WHITE PAPER September 2018

Transcription

1 WHITE PAPER September 2018 Medical Device Package Testing Case Study The Importance of Thorough Package Performance Evaluation to Support Compliance with the New Medical Device Regulations (MDR) Study Phase 1 Definition and analysis of the sealing window for different sterile packaging material configurations Authors: Nicole Kaller, Application Development Leader EMEA, and Laetitia Clerc, EMEA Regional Market Manager, DuPont Medical and Pharmaceutical Protection Background Revision of EN ISO Packaging for terminally sterilized medical devices, the guiding standard for medical device packaging, is ongoing. The Draft International Standard (DIS) document was balloted in 2017 and is progressing toward completion by the end of Revisions were made specifically to support compliance with the new EU Medical Device Regulations (MDR) emphasizing sterile packaging validations with a few new key requirements. For example, ISO/FDIS supports the general safety and performance requirement (GSPR) of the new MDR, stating that Devices shall be designed, manufactured and packaged in such a way that their characteristics and performance during their intended use are not adversely affected during transport and storage, for example, through fluctuations of temperature and humidity, taking account of the instructions and information provided by the manufacturer. The MDR insists on the point that maintenance of sterility shall be ensured until that packaging is damaged or opened at the point of use while it shall be ensured that the integrity of that packaging is clearly evident to the final user. To achieve this, the MDR requires sterile devices to be packaged by an appropriate validated method. ISO/FDIS considers packaging systems as validated when they meet the requirements of design, usability, performance testing, and stability testing and when they are produced by a validated packaging process. The MDR also contains a requirement to include validation reports, with respect to packaging and maintenance of sterility, into the technical documentation that will be reviewed by notified bodies in the frame of quality management system audits. Making a thoughtful selection of qualified materials and focusing on appropriate packaging designs are crucial steps to help maintain sterility of medical devices until the point of use and to support the regulatory compliance process in light of the new requirements of the MDR and the revised EN ISO In addition to more stringent requirements from the regulatory side, rising cost pressures and increasing cost-cutting measures continue to challenge the healthcare industry. The optimal balance between risk management, in terms of safe package performance, and economic efficiency is the key. Therefore, current and alternative medical packaging solutions are being evaluated to best meet this balance. Based on this need, DuPont developed Tyvek 40L for protecting lightweight, lower-risk and lower-cost devices.

2 All in a clean peel, low particulate generating material that is compatible with ethylene oxide (EO) and radiation sterilization modalities. The addition of DuPont Tyvek 40L to the family of Tyvek styles for medical packaging provides an economical and robust Tyvek option for applications where medical-grade papers are used and not always meeting the performance requirements. Overview A comprehensive study was conducted to evaluate the performance of flexible form-fill-seal (FFS) blisters made with either Tyvek 2FS, the new Tyvek 40L or one of two commonly used medical-grade papers (Reinforced Medical-Grade Paper >80g or Direct Seal Medical-Grade Paper 60g). A total of approximately 2,800 packages were tested in two study phases. The purpose of Study Phase 1 was to define the sealing process window of the blister seals and perform an evaluation of the seal performance prior to sterilization. This analysis was performed by Steripac GmbH, an independent contract packing service provider based in Germany. This white paper covers Study Phase 1. During Study Phase 2, which will be covered in a separate white paper, the blisters were subjected to visual inspection, seal integrity evaluation (dye penetration and bubble leak testing) and seal strength testing. Package testing was performed pre- and poststerilization (EO and Gamma) and post environmental conditioning (considering standard and wet conditions that may occur during transport) with subsequent transportation testing (shipper and pallet testing). Puncture strength on the material itself has been evaluated post the same environments. All testing for Study Phase 2 was conducted according to recognized standards listed in ISO by Anecto Ltd., an independent accredited laboratory based in Ireland. Statistical methods have been applied for the definition of an appropriate sample size. Executive Summary Study Phase 1 The sealing process window range and the optimal process parameters for producing the four seals were successfully defined for all four blister material combinations. All four material combinations met the specified requirements with some differences in seal strength performance. Most material combinations (Tyvek 2FS, Reinforced Medical-Grade Paper >80g, Direct Seal Medical-Grade Paper 60g) had a sealing window around 15 C. For Tyvek 40L, a sealing process window of 10 C has been selected to ensure optimal peel performance. In general, much less sealing temperature was needed for both Tyvek material combinations when comparing to the medical-grade papers at the same dwell time. Seal strength was very low on the Direct Seal Medical-Grade Paper 60g blisters at all sealing conditions (minimum, nominal, maximum). The highest seal strength could be achieved with the two Tyvek blisters. Seal strength variability between the different seal sides tended to be high on Reinforced Medical-Grade Paper >80g blisters. A normal peel behavior has been observed with all the blister material combinations when produced within the defined sealing conditions. During the sealing window definition process, it has been found that Direct Seal Medical-Grade Paper 60g has the tendency to tear more easily compared to the other materials. 2

