BELLCO

ARTERIOVENOUS LINES

TECHNICAL REPORT

CONTENTS

1. MANUFACTURER IDENTIFICATION 2. DESCRIPTION OF THE DEVICE AND INTENDED USE 3. MANUFACTURING PROCESS 4. PACKAGING 5. STERILIZATION 6. DEVICE SHELF LIFE VALIDATION 7. PRODUCTION ENVIRONMENTS 8. BIOCOMPATIBILITY 9. INDEX OF STANDARDS APPLIED

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TECHNICAL REPORT

1 - MANUFACTURER IDENTIFICATION

Company name: BELLCO S.r.l. ADDRESSES Registered office and Workshop: Via Camurana 1 , 41037 Mirandola (MO), Italy Tel.: +39/0535/29811 Fax: +39/0535/25501 BELLCO certifications: Quality System certification in conformity with EN ISO 13485:2003/AC2007 standards CE product certification in conformity with Directive 93/42/EEC The above mentioned certificates have been issued by the Notified Body No. 0123, TV SD- Product Service (Munich).

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2 - DESCRIPTION OF THE DEVICE AND INTENDED USE NAME OF THE DEVICE: Lines for extracorporeal circulation of the blood (hereafter called blood lines) CATEGORY OF THE DEVICE: Hemodialysis GROUP OF THE DEVICE: Medical devices for hemodialysis TYPE OF DEVICE: Arterial and venous lines for the extracorporeal circulation of blood. Single use devices. CLASS: IIa (According to MDD, all. IX, rule 2) UMDNS Classification: 11225 (Hemodialysis tubing sets) STERILISATION: Ionizing radiations, ethylene oxide. FIELD OF APPLICATION AND INTENDED USE: Hemodialysis treatments, hemodiafiltration in cases of acute or chronic renal failure. Blood purification treatments of dialyzable substances in cases of acute intoxication. Hemofiltration treatments. MODELS Blood lines are manufactured in the following types: Blood lines in PVC Blood lines in PIVIPOL dop/ dop free dop/ dop free.

The blood lines that are sterilized by ionizing radiations are divided into the following device families: BL307, BL352, BL360, Combipack. The blood lines that are sterilized by ethylene oxide are divided into the following device families: BL302, BL304, BL306, BL307, BL308, BL352, BL360, Combipack.

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TECHNICAL REPORT

3 - BRIEF DESCRIPTION OF THE BLOOD LINE MANUFACTURING PROCESS The haemodialysis blood line manufacturing process applied to production and testing of the finished product is described below. The production cycle is divided into the following phases: 1. Acceptance of raw materials 2. Manufacture of components and tubes in thermoplastic material 3. Manufacture of blood lines and testing 3.1 Line assembly 3.2 Leak test 3.3 Packaging 4. Sterilization Inspections and Quality Control are carried out for each production phase. PHASE 1 ACCEPTANCE OF RAW MATERIALS The following are considered as raw materials: Thermoplastic resins for production of components and tubes Various parts in thermoplastic resin used in the production process and in product packaging Packaging materials The components and materials are subjected to QC acceptance for correspondence to the technical specifications set out in the acceptance test sheets. PHASE 2 MANUFACTURE OF COMPONENTS AND TUBES The plastic components are manufactured by means of direct injection moulding and extrusion for the tubes. Component moulding Tube extrusion PHASE 3 MANUFACTURE OF BLOOD LINES AND TESTING The operations described below are conducted according to the procedures formalised in the Device Master Record of the product in controlled microclimatic and contamination conditions. 3.1 - Line assembly: The blood lines are assembled in the production areas. 3.2 - Leak test: 100% of the blood lines are subjected to leak test. 3.3 - Packaging: The products are packed in blister packs or in bags made of paper and plastic film. PHASE 4 STERILIZATION AND FINAL TESTS The blood lines are sterilized by ethylene oxide or ionising radiation. Products sterilized by ethylene oxide: the product is held in the desorption chamber to remove the residual ethylene oxide pending the results of the post-sterilization tests. Products sterilized by ionising radiation: the products remain in quarantine for the time necessary for post-sterilization tests.
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The identification of sterilization of lines and accessories is managed by production batch (shown on the individual and multiple package). At the end of the product testing and release procedure, the worksheets are signed by the person responsible in the Laboratory and by Quality Assurance. Release of sterile products Release of the medical devices sterilized by ethylene oxide is subject to approval of the records of the sterilization and desorption cycle parameters by the microbiologist and the results of the sterility and apyrogenicity tests. Release of the medical devices sterilized by heat or ionising radiation is subordinate to checking of the sterilization documents and the result of the apyrogenicty tests. Product suitability certificate The product suitability certificate is prepared at the time of drawing up the shipping documents. The document identifies the products forming part of a shipment by means of: Product code / Name / Batch / Sterilization date / Expiry. The suitability certificate declares the suitability of the products listed in relation to the essential requirements and the post-sterilization tests. The document is checked and signed by the microbiologist. 4 - PACKAGING 4.1 - INDIVIDUAL PACKAGE Reference standards ISO 11607-1: Packaging for terminally sterilized medical devices . Part 1: Requirements for materials, sterile barrier systems and packaging systems ISO 11607-2: Packaging for terminally sterilized medical devices . Part 2: Validation requirements for forming, sealing and assembly processes EN 868-3: Packaging materials and system for medical devices which are to be sterilized. Part 3: Paper for use in the manufacture of paper bags and in the manufacture of pouches and reels Requirements and test methods. EN 868-4: Packaging materials and system for medical devices which are to be sterilized. Part 4: Paper bags - Requirements and test methods. EN 868-5: Packaging materials and system for medical devices which are to be sterilized. Part 5: Heat and self-sealable pouches and reel material of paper and plastic film construction Requirements and test methods. EN 868-6: Packaging materials and system for medical devices which are to be sterilized. Part 6: Paper for the manufacture of packs for medical use for sterilization by ethylene oxide or irradiation. MATERIALS a. PAPER Conform to international standards for paper used for packing sterile medical devices: EN 868. b. PLASTIC FILM Product characterisation: - 12 m polyester laminate / 40 m low-density polyethylene (LDPE) - 75 m polypropylene laminate / 65 m low-density polyethylene (LDPE) INDIVIDUAL PACKAGE VALIDATION The suitability of the package is evaluated for: Protection of the product against damage and dirt Microbiological protection of the product stored in the specified conditions

