Classifying medical devices

CHAPTER

Classifying medical devices

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Let us hear the conclusion of the whole matter: Fear God, and keep his commandments: for this is the whole duty of man Ecclesiastes 12:13.

An apology from the author: I am sorry for the Yo-Yo nature of this chapter. But due to the Medical Devices Directive running out and the new Medical Devices Regulations coming into force there is a lot of “the old MDD” and “the new MDR” type sentences. If you read this post Spring 2020 there is neither e just the MDR. Unfortunately in transition periods this type of dichotomy always occurs. Let’s hope there is not such issue for Edition 3!

2.1 Why classify? There is an old joke that is worth saying here. One day an old man was leaning on a his garden fence when a car draws up. The driver gets out and asks “Is the best way to Guildford?” The old man looks at the driver and replies “Well, it is from here, but if it were me I’d have started somewhere else”. Anon.

Also Francis of Assisi writes Start by doing what’s necessary; then do what’s possible; and suddenly you are doing the impossible1

What does this all mean? The wise person picks the correct starting point. The correct starting point for medical devices design is to understand classification. There are a number of reasons why classification is important. The first concerns the patient. Clearly the more risk a given device poses to the patient then the greater the reassurance that needs to be given. Not all devices pose the same risk, consider for

1

St Francis of Assisi, 1152-1226.

Medical Device Design. https://doi.org/10.1016/B978-0-12-814962-1.00002-8 Copyright © 2020 Elsevier Ltd. All rights reserved.

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example a pacemaker compared to a support bandage. It is quite clear that the pacemaker poses the greater risk and, thus, should have more stringent controls attached to its design, manufacture, and eventual sales. The second reason concerns the manufacturer, why should the registration process be as stringent for the support bandage as compared to the pacemaker? The third reason concerns the regulatory bodies, the classification indicates to them the level of risk to the patient and the nature of the beast they are dealing with, and hence the amount of effort they need to put in to the control. After all, governments have limited budgets too and they need to target their resources at the devices that pose the greater risk. It is obvious that the prime importance is safety. Although patient safety is a priority one must not forget the users, their safety is just as important. All devices have to obey the prime criteria do no harm. But it is also clear that, for some devices, to achieve a clinical goal some harm is inevitable. The question posed is “is the risk acceptable?”. The new Medical devices Regulations and the new ISO 13485e2016 are both “risk dominated”: everything one does in the design chain (and every other decision in fact) needs to be risk managed. Not doing so will have you fail in your aim to the creation of a medical device: as you will simply be stopped by the regulatory bodies. Consider, for example, a hypodermic needle. Which is the greater harm, producing a small puncture wound in the skin, or not receiving a vaccination? Risk and doing no harm is a balancing act. Classification allows all participants in the regulatory process to understand the risk the device poses. In general the higher the classification the more chance that the device could do some harm. Hence it should come as no surprise that things such as replacement heart valves are high classification and inserts for shoes are low. However, do not be fooled into thinking that lower classification devices do not demand design rigor; the level of rigor is the same at ALL levels. The only difference is the level of rigor applied to the pre-market checks and balances applied by the regulatory bodies. If you get into the mindset of a Class I device having a Class I design methodology you will write yourself into the history books for all the wrong reasons. Table 2.1 attempts to illustrate how risk and classification are interlinked. Both the USA and EU classifications are illustrated (do not use this for cross referencing it is only indicative). The table demonstrates that low risk devices are class I, and high risk class III (note in Canada there is also class IV).

2.2 Classification rules Each regulatory authority has its own set of classification rules. In the USA these are stipulated within CFR21 Part 860 e Medical Device Classification Procedures (FDA, 2010). Within the EU they are currently stipulated within 93/42/EC Annex IX (EC, 1993), but will soon be superseded by the new Medical Devices Regulations

2.2 Classification rules

Table 2.1 Classifications in the USA and Europe. Risk

Low risk

High risk

In Europe the classifications are EU

I

IIa

IIb

III

In the USA the classifications are USA

I/510(k) exempt

II

III

Note, I have not included Custom Made Devices - we will look at these on their own as the rules have been made more stringent.

2017/745 but in now to be found in Annexe VIII.2 All documents are freely available on the world-wide-web, as are those for any other country. As a medical device designer you must have an up to date copy of the classification rules to hand at all times. There is a fundamental difference between the two systems. In the USA classification is by precedent and is undertaken by the FDA; that is you have a classification by comparison with decisions already made by a panel. In Europe there are a long list of questions to answer and you decide on your classification. However, if you try and cheat the system by ‘under-classifying’ you will fail. The classifications are based on risk to the patient (as illustrated by Table 2.1). As we will meet later, risk is a very important aspect of design control; understanding risk to the patent (and to the clinical team/operator) is fundamental. The FDA process is not a good vehicle to help us to understand patient risk and classification. We will use the EU model to understand how classifications are made. For this exercise you will need a copy of 93/42/EC Annex IX and the new MDR Annex VIII to hand. Table 2.2 illustrates how the EC medical devices rules define the classification of a device. The symbols indicate that this particular rule defines this particular class of device. You will notice that the new MDR has 4 new rules; in fact the new rules are spread throughout the MDR so, unfortunately, what was Rule 9 (for example) in the MDD may not be the same rule in the new MDR. Thus you need to have gone through all of these before Spring 2020. However the same methodology applies: if you think your device is likely to be Class III it will fall into the definitions described by one of Rules 6, 7, 8, 13, 14 & 17. Do not assume that these are the only rules you need to consider; all rules need to be examined to make sure that our classification is correct. So best to start at Rule 1 and go through to the end e cross out the ones that do not apply, and the one that is left is the one for your device.

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At the time of writing this the UK is planning to leave the EU and the medical devices framework, there is no information about what is going to replace it so we can only assume that the UK will mirror the EU regulations for the short term.

