduction of a new design of product (see also 4.4 of this standard) the manufacturing process, including any new manufacturing and test methods, should be fully evaluated The key variables and acceptance limits should be identified and validated for processes, test methods and sampling plans Similar procedures should be followed where any significant change in processing occurs The results of validation exercises should be documented and processes should undergo a regular critical appraisal to ensure that they remain capable of achieving the intended results EN 724:1994 Work-in-progress should be segregated and identified to avoid product mix-up and to ensure traceability where necessary (see 4.8 of this standard) For small parts, for bulk manufacture, and where the parts cannot be marked, the bulk containers and/or process equipment should be identified to indicate the product and/or batch This identification need not be the code used on the finished product but it should be easily related to this code Any previously used labels should be removed or obliterated Ancillary materials should be adequately identified and labelled Containers for temporary storage and handling should be suitably constructed and cleaned as necessary b) Equipment Where automated production or quality control systems are used, any software and/or hardware should be validated Software should be controlled Changes to software may be controlled in the same manner as documents, i.e programme authorized on issue, master copy of the original programme retained, control of changes to programmes with revision levels, and retention of superseded copies (see also 4.5 of this standard) The procedure for control of software should be documented and the responsibility for the control formally designated c) Maintenance of equipment Documented procedures should be available for the maintenance and checking of all equipment used in environmental control and production d) Premises The design, construction and maintenance of premises can influence product quality Buildings in which manufacture, assembly, packaging, storage, inspection and test, and labelling are carried out should be of suitable design and contain sufficient space to facilitate cleaning, maintenance and other necessary operations The following are examples of features which should be considered in the design of premises: lighting, temperature, humidity, ventilation, air pressure, filtration, airborne particulate contamination, and microbial contamination 10 Appropriate controls should be developed for features which can affect the quality of product, such as: cleanliness, environmental conditions, segregation of materials, access for personnel, storage facilities, waste disposal arrangements, and provision for eating, drinking and smoking areas Provision for the following should be considered: — flow of material through manufacturing; — access for personnel; — cloakroom and toilet facilities, segregated from production areas; — cleaning; — maintenance, repair, building activities; — pest control; — gas, electricity, water, etc.; — special manufacturing operations; — disposal of waste material; — special storage areas and conditions; — special testing and laboratory facilities The design and construction of premises should allow for the adequate segregation of “dirty operations”, e.g grinding and other dust generating processes, from “clean” manufacturing processes and any operations required to be carried out in controlled environments Where appropriate, procedures for maintenance of buildings should be documented and written records should be kept A documented preventive pest control system should be in operation This may include regular inspection and routine bait laying and/or insecticide spraying The system should be designed to prevent contamination of materials and product Where a specialist contractor is used, the contract should be in writing and define the responsibilities of both parties Written records of pest control activities should be maintained © BSI 11-1998 EN 724:1994 e) Cleaning of premises, equipment and product 1) General There should be a documented cleaning procedure for all general areas and equipment This should specify: — cleaning equipment and materials to be used; — methods to be used; — methods of protection of products from contamination during cleaning; — frequency of cleaning; — designated personnel; — records to be kept; — instructions for major periodic cleaning; — storage of cleaning equipment in a clean, dry and tidy manner When cleaning operations are carried out by a sub-contractor, there should be a written contract specifying the limits of responsibility of both parties This contract should include details of the documented cleaning procedure and specify the training to be given to cleaning staff (see also 4.18 of this standard) 2) Cleaning of product Cleaning processes may be required to remove process agents and/or particulate contamination Cleaning processes should be validated as to the efficacy of the process for the removal of contamination in accordance with a documented procedure Records of validation should be retained (see 4.16 of this standard) The cleaning process should be routinely monitored in accordance with documented procedures Records of this monitoring should be maintained (see 4.16 of this standard) f) Installation For non-active medical devices, installation does not mean implantation in or fitting to a patient If appropriate, the supplier should provide instructions for installation of the medical device and, if a non-active medical device is installed, the responsibility for installation should be clearly defined (see 4.3 of this standard) For general guidance, see 16.1.5 of EN 29004 © BSI 11-1998 4.9.2 Special processes Guidance for clauses 4.9.2 of EN 29001 and EN 46001 and for clauses 4.8.2 of EN 29002 and EN 46002 Manufacturing