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Suitability for long-term storage of the product for the chemical, physical, functional characteristics Suitability for sterilization by ionising radiation and ethylene oxide Suitability for opening without tears or delamination such as to produce particles Suitability for production.

4.2 - MULTIPLE PACKAGE Reference standards UNI EN 22206: Complete, filled transport packages - identification of the various parts for tests. UNI 7970-4: Complete, filled transport packages - vertical impact test by dropping. MATERIALS CARDBOARD BOX Product characterisation: Microthree-ply punched cardboard box containing 40 pieces in individual packages and 20 pieces for the Combipack. MULTIPLE PACKAGE VALIDATION The suitability of the package is evaluated for: Protection of the product against external agents Mechanical protection of the product against damage from handling and storage Suitability for long-term storage of the product for the chemical, physical, functional characteristics Suitability of multiple packages for palletization Suitability for production. 5 - STERILIZATION The aim of the sterilization methods of medical devices is to assure sterility of the products with a safety margin evaluated in a probability of contamination not higher than 10-6. Each cycle adopted by Bellco for sterilization of medical devices is subjected to prior validation. 5.1 - STERILIZATION BY ETHYLENE OXIDE Reference standards 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/TS 11135-2: Sterilization of health care products -- Ethylene oxide -- Part 2: Guidance on the application of ISO 11135-1 EN 556-1: Sterilization of Medical Devices - Requirements for medical devices to be designated Sterile Part 1: Requirement for terminally sterilized medical device. ISO 11737-1 - Sterilization of medical devices. Microbiological methods. Part 1: Determination of a population of microorganisms on products. ISO 11737-2 - Sterilization of medical devices. Microbiological methods - Part 2: Test of sterility performed in the validation of a sterile process. BELLCO EtO STERILIZATION SYSTEM The Bellco ethylene oxide sterilization system consists of cylindrical cross-section autoclaves with a standard load of 29 m3. The following operating parameters are checked and recorded for each sterilization cycle: Pressure/vacuum, temperature, relative humidity, EtO concentration.

