Arterial Products Ltd

Automation of Coronary Stent Manufacture

A manufacturing proposal

2009

Automation of Coronary Stent Manufacture Arterial Products Ltd

Group #8 Cathal Finch Shane Keaveney Patrick King Neville Lawless Brendan ODriscoll 2

Academic Integrity

I/We declare that the material contained in this project is the end result of my/our own work and that due acknowledgment has been given in the bibliography to ALL sources, be they printed, electronic or personal

Signed: ----------------------------------------------------------------------------------------------------------------------------------Date: Cathal Finch Shane Keaveney Patrick King Neville Lawless Brendan ODriscoll

Table of Contents
Automation of Coronary Stent Manufacture.......................................................................2 Arterial Products Ltd............................................................................................................2 Table of Contents.................................................................................................................4 1.0 Executive Summary.......................................................................................................5 2.0 Introduction ...................................................................................................................6 3.0 Overview........................................................................................................................7 ..............................................................................................................................................8 3.1 Stent Overview...............................................................................................................8 3.2 Current Stent Design Trends..........................................................................................9 3.3 Industry Overview.......................................................................................................11 3.4 Recent & Future Trends in Industry............................................................................12 4.1 Construction Introduction ...........................................................................................17 4.2 Tube Mesh construction stents.....................................................................................18 4.3 Wire/ring construction stents.......................................................................................23 4.4 Common Construction Processes................................................................................25 5.0 Manufacturing Procedure.............................................................................................31 5.1 Evaluation of Manufacturing Procedure and Production Line Setup..........................32 5.2 Critical issues that may cause Disruptions ..................................................................37 Annealing oven ............................................................................................................38 6.0 Automation Evaluation ...............................................................................................39 7.0 Proposal for Arterial Products Ltd...............................................................................48 7.1 Proposal Summary.......................................................................................................51 8.0 Appendix .....................................................................................................................53 8.1 Glossary.......................................................................................................................54 8.2 Calculations .................................................................................................................55 9.0 References ...................................................................................................................56

1.0 Executive Summary

Arterial Products Ltd, a leading manufactuer of catheters and balloon angioplasties in the medical device industry is considering expanding into stent production. The company plans to manufacture coronary stents at a rate of 10,000 per annum with a view to expanding to 20,000 per annum within a decade. The company requested a manufacturing proposal to highlight and evaluate the various manufacturing methods currently adopted in the medical industry today. A brief overview of stent manufacturing and trends in industy was also requested to aid the company in choosing which process to adopt. This manufacturing proposal highlights several differnet process and based on research in the field has concluded with a recoomendation for Arterial Products Ltd. as to which manufactung procedure would be most beneficial to their company. The result of the proposal was that a batch process involving a laser micro-jet, a tube mesh construction, micro-blasting, electro-polishing, PVD coating for Bare Metal Stents with manual inspection setup was recommended. It was decided that this manufacturing configuraton best suited the needs of Arterial Products Ltd. and hence was the setup that was presented to the company with a view to implementation.

2.0 Introduction
Arterial Products Ltd. has been producing catheter and angioplasty balloons for the past twenty years. After gaining a strong foothold in these industries across Europe and becoming leading experts in the field the company is considering adding a coronary stent production line to their facilities. Arterial Products Ltd. plans to begin producing coronary stents at a rate of 10,000 per annum (40% of their current production rates for catheters and angioplasties). Looking to the future, the company hopes to boost production rates to 20,000 per annum. The aim of this manufacturing proposal is to provide a thorough investigation of the manufacturing options for coronary stent production. On behalf of Arterial Products Ltd. a design of a leading competitors (Medtronic) stent will be investigated for manufacturability and automation possibilities. Following this research, a method of production will be chosen that is seen to be suitable for Arterial Products Ltd. requirements.

3.0 Overview

3.1 Stent Overview

A stent is a medical device used to support weakened arteries. Stents, comprising of small metal tubes are inserted into the body in procedures known as angioplasties. In an angioplasty a balloon is used to open a blockage in a coronary artery. After an angioplasty blood flow is restored and a stent helps prevent the arteries from becoming blocked again. Stents are generally made of a metal mesh but may also be made of fabric. Much research and emphasis is being placed on developing bio-absorbable stents which the body dissolves after a period of time. Stents may also be coated with drugs which slowly and continuously release medicine into the artery which help the artery becoming re-blocked. These types of stents are known as Drug Eluting Stents (DES).