3 Scope of Study Phase 1 For the study, four different material combinations were used to produce flexible blisters on a FFS machine. For DuPont Tyvek as the top web material, the styles with the lowest basis weight used in medical packaging (Tyvek 2FS and Tyvek 40L) were selected. Tyvek 2FS, with a basis weight of ca g/m 2, is ideal for FFS applications, smaller medical devices and those with rounded edges. Tyvek 40L, with a basis weight of ca. 41 g/m 2, is a cost-effective option for lightweight, lowerrisk medical devices that was recently added to the Tyvek portfolio for sterile packaging applications. In addition to Tyvek 2FS and Tyvek 40L, two medicalgrade papers commonly used for the same type of devices were selected for the top web material one low basis weight and one higher basis weight; one coated and one uncoated version Reinforced Medical-Grade Paper >80g and Direct Seal Medical-Grade Paper 60g. For each of the top web materials, appropriate PA/PE forming films were selected in consultation with Steripac GmbH, the contract packing service provider. To allow for peelability, the film has an integrated peel layer to seal to uncoated Tyvek. See Table I for a list of materials used in this study. A blood transfusion device (lightweight, not very bulky with flexible as well as sharp-edged parts) was selected as the medical device to be packaged because this low-cost and high-volume device can realistically be expected to be packaged in flexible FFS blisters (see Figure 1). The blister dimension of filled packages was 180 x 130 x 20 mm (see Figure 2). Figure 1. Blood transfusion device. Table I. Materials Used in the Study Top Web Material Bottom Web Material DuPont Tyvek 40L DuPont Tyvek 2FS Reinforced Medical-Grade Paper >80g Direct Seal Medical-Grade Paper 60g PE/PA/PE 75 µm PA/PE 80 µm Figure 2. Sample blisters filled with the blood transfusion device. 3

4 Basics of Sealing Process and Seal Quality Evaluation Seals must be strong enough to withstand the rigors of sterilization, shipping, handling and storage, yet at the same time facilitate easy access for the end-user to open the sterile package using aseptic presentation techniques. Optimizing the heat-sealing process and consistently producing packages with the appropriate seal strength is of critical importance because it can have a direct impact on product efficacy and ultimately on patient safety. The resultant material bond and seal strength of a heat seal packaging process depends on several factors, including: sealing temperature; sealing dwell time; sealing pressure; characteristics of the materials (thickness/softness of the top and bottom web) and the sealant; the sealing machine; and even the test method used to measure the seal strength. The primary heat seal factors of temperature, time and pressure are interactive. A change or tweak in one factor typically requires a change or tweak in one or more of the other factors. A balance between time, temperature and pressure must be met to achieve the desired seal strength, seal integrity, visual seal transfer and desired opening behavior. It is recommended to optimize the heat sealing process using tools such as Design of Experiments (DOE) and/or the evaluation of heat seal curves, depending on the complexity of the process and parameters. The objective is to define a sealing (operating) window with validated minimum, nominal and maximum sealing conditions. This not only results in a heat sealing process that consistently produces acceptable seals, but also can optimize energy output, operational throughput and efficiencies. There are different test methods used for package quality evaluation. Following, are a few examples. The appropriate methods will be selected depending on the requirements of the application and package/material type. These and more test methods are listed in Annex B of ISO Packaging for terminally sterilized medical devices. For additional information, consult the ASTM F2097 Standard Guide for Design and Evaluation of Primary Flexible Packaging for Medical Products. Strength of package seals: ASTM F88 Standard Test Method for Seal Strength of Flexible Barrier Materials ASTM F1140 Standard Test Methods for Internal Pressurization Failure Resistance of Unrestrained Packages ASTM F2054 Standard Test Method for Burst Testing of Flexible Package Seals Using Internal Air Pressurization Within Restraining Plates Seal and package integrity: ASTM F1886 Standard Test Method for Determining Integrity of Seals for Medical Packaging by Visual Inspection ASTM F1929 Standard Test Method for Detecting Seal Leaks in Porous Medical Packaging by Dye Penetration ASTM F2096 Standard Test Method for Detecting Gross Leaks in Medical Packaging by Internal Pressurization (Bubble Test) ASTM F2228 Standard Test Method for Non- Destructive Detection of Leaks in Packaging Which Incorporates Porous Barrier Material by CO 2 Tracer Gas Method (Porous materials to be covered) ASTM F2338 Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method (Porous materials to be covered) ASTM F3004 Standard Test Method for Evaluation of Seal Quality and Integrity Using Airborne Ultrasound A well-defined testing strategy is the basis for the qualification of a safe and reliable sterile barrier system (SBS). 4