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TECHNICAL REPORT

STERILIZATION CYCLE VALIDATION The cycle adopted by Bellco for sterilization of medical devices is subjected to prior physical and biological validation. Physical validation of the autoclaves consisting of: Test of temperature distribution in empty autoclaves Test of temperature distribution in the product Test of relative humidity distribution in the product. Biological validation of the sterilization cycle: The effectiveness of the sterilization conditions adopted is verified with the over-kill method on a bacterial population composed of spores of Bacillus subtilis not less than 106. The sterilization revalidation cycle is carried out at least every 15 months and/or for each modification of the sterilization cycle, the packaging or the type of product. RESIDUAL ETHYLENE OXIDE DESORPTION The aim of the residual EtO desorption operation of the medical devices is to assure a residual ethylene oxide content not higher than 4.6 mg per device determined on an elution fluid which simulates its use. Reference standards ISO 10993-7: Biological evaluation of medical devices - Part 7 - Ethylene Oxide sterilization residuals. FUI IX Ed.: Chemical assays on haemodialysis machines PRC 121 (internal procedure) Residual EtO desorption from medical devices. 5.2 - STERILIZATION BY IONIZING RADIATION Reference standards EN 552: Sterilization of Medical Devices - Validation and routine control of sterilization by irradiation. 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 EN 556: Sterilization of Medical Devices - Requirements for medical devices to be labelled Sterile. UNI EN 1174-1: Sterilization of medical devices. Estimation of population of microorganisms on product. Part 1: Requirements. EN 1174-2: Sterilization of medical devices. Estimation of population of microorganisms on product. Part 2: Guidance ISO 11737-2: Sterilization of medical devices. Microbiological methods - Part 2: Test of sterility performed in the validation of a sterile process. ISO/TS 15843: Sterilization of health care products. Radiation sterilization Product families and sampling plans for verification dose experiments and sterilization dose audits, and frequency of sterilization dose audit. STERILIZATION BY IONIZING RADIATION Sterilization by irradiation with Beta ionizing radiation performed at an external sterilization centre. Information on the system and the sterilization and test methods are documented by the external sterilizing company in the physical validation documentation: Method of presentation of the product to irradiation Dose distribution in the product.
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BELLCO

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TECHNICAL REPORT

The operating aspects of sterilization are dealt with in technical contract specifications: Operating flow Products and sterilization load (maximum density) Irradiation dose and acceptable exposure tolerance Irradiation batch identification Product positioning and irradiation conditions Dosimetric tests Irradiation certificates. STERILIZATION VALIDATION Each cycle adopted by Bellco for sterilization of medical devices is subjected to prior validation. a) Physical validation Physical validation consists of mapping the irradiation dose in the product; it is performed by the external sterilization company who documents the operating conditions, the dosimetric measuring and test methods as well as the irradiation distribution in the load. b) Biological validation a. The contamination conditions of the product before sterilization are evaluated prior to validation by testing the bioburden of at least 10 samples out of 3 batches of product used for the validation: 30 samples in all. b. The average bioburden of the 3 control groups is used to determine the verification dose taking it from Table B.1 of ISO 11137 for an SAL value of 10-2. c. At least 100 line samples are packed in a package/s of the maximum foreseeable density. d. The samples are exposed to the above mentioned verification dose. e. Test on the product: the effectiveness of the validation dose is verified on the 100 sample devices by performing a sterility test on the product. The results must conform to the ISO 11137 standard. f. The corresponding minimum exposure value for an SAL of 10-6 is taken from table B.1 of the ISO 11137 standard. Based on the biological validation results and the minimum irradiation dose the standard dose for routine sterilization is defined and, if necessary, the minimum dose increased as safety factor. The biological sterilization cycle is revalidated every year or for every new product that modifies the load density. Physical validation (mapping) is performed for each modification of the sterilization treatment, the packaging, the product and/or the load density, and each time the service provider is changed. 6 - DEVICE SHELF LIFE VALIDATION Validation of the shelf life of the device is carried out according to the internal procedure "Shelf life of medical devices" relative to qualification of new products that involve the use of unfamiliar materials and/or subject to treatments which may affect the physical, chemical or functional characteristics. Reference standards: EN 1283: Haemodialysers, haemodiafilters, haemofilters, haemoconcentrators and their extracorporeal circuits; European Pharmacopoeia Official Italian Pharmacopoeia (chemical-biological tests); ASTM F1980: Standard guide for accelerated ageing of sterile medical device packages. TESTS Chemical, biological and functional tests conducted on products after ageing: Chemical toxicity tests

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Functional tests Sterility and apyrogenicity test Abnormal toxicity or cytotoxicity test Test of physical-mechanical characteristics.