processes should be reviewed to identify any special processes which are employed One example of a special process to which particular consideration should be paid is sterilization (see annex A) For general guidance see also 11.4 of EN 29004 4.10 Inspection and testing Guidance for clauses 4.10 of EN 29001 and EN 46001 and for clauses 4.9 of EN 29002 and EN 46002 For general guidance, see 8.3 and 10.1.4 of EN 29004 4.10.1 Receiving inspection and testing Guidance for clauses 4.10.1 of EN 29001 and EN 46001 and for clauses 4.9.1 of EN 29002 and EN 46002 For general guidance, see 9.7, 9.8 and 12.1 of EN 29004 4.10.2 In-process inspection and testing Guidance for clauses 4.10.2 of EN 29001 and EN 46001 and for clauses 4.9.2 of EN 29002 and EN 46002 For general guidance, see 10.1.2, 10.1.3 and 12.2 of EN 29004 4.10.3 Final inspection and testing Guidance for clauses 4.10.3 of EN 29001 and EN 46001 and for clauses 4.9.3 of EN 29002 and EN 46002 For general guidance, see 12.3 of EN 29004 4.10.4 Inspection and test records Guidance for clauses 4.10.4 of EN 29001 and EN 46001 and for clauses 4.9.4 of EN 29002 and EN 46002 Inspection and test records facilitate the reconstruction of the manufacturing history of products as part of corrective action procedures (see 4.14 of this standard) Records therefore need to be prepared carefully Results of inspections and tests may be recorded: — directly in documentation accompanying the product; — as electronic records; and — in separate test reports 11 EN 724:1994 As applicable, records should: — identify the inspection/test procedure(s) and revision level used (see also 4.5 of this standard); — be signed and dated by the person responsible for the inspection or test; — clearly identify the number of items examined and the number accepted; and — record the disposition of any items failing inspection or test 4.11 Inspection, measuring and test equipment Guidance for clauses 4.11 of EN 29001 and EN 46001 and for clauses 4.10 of EN 29002 and EN 46002 In addition to the calibration of test equipment, where it is necessary to have recording or controlling instruments on manufacturing equipment, these also should be calibrated initially and at defined intervals in accordance with a planned schedule For general guidance, see clause 13 of EN 29004 4.12 Inspection and test status Guidance for clauses 4.12 of EN 29001 and EN 46001 and for clauses 4.11 of EN 29002 and EN 46002 For general guidance, see 11.7 of EN 29004 4.13 Control of nonconforming product Guidance for clauses 4.13 of EN 29001 and EN 46001 and for clauses 4.12 of EN 29002 and EN 46002 Any product returned to the supplier should be treated as nonconforming product until it has satisfied a documented acceptance procedure For general guidance, see also 11.8, 14.1, 14.2, 14.3, 14.6 and 14.7 of EN 29004 4.13.1 Nonconformity review and disposition Guidance for clauses 4.13.1 of EN 29001 and EN 46001 and for clauses 4.12.1 of EN 29002 and EN 46002 NOTE In order to group together related issues and to maintain readability, the subdivision of this clause does not correspond exactly to that of EN 46001 and EN 46002 a) Nonconforming material review Nonconforming material review is frequently undertaken by a small group of designated personnel including, where appropriate, individuals with specialized expertise Records should be retained of: — investigations into the cause of nonconformance; — corrective action taken; 12 — disposition of those products not suitable for sale or rework b) Rework Where rework is appropriate the supplier should establish and maintain documented procedures for the reworking of nonconforming products The procedures should identify responsibilities and describe the equipment and method of inspection The effect of the reprocessing should be determined and recorded The reprocessed product should meet the original or modified and approved specifications Any previous quality assurance checks should be repeated on the reprocessed product if the reprocessing could have altered any performance previously inspected c) Concessions Decisions to accept nonconforming material on concession should always be with the agreement of the quality assurance manager; it is common for the procedures either to require a unanimous decision for concessions or for the quality assurance manager to have a veto over such decisions d) Disposal of nonconforming material Control should be established over the disposal of nonconforming material which is designated as scrap in order to ensure that: — its status is clearly identified; — it cannot be confused with conforming product; — it cannot re-enter the production system; — it is disposed of safely For general guidance, see also 14.4 and 14.5 of EN 29004 4.14 Corrective action Guidance for clauses 4.14 of EN 29001 and EN 46001 and for clauses 4.13 of EN 29002 and EN 46002 NOTE In order to group together related issues and to maintain readability, the subdivision of this clause does not correspond exactly to that of EN 46001 and EN 46002 a) General Nonconformity may be detected at receiving inspection, during production or after delivery The need to identify the cause of the nonconformity and to take corrective action applies to all three situations However, in the case of quality related problems in the marketplace, additional guidance is given for the handling of customer complaints and implementing corrective action (for further information see Guidelines on Medical Device Vigilance) © BSI 11-1998 EN 724:1994 b) Feedback information Regulations may place requirements on suppliers to monitor the use of their products and inform regulatory authorities of certain defined experience in use Feedback information may include: — reports from the marketing function; — reports from authorized representatives; — customer complaints; — customer reports; — solicited information on new or modified