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GENEESS Guideline

1. e Quantify test coverage and the probability of defective PBA slipping through for the test strategy chosen Adapt if necessary e Know and agree upon what is tested and not tested in functional tests e Apply Design for Repairability rules if required Allow for sufficient clearance between components EDM Guidelines e EDM D 007 Quality and Test Coverage Quantification Design for Test EDM Tools e Pred X imec 2015 www cedm be 39 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 8 6 Basic Design for Reliability rules The list below contains design rules related to the reliability of an assembled PBA for an active medical device This list is not exhaustive it contains however some basic rules These are guidelines and can be deviated from but only after careful consideration The guidelines and tool at the end of this section can be found at www cedm be 8 6 1 General e Reliability is not absolute Explicitly specify the operational conditions and the expected lifetime Temperature cycling range and frequency are critical to reliability The operating conditions are dependent on the intended use of the medical device e Acquire basic knowledge and understanding of PBA failure mechanisms Understanding these mechanisms is key to the definition of good test plans for the medical device e Perform a failure risk analysis of the PBA early in design Risk analysis is key for the evidence you n
2. MEE Part 1 10 General requirements for basic safety and essential performance Collateral Standard Requirements for the development IEC 60601 1 8 IEC 60601 1 9 of physiologic closed loop controllers IEC 60601 1 11 MEE Part 1 11 General requirements for basic safety and essential performance Collateral Standard Requirements for MEE and medical electrical systems used in the home healthcare environment IEC 60601 2 1 MEE Part 2 1 Particular requirements for the basic safety and essential performance of electron accelerators in the range 1 MeV to 50 MeV MEE Part 2 2 Particular requirements for the basic safety and essential performance of high frequency surgical equipment and high frequency surgical accessories therapy equipment defibrillators essential performance of ultrasonic physiotherapy equipment IEC 60601 2 6 MEE Part 2 Particular requirements for the safety of microwave therapy equipment ray equipment operating in the range 10 kV to 1 MV muscle stimulators therapy equipment ventilators Critical care ventilators performance of anaesthetic systems lIEC 60601 2 2 imec 2015 www cedm be 25 71 GENEESS Guideline Best Practices for Electronics in Medical Devices IEC 60601 2 16 MEE Part 2 16 Particular requirements for basic safety and iid essential performance of haemodialysis haemodiafiltration and haemofiltration equipment MEE Part 2 17 Particular requiremen
3. Human errors occur also during device usage a safe device can result in adverse effects when used wrongly by patients or caregivers A very clear user manual and device labelling is essential Take care of good translations of user manuals Test test test A lot of testing is involved during device development varying from extensive technical functionality tests and bio safety tests to clinical trials on human volunteers Start testing very early in the device development Perform tests on materials and components of your device on subsets of your device etc to shorten the time to market of the final device Perform tests as much as possible in a standardized way and keep track of all test results this information will be essential for a faster premarket approval process imec 2015 www cedm be 65 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 14 Medical devices to comply with hazardous substances restrictions As of July 22th 2014 the substance restrictions of the RoHS Directive are applicable to medical devices Medical devices have so far been exempt from RoHS which requires the elimination of lead cadmium mercury and other substances from electronics but they will now fall under the scope of ROHS Recast ROHS2 EU Directive 201 1 65 EU In vitro diagnostic medical devices will be required to comply with hazardous substances restrictions as of July 22th 2016 Only active implantable m
4. Therefore in specific cases more optimal solutions may exist Design specification takes precedence over this guideline The regulatory guidance in this document only covers the basics Choices need to be made depending on the intended use of the medical device imec 2015 www cedm be 6 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 3 Motivation Recently the medical market has attracted attention from research institutes and electronic device manufacturers This is not surprising over the last decades the reliability of electronic devices has improved drastically Together with the continuous trend for miniaturization and for reduced power consumption seen in the electronics industry electronic devices have become extremely suitable to solve medical issues Moreover based on the knowledge of IC fabrication scientists have learned to extrapolate these fabrication processes in order to build very small reliable sensors fluidic devices or devices with mechanical functions The MEMS and microfluidic industry has learned how to successfully merge Si based components with cheaper glass or polymer components At this moment conventional electronic chips can be combined with MEMS microfluidic chips or sensors opening the road for fabrication of medical devices able to sense interpret and even act Electronic engineers discover the medical world and medical scientists discover electronics New medical electron
5. replacement or modification of the anatomy or of a ohysiological process Acontrol of conception and which does not achieve its principal intended action in or on the human body by pharmacological immunological or metabolic means but which may be assisted in its function by such means As an example the distinction between a medical device and a customer gadget can be a thin line A heart rate monitor intended to be used during sport as an indication of performance of the training can be considered a gadget The same type of monitor intended to follow up on revalidation will be a medical device The intended use of the apparatus will make the difference Definition of parties Amanufacturer means the natural or legal person with responsibility for the design manufacture packaging and labelling of a device before it is placed on the market under his own name regardless of whether these operations are carried out by that person himself or on his behalf by a third party authorised representativedmeans any natural or legal person established in the Community who explicitly designated by the manufacturer acts and may be addressed by authorities and bodies in the Community instead of the manufacturer with regard to the latter s obligations under this Directive As you can see from above the term manufacturerdis not used as the party doing the physical production of the device but more like the product owner Company xyz who will pla
6. 11 Testing of electronic devices for medical applications Testing of a device for the consumer market differs in various aspects from the test protocols for a medical device First of all very extensive testing is crucial to ensure the bio safety and effectiveness of the device Secondly next to technical functionality tests an evaluation of the biological safety of the device should be performed which is an extensive task in case the device is in close contact with the human body during usage hence for wearable or implantable devices Finally due to the regulatory framework which exists in each country all these device tests should be performed following certain inter national approved practices and they should be reported in detail in order to get permission to bring the device on the medical market 11 1 Technical functionality and reliability tests When testing the technical functionality of a medical device one should start from well known test protocols for electronics for the consumer market A myriad of test standards and guidelines exists for electronic devices in general but most of these documents are not dedicated towards medical devices Hence often testing is performed by using test protocols developed for so called diigh reliability devices e g for automotive or space applications But the concept digh reliability devicedis strongly dependent on the intended use of a device hence testing of such devices too Tests
7. 20 subparts all describing a variety of test protocols and decision criteria part 3 till part 20 while part 2 discusses lab animals welfare requirements It is important to realize that ISO 10993 is not a strict set of tests with clear and binding pass fail criteria due to the very different nature and purpose of the various medical devices As explained already biocompatibility is a contextual concept material device requirements will differ substantially depending on the type of contact made with the human body the duration of this contact etc Hence testing for biological safety might be very different from device to device 5010993 part 1 elaborates on designing the correct test schedule for each type of device as is shown in table 11 1 copied from IS010993 part 1 A first and very important biological test performed on all devices materials used on in a human body are in vitro cytotoxicity tests described in ISO 10993 part 5 Also some other tests in 15010993 are based on in vitro cell culture testing In vitro tests are popular in order to limit animal testing to an absolute minimum Nevertheless the limitations of in vitro testing compared to real implant situations are important Regarding pharmacokinetics in vitro assays are usually very different from in vivo situations regarding exposure time metabolism tissue penetration clearance and extraction Regarding metabolism many non toxic substances become toxic after being metabo
8. Agentschap A Ondernemen Center for Electronics Design amp Manufacturing O Kapeldreef 75 B3001 Heverlee tel 32 16 281282 Electronics Design amp Manufacturing edm imec be www cedm be Comments corrections or suggestions can be send to Filip Ponsaerts Filip Ponsaerts imec be imec 2015 www cedm be 71 71
9. PBA aspects verify and adhere to specification Do not assume that rexpertsOdown the supply chain will make the appropriate choices for you Lack of specification leads to non quality non reliability uncontrolled supply product variability and finally unsatisfied customers e Approve qualify technologies PCB build ups components materials component PCB amp EMS suppliers Acknowledge that o Not all that exists components PCB and PBA technologies materials is also suitable to be used in a PBA for a medical device o PCB and EMS capability varies from supplier to supplier Be selective in choosing a PCB and EMS supplier and qualify the supplier o Critically evaluate all design choices including the validity of a reuse of previous design solutions e Always design for machine assembly and machine soldering Manual work leads to high assembly cost variable low quality and reliability risks This might compromise your CE marking e Adhere to design rules They are created to translate technological manufacturing quality reliability and other aspects of the PBA into tractable rules to facilitate efficient design of the physical PBA entity e Do not put all PBA realization compromises and complications at the manufacturing side Consider electrical circuitry adaptations to fulfil Design for X requirements e Assess PBA testability early in design prior to PCB layout Take care of Design for Testability DfT and Desig
10. are applicable for all electronic designs so also for active medical devices incorporating electronics The points below do no cover the complete range of DfX but give some basic design guidance for high level design deployable in the conceptual design phase It is a good Dfx practice reference for communication with customers and as such should be background knowledge for every manufacturer of active medical devices For more in depth information you can find guidelines at www cedm be 8 1 Important when designing a Printed Board Assembly PBA Although electronics have been around for more than half a century design and production is not that straightforward LetG look at why a manufacturer of an active medical device should pay attention to DfX e Besides the realization of an electronic function for a medical device a Printed Board Assembly PBA is a highly stressed both at manufacturing and in operation thermo mechanically and other complex physical piece of hardware which mandates proper Design for X to attain the required cost quality reliability and business objectives Remember intended use and safety e A PBA and its function will involve a level of complexity To support all the aspects of the PBA design realization and implementation the medical device manufacturer should invest in the appropriate amount of PCB Printed Circuit Board PBA technology knowledge for all parties involved in PCB PBA specification design
11. cost effective way The GENEESS Guideline is not an electrical nor product design guideline The GENEESS Guideline provides the designer and medical device manufacturer the boundary conditions of industrial electronic manufacturing technology basic operational reliability and regulatory requirements It is intended to support the development of cost effective reliable medical devices with a short time to market requiring a minimum number of design iterations Some of the characteristics of the GENEESS Guideline are e The GENEESS Guideline is oriented towards the device realization and medical device reliability aspects within the regulatory framework e The GENEESS Guideline refers to the PBA DfM Guidelines of cEDM www cedm be These guidelines do not replace industrial standards but define or recommend what options in the standards to use and will fill in gaps when appropriate The information is not exhaustive While every endeavor is made to ensure that the information is correct at the time of publication the legal position may change as a result of matters including new legislative developments new case law local implementation variations or other developments GENEESS Guideline Scope e The GENEESS Guideline is intended to be used for the realization of medical devices containing electronics e The GENEESS Guideline covers design and manufacturing of the electronic part of medical devices e The GENEESS Guideline includes basic e
12. essential not only to ensure the customer requirements are met and you will deliver a product with the required quality but also to ensure your medical device adheres to the regulatory requirements It will give the manufacturer some of the needed evidence for the technical file and declaration of conformity imec 2015 www cedm be 31 71 GENEESS Guideline Best Practices for Electronics in Medical Devices V amp V best practices Remove defects and problems as early in the project as possible Use peer reviews and inspections Test at different stages in the design module tests regression tests integration test Test plans are based on product definition and specification not on design and implementation Adjust product definitions specification and test plans as changes are approved by the stakeholders Review changes Use prototypes to pre validate the product A typical figure of the cost to remove a defect problem versus the phase in the project 100 DEFECTS COST TIME Requirements Design Implementation Test Release imec 2015 www cedm be GENEESS Guideline Best Practices for Electronics in Medical Devices 8 DfX guidelines In the field of electronics design exists the concept of Design for X to take into account the physical realization aspects of the PBA Printed Board Assembly like production methods operations environment failing mechanisms These
13. o Probability of occurrence PRO Fig 5 1 For each failure mode the risk is calculated as a combination of the probability of the failure occurrence and the severity of the failure consequence imec 2015 www cedm be 21 71 GENEESS Guideline Best Practices for Electronics in Medical Devices When calculating the risk for all possible failures several issues should be kept in mind For a smooth premarket approval of the device risks can only be accepted if they are low and if all measures are taken to reduce them hence even small risks have to be avoided when possible All failures have to be assessed include foreseeable misused in the risk analysis Take so called fuman factorsGnto account which behaviour of the user care taker patient can be foreseen What is Gtandard practiceGn a hospital setting or by a patient at home when using similar devices It might be that the new device under development has to be used in a different way compared to current similar devices but due to the care takers or patients habits misuse can be expected Be aware that one should not assume that all device users have read the user manual in great detail Describing in a user manual a possible risk device failure mode and how to avoid this failure is not sufficient to conclude that the risk of the failure is reduced significantly The same is true for labels placing labels on a device to avoid a failure can be very useful
14. published in 2005 The biggest upgrade in the 3 edition is that Clause 4 2 requires a manufacturer to have a formal risk management process in place which complies with ISO 14971 The next biggest change is the introduction of essential performance into the scope imec 2015 www cedm be 24 71 GENEESS Guideline Best Practices for Electronics in Medical Devices STANDARD TITLE IEC 60601 1 MEE Part 1 General Requirements for Basic Safety and Essential Performance IEC 60601 1 1 MEE Part 1 1 General requirements for safety Collateral standard Safety requirements for medical electrical systems MEE Part 1 2 General Requirements for Safety Collateral Standard Electromagnetic Compatibility Requirements and Tests IEC 60601 1 2 IEC 60601 1 3 MEE Part 1 3 General Requirements for Basic Safety and Essential Performance Collateral Standard Radiation Protection in Diagnostic X Ray Equipment Programmable electrical medical systems IEC 60601 1 6 MEE Part 1 6 General requirements for basic safety and essential performance Collateral standard Usability MEE Part 1 8 General requirements for basic safety and essential performance Collateral Standard General requirements tests and guidance for alarm systems in MEE and medical electrical systems MEE Part 1 9 General requirements for basic safety and essential performance Collateral Standard Requirements for environmentally conscious design IEC 60601 1 10