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Table 2.2 EC classification rules in comparison with the classes they define.MDD ⌧ MDR ☼ Class in rule Rule

Class I

#1 #2 #3 #4 #5 #6 #7 #8 #9 # 10 # 11 # 12 # 13 # 14 # 15 # 16 # 17 # 18 #19 #20 #21 #22 Hip, knee & shoulder replacements

⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼

☼ ⌧ ☼

Class IIa ⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ☼

Class IIb

Class III

⌧☼ ⌧☼ ☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ⌧☼ ☼

☼

⌧ ⌧☼ ☼

⌧ ⌧☼ ☼

⌧ ☼ ☼ ☼

☼ ☼

⌧☼ ⌧☼ ⌧☼ ☼ ☼ ⌧ ⌧☼ ☼ ⌧ ☼ ☼ ☼ ☼ ⌧

Before we go further we need to understand some definitions: Invasive device: a device that penetrates inside the body either through an orifice or through the surface of the body. Surgically invasive device: Any device that enters the body other than through an established body orifice. Transient duration: continuous use of less than 60 min. Short term duration: continuous use of not more than 30 days. Long term duration: continuous use of greater than 30 days. EC (1993) and EU (2017).

2.2 Classification rules

These definitions are almost universal, so you should have these emblazoned in your memory. All regulatory requirements come with definitions; the documents are legal documents so definitions are mandatory. If you have ever seen a legal document you will note that the first few pages are definitions. They are required so that everyone, as it is said in Business School, “sing from the same song sheet”. The USA and Europe all have their own particular wording so it is important that you keep abreast of them.

2.2.1 Custom made devices Before we go any further we need to understand the new rules around custom made devices. Under the old MDD there was a “loophole” that “allowed” mass produced items to fall under the definition of a custom made device if it were “prescribed” by a clinician for a given patient. Under the new MDR (and virtually everyone else’s definition of a custom made device), this is no longer the case. MDD definition: custom-made device’ means any device specifically made in accordance with a ̒ duly qualified medical practitioner’s written prescription which gives, under his responsibility, specific design characteristics and is intended for the sole use of a particular patient. The abovementioned prescription may also be made out by any other person authorized by virtue of his professional qualifications to do so. Mass-produced devices which need to be adapted to meet the specific requirements of the medical practitioner or any other professional user are not considered to be custom-made devices;

MDR definition: custom-made device’ means any device specifically made in accordance with a ̒ written prescription of any person authorised by national law by virtue of that person’s professional qualifications which gives, under that person’s responsibility, specific design characteristics, and is intended for the sole use of a particular patient exclusively to meet their individual conditions and needs. However, mass-produced devices which need to be adapted to meet the specific requirements of any professional user and devices which are mass-produced by means of industrial manufacturing processes in accordance written prescriptions of any authorised person shall not be considered to be custom-made devices;

Although they are close, the fact that the words “shall not be considered” have been emphasised suggests the new emphasis. In fact this was tightened in the modification to the original 93/42/EC in 2007! This new definition has major impacts on device manufacturers from orthotics and limb prostheses.

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The FDA also tightened their definition in 2016: Custom devices

(1) In general The requirements of Sections 360d and 360e of this title shall not apply to a device that(A) is created or modified in order to comply with the order of an individual physician or dentist (or any other specially qualified person designated under regulations promulgated by the Secretary after an opportunity for an oral hearing); (B) in order to comply with an order described in subparagraph (A), necessarily deviates from an otherwise applicable performance standard under Section 360d of this title or requirement under Section 360e of this title; (C) is not generally available in the United States in finished form through labeling or advertising by the manufacturer, importer, or distributor for commercial distribution; (D) is designed to treat a unique pathology or physiological condition that no other device is domestically available to treat; (E) (i) is intended to meet the special needs of such physician or dentist (or other specially qualified person so designated) in the course of the professional practice of such physician or dentist (or other specially qualified person so designated); or (ii) is intended for use by an individual patient named in such order of such physician or dentist (or other specially qualified person so designated); (F) is assembled from components or manufactured and finished on a case-bycase basis to accommodate the unique needs of individuals described in clause (i) or (ii) of subparagraph (E); and (G) may have common, standardized design characteristics, chemical and material compositions, and manufacturing processes as commercially distributed devices. (2) Limitations Paragraph (1) shall apply to a device only if(A) such device is for the purpose of treating a sufficiently rare condition, such that conducting clinical investigations on such device would be impractical; (B) production of such device under paragraph (1) is limited to no more than 5 units per year of a particular device type, provided that such replication otherwise complies with this section; and (C) the manufacturer of such device notifies the Secretary on an annual basis, in a manner prescribed by the Secretary, of the manufacture of such device.

Note the limit of 5 units per year! So as you can see, the “Custom Made Device” is not an excuse to not regulate; in fact it is an area that has required even greater regulatory effort. So please do not fall into the trap that is so often bandied about by

2.3 Classification case studies

so-called consultants e that is to proceed as a custom made device manufacturer. If your device is truly custom made it will be obvious! To be brutally honest, a custom made device requires more design and analysis rigor than a mass produced one e why? Because you need to prove it will not fail under normal use and hence avoid a massive insurance claim and you will not have the evidence of “4 million have worked just fine” as a defense. It will be a one-off! So if you are a custom-made device manufacturer this book is more important than ever.

2.3 Classification case studies To understand classification and risk we will use a case study. For the purposes of this case study we will use the humble orthopedic drill bit and an orthotic shoe insert as our examples. Before we go any further we need to understand the devices. Fig. 2.1 illustrates a typical 3.2 mm drill bit. It is used for drilling holes in bones. The process takes just a few minutes and the devices can be re-used until it is blunt. They are supplied non-sterile. Fig. 2.2 illustrates a typical orthotic insert. These are foam based structures that are inserted into, say, the heel of a shoe to correct gait (walking pattern). They are mass produced and are supplied non-sterile.

FIG. 2.1 A typical 3.2 mm bone drill. Courtesy METAPHYSIS LLP.

FIG. 2.2 A typical orthotic shoe insert (hand drawing).

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2.3.1 EU classification The EU process is a step-by-step, rule based, process. At this stage we will start at Rule #1 and work our way upward. Later we will see an alternative method. Rule 1: All non-invasive devices are in class I unless one of the rules set out hereafter applies. Same in both MDD and MDR.