AGEING VALIDATION Accelerated ageing Ageing tests are conducted on new products and materials by inducing artificial ageing of the product by extended heating at temperatures higher than the storage/operating temperatures, but such as not to induce irreversible damage to the product or materials. Natural ageing For products already in use tests are conducted on the naturally aged product. 7 - PRODUCTION ENVIRONMENTS The production environments are classified in relation to the degree of cleanliness required for the type of product and processing. The areas dedicated to the manufacture of the accessory devices are characterised by a suitable degree of prevention of physical and microbiological contamination. Main characteristics of the clean rooms: Environment class: ISO 8 Degree of microbiological and microparticle contamination of the controlled environments Internal recirculation of filtered air at positive pressure Controlled microclimatic conditions: Temperature and relative humidity Constructive solutions suited to facilitate cleaning of the environments Procedures related to "Hygiene rules in the clean rooms" are applied in these areas Accesses for staff and materials; these accesses are suitably equipped in order to allow proper observance of the access procedures General room cleaning rules exist. Reference standards: ISO 14644-1: Cleanrooms and associated controlled environment. Part 1: Classification of air cleanness ISO 14644-2:Cleanrooms and associated controlled environment. Part 2: Specification for testing and monitoring to prove continued compliance with ISO 14644-1. ISO 14644-4: Cleanrooms and associated controlled environment. Part 4: Design, construction and start-up

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TECHNICAL REPORT

8 - BIOCOMPATIBILITY The raw materials and components that come into contact with blood or infusion solutions are validated for conformity with: Official Italian Pharmacopoeia / European Pharmacopoeia, and/or USP Class VI: for all materials for which precedents of use in the sector exist or for which a monograph in Pharmacopoeia exists EN ISO 10993: for the products and/or new materials for which no adequate documentation and/or experience exist. Atoxicity and biocompatibility test The applicable biocompatibility tests are deduced from ISO 10993-1 "Biological evaluation of medical devices. Guidance on selection of tests", point 5.1.3 "External communicating Devices": Devices in contact with blood: direct contact, extensive duration. - Chemical atoxicity test, Official Italian Pharmacopoeia Chemical atoxicity tests described in the Official Italian Pharmacopoeia "Chemical assays on dialysis machines".

- Acute systemic toxicity Acute systemic injection in the mouse According to the method set out in ISO 10993 Part 11; acute systemic toxicity: intravenous (ASTM F750 or USP XXII NF XVII) - ASTM F 750-82: Standard practice for evaluating material extracts by Systemic injection in the mouse. - Cytotoxicity Test for Cytotoxicity: in vitro method according to the method set out in ISO 10993 Part 5; - USP XXIII (Jan. 95): Biological reactivity test in-vitro (MEM Elution test) - Sensitisation Guinea pig maximization test: allergic sensitization test on guinea pig According to the method set out in ISO 10993 Part 10: Test for irritation and sensitization. - ASTM F 720-81 (1986) "Standard practice for testing guinea pigs for contact allergens: Guinea Pig Maximization Test" - Intracutaneous reactivity Intracutaneous injection test in the rabbit In accordance with ISO 10993 -10: Test for irritation and sensitization. - ASTM F 749-82: Standard practice for evaluating material extracts by intracutaneous injection in the rabbit. - Mutagenicity Reverse mutation in salmonella typhimurium: mutagenicity test - Ames test. In accordance with: ISO 10993 - 3: Test for genotoxicity, carcinogenicity and reproductive toxicity. - Haemocompatibility - Haemolytic effect In accordance with IS0 10993 - 4: Biological evaluation of medical devices. Selection of test for interaction with blood.