15. that the PBA out of the production facility is free of errors Several test techniques exists among them Boundary scan uses functionality if available inside ICG Automatic Optical Inspection an optical inspection of components and soldering Functional test testing the functions of a PBA in order to test some degree of components These are guidelines and can be deviated from but only after careful consideration The guidelines and tool at the end of this section can be found at www cedm be e Establish a test strategy based on PBA complexity production volume product value customer expectations troubleshooting efficiency e Make a distinction between testing to identify and repair manufacturing defects and Product Performance Verification e g on customer demand e Whenever possible provide test access to all electrical nets tracks interconnects preferably on a single PBA side using test pads and or vias with enlarged test lands e Provide boundary scan testability for PBA sections where test pads cannot be used e Automatic Optical Inspection AOI is not an alternative for providing electrical test access The test coverage of AOI for interconnection defects is too low e Functional test used as a manufacturing test must be oriented towards component testing and fill the test coverage gaps left over by the structural tests It is not a Product Performance Verification test aimed at product performance verification
16. the safety of an implant for a patient during an MRI procedure dedicated tests should be performed at specialized labs in case weak magnetic material or conductive material is present in the implanted device These tests will result in the appropriate device labelling Materials being non magnetic and non conductive are safe to use during all kind of MRI tests hence they are labelled as RI safed As explained above for certain implants an MRI test is only safe under dedicated conditions Such implants are labelled as d RI conditionald and conditions for safe MRI use should be indicated by the device manufacturer Regarding the labels RI safe and MRI conditionald one should realize that the meaning of these labels is redefined in 2005 ASTM F2503 The old label IR compatibledis confusing and should not be used anymore Valuable information regarding MRI safety can be found at the website of the Institute for Magnetic Resonance Safety Education and Research IMRSER www imrser org imec 2015 www cedm be 59 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 12 Avoid product certification testing failure This section lists some of the major product certification failures for medical devices When a product has to be reworked because it fails to conform to the standard it often results in costly delays By detecting these errors early in the design and manufacturing stages you can hel
17. to this regarding to exposure to thermal variation and vibrations the implant resides in a very easy environment in contrast with other high reliability electronics i e for space or automotive applications As a result a dedicated device package encapsulation needs to be used for electronic implants Also essential for a medical implant is the biostability of the encapsulation materials These materials should withstand their harsh bio environment for the total implantation period Materials should not degrade in order to perform their intended function without failure Note that in special cases dedicated degradable coatings are applied on the outer surface of an implant These coatings release a drug a growth factor upon degradation Such coatings are not biostable they exhibit a well controlled degradation process and the degradation products will not harm the host tissue imec 2015 www cedm be 43 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Even in case a fully biocompatible device is implanted severe adverse effects might occur due to the bioburden presence of bacteria of the device To avoid bacterial infections implantation procedures have to be performed by trained medical personnel using high level surgical procedures and the implanted device needs correct sterilization prior to its use and Hence the implantable system has to be developed such that common sterilization techniques can
18. Anti infection Therapies 2012 Expert Reviews Lid Various properties of the surface of the implant will strongly influence the risk of biofilm formation As a general rule one can state that an implant is less sensitive for biofilm attachment in case the local tissue cells have a strong affinity to attach and populate the implant surface Surface roughness used material and coatings presence of antimicrobial drugs or cell growth factors etc will influence the affinity of healthy cells versus bacteria to attach and proliferate on the implant imec 2015 www cedm be 47 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 9 4 Biocompatibility and other material properties related to material tissue interaction Biocompatibility is the ability of a material or device to perform with an appropriate host response in a specific application In practical words this means that a biomaterial does not evoke a toxic allergic or immunologic reaction it does not harm or destroy enzymes cells or tissue it does not cause thrombosis or tumours etc Note that biocompatibility is a contextual property it is always related with the intended use of the material device a certain material may perform well for a short time in close contact with the skin but may cause adverse effects after 24 hours implantation in muscle tissue The statement that biocompatible materials do not initiate a tissue body response or do not in
19. Bodiesd are private or public organizations accredited by the CA of an EU Member State to assess whether a product meets the MDD A device manufacturer will contact a Notified Body for premarket approval This Notified Body can be located in any EU country but it should be allowed to control the type of medical device under investigation since not all Notified Bodies are accredited for assessment of all types of devices Notified bodies shall be authorized to carry out inspections of manufacturers during the premarket approval process as well as after market introduction post market surveillance Device manufacturers must provide the inspectors with all relevant information upon request While device manufacturers in the USA should interact with the FDA in order to perform the control approval process as correctly and efficiently as possible manufacturers are not allowed to interact regularly with the Notified Body to discuss the approval process Also in Europe risk classes exist for medical devices the classification differs slightly from that in the USA The European classification depends on the duration of body contact invasive character use of an energy source etc MIEDDEV 2 4 1 Rev 9 Classification of Medical devicesddescribes in detail this classification and its consequences regarding assessment of conformity with the MDDs Class Is Im no risk to low risk devices with Is for devices requiring sterilization and Im
20. Manufacturing rules The list below contains design rules that affect the manufacturability of a bare PCB for an active medical device A PCB constitutes of interconnected layers of conductive copper in the pattern needed for the tracks for interconnectivity separated by insulating layers The outer laminates will require a fiinisholayer to provide good soldering quality These are guidelines and can be deviated from but only after careful consideration The guidelines and tool at the end of this section can be found at www cedm be e Use only qualified PCB technologies and suppliers e Select the PCB laminate material in accordance to the number of soldering steps including repair and PBA lifetime See also DfA rules above e Select PCB finish to provide good soldering quality Give priority to interconnection reliability in PCB finish selection see EDM guideline below e Specify quality requirements IPC class IPC standards e Specify moisture handling requirements PC 1601 specification e Keep it simple Use conventional PCB interconnection solutions Use the simplest technology possible lower cost better quality higher reliability e Use only advanced PCB interconnection features based on sound quantitative evaluation of their superiority over conventional solutions e Use the largest possible minimal track widths track spacing via land size and related features Lowest possible PCB density class e Only design PCB lay
21. O IMCC designing smart products Electronics Design amp Manufacturing GENEESS Guideline Best Practices for Electronics in Medical Devices May 2015 Contact Filip Ponsaerts Phone 32 16 283412 Mobile 32 474 921351 Filip Ponsaerts imec be IMEC Kapeldreef 75 B3001 Heverlee Copyright imec 2015 All rights reserved Only an authorized person is hereby permitted to view and use this document subject to the following conditions This document may be used for informational purposes only Any copy of this document or portion thereof must include the copyright notice This information ts provided AS IS and without warranty of any kind express implied statutory or otherwise Imec shall not be liable for any actual direct indirect incidental or consequential damages arising out of the use performance or application of this document KROhD Permission is not granted for resale or commercial distribution or use of the document in whole or in part or by itself or incorporated in another work imec 2015 www cedm be 1 71 GENEESS Guideline Best Practices for Electronics in Medical Devices The GENEESS Guidelines principle The GENEESS Guideline is designed to provide all electronic medical device actors involved in design qualification industrialization and production practical guidelines to master the multi disciplinary hardware aspects of active medical device realization and operation in a
22. acorporeally induced lithotripsy IEC 60601 2 37 MEE Part 2 37 Particular requirements for the basic safety and essential performance of ultrasonic medical diagnostic and monitoring equipment MEE Part 2 39 Particular requirements for basic safety and essential performance of peritoneal dialysis equipment electromyographs and evoked response equipment IEC 60601 2 41 MEE Part 2 41 Particular requirements for the basic safety and essential performance of surgical luminaires and luminaires for diagnosis imec 2015 www cedm be 26 71 GENEESS Guideline Best Practices for Electronics in Medical Devices IEC 60601 2 43 MEE Part 2 43 Particular requirements for the basic safety and eres gears procedures MEE Part 2 44 Particular requirements for the basic safety and essential performance of X ray equipment for computed tomograph IEC 60601 2 45 MEE Part 2 45 Particular requirements for the safety of eres S e devices tables MEE Part 2 47 Particular requirements for the safety including essential performance of ambulatory electrocardiographic systems IEC 60601 2 49 MEE Part 2 49 Particular requirements for the safety of multifunction patient monitoring equipment essential performance of infant phototherapy equipment IEC 60601 2 51 MEE Part 2 51 Particular requirements for safety including essential eel performance of recording and analysing single channel and multichannel electro
23. acterial antimicrobial material the material reduces the risk on biofilm formation i e by active killing of bacteria i e by release of dedicated antibiotics or by promoting cell adhesion over bacteria adhesion Biodegradable or bio resolvable material material is not biostable when implanted Such materials are useful for drug delivery or in case the intended function has only to be fulfilled for a limited time after which degradation is an interesting alternative over explantation i e degradable sutures stents Bio mimetic material a material is bio mimetic if its shape texture composition mimics the tissue in which the material is implanted goal limit the foreign body reaction of the organism Cytotoxic material cells can survive in close proximity of the material Cytophobic material cells don want to adhere to the material although the material is not cytotoxic bio Sterile material a device should be sterile when implanted it should be free of unwanted living organisms such as bacteria or fungal spores Bioburden type and amount of bacteria present on a material or device Bio safety of a device 1 biocompatibility of the device or 2 a medical active device should function well dangerous defects of the device should be impossible Gafe failure moded Biofouling Biofouling or biological fouling is the accumulation of bacteria and other microorganisms on wetted surfaces A biofilm is the result of this biofoul
24. ality system requirements The responsibility for meeting these requirements and for having objective evidence of meeting these requirements may not be delegated even though the actual work may be delegated It is left to manufacturers to determine the necessity for or extent of some quality elements and to develop and implement specific procedures tailored to their particular processes and devices The QS regulation applies to finished device manufacturers who intend to commercially distribute medical devices A finished device is defined in 21 CFR 820 3 l as any device or accessory to any device that is suitable for use or capable of functioning whether or not it is packaged labeled or sterilized Certain components such as blood tubing and diagnostic x ray components are considered by FDA to be finished devices because they are accessories to finished devices A manufacturer of accessories is subject to the QS regulation Manufacturers of medical devices who want to sell their product in the US must meet the QSR regulations of FDA ISO 13485 is a global standard that is voluntary in the US The Food and Drug Administration enforces 21 CFR 820 21 CFR 820 is applicable to manufacturers of finished medical devices sold in the United States including imported products imec 2015 www cedm be 13 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 3 Approval in Europe Legislation has been establishe
25. arges the impedance of the electrodes making the electrodes less sensitive to small biopotential signals are requiring a higher power consumption when a voltage shock has to be delivered Various factors modulate this FBR the chemistry of the surface of the implant the morphology the porosity of the surface material the mechanical properties all have an influence on the FBR Currently a lot of researchers investigate these complex relations in order to reduce the FBR In general one can state that the more the implant material resembles the local tissue hence the more biomimetic the material is the milder the FBR vegetable material FB giant cell N fibrous encapsulation Fig 9 1 Subsequent phases of the Foreign Body Reaction source Castner D G and B D Ratner Biomedical surface science Foundations to frontiers Surface Science 2002 p 28 60 imec 2015 www cedm be 45 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Implantation Protein adsorption mm acute inflammation m 1 Surgeon implants biomaterial 2 The biomaterial adsorbs a 3 Cells neutrophils and layer of proteins macrophages interrogate the biomaterial t 1 hr to 1 day Frustrated tebe se gt fibrous encapsulation amp neovascularization acute inflammation 2 cells try to digest the imp iaj 4 Cells fuse to form giant cells 5 In response to the cytokines 6 The biomaterial is encapsu
26. atibility and biostability refer to the interaction between a medical device and the local tissue of the patient as well as his total physiological system In vitro cell culture tests as well as in vivo animal tests have to be performed to assure biological safety of the device 11 2 1 History and need for harmonization The first biocompatibility standard was the USP US Pharmacopeia class qualification a procedure needed to receive FDA approval for a medical device Only later in 1987 the Tripartite Agreement introduced the concept of biocompatibility testing being focused on type of contact between device and tissue Guidance Memo G87 1 In 1995 the FDA replaced the Tripartite Agreement by the Blue Book memorandum G95 1 adopting the ISO 10993 as standard for biocompatibility testing The applied ISO tests tend to be more stringent than the USP tests hence tests according to the ISO 10993 standard are requested by the FDA Although the ISO 10993 standard is currently accepted worldwide for the FDA extra testing is sometimes needed see table 11 1 Also for some domains in the Japanese medical market the required test procedures are slightly different from the ISO or USP tests 11 2 2 Current test standards for biocompatibility testing Information and recommendations about such total risk management process for medical devices can be found in ISO 14971 and in ISO 10993 part1 The ISO 10993 standard is a long document consisting of
27. be applied without any device damage In case the device is used many times after short contact with human tissue exposure to many sterilization cycles should be feasible 9 2 Wearable electronic devices Wearable medical devices are used close to the body but with less intense contact compared to an implanted device Nevertheless diffusion of moisture from the skin or ions through the skin occurs which might result in adverse effects A G mart contact lensd lens with electronics will be in close contact to eye fluid and diffusion of toxic components into the body might occur as well as leaking of fluid into the electronics A 6mart pill6 small swallowable device i e with camera to investigate stomach or intestines is not considered as an implant although intimate contact with body fluids will occur Hence biocompatibility biostability and hermeticity with regard to the intended use of all these devices are important issues and sterilization has to be performed prior to device usage Always device development optimization and testing has to be performed in view of the intended use of the device and taking into account its type duration and location of body contact in order to ensure proper device functionality and efficacy and user safety imec 2015 www cedm be 44 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 9 3 Natural bio response of the human body upon implantation of foreign material Befo
28. but is not sufficient as protection for the user Risks can be reduced significantly if failure detection is provided e g if an alarm is warning the device user when using the device wrongly or when the device can run a self test which warns the user that a device failure is present imec 2015 www cedm be 22 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 9 4 2 CAPA After performing a risk analysis actions have to be taken to reduce all risks as much as possible with most attention for the high risk failure modes Most device manufacturers employ a so called APA system6 CAPA corrective action preventive action as part of the QM system During the premarket phase Manage the quality of your design fabrication by questioning and improving quality in all relevant domains during the device realization Quality and reproducibility of raw materials components hence question the quality of your suppliers Control of own facility and equipment Reliability of own processes during fabrication sterilization packaging If sterilization and packaging is not performed in house question the actions of the relevant third parties Keep track of all fabrication processes and product batches by efficient and Geadable6 internal documents track records lf software is part of your medical product question the quality of the software development too Since the legal responsibilit