5 Sealing Process Window Definition and Seal Performance Evaluation The purpose of this exercise was to define the sealing window of the four seals for each blister material combination (see Table I) and to perform an evaluation of the seal performance. Seal performance was determined by assessing the sealing window, seal strength properties, visual attributes, peelability and seal integrity of non-filled blisters. Sealing process parameters: Temperature varied Time varied Pressure fixed Sealing window definition (Non-sterile) Seal strength (SOP* based on EN 868) Visual inspection (SOP* based on ASTM F1886) Peelability Dye test (SOP* based on ASTM F1929) * SOP Standard Operating Procedure used by Steripac GmbH. Figure 3. Overview of the testing that was conducted during Study Phase 1. An FFS Multivac Machine Type R700 was used to form the blisters and create the seals, with a defined speed of 5.5 cycles/min. It is important to note that the cut was going through the side seals during blister separation on this machine. An unsealed area is present at the top seal where the blister peel open starts. In general, it is recommended to design the tooling in such a way that an unsealed area of at least 1 mm resides between adjacent blisters, also known as a skirt. Such a skirt reduces the risk of fiber tear or delamination, especially with DuPont Tyvek. Figure 4. Blister sample production on the FFS machine at Steripac GmbH. 5

6 Defining Sealing Process Window Temperatures and dwell time were varied, while the pressure was set to 6 bar based on visual evaluation of the seals and the contract packing service provider s experience. The starting temperature was defined based on experience and recommendations on the datasheets for the selected materials. The temperature was then increased in steps of 5 C. At each temperature point, the dwell time was varied. Minimum settings were defined by measuring seal strength (maximum seal strength per measurement in N/15 mm) confirming that the values are above 1.5 N/15 mm and by visual evaluation of the seals (ensure complete seal transfer) and not higher than 9 N/15 mm (as per the SOP of the contract packing service provider). Evaluating Seal Performance Additional seal strength sampling to assess the overall seal performance was done on the four seals (A, B, C and D) of each blister material combination (see Figure 6). Three measurements were taken per each condition (minimum, nominal, maximum) and seal side. The maximum seal strength per measurement in N/15 mm was recorded and the average and standard deviation of all four seals (A, B, C and D) was calculated. The minimum seal strength to be obtained was defined as 1.5 N/15 mm according to the SOP of the contract packing service provider, which is based on DIN EN Next, all samples were evaluated for peelability, seal integrity and visual attributes. All four blister seals (A, B, C and D) were assessed. See Table II for testing details. Maximum settings were defined by measuring seal strength through visual attributes (no overheated or transparent seals) and peel behavior (easy peel without any material fiber tear or delamination). 15 mm Top web MD After defining the minimum and maximum parameters in terms of temperature and dwell time, the optimized process parameters (nominal settings) were set centrally within the defined sealing window. D 15 mm A B 15 mm Defect MIN NOM MAX Defect Spotty Seals but No Defect Glazed Seals and/or Slight Tear C 15 mm Figure 5. Schematic representation of a sealing process window. Seal strength testing for the sealing window definition has only been performed on one seal side (A); see Figure 6. Experience from the contract packing service provider and data for packaging materials used on a regular basis on this machine showed that the seal strength level comparing the four seals is expected to be similar. Figure 6. Seal strength sampling locations on the blister. 6