products; — reports from regulatory authorities; — published literature c) Customer complaints The documented complaints system should cover the following: — person(s) responsible for operating the system; — evaluation of the complaint; — records and statistical summaries, enabling the major causes of complaints to be determined; — corrective action; — segregation and disposition, or reprocessing of customer returns and faulty stock (special attention may need to be given to decontamination); — filing of customer correspondence and other relevant records, the retention time for which should be defined Corrective action should be implemented without undue delay when a finished product is found to be defective, or is subject to adverse reports; such action may include one or more of the following: — withholding products available for sale; — withdrawing products from circulation; — giving advice to customers; this may take the form of checks to be carried out before use, providing additional guidance on the use of the product or for the replacement of certain products; — in extreme cases, the recall of products © BSI 11-1998 d) Advisory notices and product recall The nature and seriousness of the fault, and the risk category of the product, will determine whether it will be necessary to issue an advisory notice or to institute a recall These factors will also determine the speed and extent of the action The advisory notice and recall procedures should specify: — the methods (e.g communication system) to be used; — the system for determining the disposition of returned product, for example, rework, re-package, scrap The advisory notice or recall should include: — the description of the product and code number where appropriate; — the product batch number(s) or serial number; — the action to be taken; — the reason for the action recommended and advice on any associated hazards The progress of a recall should be monitored and amounts of product received should be reconciled All returned products should be segregated For general guidance, see also clause 15 and 16.3 of EN 29004 4.15 Handling, storage, packaging and delivery 4.15.1 General Guidance for clauses 4.15.1 of EN 29001 and EN 46001 and for clauses 4.14.1 of EN 29002 and EN 46002 The premises for handling, storage, packaging and delivery should be utilized in a systematic way, with clearly defined and labelled areas for each group of products where appropriate The goods should be stored away from floors, walls and ceilings, e.g in shelf or pallet racks For general guidance, see also 16.1.1 of EN 29004 4.15.2 Handling Guidance for clauses 4.15.2 of EN 29001 and EN 46001 and for clauses 4.14.2 of EN 29002 and EN 46002 For general guidance, see 16.1.2 of EN 29004 13 EN 724:1994 4.15.3 Storage Guidance for clauses 4.15.3 of EN 29001 and EN 46001 and for clauses 4.14.3 of EN 29002 and EN 46002 Raw materials and products should be issued in rotation according to an approved and documented procedure Stock records should be kept so that stock reconciliation can be made and traceability can be demonstrated when necessary Raw materials and products which have been rejected, recalled or returned should be placed in quarantine to prevent confusion with other materials Access to materials in quarantine areas should be restricted to authorized persons Release and disposition should be carried out according to a defined procedure 4.15.4 Packaging Guidance for clauses 4.15.4 of EN 29001 and EN 46001 and for clauses 4.14.4 of EN 29002 and EN 46002 a) Packaging Before any packaging of the product is adopted it should be evaluated to establish its suitability for the intended purpose For example, the suitability of the packaging of a product may be demonstrated by journey hazard trials designed to simulate the abuses the package will encounter during routine methods of transit and storage Packaging materials should be purchased, tested and released against agreed specifications The three inter-related levels of packaging frequently used are the primary or unit container, the secondary or shelf container, and the transport or outer container A unit container should protect the contents up to the time of use A suitable number of unit containers may be packed into a shelf container Shelf containers may be packed into an outer container to provide protection during handling and supply Guidance relevant to packaging for sterile medical devices is included in annex A b) Labels Requirements for the information to be supplied by the manufacturer with medical devices are specified in prEN 1041 14 c) Labelling The risk of labelling and packaging errors may be minimized by the introduction of appropriate controls such as: — avoidance of packaging and labelling of products of similar appearance in close proximity; — line identification; — application of line clearance procedures; — the destruction of unused batch coded materials on completion of packaging and labelling; — use of roll feed labels; — use of known number of labels and reconciliation of usage; — on-line batch coding; — use of electronic code encoders/readers and label counters; — use of labels designed to provide clear product differentiation; — inspection of labels before use; — effective segregation of packaging operations and labelling; — proper storage of labels in areas of restricted access For implantable medical devices EN 46001 and EN 46002 require a record to be retained of the identity of the person who confirms that the correct label(s) has been affixed to the medical devices For general guidance, see also 16.1.3 and 16.1.4 of EN 29004 For the purpose of this document, guidance in EN 29004 relevant to marking applies to labelling 4.15.5 Delivery Guidance for clauses 4.15.5 of EN 29001 and EN 46001 and for clauses 4.14.5 of EN 29002 and EN 46002 Consideration should be given to the conditions which the product may encounter