29. c device Such a Ti box is a well known and safe package for implants since the Ti shell is an excellent diffusion barrier and dedicated high temperature welding techniques are developed to ensure a hermetic closure of the Ti package In order to protect the electronic core during the high temperature welding this Ti box is often large compared to the conventionally packaged electronics inside Consequently during implantation a larger insertion wound is needed resulting in a more pronounced Foreign Body Reaction FBR and a higher infection biofilm risk upon implantation Also irritation and limited user comfort are more likely due to the strong mismatch between the soft body tissue and the rigid Ti box Also for specific applications a flexible and or stretchable device might be needed or local optical transparency might be essential obviously the traditional Ti box based package cannot provide such properties In the past ceramic materials have been used successfully as diffusion stopping encapsulation for electronic implants with the advantage that high welding temperatures resulting in larger implants are avoided However due to its brittleness a ceramic package is prone to cracks and breakage upon impact making this encapsulation approach less popular Recently Valtronics introduced a new implantable packaging approach based on glass 8 J M Anderson Annu Rev Mater Res Vol 23 pp 81 110 2001 G Kotzar M Freas e
30. call rate Lower overall cost e g assembly gt Monitor your suppliers amp subcontractors qualify audit Specifications changes technology Traceability Quality amp procedures gt Preventive risk management imec 2015 www cedm be Evaluate all changes also those out of direct control e g legislation supply 68 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Glossary AC Alternating Current the alternating flow of electric charge AIMD Active Implantable Medical Device AIMDD Active Implantable Medical Devices Directive 90 385 EEC AOI Automatic Optical Inspection ASTM American Society for Testing and Materials BGA Ball Grid Array package BOM Bill of Material components list C amp C Creepage and Clearance CAPA Corrective Action and Preventative Action CA Competent Authority CAF Conductive Anodic Filament CE Communaut Europ enne French for European Community cEDM center for Electronics Design and Manufacturing CDRH Center for Devices and Radiological Health cGMP Current good manufacturing practices CTE Coefficient of Thermal Expansion DC Direct Current the unidirectional flow of electric charge DfA Design for Assembly DfM Design for Manufacturing DfR Design for Reliability DfT Design for Testability DfX Design for X where X stands for different items like testability reliability cost etc EC European Community EDM Ele
31. cardiographs essential performance of medical beds essential performance of X ray equipment for radiography and radioscopy IEC 60601 3 1 MEE Part 3 1 Essential performance requirement for transcutaneous oxygen and carbon dioxide partial pressure monitoring equipment imec 2015 www cedm be 27 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 6 Project Management Best Practices Good project management supports good medical device practices It fits your QMS e g ISO 13485 and will support your technical documentation and evidence needed for CE marking Again the manufacturer is free to make his choices on what type or level of project management is used We recommend that the items below are taken into account 6 1 Design Control Processes and procedures have to be established to ensure high Q management and traceability of design from concept to finished product Project plan Design requirements Design specification Design Documentation Block diagram internal signals design choices schematics layout V amp V Test Specification criteria and acceptance levels V amp V Test reports Risk assessments FMEAG Hazard analysis Po Doo Do Do Do Do Design control will ensure all levels of requirements for your medical device are well thought about Essential requirements customer requirements patient safety and tested The risk assessments are key to support your evid
32. ce the device on the market under its name will be considered the rmanufacturera In many cases the actual manufacturing will be performed by a third party lf e g a Japanese company wants to sell a medical device on the Benelux market they will need an fauthorised representatived This is a person or company established within the Benelux imec 2015 www cedm be 15 71 GENEESS Guideline Best Practices for Electronics in Medical Devices The emphasis of the European legislation is placed onto the safety of the patient as well as the clinical condition In the MDD 93 42 EEC this is described as Mhe devices must be designed and manufactured in such way that when used under the conditions and for the purposes intended they will not compromise the clinical condition or the safety of patients or the safety and health of users or where applicable other persons provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and compatible with a high level of protection of health and safety o Risk management on health and safety illness and general is a major concern in the legislation Nor the patient nor the caregivers should be at unacceptable risks The manufacturer must provide evidence of the right compromise In each EU country a competent authority CA responsible for medical devices is appointed by the national government WNotified
33. coating at all e Evaluate tin whisker risks Specify acceptable component lead finishes and required tin whisker mitigation techniques and testing A tin whisker is tin thread of tin growing on the surface of tin containing material under specific conditions 4 CAF Conductive Anodic Filament is a conductive path semiconducting Cu2 OH s3Cl formed at the epoxy glass fiber interface under influence of moisture and electric fields which may create shorts between adjacent conductors especially closely spaced vias with a DC voltage bias imec 2015 www cedm be 41 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 8 6 5 BOM reliability Bill of Material Ensure use of the correct component grade Suppliers might have medical grade tests for specific components Use only qualified components and component suppliers Make sure that all component features are the same e g lead finish amp quality when using alternative components and suppliers Do not use highly moisture sensitive components Do not use components with an MSL value higher than 4 MSL 8 or lower is preferred this will impact your assembly process and might trigger failure modus during production Avoid the use of process sensitive components that deviate from the J STD 020 defined component soldering robustness requirements If process sensitive components are present specify assembly instructions Critically evaluate the process sensitivity
34. ctive electronic solution The development needed to introduce an electronic device successfully into the medical market differs strongly from the needs for consumer electronics Due to the large implications device failure can have in the medical world these devices need to be very safe and effective which should be considered from the very first phase of device development Special requirements exist for medical devices with close body contact such as biocompatibility sterilization and packaging of the device Furthermore the obligatory premarket approval process requires medical device testing for safety including biological evaluation and MRI safety Dedicated test protocols for medical devices are not always existing making correct and efficient testing a challenge In order to manufacture an electronic device successfully for the medical market profound risk analysis processes and oreventive corrective measures are essential during the whole lifecycle of the device starting at the early development stages and not finishing before a device is used with great satisfaction in the medical world Electronic engineers discover the medical world and medical scientists discover electronics a challenging marriage The market of active medical devices is highly regulated you have to adhere to these regulations The emphasis should be on designing manufacturing and distributing Gafe medical devices CE marking classification etc
35. ctronics Design and Manufacturing E E A European Economic Area market EF TA European Free Trade Association EMC Electromagnetic Compatibility EMS Electronics Manufacturing Services ENIG Electroless Nickel Immersion Gold surface plating ESD ElectroStatic Discharge ETO Ethylene Oxide EU European Union EUT Equipment Under Test FAGG AFMPS FAMHP Federal Agency for Medicines and Health Products FB Foreign Body FBR Foreign Body Reaction FDA Food and Drug Administration FMEA Failure Mode and Effect Analysis GENEESS rGEzonder door Nano Elektronica En Slimme Specialisatieg healthier by nanoelectronics and smart specialization GCP Good Clinical Practice GLP Good Laboratory Practice HDE Humanitarian Device exemption IC the Integrated Circuit the chip IDE Investigational Device Exemptions IEC International Electrotechnical Commission IMRSER Institute for Magnetic Resonance Safety Education and Research INEMI iNternational Electronics Manufacturing Initiative IPC Association Connecting Electronics Industries an international trade association for the printed board and electronics assembly industries ISO International Organization for Standardization IVDD In Vitro Diagnostic Directive 98 79 EC imec 2015 www cedm be 69 71 GENEESS Guideline Best Practices for Electronics in Medical Devices kGray Dose of gamma radiation LED Light Emitting Diode MD Medical Device MDD Medical Dev
36. d about the essential requirements a medical device must meet and this has been harmonised in a set of directives The technical specifications for products to meet essential requirements are laid down in harmonized standards A product manufacturer is free to follow these standards or any other specification of his choice However if a device manufacturer does deviate from harmonized standards justification is needed to the satisfaction of the notified body see later Products compliant with harmonized standards benefit from a presumption of conformitya Medical devices must meet the Essential Requirements are preferably assessed according to the harmonized standards and must achieve the specified performance levels The main directives applicable for medical devices status January 2014 e Active Implantable Medical Devices Directive AIMDD Directive 90 385 EEC covering active implantable medical devices modified by the directive 2007 47 CE e Medical Devices Directive MDD Directive 93 42 EEC covering medical devices modified by the directive 2007 47 CE e In Vitro Diagnostic Directive IVDD Directive 98 79 EC covering in vitro diagnostic medical devices e Directive 2000 70 EC covering medical devices incorporating stable derivate of human blood or human plasma Directive 2003 12 EC on the reclassification of breast implants e Directive 2003 32 EC covering medical devices utilizing tissues of animal origin e Directive 2007 47 CE amends Dir
37. e 12 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 2 1 Quality System Regulation Manufacturers must establish and follow quality systems to help ensure that their products consistently meet applicable requirements and specifications The quality systems for FDA regulated products food drugs biologics and devices are known as current good manufacturing practices CGMP 8 cGMP requirements for devices are listed in part 820 QSR 21 CFR part 820 Because the regulation must apply to so many different types of devices the regulation does not prescribe in detail how a manufacturer must produce a specific device Rather the regulation provides the framework that all manufacturers must follow by requiring that manufacturers develop and follow procedures and fill in the details that are appropriate to a given device according to the current state of the art manufacturing for that specific device Manufacturers should use good judgment when developing their quality system and apply those sections of the QS regulation that are applicable to their specific products and operations 21 CFR 820 5 of the QS regulation Operating within this flexibility it is the responsibility of each manufacturer to establish requirements for each type or family of devices that will result in devices that are safe and effective and to establish methods and procedures to design produce distribute etc devices that meet the qu
38. e a realistic schedule to complete them Involve the project team in estimating how long activities will take Set milestones which indicate critical dates during the project and write this into the project plan Get the key stakeholders to review and agree to the plan Although not essential for your medical device this will be essential to contro your cost and time to market 6 5 Communication Project plans are useless unless they have been communicated effectively to the project team All team members need to know their responsibilities Document product design and project decisions You will need this for later references defect and problem handling as well as device certification Technical file design history file Doing this during the project progress will save you a lot of problems and time Tracking and archiving your communication is part of your documentation for your medical device and might be reviewed by the Notified Body during audits CE marking and or ISO 13485 6 6 Tracking and Reporting Project Progress Once the project is underway you must monitor and compare the actual progress with the planned progress You will need progress reports from project team members You should record variations between the actual and planned cost schedule and scope You should report variations to your manager and key stakeholders and take corrective actions if variations get too large You can adjust the plan in many ways
39. e assembly of your electronics Use a specific component type only on one side of the PBA if the component count allows it Take care of BOM component assembly compatibility o Do not combine large heavy components and small high density component types on the same PBA If necessary use daughter PBA or separate PBA o Avoid components with extreme dimensions very small components error rates assembly compatibility and very large components coplanarity reliability Take care of BOM component compatibility with the soldering processes The maximum thermal load of a component and the metallurgy of the component leads are key design parameters regarding compatibility with respect to lead containing SnPb resp lead free soldering Take care of lead free soldering compatibility and via reliability of PCB Select and specify suitable PCB laminate material PCB laminate is one of the base materials of a PCB Design for machine assembly and machine soldering Provide fiducials component free areas and sufficient component clearance for automated processes Fiducials are ohysical markers needed for automated assembly Select PBA build up and assembly sequence early in design prior to layout In case of third parties for assembly of the electronics involve them early Minimize the number of component placement runs This is linked to the number of component types on your PBA and diversity of components Put everything on one side
40. e manufacturer s conformity to the Essential Requirements listed in the Directive e g MDD IVDD and AIMDD Typical assessment methods are e Inspection e g one batch e Quality assurance e Type examination e Design examination A notified body can issue CE certificates and ISO 13485 compliance quality system A notified body nominated in Belgium can next to assessments in Belgium also work for e g a device manufacturer in the UK as well as an Authorised Representative for an overseas manufacturer It is strictly forbidden by Authorities that Notified Bodies give consultancy to manufacturers due to conflict of interest Although Notified Bodies are not to deliver consultancy they are open for discussion and guidance They can in an early stage evaluate the choices a manufacturer makes This guidance will however never be a replacement for consultancy imec 2015 www cedm be 17 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 3 2 CE marking CE marking is a process in the EU region for several types of products put on the EU market For medical devices on the EU market CE marking is required by law The labelling of products with C indicates conformity with legislation For medical devices the CE marking states that the medical device meets EU essential requirements safety and performance These requirements have to be assessed before the medical device is being placed o
41. ective 90 385 EEC and Directive 93 42 EEC The directives are supplemented with medical devices guidelines MEDDEV These guidelines Apromote a common approach by manufacturers and notified bodies Aare intended for representatives of authorised authorities Commission Services notified bodies industry and other interested parties Athese guidelines are not legally binding Athe guidelines are subject to a regular updating process The directives and guidelines above provide the framework by which the manufacturer can make his choices The directives are applicable depending on the function of the device and the application of this device The guidelines are not legal documents but it is good practice and appreciated by notified bodies to follow their guidance imec 2015 www cedm be 14 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Definition of medical device according to MDD 93 42 EC Any instrument apparatus appliance software material or other article whether used alone or in combination including the software intended by its manufacturer to be used specifically for diagnostic and or therapeutic purposes and necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of Adiagnosis prevention monitoring treatment or alleviation of disease Adiagnosis monitoring treatment alleviation or compensation for an injury or handicap Ainvestigation
42. edical device FDA approval CE labelling etc is essential This procedure is difficult costly and time consuming hence in case of lack of experience in this approval procedure outsourcing should be looked at already in an early phase of device development Finally during device development a lot of testing is involved For tests in unknown areas such as biosafety tests for an electronic device manufacturer outsourcing is essential Look for certified labs for such tests in view of the later premarket approval process Obviously outsourced partners should be selected very carefully since the final responsibility of a medical device is with the manufacturer not with the subcontractors or suppliers But using the knowledge of an experienced partner will lead easier to success than trying something a device manufacturer is not familiar with 12 htto www tda gov downloads AboutF DA CentersOffices OfficeofMedicalProductsand I obacco CDR H CDRHTransparency UCM388442 pdf 13 Stephen Levy http Awww qmed com news medical device recalls growing slower pace industry imec 2015 www cedm be 64 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 13 3 Avoid most common failure modes When looking at device failures a lot of them can be categorized in a few failure modes resulting in the following advice Analyse very well the medical problem which should be solved by the device under development Too often contacts w