Figure 1: Stent deployed 8

3.2 Current Stent Design Trends

In order to thoroughly investigate the manufacturing options of coronary stents by Arterial Products Ltd. a full and proper understanding must be gained by examining current trends in stent manufacturing. Today there is a wide range of stents on the market with varying designs and physical dimensions. These various stents offer solutions to a broad range of lesions within the coronary circulation. During the last ten years stents have evolved with improvements in technology and general stent design, the design of delivery systems, techniques specifically designated for certain lesions, and a change in the perceived need for anticoagulation. Obstacles to stenting such as large branches, long lesions, lesions on sharp bends and increased risk of anticoagulants are no longer considered to be so significant. Even the left main stem is no longer immune from stenting as a bailout procedure, even when not protected by one or more bypass grafts. Longer stents allow a range of lengths to be covered. Greater awareness of the role of anti-platelet agents, including IIb/IIIa receptor inhibitors, has reduced the risk of sub acute stent occlusion and hemorrhage. Lesions in vessels where the approach to the site of the stenosis is extremely tortuous continue to present a challenging problem but improvements in delivery system design and the use of stiffer wires to straighten the target vessel temporarily make these lesions more amenable. There are some areas where stents are still not suitable solutions and trends in industry look to be fixed on solving these issues. Stents may not be applied to lesions that cannot be predilated. If these types of lesions are stented the risk of sub acute occlusion is high. 9

Lesions in vessels smaller than 2-5 mm diameter are not stented because of the incidence of thrombosis and restinosis.

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3.3 Industry Overview

One of the main design considerations stent manufacturers are focusing on is the strut width of the stent. When a stent is inserted and expands, some damage to the arterial wall is incurred. Manufacturers are seeking to minimize the contact surface area by decreasing -the strut width. To achieve this goal, the control system must maintain tighter tolerances during the cutting processes. Any small deviations from the initial design result in larger percentage errors in the overall strut width leading to adverse effects. A second area manufacturers are redesigning is the thickness of the stent. The trend is leaning towards thinner stent structures to improve flexibility and overall performance. An advantage to striving towards thinner stents is that thinner stents sustain higher cutting speeds which are more efficient. Bioabsorbable stents are being researched. These stents, made of polymers, dissolve over time. Producing stents made from polymers requires a different manufacturing setup with different laser wavelengths and involves an ablation process where the material is vaporized during the machining process. Manufacturers are experimenting with multiple pass procedures to produce these types of stents.

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3.4 Recent & Future Trends in Industry

Balloon angioplasty was somewhat replaced by Bare Metal Stents in 1994. Balloon angioplasty has a high restinosis rate of 30-40 percent. The introduction of such stainless steel stents helped to reduce levels of restinosis to rates of 15-20 percent a significant improvement. However the introduction of BMS increased the risk of early in-stent thrombosis immediately after the procedure and neointima scar tissue.

Figure 2: Bare Metal Stent The issue of thrombosis was counteracted with anti-platelet therapy. It was not until the introduction of Drug Eluting Stents (DES) that the issue of neointima scar tissue could be addressed. DES was introduced by Cypher (Cordis) in 2003 and Taxus (Boston Scientific) in 2004. They were followed by Endeavor (Medtronic), Xience (Abbott) and Promus (Boston Scientific) in 2008. These stents took advantage of the same types of drugs used to fight cancerous tumors. Some of the stent manufacturers designed the DES to elute their drug early during the initial vessel healing process whereas some DES eluted the drugs later on in the recovery period. 12

However most DES elute their drug in the first three months, which is the period when scar tissue typically forms in bare metal stents. Endeavor elutes in about two weeks, Cypher in about 100 days, and Xience and Promus well after 100 days. Like the introduction of earlier technology DES have some obstacles which too must be overcome. DES solutions create a rise in rates of late-stent thrombosis. Studies and experiments carried out have shown that this adverse affect is caused by the drug delivery polymer irritating the vessel.