during delivery Factors to be considered may include: — climatic conditions; — type and cleanliness of transport; — other journey hazards For general guidance, see also 16.1.6 of EN 29004 © BSI 11-1998 EN 724:1994 4.16 Quality records Guidance for clauses 4.16 of EN 29001 and EN 46001 and for clauses 4.15 of EN 29002 and EN 46002 a) General Quality records can be divided into three broad categories: 1) those which are related to the manufacture of an individual product or batch of product (batch records); 2) those which relate either to all products of a particular type, or to general activities affecting a number of batches of product (pre-production records); 3) other quality records which demonstrate the effective operation of the overall quality system (system records) b) Batch records Quality records which facilitate traceability and review of the manufacture of a batch of product, derived during the manufacture of that batch, should be contained in a batch record and are frequently collated in a single file Such files can be referred to as a “Device History Record”, “Batch Manufacturing Record”, “Lot History Record” or “Lot Record” If it is not practical to include all the relevant documents in the batch record, then it should list the titles of those documents and their location The system for record retention should allow retrieval of quality records without undue delay if required for corrective action (see 4.14 of this standard) Batch records should be prepared from the currently approved versions of the specifications The forms which constitute the batch records should be designed and reproduced by an appropriate method to avoid clerical errors A batch record should have a unique batch identification and relate to an individual manufacturing batch During manufacture, relevant information should be entered on to the batch record such as: — the quantity of the raw materials, components and intermediate products, and their batch number, where appropriate; — the date of start and completion of different stages of production, including sterilization records where appropriate; — the quantity of product manufactured; — the signed results of all inspections and tests; — designation of the production line used; © BSI 11-1998 — any deviation from the manufacturing specifications c) Pre-production records Examples of records in this category include: — the contents of the Device Master Record (see 4.2 of this standard); — design verification and design review records; — records of process validation, including sterilization validation d) System records Examples of activities generating records in this category include the following: — management review; — contract review; — complaint handling; — training; — internal audits; — cleaning and maintenance of buildings and equipment; — environmental monitoring; — calibration For general guidance, see also 5.3.4 and 17.3 of EN 29004 4.17 Internal quality audits Guidance for clauses 4.17 of EN 29001 and EN 46001 and for clauses 4.16 of EN 29002 and EN 46002 The internal audit documentation may include a checklist of features of the quality system which should be reviewed It should be recognized that the items listed may not be all-inclusive and care should be taken to ensure that the audit is not confined to only those items so listed Internal auditing may be sub-contracted Only records which demonstrate that an effective internal audit system is in operation need to be made available to third party auditors This may be done by: — providing documented procedures for the conduct of audits; — providing audit schedules; — demonstrating that internal audits have been performed; — demonstrating that corrective actions have been initiated and completed A series of small well-defined audits may be as effective as a single large and comprehensive audit For general guidance, see also 5.4 of EN 29004 15 EN 724:1994 4.18 Training 4.19 Servicing Guidance for clauses 4.18 of EN 29001 and EN 46001 and for clauses 4.17 of EN 29002 and EN 46002 The training programme should: — include the intended use of the products; — identify quality problems which could arise from the inadequate or improper performance of the specified tasks; — describe any specific hygiene requirements (see 4.9 of this standard); — include instruction on conduct to avoid jeopardizing the integrity of special environmental conditions, when applicable; — include, when appropriate, procedures to be followed on receipt of customer feedback Training should be given as an introduction to new employees and for all personnel at intervals Records of training should be maintained to demonstrate the suitability of a person for a specific task For general guidance, see also 18.1 and 18.2 of EN 29004 Guidance for clauses 4.19, of EN 29001 and EN 46001; not applicable to EN 29002 and EN 46002 Whilst servicing may not be a requirement for non-active medical devices intended for single use, other products which are designed to be repeatedly used may require periodic servicing to ensure they remain suitable for their intended purpose They may also need to be cleaned and decontaminated prior to servicing In such cases, a validated method should be established and documented For general guidance, see also 16.2 of EN 29004 16 4.20 Statistical techniques Guidance for clauses 4.20 of EN 29001 and EN 46001 and for clauses 4.18 of EN 29002 and EN 46002 The use of statistical methods can be beneficial in data collection and data analysis They assist in deciding what data to obtain and in making best use of the data so obtained The selection of statistical methods should be made wherever possible from recognized published techniques/standards or, if not, it is essential that the validity of the statistical tool being used has audit traceability to base statistical theory For general guidance, see also 20.1 and 20.2 of EN 29004 © BSI 11-1998