43. edical devices remain outside the scope of ROHS requirements for now Since the RoHS Recast Directive has come into action in 2011 ROHS is now a CE marking directive This means that if you manufacture an electrical electronic product device or equipment you can no longer CE mark in accordance with just the Medical Device Directive MDD or Machinery EMC or Low Voltage directive for that matter Compliance with the RoHS directive is required before you can place the CE mark on your product and this should be clear on your Declaration of Conformity Compliance with the requirements of the EU RoHS2 Directive requires manufacturers to adhere to the conformity assessment procedures presented in Annex II of EU Commission Decision No 768 2008 EC The manufacturer shall establish the technical documentation The documentation shall make it possible to assess the product s conformity to the relevant requirements and shall include an adequate analysis and assessment of the risk s The technical documentation shall specify the applicable requirements and cover as far as relevant for the assessment the design manufacture and operation of the producta Although there still are exemptions to the regulation under specific circumstances regardless of inclusion or exemption manufacturers must demonstrate that their equipment has been designed and manufactured in accordance with the requirements set out in ROHS prepare the required technical documentatio
44. eed carefully designed current pads to avoid heating during MRI just electrically insulating the implant from the patient will not be sufficient to avoid all risk on heating MRI specialists from their side will take all preventive measures to avoid long loops are formed by the body placement of insulation between arms legs imec 2015 www cedm be 58 71 GENEESS Guideline Best Practices for Electronics in Medical Devices and body For subcutaneous implanted devices which produce mild heating the patient can be covered locally with cold packs or wet bandages to absorb the heat generated during MRI tests Certain medical implants will stop functioning or will malfunction during MRI tests but they will not be damaged Such implants have to be switched off during MRI testing but they can be switched on again after the MRI procedure Other types of implanted device might be damaged during MRI and should not be switched on afterwards or no MRI procedure should be performed to safe the device Materials which are weakly magnetic will disturb the magnetic field during MRI tests hence artefacts imaging defects are generated which might result in unclear images making a diagnosis impossible Conductive loops carrying weak currents during MRI cause artefacts too In such cases MRI tests should not be performed since the tests will not deliver useful information to the medical specialists MRI safety labelling In order to assess
45. eed in the technical documentation to support the declaration of conformity Also the earlier you can take actions to lower risks the lower the time and resources involved e Provide sufficient margin Lifetime cannot be determined accurately e Always select lead free soldering compatible PCB laminates in case lead free soldered PBA Lead free soldering will involve higher solder temperatures 8 6 2 PBA subjected to strong thermal cycling As mentioned in 8 6 1 temperature cycling and frequency are critical to reliability The range and speed it cycles both in duty time as well as the rate of temperature change will trigger different failure modes in the electronics e Evaluate PCB via reliability Select PCB laminate adapt via design diameter and specify minimal plating thickness A via is the interconnect between at least two tracks or layers of copper in a PCB e Difference in coefficient of thermal expansion CTE between component and PCB is the main cause of interconnection failure solder conductive glue Thermal stress increases with the difference in CTE the temperature range and the maximum temperature component size and decreasing component stand off Therefore in medical devices subjected to large or high cycle count thermal cycling avoid o large ceramic and silicon WL CSP based components o large gt 4mm leadless components QFN o large TSOP with low CTE moulding compounds and or Alloy 42 lead frame
46. eeeeseeeseaseseueeseeessneesaees 40 of of ee e 2 ne ee ne nee ee ee a E E E 40 8 6 2 PBA subjected to strong thermal cycling cccccccsececeeeeeeeeceeeeseeeeeeeeseeeeseeeaes 40 8 6 3 Mechanically stressed PBA bending vibration and ShNOCK c 0cceeeeeeeees 41 8 6 4 Insulation reliability cece ececeeeceeeceeeeeeeeeseeeeseeesaeeeseueesaeeseusesaueeseeesueeseeesaes 41 8 6 5 BOM reliability Bill of Material ce eccccccceseeeeceeeeeseeeeseeeeeseeseseeeeeseeeesaeeees 42 Biocompatibility biostability and sterility issues for electronic GeVICES cceeeeeeeeee es 43 9 1 Implantable electronic GEVICES cccecccseeccseeceececeueeceeeceucecueeceeecsueesseessusessusensess 43 9 2 Wearable electronic GEVICES ccccccceccceececseeceececeuceceecsuceceueeseeecsuessaeessaeessusenaes 44 9 3 Natural bio response of the human body upon implantation of foreign material 45 9 4 Biocompatibility and other material properties related to material tissue interaction 48 imec 2015 www cedm be 4 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 9 5 Biocompatibility realized by dedicated encapsulation for implantable electronic AEVO oe ee re ee eee eee ee eee ee 50 10 Device cleaning sterilization and packaging of medical implants ccccsceeeeeeees 52 10 1 Development of Medical devices cccccceeccceeeeceeeceeeeceeeee
47. eeeseeeeseeeseeeseeesseesaeees 53 11 Testing of electronic devices for Medical applications ccecceeeeceeeeceeeceeeeseeeeseeeeaes 55 11 1 Technical functionality and reliability tests cc cececeeceeeeeeeeeeseeeeeeeseeeeseeeseeeees 55 11 2 Biocompatibility testing biological evaluation Of device ec eeeeeeeeeeeeeeteeeeeeeees 56 11 2 1 History and need for NArMONIZATION cecccseecceeeeceeceeeeseueeseuecseeeeeeeenseeeaees 56 11 2 2 Current test standards for biocompatibility testing ccceeceeseeeeeeeeeeeeeeenees 56 11 2 3 Note about the USP In Vivo Biological Reactivity Tests Class I VI Plastics SS eee ee ee ee ee ee 58 11 2 4 Tests regarding sterilization and sterile packaging ccccceseeeeeeeeeeeeneeeeneees 58 113 IIR GALS EIS GCS eniron ah a e ai a i eA a Eae 58 12 Avoid product certification testing failure ccccccccecccceeeceeeeceeeeeeeesaeeseeeeaeeseeseneeeeaes 60 t ENC TWU e E E E sequesnndsetecancess 60 12 2 Creepage and clearance distances cccseccceececeeeceeeeseeeeseeseeeeseeeeeeeeseeeeseeesaeess 60 12 3 MdiCator CO IONS ass oreespractscroeccicera se Satiseros diester cnenseieneareecaemmsmmatiencetndeceisenaseesaneanewosmeoaereeeeciine 61 12 4 VTANSIOMMETS and PSUS anessin Es 61 12 5 Wiring cross Sectional Ara ticumsaihuusiet rains inaia a kaanib 62 12 6 Colours OF ground earth WIES xeccsacd siccenssasccsnedetacencassinaenedeSaennsaneasnede
48. eennsansdexneds tens 62 12 7 How to avoid these failUres cccccccccceeeeeeeeceeeeeeeeseeeeseeeeeeeeseeeeseeeeseeeseeeeseeeseeeees 63 13 Development of safe and effective medical devices use other peopleG experience 64 13 1 Learn from the failures of others ec cccceccecceeeceeeeeeceeeseeceeeeeeseeeseesaeeaeesseeseeees 64 13 2 Use outsourced manufacturing for unknown process StEPS cceceeeeeeeeeeeeeeeee 64 13 3 Avoid most COMMON failure MOCES cccceccceececeeeceeeceeeeeaeeseeeeseeeeseeeseeeseeesaeeess 65 14 Medical devices to comply with hazardous substances restrictions cccceseeseeeeees 66 Ta OCU SIONS oaa E E E E E A E 67 Elo SSI EENE EE EE E E E E E E E EE A E EE E 69 imec 2015 www cedm be 5 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 1 Applicable Documents Interesting websites Official websites of national authorities regarding medical device safety http ec europa eu health medical devices index en htm http www fda gov MedicalDevices default htm htto www hc sc gc ca dhp mps md im activit fs fi meddevis matmedfd eng poh 2 Applicability of the GENEESS Guideline Best Practices e The recommendations given in the guideline are intended to help the user in making choices that improve the manufacturability reliability testability biocompatibility etc of the medical device These recommendations are of a generic nature
49. eeseessaeeseueeseeesueeseeesaeeegs 6 2 Applicability of the GENEESS Guideline Best PractiCes cccccceceeeeeeeeeeeeeeeeeeeeeeeeaees 6 On MOU QUOM e E E E EE E edema E 7 Ade NTO CIC Ollie soe raer E EE E EE E E N R 8 5 Approval process and the Medical Devices Directive cccccecceecceeeeeeseeeeeeteeeseeeeeseees 9 5 1 General approach of premarket approval processes cceecceeeceeeeeeeeeeeeeeeeeeeeeees 9 5 2 Premarket approval in the USA cccccccceececeeeceeeeaeeeeseeeeaeeeseeeeseeeseusesaueesaeessneeseees 11 5 2 1 Quality System REQUIATION ccserpinrarrospinep ranteen EEEN EEEREN e aS 13 SOAP OVIT EGONG sirsa iar E a E E 14 Ue No uod DOV erisia E E EER 17 Oo MAKIN eaer nE EE EES EE E SEE EESE OE OERE RSS 18 5 3 3 Quality Management System cccccecccccssececeeeeeceeeeesseeceesaeecesseeeeeseeeeeseaeeeeas 19 5 3 4 Technical documentation ccccccceeeeceeeceeeeseeeeseeecaeeseueeseeeseueesaeeseeeesaueeseeeaes 20 Oe WS GCG EE E A EE E A A E A E E E 20 5 4 Risk analysis and risk reduction by CAPA as part of quality management system 21 ie Ve FAIS NaI Ol E E A E E E E E A sealant 21 EENE O E a ee a T A A ee ee 23 5 5 The use of IEC 60601 1700 cece cccccceeeeeeeeeeseeeeseeeeeseeeeseeeeeseeeeseaeessaeeeseeeessaeeesaes 24 Project Management Best Practices ccccecccsecceeeeeeeceeeeeeeeeeeeeeeeeeeeeeeeeeeseeeseeeseeesaeees 28 Gite HOS SIC CC MMO ects napcacteceunaconnepertuce
50. en globally standardized to Green Yellow where the single yellow stripe constitutes 40 of the total surface We see many variations on this such as all yellow with a green stripe green with two yellow stripes and so on In general identification by green and yellow insulation must only be used for Protective earth conductors see sub clause 18 b Any insulation on conductors inside equipment which connect accessible metal parts or other protectively earthed parts with a protective function to the protective earth terminal These shall be identified by the colors green and yellow at least at the termination of the conductors Potential equalization conductors see sub clause 18 e Conductors connecting to either protective earth or functional earth should be green and yellow We often see incorrect colors being used for grounding purposes Green and yellow are distinctive and help prevent conductors from being placed in the wrong position Protective and functional earth are distinguished from each other by different markings see also Clause 18 imec 2015 www cedm be 62 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 12 7 How to avoid these failures Why do these errors happen in the first place Often design engineers do not have copies of the standard s they need to meet They tell us that they resign to the specificationdgiven to them by marketing or the edition or revision of the sta
51. en parts of the device Errors with creepage and clearance distances will usually result in redesign and delays in getting to market Creepage and clearance distances are related to both working voltage peak and the required level of insulation In essence when the working voltage increases the distance between conductors of circuits must also increase to prevent currents flowing over the surface of insulation creepage or between circuits through air clearance 11 Intertek testing services March 2012 imec 2015 www cedm be 60 71 GENEESS Guideline Best Practices for Electronics in Medical Devices EMC and C amp C problems normally require significant redesign It is not difficult to achieve the correct C amp C distances dielectric withstand and insulation type The five fundamental reasons for errors are as follows The definition of the type of circuit was not understood This typically occurs where the working voltage has been incorrectly defined by the manufacturer during the design phase The type of insulation that was needed was not understood The component was not evaluated prior to designing it into the equipment The differences between Information Technology Equipment and Medical Equipment Standards were not understood The standard was not available when designing the equipment gt Pope be 12 3 Indicator colours Despite IEC 60601 1 clearly stating that the colour red on equipment is for exclusive u
52. ence needed for CE marking the medical device 6 2 Define the Scope and Objectives Understand the project objectives Making decisions on the real objectives will help you to plan the project The scope defines the boundary of the project deciding what s in or out of scope will determine the amount of work which needs to be performed Understand who the stakeholders are what they expect to be delivered and enlist their support After defining the scope and objectives get the stakeholders to review and agree to them As for any product you have to make sure your medical device will meet the intended use for the intended public 6 3 Define the Deliverables Define what will be delivered by the project Decide what tangible things will be delivered and document them in enough detail to enable someone else to produce them correctly and effectively Key stakeholders must review the definition of deliverables and must agree they accurately reflect what must be delivered imec 2015 www cedm be 28 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 6 4 Project Planning Planning requires that the project manager decides which people resources and budget are required to complete the project Define what activities are required to produce the deliverables using techniques such as Work Breakdown Structures Estimate the time and effort required for each activity dependencies between activities and decid
53. es before it can be sold This regulatory framework for market access is organized by each country i e by the FDA for the USA by Health Canada for Canada etc Since the 19906 all countries in Europe follow the same regulatory framework controlled by approved notified bodies in all EU countries International harmonization of the procedures for market approval essential for efficient development and market introduction of medical devices is also seen in the global acceptance of various test standards such as the 15010993 standard for biocompatibility testing of medical devices After an approved device is introduced in the medical market a strict post market surveillance procedure is applied in many countries resulting in public information ranging from safety warnings and field alerts to device recalls when the device is not performing well regarding medical safety imec 2015 www cedm be 8 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 Approval process and the Medical Devices Directive 5 1 General approach of premarket approval processes User safety is crucial for all medical devices hence such a device needs approval from the local national authorities before it can be introduced to the medical market This regulatory framework for market access is organized by each country i e by the FDA for the USA by Health Canada for Canada etc This national approval process makes market introduction cos
54. est Practices for Electronics in Medical Devices 10 Device cleaning sterilization and packaging of medical implants A device for medical applications should not only be biocompatible in case it is in contact with the human body it should also be sterile prior to usage Hence after manufacturing severe device cleaning is required If the intended use of the device includes direct contact with a human body wearable or implantable device device cleaning is followed by sterilization and dedicated packaging to maintain the sterility during transport and storage For some sterilization techniques a dedicated package is used first followed by a sterilization process which is active through the package material This approach eliminates the risk of device contamination during a final packaging step In case sterilization of the device is essential all materials used in the device should allow at least one common sterilization technique The 3 most used types of sterilization and with well known effects interesting for smooth premarket approval are the following 1 Radiation based techniques Remark that exposing active electronics to radiation might be a challenge a Gamma radiation most common highest penetration b Electron beam radiation c X ray radiation 2 ETO sterilization Chemical treatment by ethylene oxide ETO a very toxic gas to which the device is exposed The treatment is performed at room temperature making this techni
55. for devices measuring a function No assessment by a Notified Body is required for class I marketing is allowed purely by self certification For class Is or Im devices self certification is not allowed Class lla Class llb Class Ill highest risk such as implants Obviously higher risk class devices need more rigorous device testing to get market approval and such devices will receive more attention during post market surveillance imec 2015 www cedm be 16 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 3 1 Notified body A notified body is a private organisation operating in a competitive market A medical device manufacturer is free in its choice of notified body for its regulatory compliance A notified body is nominated by a member state and can operate within the entire EU A notified body is also nominated based on designated requirements such as knowledge experience independence and resources to conduct the conformity assessments Most of the notified bodies are specialized in specific subjects for medical devices The notified bodies are monitored by a member state through a Competent Authority e g in Belgium FAGG AFMPS FAMHP Federal Agency for Medicines and Health Products The choice of a notified body can be based on locality specialisation and experience A Starting point can be http ec europa eu enterprise newapproach nando The notified body will assess th
56. for endurance towards harsh vibrations long term exposure to temperatures up to e g 400 C extensive thermal cycling tests are all rather useless for wearable or implantable devices Such devices need to be tested for temperature shock vibrations etc for a period corresponding to transport and storage of the device only Further testing should be performed taking into account the special environment of the device e g a chemically harsh wet environment with a rather constant temperature around 37 C for implants Furthermore accelerated testing to predict failures and the device lifetime is typically performed by testing under elevated temperature conditions This kind of tests is sometimes impossible or useless for medical devices since they contain materials polymers proteins which degrade at higher temperatures while these materials will serve their function perfectly at 37 C The need for more dedicated standard tests for electronic implants is clearly existing Some research groups spend severe efforts to address this gap The International Electronics Manufacturing Initiative INEMI is an R amp D consortium of 100 leading electronics manufacturers suppliers associations government agencies and universities INEMI roadmaps future technology requirements of the global electronics industry identifies and prioritizes technology and infrastructure gaps and helps eliminate those gaps through dedicated projects For the medical ma