Basically, the rule asks us the question “is it invasive?”. Clearly being invasive is risky, so one would expect invasive devices to be high risk. A non-invasive device must be less risky . or it should be. The first part of this rule says “all noninvasive devices can be assumed to be non-risky” e the second part says “but if we have evidence that its particular use is risky then we have the right to make the classification higher”. Do not stop here! It is tempting to, but do not we must work our way through all of the rules. Q: Is our drill invasive or non-invasive? A: The drill enters the body through a surgically made incision (there is no other way to get at a bone). Hence it is invasive. It is NOT a class I device. Hopefully you get the idea. Classification is very simple if you follow the steps. It is a step-by-step approach. In some cases, where you have not fully developed your ideas, doing a classification analysis actually helps you to develop a specification. Thus it is worth doing at the start. The classification may change later but we can address that later too. Let us now consider the multi-purpose orthotic shoe implant. Q: Is it invasive? A: An emphatic no. Hence Rule 1 states it is class I. But we must wait till later to check if other rules cause the classification to change. I will not go through each rule one by one as this would make the text really boring. But you need to read the rules completely and follow them through. It is important to note that it is the rule that classifies the device that we need to concern ourselves with. The rules that do not apply are, ultimately, of little concern. However, we will see later that monitoring this process and recording our judgment is very important. In the old MDD, rules 2, 3 and 4 are concerned with how non-invasive devices are used. Rule 2 is about storing blood etc.; rule 3 is about modifying body fluids; and rule 4 concerns contact with injured skin (wound treatment for example). I think you will all appreciate the risk of storing blood for transfusion! The bone drill is invasive so these rules do not apply (are you getting the idea?). The orthotic insert is noninvasive but its use does not fall into any of the three rules so is still class I.

2.3 Classification case studies

Again, in the old MDD, rules 5 and 6 are concerned with how invasive devices are inserted. Rule 5 concerns entry via normal body orifices (e.g a proctoscope); rule 6 concerns entry via a surgically produced entry window (e.g. an arthroscope). Clearly the orthotic shoe insert does not enter an orifice; but the drill does. Rule 6 (modified by 2007/47/EC) states: All surgically invasive devices intended for transient use are in Class IIa unless they are: d intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with these parts of the body, in which case they are in Class III, d reusable surgical instruments, in which case they are in Class I, d intended specifically for use in direct contact with the central nervous system, in which case they are in Class III, d intended to supply energy in the form of ionising radiation in which case they are in Class IIb, d intended to have a biological effect or to be wholly or mainly absorbed in which case they are in Class IIb, d intended to administer medicines by means of a delivery system, if this is done in a manner that is potentially hazardous taking account of the mode of application, in which case they are in Class IIb

Is the drill surgically invasive? e yes. Is it transient use (<60 min)? e yes. Does it fall into any of the other 5 sub rules? e yes. It could be classed as a reusable surgical instrument? Well logic suggests that drills are sharp when used the first time and get blunt after a few uses, but they can be washed, re-sterilised and are reusable until blunt, broken or bent. Our drill bit is reusable so it falls into - reusable surgical instruments - it is class I. We check with the agreed definition of a reusable surgical instrument: An instrument intended for surgical use by cutting, drilling, sawing, scratching, scraping, retracting, clipping or similar procedures, without connection to any active medical device and which can be reused after appropriate procedures have been carried out EC (1993).

This wording is, almost, universally accepted as the definition of reusable surgical instrument. Clearly the drill bit fits this definition and it is a Class I device.

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So, how has the new MDR changed this ruling? From the new MDR Rule 6 states: All surgically invasive devices intended for transient use are classified as class IIa unless they: d are intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with those parts of the body, in which case they are classified as class III; d are reusable surgical instruments, in which case they are classified as class I; d are intended specifically for use in direct contact with the heart or central circulatory system or the central nervous system, in which case they are classified as class III; d are intended to supply energy in the form of ionising radiation in which case they are classified as class IIb d have a biological effect or are wholly or mainly absorbed in which case they are classified as class IIb; or d are intended to administer medicinal products by means of a delivery system, if such administration of a medicinal product is done in a manner that is potentially hazardous taking account of the mode of application, in which case they are classified as class IIb.” EC (2017).

Phew, nothing new there! But do not take this as gospel for all rules. We have already seen there are more rules un the nee MDR, and some of them have changed dramatically. Note that in both MDD and MDR, if the drill was intended to be single use only it falls into class IIa. However a side issue is that you MUST justify why it is single use (as this incurs extra cost to the healthcare provider and can be, simply, the creation of a cash-cow3). Note how the phrase intended use is very important e as a simple change of wording from single use to reusable can result in a 30X increase in regulatory costs. In the MDD (and the MDR), Rule 7 takes into account longer durations of use. If the use of the drill was for longer than 60 min then its use would change from transient duration to short term duration. Hence the potential for risk to the patient increases and as such the class increases, but not enough to change the standard classification. But note that the sub-rules have changed as their potential risk increases with use. Rule 8 takes this one stage further and puts implants and long term surgically invasive devices into class IIb because their risk is greater. Note that this has been the

3

The term “cash-cow” is used for a product, company or system that produces cash long after the initial investment has been covered (like a dairy cow and its product - milk). It was first used in the 1960’s and has been attributed to PF Drucker and the Boston Consulting Group.

2.3 Classification case studies

matter of much debate and has resulted in re-classification. The directive 2005/50/ EC reclassified hips, knee and shoulder replacements as By way of derogation from the rules set out in Annex IX to Directive 93/42/EEC, hip, knee and shoulder replacements shall be reclassified as medical devices falling within class III. EC (2005).

This higher classification for these types of device is universally accepted. The term implant has been universally adopted for a device that has been designed to remain within the body with long-term duration. This sub-clause is no longer in use in the MDR as it has been included in the rules. There are a total of 18 rules (19 if you include the derogation above) in the old MDD, and 22 in the new MDR. I do not intend to go any further as the point has been made. There is only one last technicality to include and that is the use of animal byproducts. Rule 17 states: All devices manufactured utilizing animal tissues or derivatives rendered nonviable are Class III except where such devices are intended to come into contact with intact skin only.