7 Table II. Defined Test Characteristics for Packaging Seal Evaluation at Steripac GmbH, the Contract Packing Service Provider Test Test Method Test Details/Notes Unit Acceptance Criteria Sample Size Seal strength SOP* based on DIN EN Annex D and ASTM F88 Test speed 200 mm/min Free tail (test method A) N/15 mm Measuring maximum load seal strength Reporting minimum, maximum, mean and standard deviation per seal side Minimum 1.5 N/15 mm Maximum 9 N/15 mm (based on DIN EN and on maximum load seal strength) 27 blisters of each material combination (9 per material sealing condition) Note that 4 separate samples were taken from the seals per blister = 36 measurement points per material and sealing condition; refer to Figure 6 for sampling locations Peelability Internal SOP* Manual opening of the pouches Peelability (Yes/no; fiber tear reported if any) Seal to be opened without difficulty (all yes); no fiber tear or material delamination 27 blisters of each material combination (9 per material and sealing condition) The following quality properties were considered: Visual inspection SOP* based on DIN EN ISO paragraph 5.3.2b Seal: Intact seal for a specified seal width 4 mm; no channels or open seals; continuous without interruptions; no transparency; no wrinkles, breaks, damages or pressure marks Pass/fail No fail 27 blisters of each material combination (9 per material and sealing condition) Material: no puncture or tear; no material delamination or separation; no discoloration Seal integrity SOP* based on ASTM F1929 Dye injected into the pouch, seals wetted for a minimum of 5 seconds and a maximum of 20 seconds; observed for evidence of leakage Pass/fail No fail 9 blisters of each material combination (3 per material and sealing condition) *SOP Standard Operating Procedure used by Steripac GmbH. 7

8 Study Phase 1 Results Sealing Process Window Definition The sealing window range and the optimal process parameters for producing the four seals were successfully defined for all four blister material combinations. Based on this study, it was found that the blisters made with DuPont Tyvek 2FS (starting at 105 C) and the two medical-grade papers (Reinforced Medical-Grade Paper >80g starting at 130 C and Direct Seal Medical-Grade Paper 60g at 150 C) had a sealing process window of 15 C and 1 sec. For the blister made with Tyvek 40L, a sealing process window of 10 C and 1 sec was defined (starting at 100 C), which is mainly due to the lightweight nature of the material. Refer to Table III and Figure 7 for details on the defined sealing process parameters and sealing process window. In general, much less sealing temperature was needed for both Tyvek material combinations when comparing at the same dwell time. Table III. Defined Sealing Process Parameters for All Four Blister Material Combinations Sealing Temperature ( C) Dwell Time (sec) Minimum Nominal Maximum Minimum Nominal Maximum Pressure (bar) # Cycles/ min DuPont Tyvek 40L DuPont Tyvek 2FS Reinforced Medical-Grade Paper >80g Direct Seal Medical-Grade Paper 60g Seal Performance Evaluation Seal Strength Tyvek 40L blister: The average nominal seal strength was in a normal range between N/15 mm and did show normal variability (maximal 0.43 N/15 mm at nominal sealing conditions). All tested blisters met the defined minimum seal strength requirements. Tyvek 2FS blister: The average nominal seal strength was in a normal range between N/15 mm and did show normal variability (maximal 0.54 N/15 mm at nominal sealing conditions). All tested blisters met the defined minimum seal strength requirements. Reinforced Medical-Grade Paper >80g blister: Nominal seal strength of seal A and seal B was on average lower than that of seal C and seal D (overall range between N/15 mm). The variability tended to be higher on the C and D seals compared to the A and B seals (especially when looking at all sealing conditions). The variability is most probably not linked to the machine because the same equipment and tool were used for all blister material combinations. There should also be no relation to the film because the same film was used for the Direct Seal Medical-Grade Paper 60g. All tested blisters met the defined minimum seal strength requirements. Direct Seal Medical-Grade Paper 60g blister: The average nominal seal strength was found to be very low between N/15 mm, becoming lower when approaching the minimum sealing conditions. Increasing temperature and dwell time did not have a significant influence on the seal strength level. Variability was normal (maximal 0.42 N/15 mm at nominal sealing conditions). Refer to Figure 8. 8

9 Interval Plot of Seal Strength (N/15 mm) 95% CI for the Mean 5 Sealing window 10 C 1s Sealing window 15 C 1s Sealing window 15 C 1s Sealing window 15 C 1s Seal Strength (N/15 mm) Minimum Seal Strength 1.5 N/15mm 0 SEALING CONDITIONS 0-Min 1-Nom 2-Max 0-Min 1-Nom 2-Max 0-Min 1-Nom 2-Max 0-Min 1-Nom 2-Max TOP WEB 1-DuPont Tyvek 40L 2-DuPont Tyvek 2FS 3-Reinforced Medical- Grade Paper >80g Individual standard deviations are used to calculate the intervals. 4-Direct Seal Medical- Grade Paper 60g Figure 7. Sealing process window per blister material combination. Data supplied by Steripac GmbH. Figure 8. Sealing strength per blister material combination, sealing condition and seal side. Data supplied by Steripac GmbH. 9