57. hazards Nevertheless providing correct and especially complete answers is not straightforward First of all a manufacturer has to look for possible risks during all phases in the lifecycle of the medical device from design over development R amp D transfer to production manufacturing sterilization packaging storage up to post market use of the device including implantation and active use of the device till its end of life To get premarket approval for the device most attention will go to the post market phase but in order to develop an effective medical product for safe use later risk analysis starts during the very initial design phase already When performing a risk analysis one has to look for possible failures nazards but also for their probability PRO and the severity of the possible consequences effects SEC Hence for each failure the risk can be calculated as follows RiSK failure PRO failure x SEC failure For all non acceptable risks solutions have to be found to reduce the risk by avoiding the failure occurrence and or reducing the severity of the consequences In case risk analysis is only performed at the end of the R amp D phase or manufacturing phase risk reduction might require severe product redesign Hence it is of utmost important to start with a mossibledrisk analysis at a very early stage in the device development _ I Low risk YU Su S w DO High risk t 9 og gt 3 o a wv Va gt c 2
58. ic devices are constantly under development and a myriad of opportunities are still open since many medical conditions are still waiting for a well designed safe and effective electronic solution Nevertheless developing an electronic device for the consumer market the gaming world etc is very different from the developments needed to introduce an electronic device into the medical market successfully Due to the large implications device failure can have in the medical world these devices need to be very safe and effective and hence severe premarket and post market surveillance from national authorities is standard for medical devices In order to be successful in medical electronics device safety and effectivity should be considered from the very first phase of development Risk analysis and preventive corrective measures are part of the early development stages too This document has the goal to introduce the reader in the world of medical electronics by providing an introduction to the special requirements for medical devices such as biocompatibility sterilization and packaging of the device the obligatory premarket approval process risk analysis processes and medical device testing for safety including biological evaluation and MRI safety imec 2015 www cedm be 7 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 4 Introduction A medical device is a tool which is used in order to diagnose treat cure
59. ical device can involve a complex design The device will be stressed during its intended use yet has to comply with the essential requirements throughout its useful life Due to legislation and new technologies the manufacturing and failure mechanisms have changed significantly This can and will also impact medical device related items like field failures risk for device recalls patient safety etc It is obvious a Medical device manufacturer must pay attention to DIX imec 2015 www cedm be 34 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 8 2 Do s and donds of good DfX practice The doG and donds below are a list of quick and relatively easy wins to come to a reliable and manufacturable active medical device These are guidelines and can be deviated from but only after careful consideration e Provide sufficient room for the PBAG in the medical device assembly Avoid exotic PCB form factors and shapes or exotic PBA constructions to accommodate for insufficient PBA space e Keep the design simple to minimize cost and maximize quality and reliability Go for conventional PCB build ups and component packages Use only advanced high density interconnection technologies when mandatory and based on comprehensive quantitative argumentation e Diversity leads to increased costs and risks both in supply and in assembly Minimize the number of component types per PBA e Avoid ambiguity Specify all
60. ice R amp D Technical functionality gt Prototyping Reliability Lifetime testing gt Sterilization amp packaging if needed Animal testing following GLP rules gt Good Laboratory Practice Transfer to production Safety biosafety gt Production Efficacy ts Clinical trial depending on device risk class e Tests on people all volunteers e Investigation of efficacy and bio safety of device to get market approval e Test protocols based on GCP good clinical practice rules and controlled by a supervising ethics committee ice improvemen Low risk devices dev Approval process e The national competent authorities or authorized organizations FDA notified bodies investigate bio safety and effectiveness of device e Device manufacturer provides all relevant information D Market introduction D Postmarket safety monitoring e The national competent authorities or authorized organizations investigate bio safety by tracking of devices esp high risk class devices and by performing inspection at facilities of manufacture and or suppliers e Public reporting of adverse effects field alerts and device recalls Fig 10 1 Various phases of medical device develooment In other sections of this document various aspects of these development phases are discussed in more detail imec 2015 www cedm be 54 71 GENEESS Guideline Best Practices for Electronics in Medical Devices
61. ices Directive 93 42 EEC MDEG Medical Devices Expert Group The MDEG is a group of Member States industries and other stakeholders representatives for the implementation of the MD directives MEDDEV Commission Guideline relating to medical devices directives the MEDDEV aim at promoting a common approach by Member States manufacturers and Notified Bodies and are carefully drafted through a process of consultation with various interested parties MEE Medical Electrical Equipment MEMS Micro Electro Mechanical systems MRI Magnetic Resonance Imaging MSL Moisture Sensitivity Level part of the packaging and handling precautions for some semiconductors NiAu Nickel Gold PCB Printed Circuit Board PBA Printed Board Assembly a PCB with components mounted PMA Premarket Approval PMN Premarket Notification also called 510k PSU Power Supply Unit Q Quality QFN Quad Flat No leads package QM Quality Management QMS Quality Management System QS Quality System QSR Quality System Regulation R amp D Research and Development RF Radio Frequency RoHS Restriction of Hazardous Substances SMD Surface Mounted Device SnPb Tin lead solder Ti Titanium TSOP Thin Small Outline Package USP United States Pharmacopeia V amp V Verification and Validation WL CSP Wafer Level Chip Scale Package imec 2015 www cedm be 70 71 O GENEESS Guideline Best Practices for Electronics in Medical Devices af d mec
62. ill carry out an unannounced audit once every 3 years This will be at least one day with 2 auditors For this the manufacturer must keep the QMS and technical documentation up to date at all time As a principle of good practice the manufacturer will perform post market surveillance including post market clinical follow up written down plan and record of results and actively follow up on state of the art for its products Complaints and incidents are to be recorded and tracked in a CAPA system corrective and preventative actions and a recall plan has to be in place severe incident imec 2015 www cedm be 20 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 4 Risk analysis and risk reduction by CAPA as part of quality management system A device manufacturer has to invest in a good quality management QM system in order to ensure delivery of a safe and effective product It is not only essential to prove the safety and effectivity of a medical product in order to receive approval for introduction on the market a good QM system results also in a more efficient and hence cheaper device development since product redesign in a later phase of the development can be limited or even avoided 5 4 1 Risk analysis Good QM starts with risk analysis also called Failure Mode and Effect Analysis FMEA or product hazard analysis Simple questions have to be answered what can go wrong d0and How can we avoid these
63. industrialization qualification production purchasing quality control installation and related management e Low cost manufacturing mandates high yield manufacturing e g cost of scrap cost of field failures risk and cost of medical device recall e The impact of design on PBA yield cost quality and reliability is at least one order of magnitude larger than the impact of manufacturing e Treat Design for X aspects of a PBA at the same level of importance as its functionality A PBA design that does not meet functional requirements most likely will not create a profit A poorly manufacturable unreliable PBA design will create a loss e g cost of scrap cost of field failures risk and cost of medical device recall e Designing a PBA is more than PCB layout It also includes PCB quality material and process specification component BOM selection and specification assembly specification including materials process flow and boundary conditions 3 PBA Design for Manufacturing Guideline EDM D 000 Good Design for X Practice V1 0 July 2013 www cedm be imec 2015 www cedm be 33 71 GENEESS Guideline Best Practices for Electronics in Medical Devices e There are limits to what can be assembled and interconnected per unit of area of a PBA High density interconnection an advanced technique comes at the price of increased manufacturing cost and risks and reduced quality reliability and delivery performance due to additiona
64. ing of a device before it is placed on the market under his own name regardless of whether these operations are carried out by that person himself or on his behalf by a third partyd Hence the device manufacturer is also held responsible for device errors related to its suppliers such as a change in production of subcomponents a raw material change Moreover the manufacturer is even responsible for doreseeable misusedof his device so reducing the change of misuse by smart device design is important In spite of that not all misuse can be prevented and remaining foreseeable misuse should be considered during the product risk analysis of your medical device see section 5 4 1 Risk analysis 1 Article 1 2 i Directive 90 385 EEC as last amended by Directive 2007 47 EC Article 1 2 f Directive 93 42 EEC as last amended by Directive 2007 47 EC and Article 1 2 f Directive 98 79 EC on in vitro diagnostic medical devices as last amended by Directive Regulation EC No 1882 2003 imec 2015 www cedm be 9 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Device classification based on intended use and on risk Very important to obtain market approval and to carry out a correct product risk analysis is the definition of the intended use of a medical device Based on this intended use the device will belong to one of the following international harmonized categories of medical devices 1 Drugs 2 Devices f
65. ing process Anti fouling coatings are surface coatings applied to prevent biofouling imec 2015 www cedm be 49 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 9 5 Biocompatibility realized by dedicated encapsulation for implantable electronic devices As mentioned before the electronic core of an electronic device itself always contains materials which are not biocompatible such as copper Furthermore commercially available chip packages are not biocompatible as well as conventional PCB6G soldermasks glues It is impossible to replace all these materials with biocompatible alternative materials Hence biocompatibility of an electronic device for implantation needs to be realized by separating very well the device from the host This is realized by the device packaging or encapsulation which should give the required mechanical support but should also prevent diffusion of toxic materials from the electronic core into the human tissue as well as avoid any leaking of biofluid inside the device itself Due to these very special requirements for packaging an implantable system and due to the diversity of the implanted devices various dedicated packaging technologies are used or currently under development Implantable electronic devices such as pacemakers or cochlear implants are traditionally packaged in a rigid Titanium Ti box to ensure hermetic and biocompatible packaging of the microelectroni
66. ired due to very low risk of the device Nevertheless general controlsOare essential the device needs to be listed and registered it needs the correct labelling and it should be proven that Good Manufacturing Practices GMP are applied for fabrication of the device 4 Humanitarian Device exemption HDE approval for a device that is intended to benefit patients for a condition that affects fewer than 4000 individuals in the USA per year For such small patient groups the cost of a normal approval process would be too high the device manufacturer s R amp D costs could exceed its market returns The FDA approves also mvestigational device exemptionsGIDE submissions An IDE allows the manufacturer to use his investigational device in a clinical study to collect the required safety and effectiveness data fora PMA application or a 510 k submission to FDA For higher risk devices the IDE approval process is more complex The FDA has a website containing lots of information topics are well explained and all available for free In case a non American device manufacturer wants to get FDA approval he needs first to appoint a representative living in the USA This person should perform all FDA submissions communications etc The FDA will help a manufacturer with his approval file the FDA tries with the help of the manufacturer to check if a product is effective and safe and can be introduced into the medical market imec 2015 www cedm b
67. is not a free choice Choose and contact a Notified Body in an early stage Choose a gespecteddONotified Body as he is your partner for long time If you do not achieve a CE certificate for your active medical device you are not allowed to put devices on the EU market Even if a CE certificate is some days too late due to some administrative reason you will have to delay market introduction Keep your technical file documentation up to date In case of incorrect certification the company is responsible for its medical devices and the certification and as such is liable imec 2015 www cedm be 67 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Manage the complexity and focus on reliability of your medical devices and the electronics within e Design Control Know the relevant standards Establish good specifications and product definition Pay attention to project planning and management Perform risk assessment and FMEA Documentation Technical file design history file e Verification amp validation Verification and validation is a very important tool to get the right product right Review product definition specification and derived test plans as early as possible Keep documentation and test plans up to date changes Perform tests throughout the design phase module tests integration test e Design with attention for DfX Save on redesign Higher production yields Lower field
68. it is a medical device the classification of the device will show if a notified body is required in the CE marking process or not Annex IX of the MDD In case of a class product without measuring function no Notified Body is required the CE marking goes via self certification The different classifications possible for a medical device e class low risk class with measuring function class in a sterile condition class Ila medium low risk class Ilb medium high risk class III high risk imec 2015 www cedm be 18 71 GENEESS Guideline Best Practices for Electronics in Medical Devices For the Quality management System QMS see below A typical route with a QMS is to comply with ISO 13485 See also below Note this is not the same nor part of ISO 9001 After all verification certification and review activities needed for the CE process the manufacturer has to issue a declaration of conformity This underlines once more the liability of the manufacturer Although other parties are involved third parties for design and or manufacturing notified body consultants the manufacturer makes the sole decisions based on the evidence available to put the device on the market and declares its conformity When a notified body is involved the final CE label will have a number indicating the notified body 5 3 3 Quality Management System The medical device manufacturer must choose a conformity assessment procedu
69. ith the final device users are present during the initial device concept phase but they are lost during further device development These contacts are important regarding the knowledge of the human factors as well as to address correctly the medical needs Human factors are important Typical ways of performing a medical procedure typical habits in the medical world it is all important to prevent device and treatment failures A device manufacturer should invest in learning to know all stakeholders the patients the hospital wards the nurses and doctors etc and their standard work procedures Outsourcing of device manufacturing steps or testing Is crucial if a device manufacturer has no relevant experience Especially start ups with limited experience should look for outsourcing possibilities Contract manufacturers and suppliers should be selected very carefully since the national competent authorities will always consider the device manufacturer as responsible for his device If possible use contract manufacturers which have experience in the fabrication testing of similar medical devices Human errors remain an important concern Human errors are possible during device development manufacturing sterilization and packaging hence a good quality management system is essential with an efficient error tracking system in order to perform a correct root cause analysis followed by preventive actions after error detection
70. l process steps and processes used at their performance limits This needs to be acknowledged in the equipment design and when selecting high pin count and or small pitch component packages e PCB and PBA technologies have limited accuracy regarding dimensional and physical properties A good PBA design does not require better than 10 dimensional and physical property accuracy for the PCB e RoHS compliancy lead free and being lead free solderable are three different properties of electronic components and parts A lead free solderable component might still contain lead A ROHS compliant component might not be lead free solderable e A science based Design for Reliability approach is the only viable way to realize long product lifetimes with sufficient confidence under given use conditions rReliabilityOtesting at board module or system level cannot predict or guarantee the long lifetime requirement of professional electronics since o The multitude of failure mechanisms present in a PBA under test have different acceleration factors You will not find a magical accelerated test which will be able to cover all the different possible failures of electronics o The experience based extrapolation of environmental test results to real life conditions is obsolete due to the numerous material changes that have taken place in 21 century electronics Too much has changed in materials and methods in a short time span The electronics of an active med