Now this is one rule that has changed e not so much as in text but in number. In the new MDR it is rule 18. It’s new wording is All devices manufactured utilising tissues or cells of human or animal origin, or their derivatives, which are non- viable or rendered non-viable, are classified as class III, unless such devices are manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable and are devices intended to come into contact with intact skin only. EC (2017).

The rise of the prion and the fear of transmission of human variant CJD has made this clause ever more powerful (we shall see this later when we look at application processes). As a designer we must be aware of our material and process choices. Do not forget that animal tissue is used as the lubricant of injection molding machines and for thread cutting so whilst you may not have specified a non-animal based material your design and selection of manufacturing process may put your product into class III without you realizing it. It is, therefore, wise for you to make sure you are aware of all 18 rules in the MDD and, now, all the 22 rules in the MDR. Thus the classification we make for the drill bit is: Classification: MDD: Class I as defined by 93/42/EC (modified by 2007/47/EC) Annex IX Rule 6. But under MDR this is now Class I Reusable Surgical Instrument and will require CE marking by a notified body.

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MDR: Class I as defined by 2017/745 Annex VII Rule 6. For the orthotic shoe insert the classification would be. Classification: MDD: Class I as defined by 93/42/EC (modified by 2007/47/EC) Annex IX Rule 1 MDR: Class I as defined by 2017/745 Annex VII Rule 1.

2.3.2 USA classification case study Now let us examine how this classification would be undertaken using the FDA process. The idea is to find a precedent, or something like your device that has gone before. Let us take each item in turn and demonstrate. The first port of call is the database section of the FDA/cdrh website (http://www.fda.gov/MedicalDevices/ default.htm). The FDA host a classification database where you can search for your precedents; this is the product classification database. All one is required to do is enter a relevant search term. Using the bone drill as an example let us consider the correct terminology to enter. If we use bone drill then we will get hand drills and power tools; the correct term is a drill bit. Conducting a search results in: A selection of records should appear; all we need do is select the correct one (bit, drill as highlighted). Following the link takes us to the device classification: Fig. 2.5 illustrates the official statement. It clearly demonstrates that in the USA the drill bit is class I. Note that the important bits of data are the classification (I), the product code (HTW), that it is 510(k) exempt, and the regulation number (888.4540). These will become more important once we start to apply to the FDA for clearance to market.

FIG. 2.3 FDA product classification database window. Courtesy FDA.

2.3 Classification case studies

FIG. 2.4 Search solution for drill bit. Courtesy FDA.

FIG. 2.5 FDA classification statement. Courtesy FDA.

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The classification for the drill bit would be. Device: Bit, Drill. Class I. Product Code: HTW. Regulation No.:888.4540. At the bottom of the table is a further useful piece of information, recognized consensus standards. Basically this section is saying if you use these standards as a part of your design process then you are on the right track! A valuable starting point for any design engineer. Seeing the FDA process does make one wonder why Europe makes it so hard. There is one very good reason, for existing products the process is long but can be determined with a little bit of work. It is when a brand new device comes along when the European system shows its true colors. It is down to the manufacturer to do the classification and this will be confirmed once CE marking is applied for. In the USA a classification panel makes the decision; the manufacturer has to put forward a case for the classification. A subtle difference, but different none the less. Let us check the FDA classification for the orthotic insert. Searching for orthotic insert will not find anything, search for orthotic and one finds: Fig 2.6 shows the results of the search. Once again note the relevant data, it is class I and 510(k) exempt. However the device is GMP exempt. The value of this piece of information will be explored in more detail later. The classification would be: Device: Shoe, Cast. Class I. Product Code: HPG. Regulation No.:890.3025. Table 2.3 illustrates some comparisons between classifications of devices in Europe and in the USA. By and large (apart from IIa and IIb) the classifications match. But do not let this fool you, you must check the classification and not simply assume. . when you assume, you make an ASS out of U and ME4

2.3.3 Special cases There is one further special cases to consider: a device intended for clinical investigation.

4

Attributed to Benny Hill e much maligned British comedian - from his television series of the 1970’s.

2.3 Classification case studies

FIG. 2.6 Orthotic classification. Courtesy FDA.

Table 2.3 Comparison of classifications in the USA and Europe. Class Device

USA

Europe

Reusable Surgical Instrument Disposable Suture Needle Bone Screw

I I II

Blood Sample Container Hip Prosthesis (implant)

I II

I IIa IIa/IIb (short duration) (long duration) I III

Do not use this table for classification purposes it is only for comparison.

Medical devices for clinical evaluation come under a whole different regime. Surgeons, engineers and scientists often need to conduct evaluations before obtaining clearance to market. This means that the device they intend to use must be cleared for clinical investigation. We will examine this in more detail in later chapters.

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Once again, this is not a ‘get out clause’ and the diligence required is probably higher than with a commercial device. It is ‘experimental’ so not all of the pitfalls, side effects or clinical issues will have been ascertained. Therefore the design process needs to be failsafe in its approach.

2.4 Further case studies 2.4.1 OTC joint support device If you have ever sprained a wrist, twisted your knee or strained the ligaments of your ankle you will be well aware of the Over The Counter (OTC) elasticated support. In the past these were simple elasticated hose, however nowadays there are a plethora of items from simple elasticated hose through to velcro attached mechanical structures. However they all have one thing in common, in the EU they are Class I devices and in the USA they are. Generally, Class I - 510(k) exempt. The only addendum to this, as we shall see, are those supplied in a sterile condition. This case study brings the concept of Over the Counter (OTC) products to medical devices. I am amazed how many times I have heard the comment “oh it’s not a medical device as it is only for sale to the general public and not to a hospital” e wrong! Any simple analysis of the medical devices regulations, across the World, shows the most Hogarthian5 of designers that they are indeed medical devices designers. Figs. 2.7e2.9 illustrate the range of devices that fall into this category. All three figures are, effectively, for the same thing. They all provide some form of support for areas about the knee. However, their complexity increases from Figs. 2.7e2.9. Fig. 2.7 illustrates a simple elasticated bandage. This is normally in some form of tubular fashion and is a mix of textiles and elastic material. The object of the hose is provide compression, and is it is an elasticated textile, this is all it can provide. It has no structural stability and can provide no axial, or bending support at all. Fig. 2.8 gives an example of the influx of new materials to this discipline. Neoprene has been incorporated to give the elasticated nature of the support, but also adds other beneficial properties. The addition of a Velcro (or hook and eye) strap creates mechanical compression as opposed to elastic compression; it also adds enhanced location. Fig. 2.9 illustrates a functional knee brace. In these types of devices the compression provided by the straps is for location only; it is the “mechanical scaffolding” that provides axial, torsional and bending support. Normally there is little compression.