Figure 3: Drug Eluting Stent The American College of Cardiology proposes using anti-platelet technology to combat this issue. However this remedy also has side effects. This led to research into Bioabsorbable polymer stents mentioned earlier. This recap brings us to the present day where Boston Scientific is waiting for FDA approval for a new stent which uses dots of polymer along the struts to limit vessel/polymer contact. Another stent being developed by Boston Scientific named the Cordis Nevo uses tiny holes in the struts which act as reservoirs for the drug polymers to cut the amount of polymer on the stent and its contact with the vessel wall. Looking into the future, Abbott plans to release a fully Bioabsorbable stent which it hopes to release sometime in the next 10 years. 13

Figure 4: Bioabsorbable Stent

This recap of stent industry allows for a greater understanding of future stent manufacturing prospects and allows for a greater insight into how Arterial Products Ltd. may produce coronary stents in the future. By understanding the technology currently in practice and reviewing future advancements, this sets a plateau from which a method of production for Arterial Products Ltd. can be proposed and examined.

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4.0 Construction

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4.1 Construction Introduction

Below are the two different construction methods we considered for the stent which will be produced by Arterial Products Ltd. The first is a tube mesh construction. This method is detailed below with a step by step guide to the processes involved. The Wire/Ring constructed stent and the processes involved in its construction are also examined. Finally the general construction processes involved in both methods are reviewed.

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4.2 Tube Mesh construction stents

For a balloon expanded stent, the stent is cut from a blank tube of material (generally stainless steel). The blank tube is cut to length and uniform slots and shapes are cut out to give the stent its mesh form. This allows the stent to be crimped so it can be inserted into the artery. The mesh structures are joined together via struts. The design of these struts is critical to the efficiency of the stent. For this reason the quality of their cutting and finish is of high importance in the stent production. The process flow diagram below highlights the main processes involved in the tube mesh construction of stents. These processes are then reviewed in more detail below.

Blank

Laser Cutting Unfinished Expanded Metal Stent Finishing Finished Expanded Metal Stent Coating Process Coated Expanded Stent Crimping Assembled Stent System Catheter/Ballon Catheter

Figure 5: Process Flow Diagram Tube Mesh

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When choosing tube mesh construction, two different types of laser cutting processes may be adopted. The two processes are evaluated below. a) Dry Nd: YAG Laser cutting This process, also known as fine laser cutting, is an advanced machining process used for cutting thin materials in tube mesh construction. It is an extremely fine cutting process compared to rougher laser cutting such as CO2 laser cutting. It is used for cutting fine detail into delicate parts which require a high degree of accuracy. This process is typically carried out on machines which have accurate axis movements and, in the case of stents, a rotating axis.

Figure 6: Nd: YAG laser cutting on a stent For tube mesh construction, the cutting of the slots in the stents can be done by the Nd: YAG laser process. The equipment used in this process would have very high tolerances, up to +- 2.54m, thus making it an extremely precise process. An adverse effect of this process is that it can cause damage to the surface of the stent. It leads to an oxide layer on the stents surface along with remelt on the sides of the struts as the laser beam becomes more diffuse. The beam usually becomes more diffuse when used to machine thicker walled tubes.

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The laser cutting machine, for use with stents, would have an Nd: YAG laser device used for the cutting. The work piece would be mounted in a rotatable fixture. The laser its self would be able to move laterally along the length of the stent. Both the rotation of the stent and the lateral movement of the laser would be computer controlled. In terms of using this process in the production of the Arterial Products Ltd stent, it is a very good and precise process but due to the problems associated with it, mentioned above, the stent requires post-cutting processes to improve surface quality and material properties.