71. lated and secrete pecten s signaling fibrobasts arrive and begin in an acellular collagenous bag agents cytokines SE synthesizing collagen Say A ood C e DAN t 1 day to 5 days Fig 9 2 result of Foreign body reaction after inhalation of vegetable material in lung a fibrous encapsulation is formed to insulate the foreign material The macrophages which fused to form foreign body FB giant cells are still visible Picture source www granuloma homestead com Infection upon implantation is a definitive risk associated with implants causing a lot of problems and costs related to extra medication longer hospitalization and ina considerable amount of cases total removal of the implant In spite of implant sterilization and stringent rules regarding prevention of infections in the operation room bacteria might enter the body during implantation White blood cells present in the implant area will try to clean up all debris and bacteria but when sufficient bacteria are present they might attach to the implant surface and form so called biofilms bacterial colonies covering the implant surface Such colonies are very difficult to destroy by antibiotics hence prevention is of utmost importance imec 2015 www cedm be GENEESS Guideline Best Practices for Electronics in Medical Devices Quorum sensing induction of disassembly factors Fig 9 3 development of a biofilm on a surface Source Expert Review
72. lements of Design for X Design for Test Design for Reliability Design for ROHS etc e The GENEESS Guideline includes basic elements of regulatory requirements for medical devices e The GENEESS Guideline includes basic elements of project management for medical devices e The GENEESS Guideline includes a basic overview of biocompatibility for medical devices imec 2015 www cedm be 2 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Acknowledgement Funding organizations Agentschap Ondernemen is acknowledged for funding the GENEESS project imec contributors Filip Ponsaerts Maaike Op de Beeck DSP Valley contributors Frederik Horemans imec 2015 www cedm be 3 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Table of Contents The GENEESS Guidelines principle ccccccccccseececeeeeseeeeeceeeeseeeeeseeeessaeeseeseeseueesseeeeas 2 GENEESS Guideline SCODC ccccccccccceececeeeeceeeeeceeeeceeeeeceeeeeseeeeseusesseeeeseueessueesseesesaees 2 PGKMOWIC OG CIN IM peta ccocnc ceaedencncssq E E ss egueesuencne E E EE 3 PUG Organizan S sesona E E E E E E 3 gatclegiere aiile 3 ocean mene ee ener en en mene re ere tre tre mete ret ere tr tts 3 DSP Valley contributors ccccccccseccsececeeeceececeuceceeeceucecsueeseeceussseessueessueeseeesuseneessags 3 1 Applicable Documents ccccccceecceeeece cece eeceeeeseeeseeeeseeeeseeeeee
73. lised by the liver and many substances that are toxic in vitro may be detoxified by liver enzymes imec 2015 www cedm be 56 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Regarding tissue response a toxic response in vitro may be measured by changes in cell survival or metabolism while the major problem in vivo may be a tissue response In view of both animal welfare and patient safety investigations are performed to test biological safety of materials devices on cell cultures using primary cells and on tissue cultures These tests are valid for premarket approval if their rationale is explained but they can not yet completely replace animal testing ie for implantable devices Medical Device Categorization by Contact Duration Initial Evaluation Tests Biological Effect Supplementary Evaluation Tests Fe t G a T A Limited 3 Mature of Body Contact lt 24 hours a amp 9 B Prolonged E G 24 hours 30 days gt 5 2 O S 2 o C Permanent 2 5 amp gt 30 days be B Category Contact oO Mn A o o o Skin B ad e ad C o a o o o a Surface Mucosal B m m m Device Membrane C o a a A o o o Breached cr Compromised B iai iai iai Surface c A o o o Blood Path B m m m Indirect C e e F A o o o External R EARRA Tissue Bone Dentin B Communicating Device CG o o o A o o o Circulating Blood B e e e o 0 o A o o f F Ti
74. lways ensure that circuits are protected with an overcurrent protection device of a suitable type and rating and where possible certified Thermal protection devices used in transformers must be Certified Components otherwise several weeks of additional testing will be required 6 Buy copies of the standards and extract the tables that apply to your product this saves a lot of time flipping backwards and forwards 7 Using the tables you extracted from the standards clearly define the required elements for compliance in the design specification This may sound simple but very few do this Those that do can save themselves thousands of dollars in rework 8 Produce an isolation diagram and discuss this with your test lab This will save you time and money when doing conformity assessment testing imec 2015 www cedm be 63 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 13 Development of safe and effective medical devices use other people s experience 13 1 Learn from the failures of others FDA s fMedical Device Recall Reportd published by CDRH s Office of Compliance shows that the total number of recalls almost doubled from FY 2003 to FY 2012 This increase in medical device recalls might suggest that recent medical devices are less safe but this is probably not the case First of all the medical device industry is growing and this growth is still faster than the increase in device recall
75. mpatibility issues deserve a lot of attention For passive devices consisting of only a few materials biocompatibility can be realized just by selecting the proper materials various materials are biocompatible hence they do not Cause an adverse reaction even when implanted in a human body during the intended usage period of the implant Noble metals such as gold or platinum are such materials as well as titanium which is used often for dental implants But also some polymers such as polyimide or parylene are biocompatible and biostable for a considerable period of time For electronic devices the situation is more complex The electronic core of the device itself contains always materials which are not biocompatible such as copper Furthermore commercially available chip packages are not biocompatible as well as conventional PCB soldermasks glues Hence diffusion of these toxic materials into the human tissue has to be prevented Up Moreover the electronic implant will function in a chemically aggressive wet environment with the specific chemistry of the local tissue depending on the implant site Leaking of body KS fluids into the electronic core of the device will result in device 7A failure and should be prevented too Hence an electronic tissue device needs to be isolated from the body and vice versa by encapsulation of the electronic implant using barrier materials with strong diffusion stopping power for fluids and ions Opposite
76. n and implement the internal production control procedures in line with the directive ROHS does not only impact your supply chain as your suppliers must provide ROHS compliant components and sub assemblies for which you need proof from your supplier It impacts your own procedures like procurement and logistics and most of all design and manufacturing With respect to the transition for products in case they currently are not ROHS compliant according to ROHS2 stocks of spare parts designed for these products placed on the market before July 22th 2014 can still be used for repair reuse refurbishment updating of functionalities and upgrading of capacity of medical devices Non RoHS spare parts and components for the above listed activities can be manufactured and sold after July 2014 but cannot be used on new RoHS compliant equipment You will need to have proper traceability in place to prove prior past July 2014 manufacturing and selling imec 2015 www cedm be 66 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 15 Conclusions Recently medical problems are addressed more and more by electronic devices Conventional electronic chips are combined with MEMS microfluidic chips or sensors resulting in medical devices able to sense interpret and even act A lot of medical electronic devices are currently under development while many medical conditions are still waiting for a well designed safe and effe
77. n Medical Devices 5 3 4 Technical documentation As part of the CE marking and the QMS the product manufacturer is required to maintain a set of technical documentation per product type In case of personalised product this might even be per product piece The technical documentation shall reflect the status of a medical device at a particular moment in time This documentation should at least contain the items below Device description and product specification d abellingd or draft labellingd Design and Manufacturing Information Essential Requirements Checklist Risk management file Verification and validation of the device Required declarations or proof if such a declaration is not possible Declaration of Conformity a ee eS 5 3 5 Life cycle The manufacturer is responsible for the product quality and safety throughout the complete lifetime of the device The manufacturer will manage the life cycle For the initial certification the manufacturer will arrange for a review of the technical documentation and certification audit by your Notified Body Depending on this review and audit the manufacturer can affix the CE mark or will need to resolve major and minor non compliance first Periodically and at least once a year surveillance audits will be carried out by the Notified Body Next to this the Notified Body will periodically re review the technical documentation at least once every 5 years The Notified body w
78. n for Repair requirements e Specify the operational profile of the PBA environment and power cycling Achieve product reliability by science based Design for Reliability DfR imec 2015 www cedm be 35 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 8 3 Basic Design for Assembly rules The list below contains design rules that affect the assembly of the electronics of an active medical device Most common soldering techniques are wave soldering a wave of hot liquid solder moving over the PCB and reflow soldering PCB goes through an oven liquefying solder paste Lead free soldering requires higher temperatures compared to lead containing SnPb soldering Prior to soldering the components are typically placed on the bare PCB with an automated placing machine These are guidelines and can be deviated from but only after careful consideration The guidelines and tool at the end of this section can be found at www cedm be Use approved qualified components The availability of components does not imply these are suitable for your assembly environment nor for the essential requirements of your medical device for that matter Select components that lead to low manufacturing error rates and that fulfil operational profile based reliability requirements for your medical device Limit the number of component types on PBA and per PBA side to reduce set up cost as well as supply and set up error risks at th
79. n the European Economic Area market E E A The intent of CE marking is to remove technical barriers to trade within the E E A and guarantee the free movement of safe and performing products within the E E A Specifically for medical devices the applicable region for CE marking is extended with the EFTA countries European Free Trade Association and Turkey It is a criminal offence to label a device with CE in case it does not fully comply with legislation The liability rests with the manufacturer A brief overview of the CE marking process 1 Identify the Directive s that are applicable 2 Choose the conformity assessment procedure 3 Identify any Harmonized European Standards applicable not mandatory but implies presumption of conformity 4 Determine if a Notified Body is required Ask a proposal for certification 5 Ensure to comply with all the Essential Requirements 6 Maintain the Technical Documentation for the medical device see below 7 Certification of the QMS and review of the Technical Documentation by the Notified Body if applicable 8 Declaration of Conformity and the supporting evidence 9 Check that no other purely national requirements exist 10 Affix CE marking on your product A first step in the CE marking process is to determine whether the product is a medical device according to the directives a listed in 3 1 This will be determined by the intended use of the product See above If
80. ndard they followed is out of date Pressure to cut costs and get to market faster also have their effects resulting in the selection of components that will not adequately integrate into a medical device One way to avoid these failures is to perform a full and detailed risk analysis of the intended use of the device including an EMC risk analysis based on the modes of operation Start the risk analysis before starting the design it will call up most hazards based on the intended use and the indications for use Redo the risk assessment at regular intervals to make sure your design is addressing the risks Designing your device using a risk based model usually means that the device will be compliant Here are some other simple steps you can take to improve your success rate 1 Seek assistance from qualified sources early in the design cycle For example call your test lab for a design review You will be able to see what is needed and keep that information for future products 2 Qualify the components you intend to use Do not take the salesmanG word for it 7 ask him to prove that the component is medically approved o 3 If you are using an autorouter for PCB layouts ensure that you have set the correct creepage and clearance values and do not accept the defaults Check the plots for errors before committing to production 4 Ensure that the wiring you use is the correct type and rating for the circuit it will be connecting to 5 A
81. nded for use in the diagnosis of disease or other conditions or in the cure mitigation treatment or prevention of disease in man or other animals or e intended to affect the structure or any function of the body of man or other animals and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes Classification procedures Code of Federal Regulations Title 21 part 860 usually known as 21 CFR 860 imec 2015 www cedm be 11 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Four types of premarket approval procedures exist 1 Premarket Approval PMA most rigid control for devices with higher safety risk takes max 180 days for final approval decision is the most expensive of the 4 approval methods 2 Premarket Notification also called 510k or 510 k reduced procedure for approval takes max 90 days for final approval decision and is cheaper than a full PMA a for devices with low to moderate safety risk Class and Il b for high risk devices Class Ill for which a Gubstantially equivalent6device is already approved by the FDA Substantial equivalence means that the new device is at least as safe and effective as the predicate 3 Exempt for certain devices of Class and Il no dedicated premarket approval is requ
82. of all passive components especially the lead free soldering compatibility maximum temperature and time above liquid Avoid highly ESD sensitive components Provide PBA on board ESD protection if necessary EDM Guidelines e EDM D 001 PCB Specification e EDM D 002 Component Specification e EDM D 003 PBA Assembly Material Specification e EDM I 001 Mechanical Integration EDM Tools e FMEA tool PBA failure risk assessment e Via lifetime calculator imec 2015 www cedm be 42 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 9 Biocompatibility biostability and sterility issues for electronic devices 9 1 Implantable electronic devices As mentioned already medical device safety is a crucial issue This results in special requirements for electronic devices which are used in close contact to the body as is certainly the case with implantable devices A human body is very different in nature from an electronic device Consisting merely out of water and containing many chemical components human bodies damage electronics when direct contact exists corrosion of electronics by body fluids will cause device failure On the other hand the human body will suffer from the presence of an electronic device too diffusion of toxic materials from the electronic device into body tissue will cause local or systemic adverse effects Since two very different worlds have to be combined the so called bioco
83. of the PBA if this can be achieved without entering the domain of high density assembly at least one soldering step less Exception If there are through hole components on top and SMD surface mounted components on the bottom wave soldering only the bottom layer is sufficient Do not place through hole components on both sides of the PBA This will make soldering extremely complex Exception press fit connectors imec 2015 www cedm be 36 71 GENEESS Guideline Best Practices for Electronics in Medical Devices e Cluster through hole components to facilitate selective soldering If selective soldering is needed restrict it to one location e Avoid wave soldering large numbers of SMD components Manufacturing error rate of wave soldering is ten times higher than that of reflow soldering for the same size of components e Use the correct footprint design Do not combine footprints to accommodate different component types sizes e Specify assembly requirements IPC class assembly materials process boundary conditions especially with process sensitive components cleaning EDM Guidelines e EDM D 001 PCB Specification e EDM D 002 Component Specification e EDM D 003 PBA Assembly Material Specification e EDM D 004 Design for Assembly EDM Tools e Pred X imec 2015 www cedm be 37 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 8 4 Basic Printed Circuit Board PCB Design for
84. on Technology equipment The leakage current may be acceptable but the isolation required from the mains to low voltage is usually lacking causing the manufacturer of the PSU to put a disclaimer in the use instructions or data sheet such as Not suitable for use with equipment having a direct patient connection o imec 2015 www cedm be 61 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 12 5 Wiring cross sectional area Somewhere in most medical devices the cross sectional area wiring insulated or printed wiring is too small for the circuit into which it is connected The same dimensions apply for Printed Circuit Boards PCBs which is frequently overlooked especially where outputs for power are provided AC or DC The wires coming off a connector on a PCB could be compliant but the traces to the female connector on the PCB are frequently undersized This means that the pins of the connector on the PCB and the traces connecting to the connector will heat up possibly resulting in an open circuit and failure to reliably perform as intended If the nominal voltage multiplied by current is 15 Watts or more this represents a fire risk 12 6 Colours of ground earth wires Manufacturers of large equipment with multiple earth connections grounding connections are frequently non compliant with Sub clause 6 5 which defines the colours for earth conductors The colours of ground wires for medical devices have be