5

Hogarth was an artist of the early 18th century (1697e1764). He was particularly famous, amongst other things, for cartoon characters known as Hogarthian Grotesques whose visualizations hyperextended their personal traits.

2.4 Further case studies

FIG. 2.7 simple elasticated support.

FIG. 2.8 neoprene knee support using Velcro strapping.

2.4.1.1 Exemption? Firstly, are these items medical devices at all? Going back to the definition of a medical device, one would find it hard to justify a null response. However, here it is worth taking the time to look at exemptions. It is common for people to think of calling their product a “medical device” as some kind of badge of honor or marketing tool. Why? If there is no need for the status of “medical device” why do it e it only leads to paperwork and costs. Is Joe Public really going to understand the difference?

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FIG. 2.9 Knee brace using frameworks and Velcro strapping.

In virtually all markets there are some things that one would think are medical devices, but under the current rules they have been granted an exemption (for what reason I cannot say e but they exist). The list changes from day-to-day (as classification rules do) so it is well worth keeping a copy to hand and updating all the time. In the UK this list of exemptions is maintained by the MHRA (who we met earlier in the book). However, whichever country you operate in the list of exemptions (or in some cases inclusions as the list of medical devices is so small!) would be easily found on the web, or by a quick telephone call (or email) to the regulatory body concerned. This just may save you time and money.

2.4.1.2 Classification? EC: MDD (and MDR in fact). Invasive? No: Class I by rule 1. Any other rules apply: No. Hence for both MDD and MDR, class I. FDA: Using the search engine we met earlier, and using the search text “knee brace” the following is found (Fig. 2.10). As we can see it is not only Class I it is 510(k) exempt e phew! But this is for the knee brace alone e we have not yet looked at all the other variations: I leave that for your homework!

2.4 Further case studies

FIG. 2.10 FDA result of “knee brace” classification.

2.4.2 A device that can jump classification! Let us consider the humble K-Wire.6) ) For those of you unaware of this device it is probably the most simple device in the medical devices catalog as it is simply a length of wire with one end sharpened to a point. It is used in a variety of areas and for many different reasons hence it is a really good example of how intended use can affect classification. In order to avoid the need for about 100 different photographs of their uses I suggest you do a literature search (indeed this will be good practice for the later sections on Clinical Evaluation). In practice the wire is driven through the skin and bone using a simple drill. The sharp point penetrates the skin and also creates the hole in the bone for the wire to pass through. Commonly its diameter is about 1.8 or 2.0 mm e so it is very thin. Some wires have simple points, some have actual drill-bit tips: but in essence they are all

6

The “K” in K-wire is short for Kirschner: he developed this simple device in the early 1900’s e and they are still very widely used today! You can find out more about k-wires by simply typing this into a search engine.

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the same e a length of stainless steel wire. The device is, therefore, invasive. In the MDD and MDR this is Rules, 5e8 (I suggest you read them now before you go on). This is a really good example of how your “intended use” can really affect the outcome of your classification process (and as your intended use came from the “end users” and your specification a really good example of how if you do not involve end users you can go completely wrong and make a right Horlicks7 of it!). Rule 5 of the MDD and MDR are not applicable as the device does not enter a normal body orifice. Rules 6 and 7 are interesting as it brings in the duration. If the k-wire was only to be used in the OR for temporary stabilization and then removed it is likely to be transient or short-use: this results in the k-wire being classified as Class IIa. Rule 8 complicates the issue. If the k-wire) will remain in-situ for more than 30 days it moves into the long term use category (and this would be the case if the wire were to be used as a fixing mechanism for an external fixator of the Illizarov8 design) e again do a web search to find out more). In this case the device would be Class IIb. Hence you can now see why the phrase “intended use”) is so important. If in your documents you state the device is only for use in the OR for temporary stabilization then Rule 7 applies. If, however, you state that it is for use with external fixation Rule 8 applies. But if you say nothing at all about duration of use in your intended use statement e what happens then? Well you are at the mercy of the auditors who will probably force you to go down the Class IIb path! Hence take care when developing your intended use) statement. What does the FDA say e I here you shout. Once again we go the wonderful FDA classification database and type in a search for k-wire. You will find loads of entries for wire. The one we are interested in is the wire, surgical entry. This demonstrates any k-wire for any use is Class II and requires a 510(k) submission (I leave you to find the entry as homework).

2.4.3 An In-vitro diagnostic device For this case study I will adhere to the new MDR only e I leave it to you to do the same for both the MDD and the FDA classification rules. Firstly, unlike, devices, 7

Making a “Horlicks of it”: this basically means making a right mess and is attributed to making a ruder phrase “making a right $%**&# of it” more polite. It does NOT mean that the hot drink Horlicks is somehow a mess. 8 Illizarov was Russian surgeon working in Siberia, not only did he devlelop the “ring-fixation” system e which you see all over the world but he also developed the clinical procedure of Callotasis e or to you and I growing bone. What a dude!.