10 Seal Performance Evaluation Peelability, Seal Integrity Testing and Visual Inspection All four blister material combinations showed a normal peel performance when produced within the defined sealing conditions. During the sealing window definition process, it has been found that Direct Seal Medical- Grade Paper 60g has the tendency to tear more easily compared to the other materials. All samples of the four blister material combinations passed the dye penetration test, confirming the integrity of all seals (A, B, C and D). In addition, all blister samples passed the visual inspection. See Table IV for the summary of test results for seals produced under nominal conditions. Figure 9. Dye penetration testing on a blister made with DuPont Tyvek 40L. Figure 10. Visual evaluation on a blister made with DuPont Tyvek 40L. 10

11 Table IV. Reference Summary of Test Results from Study Phase 1 Seal Performance Evaluation at Nominal Conditions Test Materials Test DuPont Tyvek 40L DuPont Tyvek 2FS Reinforced Medical- Grade Paper >80g Direct Seal Medical- Grade Paper 60g Seal strength - Seal A* Mean: 3.06 Stdev: 0.44 Mean: 3.52 Stdev: 0.54 Mean: 2.92 Stdev: 0.18 Mean: 1.80 Stdev: 0.22 Seal strength - Seal B* Mean: 3.01 Stdev: 0.43 Mean: 3.74 Stdev: 0.35 Mean: 2.94 Stdev: 0.20 Mean: 1.84 Stdev: 0.18 Seal strength - Seal C* Mean: 2.81 Stdev: 0.31 Mean: 3.42 Stdev: 0.34 Mean: 4.67 Stdev: 0.70 Mean: 1.78 Stdev: 0.23 Seal strength - Seal D* Mean: 2.61 Stdev: 0.28 Mean: 3.47 Stdev: 0.39 Mean: 3.98 Stdev: 0.24 Mean: 1.88 Stdev: 0.42 Peelability Yes Yes Yes Yes Visual Inspection Pass Pass Pass Pass Seal integrity Pass Pass Pass Pass *In N/15 mm. Seals produced at nominal conditions. 11

12 Summary & Conclusions The sealing window range and the optimal process parameters for producing the four seals were successfully defined for all four blister material combinations. All four blister material combinations met the specified requirements with some differences in seal strength performance. Most material combinations (DuPont Tyvek 2FS, Reinforced Medical-Grade Paper >80g, Direct Seal Medical-Grade Paper 60g) had a sealing window around 15 C. For Tyvek 40L, a sealing process window of 10 C has been selected to ensure optimal peel performance. In general, much less sealing temperature was needed for both Tyvek material combinations when comparing at the same dwell time. Seal strength was very low on the Direct Seal Medical- Grade Paper 60g blisters at all sealing conditions (minimum, nominal, maximum). Seal strength variability was high with Reinforced Medical-Grade Paper >80g comparing different seal sides. Considering all sealing conditions, the highest seal strength could be achieved with the two Tyvek blisters. A normal peel behavior was observed with all blister material combinations when produced within the defined sealing conditions. During the sealing window definition process, it has been found that Direct Seal Medical-Grade Paper 60g has the tendency to tear more easily compared to the other materials. Next Steps In Study Phase 1 it could be demonstrated that: The sealing window range and nominal sealing conditions could be defined. All four blister material combinations met the specified requirements. Therefore, Study Phase 2 could be initiated: Production of blisters according to the defined nominal process parameters (from Study Phase 1) and filling with the selected transfusion device by the contract packing service provider, Steripac GmbH. Packing of the produced blisters in transport boxes compatible with the respective sterilization method. Shipment to the contract sterilizers for sterilization with either EO or Gamma radiation. Subsequent shipment to Anecto Ltd., an independent accredited laboratory based in Ireland, for Study Phase 2 testing. Testing by Anecto according to recognized standards listed in ISO Statistical methods have been applied for the definition of an appropriate sample size. A second white paper discussing Study Phase 2 will be published in the near future. If you have questions or need additional support with submission challenges, troubleshooting, analytical services, or packaging and regulatory compliance, contact your local DuPont representative or visit our website MedicalPackaging.DuPont.com. 12