85. ond underfill if all the above measures are insufficient Note this increases assembly cost Fixation has to be determined as early as possible preferably before final layout of the PCB 8 6 4 Insulation reliability Insulation is one of the top failures in medical device certification testing See chapter below creep and clearance To improve insulation handling and cleaning is key to avoid ionic contamination of the PCB and PBA of your medical device To avoid contamination during operation one can cover the device and or PBA On the PBA this can be done with a conformal coating e Specify acceptable solder materials flux classes e Do not cover via holes with solder mask to allow proper via cleaning if post solder mask cleaning is required in PCB manufacturing or assembly e Qualify PCB supplier w r t handling and cleaning e Qualify EMS supplier w r t handling and cleaning e Maximize electrical clearance between closely spaced copper features to maximize surface insulation resistance especially on PCB for outdoor applications and where DC voltages are present e Avoid DC voltages on closely spaced 1mm vias e g in BGA footprints to avoid CAF Select and specify CAF resistant PCB laminates if necessary e Use conformal coating if condensation or debris may create insulation failure risk Specify coating and cleaning requirements Note that conformal coatings with voids at the PCB surface are worse than having no
86. or medical application focus of this document 3 Biologics for medical application i e cells 4 Combination products combination of drug device en or biologics i e drug eluting stent drug device 1 e scaffold with stem cells device biologics For each of these categories the test procedures for market approval are different In this document we will focus only on the category evices6 Be aware that a device can be a hardware device only a software product only or a hardware device combined with software Devices are further classified based on their risk this classification is different between countries and defines the required risk assessment and test procedures As an example this risk classification and corresponding approval procedures for the USA and for Europe will be explained imec 2015 www cedm be 10 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 2 Premarket approval in the USA The CDRH Center for Devices and Radiological Health a subdivision of the FDA is controlling the medical devices approval for market introduction as well as post market surveillance Mission of the CDRH is to protect the health of the public by e ensuring market release of safe and effective medical devices e making sure that medical devices remain safe and effective e giving information and promoting the public health Based on their intended use and their risk all medical devices are categori
87. or prevent a medical condition or a tool used to improve the quality of life of people suffering from disabilities The diversity of such devices is enormous and still growing due to the innovativeness of the medical device industry Such devices range from small and simple tools such as a bandage or a thermometer to more complex and invasive devices as implantable pacemakers and highly complex large devices as MRI scanners Such devices can be used in a hospital setting or at home handled by trained medical personnel or by the patient himself or his relatives Some tools can function without human interference once installed implanted while others need permanent handling follow up by the caregiver or patient Medical devices can be passive hence no action is delivered i e a thermometer or active i e a pacemaker Due to the very nature of medical devices their use can have a strong impact on the health and quality of life of the user Each device should bring benefits to the patient and this without bringing the patient into unacceptable risks No matter what kind of medical device is under discussion the medical safety of the device is an unconditional demand For complex devices such as an electronic implant medical safety is one of the most important factors during the device development and production process To ensure user safety for all devices on the medical market a medical device needs approval from the local national authoriti
88. out features using boundary min max dimensions of the chosen density class where necessary Use more relaxed dimensions whenever possible to improve yield cost quality and reliability e Strictly obey layout design rules e Becritical about the need for controlled impedance tracks Advanced technique Use it with restraint Impedance requirements which require better than 10 accuracy exceed conventional PCB PBA technology capabilities e Ensure a good copper balancing Create a symmetrical PCB build up to avoid warpage e Use thermal relief to connect vias for through hole components to copper inner and outer planes e Use thermal relief to connect SMD pads to copper planes e Design the solder mask pattern according to appropriate design rules especially for solder mask defined pads and verify its implementation e Do not cover via holes with solder mask when subsequent PCB finishing is needed to allow proper via cleaning in PCB manufacturing EDM Guidelines e EDM D 001 PCB Specification e EDM D 005 Rigid PCB Build Up and Density Classification EDM Tools e PCB delamination and via lifetime calculator e PCB laminate overview imec 2015 www cedm be 38 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 8 5 Basic Design for Test rules The list below contains design rules that affect the testability of an assembled PBA for an active medical device Testing is needed to ensure verification and
89. p your device get to market on time and on budget This section lists the ten most common failures gives some explanation as to why they occur and offers tips on how to avoid them from the beginning Note All clause numbering used in section refers to IEC60601 1 unless otherwise indicated 12 1 EMC failure The most frequent source of problems for Electromagnetic Compatibility EMC is related to the Radio Frequency Emissions being broadcast by the Equipment Under Test EUT EMC is defined as The ability of an equipment or system to function satisfactorily in its electromagnetic environment without introducing intolerable electromagnetic disturbances to anything in that environment or being disturbed itself by an external influence in that environment The most common design errors causing EMC problems are Using generic components not specifically designed for medical devices Not making good metal to metal contact around enclosures Large holes in enclosures Using plastic enclosures around very moisyocircuits Ground wires that are too long and not large enough to be of a low impedance Electrostatic discharge ESD to membrane switches keyboards monitor bezels etc Jo J gt J gt J gt J gt oo 12 2 Creepage and clearance distances A large percentage of medical devices that are under evaluation have problems with creepage and clearance distances C amp C6 amp and or the insulation provided within the device or betwe
90. published by the International Electrotechnical Commission and consists of a general standard about 10 collateral standards and about 60 particular standards The general standard IEC 60601 1 Medical electrical equipment Part 1 General requirements for basic safety and essential performance contains general requirements They are further explored in the series of standards IEC60601 is a widely accepted benchmark for medical electrical equipment Compliance with the IEC 60601 1 International Standard and or the relevant national version does not equal to medical device approval However it is a step towards medical device approval IEC60601 1 may be overridden or bypassed by the standards for a particular product Collateral standards 60601 1 X define the requirements for certain aspects of safety and performance e g Electromagnetic Compatibility IEC 60601 1 2 or Protection for diagnostic use of X rays IEC 60601 1 3 Particular standards 60601 2 X define the requirements for specific products e g MR scanners IEC 60601 2 33 or Electroencephalograms IEC 60601 2 26 For example IEC 60601 1 9 for Environmentally Conscious Design of Medical Electrical Equipment is a collateral standard to IEC 60601 1 The Part 9 standard asks manufacturers of medical devices to consider the environmental impacts of their devices throughout the product s entire life cycle and to minimize these where possible The 3 edition of IEC 60601 1 was
91. que very suitable for most polymers Due to the high toxicity of ETO this technique is only performed by dedicated companies in service mode typically for devices needing only one sterilization treatment e g implants 3 Autoclave sterilization steam treatment at elevated temperature gt 100 C this technique is most used in hospitals for repetitive sterilization of medical tools Tools should withstand high temperatures Also under development are new alternative sterilization techniques such as treatment by hydrogen peroxide ozone nitrogen dioxide and supercritical carbon dioxide esp interesting for combinatorial devices e g devices coated with a protein containing material or a sensor loaded with proteins These techniques are gaining popularity but the rationale behind the use of these alternative techniques should be given during the premarket approval process Since sterilization and sterile packaging are very specific processes device manufacturers will often use a specialized company Subcontractor to perform these final process steps on their devices As afinal remark be aware that some medical devices are sterilized more than once Hence when the effect of sterilization on your device materials has to be tested consider all sterilization treatments as cumulative Example 3 times a gamma radiation of 20 kGray dose has the same effect as 1 radiation of 60 kKGray a dose which should be acceptable for all your device ma
92. re as described in the directive annexes II to VII of the MDD This choice can be influenced whether production will be high or low volume or whether the product will be designed personally for the patient The intent of a QMS is to demonstrate the ability to provide medical devices and related services that consistently meet the customer requirements as well as the regulatory medical devices requirements Furthermore the QMS helps to identify risks related to the process and the product and to control processes and interactions market feedback and supply chain processes Full Quality Assurance audits of the full QMS Annex III EC Type Examination type testing by the Notified Body Annex IV EC Verification batch or 100 testing by the Notified Body Production Quality Assurance audits of the QMS without design Annex VI Product Quality Assurance audits of the QMS without design and manufacture A quality management can be set up according to the harmonised standard EN ISO 13485 2012 Most organisations apply the ISO 13485 standard to achieve compliance Note that organisations that meet ISO 13485 requirements cannot claim conformity to ISO 9001 ISO 9001 is not covered by ISO 13485 and must be certified separately Although ISO 13485 is not a requirement in many cases it is considered good practice to set up a quality system in line with 13485 imec 2015 www cedm be 19 71 GENEESS Guideline Best Practices for Electronics i
93. re discussing packaging approaches for implanted medical devices to make an electronic device and a human body compatible with each other two major problematic issues related to device implantation need more explanation 1 the foreign body reaction FBR which is the natural reaction from tissue upon an implanted foreign material and 2 infection biofilm formation a risky complication which might occur after device implantation The Foreign Body Reaction FBR is the natural reaction from a body on the implantation of foreign material starting from acute inflammation of local tissue and accumulation of monocytes macrophages at the wound site These white blood cells clean the wound area from debris and bacteria but they also try to digest the implanted material first as individual cells later by fusing together to form so called foreign body giant cells Finally after unsuccessful attempts of these foreign body giant cells to digest the implant a dense layer of connective tissue is formed walling off the implanted material device from the body This connective tissue will ensure mechanical anchoring of the implant which might be advantageous But for most implanted sensors this walling off by connective tissue results in unreliable sensor measurements since the sensor surface is not in direct contact anymore with the soft tissue Electrochemical sensors and pressure sensors will not function properly For electrodes this connective tissue enl
94. rhaat ga E E 28 6 2 Define the Scope ANA ODJeECTIVES cceccccseececeececaeceeseeeeceeeeeseueessueesseeeeseesessaeeesaes 28 6 03 Demne de WE IVEl Al CS xcstadcessnemcnteenedenccietetrente E EE 28 6 4 Project Planning jisssctssusasatucesaintencrGnntyhchaketuicndaciocesabetsicednetytdraetstcnducinietabetuicubuedebcias 29 Co COMMUNICATION see sxesnccaesieccnonandsmsaaesctendasedesedsesmeeceidenseedacenaaiaheengencaseneieaneonaeneeenmscianeee 29 6 6 Tracking and Reporting Project Progress ccccceeceeeeeeeeeeseeeeeeeeeeeeesaeeeseeesseeesaees 29 67 Ohang Management eee ee ee ne ee ee eee ee ee ee 30 6 8 RIIK Man gemen srera nee teeter net N tees ten nett eee 30 Verification and validation ccc ccccceccececceccececceccacccceceaueecneateneeneaueceenesneaeenesueaneneeneaneats 31 Eeto e E E E E AE T ee ae 33 8 1 Important when designing a Printed Board Assembly PBA ccceseceeeeeeeeeeeees 33 8 2 DoG and donds of good DfX Practice ccccccccccceeeeeeeeeeaeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeanenees 35 8 3 Basic Design for Assembly rules saicsaisrxccrresanarnsesniarenennqas tiaras taneiesineennnaxeiustoes 36 8 4 Basic Printed Circuit Board PCB Design for Manufacturing rules 0 00n000000000n 38 8 5 Basic Design for TeSt rules cccccccececeeeceeeceeese cece eeseeesaeeseeeseesseeseeeseeeseeeseeeseeenes 39 8 6 Basic Design for Reliability rules ccccccccceeccseeeceeeeseeesaees
95. rket the INEMI consortium partners identified a clear gap regarding dedicated test protocols for reliability and safety evaluation of medical electronics To address this gap two projects have been started 1 qualification Methods for Portable Medical Products9 and 2 Reliability Requirements for Implantable Medical Devices6 Both activities will result in various publications presentations including a white paper available for a broad public on the iNEMI website expected publication date end of 2014 10 INEMI website http www inemi org focus medical electronics imec 2015 www cedm be 55 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Currently a device manufacturer should derive his test protocols from existing standards and guidelines to test electronic devices but these standards guidelines should be evaluated critically and adjusted appropriately towards the intended use of the medical device When device testing is performed using deviations from an existing test standard the authorized authority for medical market approval should be informed very well about the motivation of the test deviations 11 2 Biocompatibility testing biological evaluation of device For medical devices in close contact with the human body such as wearable and implantable devices special dedicated testing is needed regarding biocompatibility sometimes also called the iological evaluation of a deviced Both biocomp
96. roval is needed 11 2 4 Tests regarding sterilization and sterile packaging For devices in close contact with the human body during usage sterilization prior to device use is essential Since sterilization is most often performed immediately after device fabrication a sterile package is essential to ensure the device remains sterile during transport and storage Packaging and sterilization are typically outsourced by the device manufacturer to dedicated companies Directives and standards for cleaning packaging and sterilization exist and are well known by these companies These documents are obviously dedicated towards medical devices hence they provide a clear guidance without room for confusion or uncertainties 11 3 MRI safety issues Wearable devices typically do not cause major problems during MRI procedures since they can be removed from the body during the MRI procedure In the special case a life saving device has to be removed during MRI a dedicated medical specialist should be present during the procedure in order to give the correct medical treatment in case the patient encounters severe problems Implantable devices cannot be easily removed and they might cause various serious problems during an MRI investigation as listed below An MR system uses a static magnetic field typical magnetic field strength 1 5T or 3T and superposes a gradient electromagnetic field to enable 3D imaging The static magnetic field is ver
97. s o Partially populated plastic BGA with low CTE moulding compounds e Evaluate solder joint reliability of critical components Contact component suppliers for solder joint reliability test data imec 2015 www cedm be 40 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 8 6 3 Mechanically stressed PBA bending vibration and shock As mentioned above temperature can induce mechanical stress which will trigger failure modes in the electronics of the medical device Also direct mechanical stress will do this Mechanical stress can be linked to the intended use of the mechanical device It can occur through bending shock or vibration In case of shock and vibration the Eigen frequencies are important resonance e Evaluate Eigen frequencies of the PBA Provide adequate fixation to push Eigen frequencies out of the mechanical loading spectrum Fixation has to be determined as early as possible preferably before final layout of the PCB e Only use PCB finishes that provide soldering to copper to avoid the brittle failure of a solder Ni interface Do not use ENIG NiAu as specific type of finish in combination with lead free soldering e Ceramic components are susceptible to cracking under mechanical stress Do not place ceramic components e g capacitors close to locations where strong bending may occur or take appropriate measures to avoid bending e Provide mechanical fixation adhesive corner b