2.5 Classification models

IVD devices are classified as A,B,C or D depending on intended use and inherent risk: A being the least and D being the highest (as class I and class III in devices). Also there are only 7 rules to contend with. For this case study let us consider the simple liquid specimen receptacle (be that blood, sputum or urine). The first thing to consider is it a medical device of is an in-vitro diagnostic device. From the MDR: Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices;

and (3) ‘specimen receptacle’ means a device, whether of a vacuum-type or not, specifically intended by its manufacturer for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination; EU (2017)

From these quotes, I think we can assume that any specimen receptacle is an in-vitro diagnostic device. Now we go through the rules, one by one, as before. According to Rule 5: The following devices are classified as class A: . (c) specimen receptacles.

I think that makes it quite clear that specimen receptacles are the lowest classification: class A. As with Class I devices, this level of classification only requires self certification. But as with medical devices, this does NOT mean design control is ignored!

2.5 Classification models One of the big issues with medical devices companies is the number of times they have to apply for a CE mark or for an FDA clearance to market. However, it is rare for a company to step outside of their comfort zone; and even more rare to review the process that took them to the eventual outcome. It is possible to learn from the activity itself, be it a success or a failure. Hence it makes sense to learn from the, but even better to plan to learn from the now. The regulatory steps that were taken to reach the ultimate outcome need to be recorded and analyzed. It is possible to save the company a lot of time by learning from previous successes and previous failures.

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Processes govern the whole of the medical devices industry, yet one of the most important tasks (the determination of classification) is often overlooked. It should be the first thing to be done, even at the ‘oooh what about this for an idea’ stage, there should be an initial estimate of classification. Hence the idea that all medical devices companies have a classification process is not such a daft idea. One must remember that the costs of administering medical devices grow disproportionately with each classification level; removing an idea, at an early stage, due to offensively large expenditure profile is just as important as developing a new, money spinning, idea. Fig. 2.11 illustrates a typical flow chart developed for determining if a device is class I (within Europe using the old MDD). Whilst this does not match completely with the USA it is worthwhile doing, if only to understand your idea better or even to second-guess the classification panel. There is no reason why you shouldn’t produce one of these for each of the devices you intend to market. At the very least it tracks your decision making process and can be signed off as a part of your technical file. Note that all of the rules that do not end with a class I device have been removed. This flow chart has turned the classification rules on their head; instead of ‘what is the classification?’ the question has become ‘is my device class I’ and this is probably the best, bottom-up type of approach to take. After all we would all save loads of money in relation to auditing, administration and insurance if all or our products were the lowest class possible. There is no credit, no medal, and no prestige in having your devices in a class too high for its worth. Do not fall into the trap of ‘I will

Rule 1 - Invasive?

No Does Rule 2 apply?

No Does Rule 3 apply?

Yes

Does Rule 4 apply?

Yes

Do Rule 2 sub- clauses apply?

Do Rule 5 Class I clauses apply?

No

No

No

Yes No

CLASS I

Are the active? No

Do Rule 6 Class I clause apply?

Yes

NB: Under new MDR this leads to Class I Reusable Surgical Instrument

Yes

Do Rules 9, 10 or 11 apply

FIG. 2.11 Is my device class I?

No

2.6 Classification and the design process

play safe and make it a higher classification’; this is not the idea and defeats the whole purpose of this chapter.

2.6 Classification and the design process In both the USA and within Europe the degree of control one applies to the whole life cycle of the device increases with classification (as illustrated by Table 2.4). However this does not mean there is NO control at class I; it is virtually the same quality of design activity as Class IIb (for example), but there is a greater level of checks and measures to mitigate against the risks. The FDA use specific terms for the level of control, and these are worth remembering wherever you intend to work: Class I means the class of devices that are subject to only the general controls . Class II means the class of device that is or eventually will be subject to special controls . Class III means the class of device for which pre-market approval is or will be required . FDA (2010).

Basically this means that the level of investigation into your design processes before giving any CE mark, or clearance to market, is negligible for class I products. Indeed it is virtually self-regulated. You may be tempted to think that this means you do not need to do any ‘real design’ e you would be wrong. You have to think about the situation when something goes wrong; when you are placed in court defending your product that has just maimed someone; when you have to defend your design to an expert designer with no evidence. Self-regulation, therefore, means you make sure you have the design files in place. The higher the classification means your design’s file becomes ‘thicker’; it will contain more investigations to make sure it is safe to use. Indeed for the highest classifications you WILL NEED to submit the design file FIRST before you can even start to think about applying for regulatory approval, and certainly before any clinical studies can start. The overall process is the same; it’s the amount of checks and Table 2.4 Device classification versus control measures. Design control

Lower

EU Class USA Class Self Regulation

I I High

Higher IIa II

IIb

III III Low

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balances that increase. Your company will have to defend it’s submission to the authorities before it can be placed on the market. The file has to be bullet proof; the higher the classification the bigger and faster the bullets. The people that audit your files are not stupid, they are highly intelligent scientists and engineers so do not try to fool them e you will fail. Fig. 2.12 illustrates the amount of effort required for each classification. The amount of external control is negligible for class I products, but the company’s internal control is significant. For class III devices the amount of control exerted by external factors is probably equal to (if not more than) that of your company. This does not means your hands are tied and you cannot make any design decisions, it simply means you have to justify them e fully. Hence the amount of effort you must apply to the design process increases too. But, this does not mean that there is NO design effort for lower classifications e in fact I would argue there is little difference in the design effort e just more audit activities; and this is indicated by the increase in internal and external control. Another way to look at the design effort is using standard Pareto9 analysis. In essence 80% of the design effort is allocated to 20% of the activity related to the outcome. Our job is to make sure that 80% of effort is used in the right places, for the right things and, of course, efficiently.

design effort

external control

internal control

I

II

III

FIG. 2.12 Control effort versus classification.

9

The Pareto principle is named after Vilfredo Pareto after he noted that 80% of the land in Italy was owned by 20% of the population.