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TECHNICAL REPORT

9 - INDEX OF STANDARDS APPLIED List of the national, international or internal standards applied wholly or partially to assure that the essential requirements are met (MDD Appendix I). NOTE: Unless otherwise specified the standards quoted are to be considered in current revision. ISO 13485 - Quality Systems - Medical Devices - Requirements for regulatory purposes. EN 1283 - Haemodialysers, haemodiafilters, haemofilters, haemoconcentrators and their extracorporeal circuits. ISO 8638 - Exrtracorporeal blood circuit for haemodialysers, haemofilters and haemoconcentrators ISO 594-1 - Conical fittings with a 6% (Luer) taper for syringes, needles and certain other medical equipment. Part 1: General requirements ISO 594-2 - Conical fittings with a 6% (Luer) taper for syringes, needles and certain other medical equipment. Part 2. Lock fittings UNI EN 20594-1 - Conical fittings with a 6% (Luer) taper for syringes, needles and certain other medicalinstruments. General requirements EN 1707 - Conical fittings with a 6% (Luer) taper for syringes, needles and certain other medical equipment. Part 2. Lock fittings ISO 8536-4: 1998 - Infusion equipment for medical use. 4: Infusion sets for single use, gravity feed ISO 1135-4: 1998 - Transfusion equipment for medical use. 4: Transfusion sets for single use 42/93/EEC: - Implementation of Directive 42/93/EEC regarding medical devices. European Pharmacopoeia Official Italian Pharmacopoeia British Pharma 1993 ISO 14644-1 - Cleanrooms and associated controlled environment. Part 1: Classificaation of air cleanliness ISO 14644-2 - Cleanrooms and associated controlled environments. Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1. ISO 14644-4 - Clean rooms and associated controlled environment. Part 4: Design, construction and start-up UNI ISO 2859-0 - Sampling procedure for inspection by attributes. Part 0 UNI ISO 2859-1- Sampling procedures in testing by attributes. Sampling plansindexed according to LQA for batch-by-batch testing UNI EN ISO 868 Plastics and ebonite Determination of indentation hardness by means of a durometer (shore hardness) ASTM F1980 - Standard guide for accelerated ageing of sterile medical device packages. ISO 10993-1 - Biological evaluation of medical devices - Part 1: Evaluation and testing. ISO 10993-3 - Biological evaluation of medical devices - Part 3: Test of genotoxicity, carcinoogenicity and reproductive toxicity. ISO 10993-4 - Biological evaluation of medical devices - Part 4: Selection of tests for interaction with blood. ISO 10993-5 - Biological evaluation of medical devices - Part 5: Test for cytotoxicity: in-vitro methods EN ISO 10993-7 - Biological evaluation of medical devices - Part 7: Ethylene Oxide sterilization residuals. ISO 10993-10 - Biological evaluation of medical devices. Test for irritation and delayed type hypersensitivity ISO 10993-11 - Biological evaluation of medical devices - Part 11: Tests for systemic toxicity ISO 10993-12 - Biological evaluation of medical devices - Part 12: sample preparation and reference materials EN 1041 - Terminology, symbols and information provided with medical devices. Information supplied by the manufacturer with medical devices EN 980 - Graphical symbols for use in the labelling of medical devices. ISO 15223-1 - Medical Devices Symbols to be used with medical devices labels, labelling and information to be supplied. Part 1: General requirements
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ISO 14971 - Medical Devices - Application of risk analysis management to medical devices. EN 556-1 Sterilization of medical devices - Requirements for medical devices to be labelled "Sterile" Part 1: Requirement for terminally sterilized medical devices. 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/TS 11135-2 - Sterilization of health care products -- Ethylene oxide -- Part 2: Guidance on the application of ISO 11135-1 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 11737-1 - Sterilization of medical devices. Microbiological methods. Part 1: Determination of a population of microorganisms on products. ISO 11737-2 - Sterilization of medical devices. Microbiological methods - Part 2: Test of sterility performed in the validation of a sterile process. 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 11138-1 - Sterilization of health care products Biological indicators General requirements ISO 11138-2 - Sterilization of health care products Biological indicators Biological indicators for ethylene oxide sterilization processes ISO 14161 - Sterilization of health care products - Biological indicators - Guidance for the selection, use and interpretation of results EN 1422 - Sterilizers for medical purposes Ethylene oxide sterilizers Requirements and test methods UNI EN 22206 - Complete, filled transport packages - identification of the various parts for tests. UNI EN 22233 - Complete, filled transport packages - Conditioning for execution of tests. UNI EN 22248 - Complete, filled transport packages - Vertical impact test by dropping. ISO 11607-1 - Packaging for terminally sterilized medical devices Part 1: Requirements for materials, sterile barrier systems and packaging systems EN 868-3 - Packaging materials and system for medical devices which are to be sterilized. Part 3: Paper for use in the manufacture of paper bags and in the manufacture of pouches and reels Requirements and test methods EN 868-4 - Packaging materials and system for medical devices which are to be sterilized. Part 4: Paper bags - Requirements and test methods EN 868-5 - Packaging materials and system for medical devices which are to be sterilized. Part 5: Heat and self-sealable pouches and reel material of paper and plastic film construction requirements and test methods EN 868-6 - Packaging materials and system for medical devices which are to be sterilized. Part 6: Paper for the manufacture of packs for medical use for sterilization by ethylene oxide or irradiation Requirements and test methods.

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