98. s Secondly there is a growing awareness regarding device safety and a better device tracking reporting This results in an increased amount of device recalls but that does not mean that the medical market became more unsafe on the contrary Device recalls are mostly the consequence of adverse effects on patients sometimes with a severe outcome for the patient Hence nobody is happy with a device recall But such device recalls as well as field alerts and warnings from national authorized organizations are not only essential to ensure safe products are on the medical market they are also very instructional for all device manufacturers since these warnings and recalls can contain very useful information regarding device safety in general Indeed learning from the errors of others is a very interesting way to improve the safety of your own devices Keeping an eye on public safety information of devices similar to your own devices is certainly what a smart manufacturer should do But also the general overall trend regarding device recalls is interesting and might warn device manufacturers for certain risks during device development 13 2 Use outsourced manufacturing for unknown process steps Device manufacturers should outsource device manufacturing steps they are not familiar with Device cleaning sterilization and packaging are typical manufacturing steps which are outsourced but also steps during development might be outsourced For each m
99. s fail As for any product you have to make sure your medical device will meet the intended use for the intended public For medical devices it is imperative the project manager consults the stakeholders and medical decision maker with respect to the product changes either requested or rejected 6 8 Risk Management Risks are events which can adversely affect the successful outcome of the project Risks will vary for each project but the main risks to a project must be identified as soon as possible Plans must be made to avoid the risk or if the risk cannot be avoided to mitigate the risk to lessen its impact if it occurs This is known as risk management You will not manage all risks because there could be too many and not all risks have the same impact So identify all risks estimate the likelihood of each risk occurring 1 not likely 2 maybe likely 3 very likely Estimate its impact on the project 1 low 2 medium 3 high then multiply the two numbers together to give the risk factor High risk factors indicate the most severe risks Manage the ten with the highest risk factors Constantly review risks and look out for new ones since they have a habit of occurring at any moment Not managing risks effectively is a common reason why projects fail Do not manage only direct product risks but also external risks like changing legislation standards amp user requirements The risk assessments are key to support
100. se to indicate a warning of danger and or a need for urgent action red indicator lights are often used for indication purposes There is an exclusion for dot matrix and alphanumeric displays e g 7 segment displays which are allowed to be red However any other function using LEDs or lamps must be a colour other than red Additionally yellow or amber indicators are often inappropriately used where green lights should be used 12 4 Transformers and PSUs In over 70 of cases we find that there is a problem with transformers and power supplies Unlike other product types medical devices tend to be tested more severely One of these tests is the Overload Test each winding is loaded as normal until the transformer reaches thermal equilibrium thereafter each winding is overloaded in turn If a transformer is wound for 60 Hz it usually overheats badly at 50 Hz but not the other way around Medical device standards have more stringent construction requirements for transformers Many of the transformers tested fail due to their construction including Insufficient creepage and clearance distance between windings Inadequate insulation between windings and between windings and the core Unapproved materials used for the construction Very few switching power supplies are designed specitically for use in medical devices Many are sold as medically approved Obut this usually means that the PSU is an adaptation of one built for Informati
101. ssue Bone B e e e e C o o Implant Device A o o o o Blood B e e e e C o 0 o o 1 tissue includes tissue fluids and subcutaneous spaces 2 for all devices used in extracorporeal circuits 3 depends on specific nature of the device and its component materials Table 11 1 Biocompatibility test matrix to be used only as guideline for the development of a safety assessment for a medical device indicating tests advised by ISO 10993 and additional testing F which might be needed for FDA approval Source Pacific Biolabs imec 2015 www cedm be e 9 9 9 9 n O O oNN eo ie 2 nN Subacute and Subchronic Toxicity Genotoxicity Implantation Hemaocompatikilits Reproductive Developmental rm oO 2 G G x Q Q C amp Sk a O a E T i ti wm o o o o 9 o o 9 GENEESS Guideline Best Practices for Electronics in Medical Devices 11 2 3 Note about the USP In Vivo Biological Reactivity Tests Class I VI Plastics Tests As stated before for FDA approval of a medical device ISO testing is essential Hence USP classification for materials has no legal value anymore Nevertheless for materials esp for polymers USP tests are still popular since this USP classification for materials remains useful for potential customers who are looking for materials to fabricate their devices or for users of products in laboratory settings for which no FDA app
102. t al fEvaluation of MEMS materials of construction for implantable medical devices Biomaterials 23 2002 pp 2737 2750 imec 2015 www cedm be 50 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Recently due to the myriad of implantable devices currently under development a whole variety of packaging solutions is heavily researched each to solve the specific needs of the implant Polymer based bi direction diffusion barriers and polymer encapsulations are gaining popularity Biocompatible polymers are developed with interesting properties regarding diffusion stopping power elasticity biostability optical transparency etc In addition various materials with antibacterial properties are under development enabling the application of a dedicated coating to an implant to reduce the risk on biofilm formation These materials are antimicrobial in nature or they release antimicrobial products drugs 8 Maaike Op de Beeck et al rBiostability and corrosion resistance of a biocompatible encapsulation and interconnect technology for implantable electronicsg Proc Of 45th Intern Symp on Microelectronics San Diego USA Sept 2012 Maaike Op de Beeck et al Amproved chip amp component encapsulation by dedicated diffusion barriers to reduce corrosion sensitivity in biological and humid environments oOEMPC 2013 September 9 12 Grenoble France imec 2015 www cedm be 51 71 GENEESS Guideline B
103. teract when implanted in biological tissue of a living organism is clearly wrong There is always a reaction upon implantation of foreign material Foreign Body Reaction but for biocompatible materials devices this reaction should be mild and limited in time A material device used in the body should also be biostable once implanted in the body it should stay stable i e no unwanted changes in mechanical or chemical properties of the materials should occur For some applications an external coating might be designed to be not bio stable but bio degradable but degradation should be a well controlled process Both biocompatibility and biostability are important properties of a medical device hence in vitro and in vivo tests have to be performed to assure its biological safety as part of the total risk management assessment of this device More information about these tests can be found in section 11 Testing of electronic devices for medical applications Ratner 2004 imec 2015 www cedm be 48 71 GENEESS Guideline Best Practices for Electronics in Medical Devices Some more properties regarding the interaction of a material with biological tissue are listed below Bio active or bio functional material a material is bio active if it is enhancing certain mostly beneficial biological processes A material can be bio active by nature or it can be made bio active by loading it with a drug a protein a growth factor Antib
104. terials imec 2015 www cedm be 52 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 10 1 Development of medical devices The development of a device for the consumer market differs in various aspect from the development of a medical device due to its high importance and possibly severe consequences for the user Due to this extensive device testing is crucial to ensure the bio safety and effectiveness of the device The testing protocols are partly similar to electronic device testing for the consumer market although typically more rigorous testing is performed and for devices in close contact with the human body special dedicated testing is needed regarding biocompatibility and MRI safety for implants To ensure all devices on the medical market are properly tested and hence biosafe all countries have a regulatory framework in place controlling premarket approval and post market device follow up In Fig 10 1 an overview of the development phases of a medical device is shown The various development phases can overlap somewhat in time due to re iterations of the device design to improve safety and or effectiveness imec 2015 www cedm be 93 71 GENEESS Guideline Best Practices for Electronics in Medical Devices problem Feasibility device concept possibility Preclinical Research Device developm amp fabrication Laboratory testing to explore l Safety incl biosafety gt Dev
105. tly and time consuming hence the need for more harmonization is obvious Since the 19906 all countries in Europe follow the same regulatory framework controlled by approved notified bodies in all EU countries Once the CE label hence approval is given to a product it can be sold in all EU countries For other countries international harmonization is seen in the global acceptance of various test standards for medical devices such as the 15010993 standard for biocompatibility testing of medical devices which is accepted in most countries although still minor differences in test requirements are present In most countries the authorities giving approval to bring a product onto the medical market will also apply a strict post market surveillance procedure resulting in public information ranging from safety warnings and field alerts to device recalls when the device is not performing well regarding medical safety Hence even after device approval all medical device manufacturers should track the use of their products being open for all complaints and remarks and use this information for further enhancement of their existing devices as well as for better design of new developments It is important to realize that a device manufacturer remains responsible for his medical devices also after device approval The manufacturer is defined by the FDA as he natural or legal person with responsibility for the design manufacture packaging and labell
106. to get the project back on track but you will always end up juggling cost scope and schedule If the project manager changes one of these then one or both of the other elements will inevitably need changing It is juggling these three elements known as the project triangle that typically causes a project manager the most headaches As Stated at 4 4 Project management although not essential for your medical device this will be essential to control your cost and time to market imec 2015 www cedm be 29 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 6 7 Change Management Stakeholders often change their mind about what must be delivered Sometimes the business environment changes after the project starts so assumptions made at the beginning of the project may no longer be valid This often means the scope or deliverables of the project need changing If a project manager accepted all changes into the project the project would inevitably go over budget be late and might never be completed By managing changes the project manager can make decisions about whether or not to incorporate the changes immediately or in the future or to reject them This increases the chances of project success because the project manager controls how the changes are incorporated can allocate resources accordingly and can plan when and how the changes are made Not managing changes effectively is often a reason why project
107. ts for the safety of automatically controlled brachytherapy afterloading equipment essential performance of endoscopic equipment essential performance of infant incubators essential performance of infant transport incubators essential performance of infant radiant warmers MEE Part 2 22 Particular requirements for basic safety and essential performance of surgical cosmetic therapeutic and diagnostic laser equipment IEC 60601 2 23 MEE Part 2 23 Particular requirements for the safety including essential performance of transcutaneous partial pressure monitoring equipment pumps and controllers electrocardiographs electroencephalographs MEE Part 2 27 Particular requirements for the safety including essential performance of electrocardiographic monitoring equipment MEE Part 2 28 Particular requirements for the basic safety and essential performance of X ray tube assemblies for medical diagnosis essential performance of radiotherapy simulators IEC 60601 2 31 MEE Part 2 31 Particular requirements for the basic safety and el essential performance of external cardiac pacemakers with internal power source IEC 60601 2 33 MEE Part 2 33 Particular requirements for the basic safety and essential performance of magnetic resonance equipment for medical diagnosis MEE Part 2 34 Particular requirements for the safety including essential performance of invasive blood pressure monitoring equipment extr
108. y of the final medical device is in hands of the device manufacturer it is essential to control also the quality and reproducibility of the input of all involved companies material and component suppliers third parties for sterilization and packaging contract manufacturers Ideally open discussions are held and the legal device manufacturer has a good understanding of the QM system risk analysis amp CAPA of all involved third parties Post market phase After introduction on the medical market a device will be tracked and reports on the device usage have to be made For high risk medical devices invasive for patients and or lifesaving even detailed tracking of each individual device is required by the competent national authorities who provided market approval to the device Such device tracking might result in field alerts or even device recalls to ensure safe products are on the market although smaller device issues can often be solved by device corrections performed by the device manufacturer For devices with moderate to low risk post market tracking might be stopped after an initial period during which the national authority is convinced about the safety of the device imec 2015 www cedm be 23 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 5 5 The use of IEC 60601 1 IEC 60601 is a series of technical standards for the safety and effectiveness of medical electrical equipment It is
109. y strong and can induce a static force hence displacement or torque on both active and passive implants in case implant materials are weakly magnetic Hence even weakly magnetic materials implanted in soft tissue are not safe for a patient during MRI procedures the first 6 weeks after implantation About 6 weeks after implantation the Foreign Body Reaction tissue ingrowth scarring has provided sufficient incorporation of the implant into the tissue and hence an MRI procedure is not causing a device displacement anymore An MRI investigation can be performed directly after the implantation for weak magnetic material which is fixed rigidly in the body e g by bone screws In case of subcutaneous implants the movement of magnetic material during an MRI procedure can sometimes be limited by using special bandages which hold the implant in place The gradient RF field in an MRI system produces a movement of electrons hence electronic current in all conductors which might produce potentially dangerous heating of these conductors These conductive loops can consist of implanted materials e g pacemaker leads and guidewires but also the human body is sufficient conductive and the high frequency of the RF field allows that energy is even passing through small insulating areas in the loop For certain lengths of conductive loops resonance effects can occur which create high currents causing very severe heating Hence implanted devices n
110. your evidence needed for CE marking the medical device imec 2015 www cedm be 30 71 GENEESS Guideline Best Practices for Electronics in Medical Devices 7 Verification and validation Verification is the process of checking whether the product adheres to the policies standards requiremenis The verification process should test the specified requirements the product specification Validation will check if the product fulfils its intended use in its intended environment if it is what the customer wants The validation process should test the product definition So verification should answer the question Am building the product right Validation should answer the question Am building the right product Medical Device Market requirements Product requirements i q Validation plan 1a 4 Product definition Validation amp Product requirement analysis manufacturing transfer Grey Box Project plan Verification pla 1b Product specification X X Integration amp c verification N L g Q Prototype Design Input Freeze 2 Design amp Test Bread Board Hardware and Software V amp V activities are important because they Ensure the requirements are met Remove defects from the product reduce cost of poor quality and rework Ensure the user needs are met Improve the quality of product and process Improve productivity and performance V amp V is
111. zed by the CDRH into 3 classes Class very low to low risk Class Il moderate risk Class Ill high risk all implants are class Ill For each class different approval procedures apply with the most rigid approval procedure for highest risk devices When a new device in developed it will be classified by the CDRH based on intended use and risk In case no medical devices with similar intended use risk exist yet the device will automatically be classified as high risk 1 Class Ill since no historical information is available to judge risk In case it is obvious that this new device has a lower risk advantageous for an easier approval process the device can be placed in a lower risk class after going through the so called e NovoOprocess If a product is labeled promoted or used in a manner that meets the following definition in section 201 h of the Federal Food Drug amp Cosmetic FD amp C Act it will be regulated by the Food and Drug Administration FDA as a medical device and is subject to premarketing and postmarketing regulatory controls Definition according to section 201 h of the Federal Food Drug amp Cosmetic FD amp C Act e an instrument apparatus implement machine contrivance implant in vitro reagent or other similar or related article including a component part or accessory which is recognized in the official National Formulary or the United States Pharmacopoeia or any supplement to them e inte

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