2.7 Classifying software

External control does not only come from the regulatory bodies. As the classification increases so do the number of standards that apply. There are many standard bodies to work with but in general we will be talking about ASTM(American Society for Testing and Materials), ISO(International Standards Organisation) and BS (British Standards). These are the three standard bodies for the USA, for International (global) and for Britain. Unfortunately working with a standard in the USA does not necessarily make this compliant with a standard within the EU, hence the recognized consensus standards become a very good starting point to determine which standards apply. Also your device may cross discipline boundaries, one example being a simple orthopedic drill (Fig 2.13). Whilst this is clearly a medical device, but because it is powered it also falls under the remit of powered hand tools; it could well be subject to electro-magnetic compatibility too, and because it makes a noise falls under noise emissions regulations. Also, many new electronic devices are digital e and that meands they have a programmable chip on board. This means it is also governed by Software regulations, standards and guidelines. Indeed it is software that is by far the biggest hole to fill in many new medical devices as both designers and programmers alike just do not understand the ramifications e hence this edition has a much larger section on design control in software. As the designer you must make sure that your device meets all relevant standards and guidelines. Unfortunately class I designers only find this out when it is too late; class II, and above, design teams have the failings pointed out to them when they have their first audit. This is the main drawback of self-regulation!

2.7 Classifying software Due to the very nature that software (either on-board or free standing) can have a variety of functions it has both a “medical devices” classification and a “software” classification.

FIG. 2.13 A common orthopedic power drill. Courtesy Desoutter.

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The general rule of thumb is that if software is associated with a device (or embedded on a chip) than it takes the classification of said device. For example a digital room thermometer would have a classification of Class I measuring, hence the embedded software must have the same classification. However, due to the potential risks of badly designed software, some regulatory bodies are looking at making all software as Class IIa level as the default. Unfortunately this is mostly down to software developers and their flagrant attitude toward design and design controls e often the word “agile” is used as a defense against control: honestly it is not a defense! A well controlled design process IS agile as it promotes a “right first time” philosophy e agile does not mean “get it done as fast as possible and ignore the consequences”. Stand alone software must be classified using the normal processes described earlier (we will look at stand alone software later). But the first question often asked, is “is it really a medical device?”. The EU have produced a neat flow chart (Fig. 2.11) for this decision process e but bear in mind software rules are changing very quickly due to the very nature of the discipline. Also bear in mind that the definition of “software” varies from country to country e person to person and programmer to programmer. As far as the EU is concerned software “is defined as a set of instructions that processes input data and creates output data” (EU, 2016). Not entirely satisfactory e but does the job. A few items pop up from Fig. 2.14. The first is the definition of standalone software. Basically it means software that is not associated with any existing medical device or as the EU state: stand alone software’ means software which is not incorporated in a medical device at the time of its placing on the market or its making available EU (2016).

The problem with this definition is that even within the guidelines the lines are blurred e for example it is stated in MEDDEV 2.1/6 that standalone software may control an apparatus e I am sure by this they mean the software can provide information that helps settings to be better adjusted, I am sure it does not mean control as we would interpret control. I would interpret this as: if the device can function without the software and there is no need for it to operate said device then it is standalone; if the software plays a part in the control of said device but the software is remote and use of it is by choice rather than necessity it is standalone and is an accessory to said device; if however the device cannot be used without the software then it is NOT standalone. But, as usual, I stand to be corrected! Just so you are quite clear, MEDDEV 2.1/6 also contains a similar decision flowchart for IVD devices. You are not exempt! This document is well worth downloading as it even gives some worked examples e and that is a useful addition to the MEDDEV series of documents.

2.7 Classifying software

FIG. 2.14 Software medical device decision. Adapted from MEDDEV 2.1/6.

For those of you considering the USA a similar process has been developed by the FDA. However the USA seem to be far more relaxed about certain software issues and what is highly regulated in the EU is less so in the US e but that is not a certainty. You should have learned, by now, that it is down to you to do the leg-work. So as another piece of homework you need to find the FDA software classification process.

2.7.1 Software safety classification We have not reached Risk Management and Risk Analysis yet, but so that I impress upon you how import the analysis of risk is I will briefly discuss software safety classification. The classification process illustrated in Fig. 2.15 has been adapted from BS EN 62304. The more risky the software, the higher the classification, the greater the degree of design control required (and hence checks and balances). Note that the flowchart MAKES you use ISO 14971 to do the risk analysis. We shall meet this standard and how to perform a risk analysis to meet its requirements later in this book.

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All software Class C by default

Can a HAZARDOUS situation arise from software failure?

NO

YES

Evaluate risk and mitigate (ISO 14971)

Does any software failure mode result in an unacceptable risk?

CLASS A

INCREASING LEVEL OF DESIGN CONTROL

NO

CLASS B YES

What is the severity of the hazard?

NON SERIOUS injury CLASS C SERIOUS INJURY / DEATH

FIG. 2.15 Software classification based on risk.

2.7.2 Case Study Consider a simple blood pressure monitor (or sphygmomanometer). A first examination of the MDD and MDR rules suggest: MDD: Annexe IX, Rule 1 Class I with measuring function (hence it is required to be CE marked by a Notified Body). MDR: Annexe VIII, Rule 1: Class I with measuring function(hence it is required to be CE marked by a Notified Body). FDA: Conducting a search using “blood pressure” results in 25 entries of which the first ten are illustrated in Fig. 2.16: Selecting “system, measurement, blood pressure, non-invasive” from the list results in Fig. 2.17. An examination of all results illustrates that all blood pressure monitoring systems are Class 2 in the USA and require a 510(k) examination.

2.7 Classifying software

FIG. 2.16 Results of FDA search using “blood pressure”.

Why are they so varied? This is an example of why it is important to go through all the rules in Annex IX (MDD) or Annex VIII (MDR). A check of the definitions in the MDD and MDR results in the following Active device intended for diagnosis and monitoring’ means any active device used, whether alone or in combination with other devices, to supply information for detecting, diagnosing, monitoring or treating physiological conditions, states of health, illnesses or congenital deformities. EC (1993) & EU (2017).

This suggests we should go to the “active devices section” of the rules. In the MDD, rule 10 (and the MDR) states: Active devices intended for diagnosis and monitoring are classified as class IIa: . if they are intended to allow direct diagnosis or monitoring of vital physiological processes, unless they are specifically intended for monitoring of vital physiological parameters and the nature of variations of those parameters is such that it could result in immediate danger to the patient, for instance variations in cardiac performance, respiration, activity of the central nervous system, or they are intended for diagnosis in clinical situations where the patient is in immediate danger, in which cases they are classified as class IIb . EU (2010), EC (2017).