13 Test Methods Standard / Reference Description ASTM D4169 Standard Practice for Performance Testing of Shipping Containers and Systems ASTM D4332 Standard Practice for Conditioning Containers, Packages, or Packaging Components for Testing ASTM D4728 Standard Test Method for Random Vibration Testing of Shipping Containers Method A ASTM D5276 Standard Test Method for Drop Test of Loaded Containers by Free Fall ASTM D6055 Standard Test Methods for Mechanical Handling of Unitized Loads and Large Shipping Cases and Crates Method A ASTM D6179 Standard Test Methods for Rough Handling of Unitized Loads and Large Shipping Cases and Crates ASTM D6344 Standard Test Method for Concentrated Impacts to Transport Packages ASTM D642 Standard Test Method for Determining Compressive Resistance of Shipping Containers, Components, and Unit Loads ASTM D6653 Standard Test Methods for Determining the Effects of High Altitude on Packaging Systems by Vacuum Method ASTM D880 Standard Test Method for Impact Testing for Shipping Containers and Systems ASTM D999 Standard Methods for Vibration Testing of Shipping Containers Method A1 ASTM F1306 Standard Test Method for Slow Rate Penetration Resistance of Flexible Barrier Films ASTM F1886 Standard Test Method for Determining Integrity of Seals for Medical Packaging by Visual Inspection ASTM F1929 Standard Test Method for Detecting Seal Leaks in Porous Medical Packaging by Dye Penetration ASTM F2054 Standard Test Methods for Internal Pressurization Failure Resistance of Unrestrained Packages ASTM F2096 Standard Test Method for Detecting Gross Leaks in Medical Packaging by Internal Pressurization (Bubble Test) ASTM F88/F88M Standard Test Method for Seal Strength of Flexible Barrier Materials DIN EN Appendix D: Packaging materials and systems for medical devices that are to be sterilized ISO 2233 Packaging Complete, filled transport packages and unit loads Conditioning for testing ISTA 2A Simulation test for individual packaged-products less than 150 lbs 13

14 Guide to Some Common Industry Acronyms ASTM...American Society for Testing and Materials CEN...European Committee for Standardization DIN...Deutsches Institut für Normung (German standards organization) DIS...Draft International Standard DOE...Design of Experiments EN...European Norm EO...Ethylene Oxide FDA...Food and Drug Administration FFS...Form-Fill-Seal HDPE...High-Density Polyethylene ISO...International Organization for Standardization ISTA...International Safe Transit Association MD...Machine Direction MDD...Medical Device Directive MDM...Medical Device Manufacturer MDR...Medical Device Regulations PA...Polyamide PE...Polyethylene RH...Relative Humidity SBS...Sterile Barrier System SOP...Standard Operating Procedure SPM...Sterile Packaging Manufacturer STDEV...Standard Deviation UDI...Unique Device Identification References 1. Council and European Parliament, Regulation (Eu) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC, in 2017/745, 2017: Brussels. 2. International Organization for Standardization, ISO :2006/Amd 1:2014 Packaging for terminally sterilized medical devices Part 1: Requirements for materials, sterile barrier systems and packaging systems, 2014: Geneva. 3. International Organization for Standardization, ISO :2006/Amd 1:2014 Packaging for terminally sterilized medical devices Part 2: Validation requirements for forming, sealing and assembly processes, 2014: Geneva. 4. European Committee for Standardization, EN ISO :2017/Amd 1:2014 Packaging for terminally sterilized medical devices Part 1: Requirements for materials, sterile barrier systems and packaging systems, 2017: Brussels, Geneva. 5. European Committee for Standardization, EN ISO :2017/Amd 1:2014 Packaging for terminally sterilized medical devices Part 2: Validation requirements for forming, sealing and assembly processes, 2017: Brussels. 14

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16 This information is based upon technical data that DuPont believes to be reliable. It is subject to revision as additional knowledge and experience are gained. DuPont makes no guarantee of results and assumes no obligation or liability in connection with this information. It is intended for use by persons having technical skill for evaluation under their specific end-use conditions at their own discretion and risk. Since conditions of use are outside our control, DUPONT MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING WITHOUT LIMITATIONS, NO WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR USE AND ASSUMES NO LIABILITY IN CONNECTION WITH ANY USE OF THIS INFORMATION. This information is not intended as a license to operate under or a recommendation to infringe any trademark, patent or technical information of DuPont or others covering any material or its use. medicalpackaging.dupont.com medicalpackaging.dupont.co.uk Copyright 2018 DuPont. All rights reserved. The DuPont Oval Logo, DuPont, Tyvek and Tyvek 2FS are trademarks or registered trademarks of E.I. du Pont de Nemours and Company or its affiliates. (09/18)