This suggests that e in fact e the real classification is CLASS IIA by Rule 10, unless their use is vital to life (such as in the OR or intensive care) in which case the subclause makes the CLASS IIB. And we shall see the impact of that in the next section.

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FIG. 2.17 Expansion of one result of search for “blood pressure”.

Re-examining MEDDEV 2.4/9 (EU,2010) we see that blood pressure monitoring is an actual example of Rule 10:

- if they are intended to allow direct diagnosis or monitoring of vital physiological processes: - Electrocardiographs; - Electroencephalographs - Cardioscopes with or without pacing pulse indicators2 - Electronic thermometers - Electronic stethoscopes - Electronic blood pressure measuring equipment. EU (2010).

Another reason why it is so important to keep an eye on the regulations! Not the inclusion of the thermometer in this list!

2.8 Impact of classification on conformity assessment

What about the software? Well, a modern blood pressure monitoring device is based on electronics e and normally have a display of some kind of electronic display (has anyone seen one of the old mercury sphygmomanometers recently e well I hope not or the poor clinician may have acquired mercury poisoning!). Using Fig. 2.11 the software is also at the same classification as the device. Using Fig. 2.12, if the device is for use in a non-critical environment then the software would be CLASS B, if it were for use in the OR or intensive care it would obviously rise to CLASS C. An interesting aside, if it were only for home use would the software be CLASS A? discuss! Also, do not forget it is now running on electricity (mains or battery) in which case ISO 60601 is really important e but also note that the results from the FDA search has also given other standards to refer to (Fig. 2.14).

2.8 Impact of classification on conformity assessment Conformity assessment is the method by which either a CE mark or FDA clearance to market is obtained (which we will discuss later). Although we shall be discussing the methodology later on in this book it is worth looking at the impact of classification on the assessment method now as this indicates how important design control is. I do not intend to cover MDD, MDR and FDA but instead I shall give the old MDD matrix as an example. Hopefully you will have recognised that Table 2.5 becomes redundant in Spring (2020) and will be replaced by the new MDR conformity assessment methodology. Hence MEDDEV 2.4.1/9 will become MEDDEV 2.4.1/10 (or some other new Table 2.5 Conformity versus classification as taken from MEDDEV 2.4.1/9 ( ). Classes MDD Annexes

I

I (Sterile, measuring, and reusable surgical instrument)

IIa

IIb

III

VII VI V IV III II (not including section 4) II (including section 4) Design control increasing Under the new MDR another another classification has been created (basically rule 6): Class I (Reusable Surigal Instrument) that has the same requirements as Class I sterile and Class I measuring.

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reference number). This is one very good reason to keep a watching eye on the EU and FDA websites for any changes e and this watching eye should by Sauron10 like.

2.9 Summary In this chapter we were introduced to classifications. We saw that there are two different approaches in the USA and Europe but that they ultimately end in the same place. We saw that the classification in USA may not directly match to that in the EU. We learnt how to classify our devices and determined what the classifications mean to our design controls and our development costs. Therefore you now have a few tasks to complete to ensure that you are fully au-fait with the classification methodology. By the way, if you thought I had forgotten In-Vitro Diagnostic Devices e nope, I have not. I have done one small example for you, but I have left this for you to look at for homework (Task 7). The same sort of processes apply as I have shown above: you need to download the new IVD regulations (and the old ones too) and read through the classification section and the implications thereof.

2.9.1 Homework Task 1: Make yourself full aware of the FDA database of product classifications. Task 2: Create a gap analysis of the differences between the rules for the MDD and the MDR. Determine which are the new rules. Task 3: Determine the classification (EU, MDD and MDR, and USA) for i) Single use scalpel ii) A dental filling (you will need to think to find this) iii) An x-ray imaging machine iv) Software used to enhance and better interpret x-ray images. Task 4: Produce a chart similar to Fig. 2.7 for Class IIa devices for both the MDD and MDR. Task 5: Produce a flowchart similar to Fig. 2.11 for the classification of software under FDA guidelines. Task 6: Produce a new Table 2.5 from the new MDR. Task 7: Repeat the process I have shown you for the In-Vitro Diagnostic Device classifications: use devices such as a glucose meter as examples.

10 Sauron was the evil “baddie” in both the Hobbit and the Lord of the Rings written by JRR Tolkein. In the books the “Eye of Sauron” was ever vigilent and watching Middle Earth. By the way if you have only watched the films and never read the books you have missed out on something quite special.

Websites for further information

References British Standards, 2006. BS EN 62304: Medical Devices Software e Software Life Cycle Process (Note This Standard Is Being Replaced in July 2018 by a New Version). European Community, 1993. Medical Devices Directive. 93/42/EC. European Community, 2005. Reclassification of Hip, Knee and Shoulder Joint Replacements in the Framework of Council Directive 93/42/EEC Concerning Medical Devices. 2005/50/ EC. European Union, 2010. Classification of Medical Devices. MEDDEV 2.4.1/9 June 2010. European Union, 2016. Guidelines on the Qualification and Classification of Stand Alone Software Used in Healthcare within the Regulatory Framework of Medical Devices. MEDDEV 2.1/6 July 2016. European Union, 2017. Medical Devices Regulations, 2017/745. FDA, 2010. CFR -21. Subchapter H, p. 860. ISO, 2012. ISO 14971 Risk Management for Medical Devices. Staffordshire University, 2008. A Systems Approach for Developing Class I Medical Devices. BEng(Hons) Thesis.

Websites for further information American Society for Testing and Material (ASTM): http://www.astm.org. British Standards Institute (BSI): http://shop.bsigroup.com. FDA: Databases, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ Databases/. FDA: Recognized Consensus Standards, http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfStandards/search.cfm. International Organisation for Standardisation (ISO): http://www.iso.org. EU MEDDEV documents, https://ec.europa.eu/growth/sectors/medical-devices/guidance_en.

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