Figure 6a: Stent cut using an Nd: YAG laser

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b) Water jet Guided laser Technique An improvement on the plane Nd: YAG laser cutting process is the Water Jet Guided Laser Technique. This method of cutting was discovered by scientists at the Institute for Applied Optics at the Swiss Federal Institute of Technology Lausanne. The Laser Micro-Jet involves guiding a laser beam by a water jet. The laser beam is focused in a nozzle and passed through a low pressure water jet. The water jet bounds the laser beam and guides it. The geometry of the chamber and nozzle are very important for holding the high energy laser beam in the water jet. The laser beam is guided by means of total reflection at the transition zone between the water and air of the inner wall of the water jet. The water jet can be referred to as a fluid optical wave-guide of a variable length. For this method a pulsed laser is used. This in turn means that as the cutting process is taking place the water can cool the cut. Due to this cooling effect of the water a very slight thermal penetration is achieved. This leads to a very narrow clean cut which is parallel with no burrs and no thermal damage. With this process an IR laser is used. Due to the fact that no remelt is created during the cutting process, the need for micro blasting can be largely reduced or even removed. This is a big advantage as it reduces the chance of weakening the struts of the stent. The quality of the stent manufacturing is increased and product liability is greatly reduced. The quality difference of the Laser Micro-Jet compared to the Nd: YAG is huge. The Laser Micro-Jet cut stent has a far higher biocompatibility than stents cut with the Nd: YAG process. Advantages of this water guided system compared to the dry cutting laser process include high cutting speeds, excellent surface finish and accuracy, no damage due to heat, very small parallel cuts (28-60m), reduced post-processing and reliable consistent product with any cutting geometry possible. 20

The equipment used in this process is very similar to that described in the Nd: YAG laser cutting process. The main difference between the two machines used is the use of the water guided jet. This adds to the foot print of the machine as water supply such as pumps, pipes etc will need to be taking into consideration compared with the dry laser cutting machine. The quality achieved by using the water guided cutting machine when compared to dry laser cutting is huge. This in turn reduces product liability. The Laser Micro-Jet cut stent has a far higher biocompatibility than stents cut with the Nd: YAG process. By comparing the figures illustrating the Laser Micro-Jet cut stent and dry laser cut stent we can see the marked improvement in the cut and finish quality. This is one of the main reasons the Laser Micro-Jet machine is deemed to be more suitable for Arterial Products Ltd stent production. It reduces post processing and improves overall quality, along with have having higher cutting speeds and being very suitable for automation.

Figure 6b: Diagram of water guided laser cutter

Figure 6c: Stent cut using a Water jet guided laser

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4.3 Wire/ring construction stents

This second, older stent construction method is evaluated below. These stents formed using the wire/ring construction method are constructed from rows or shapes of material and are arranged in a cross-hatched, braided or interconnected arrangements. They are assembled in a tube-like structure on a tungsten rod. Next they are fused together, usually using laser welding or something similar. Fusing is a complex and inconsistent process. Vision detection software is used to locate the fusing point. The operator can adjust this location. The laser welding mechanism to fuse the fusion point is then activated. After this initial fusing the machine will automatically rotate and move to the next fusion point depending on the stent type it is fussing. The machine fuses all fusion points automatically apart from the first. The equipment used in the fusing process is complex. It includes a laser welding device and a vision detection system as mentioned above. The laser welder must be able to reach all fusion points on the stent. This means the stent may need to be placed on a rotatable mounting and the laser welder moveable in the lateral direction. This is similar to the laser cutting equipment described previously. The machine requires the accuracy of an operator for the correct fusion of the initial fusion point. If the first fusion is incorrect the rest of the fusion points will be missed by the laser and thus the stent will be unusable. As said above the machine is complex and inconsistent. There may also be quality issues due to fusion points which may lead to poor surface quality and remelt problems along with heat affected zones. Due to all of these issues the wire/ring construction method for stents would not be recommended for Arterial Products Ltd stent.

After the fusing process the stent may be swaged. This is a process which increases the surface of the stent by removing material from the outer surface. This process is used for drug eluted stents so as to increase the capacity of them for a greater surface coating of 22

the drug on its surface. The stent is then chemically cleaned before being annealed and subsequently electro polished. The process flow diagram below illustrates the order of the processes in this construction method.

Figure 7: Process Flow Diagram Wire/Ring

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4.4 Common Construction Processes

Whether the tube mesh or wire/ring construction method is adopted, both methods incorporate the following processes. Swaging In this process material is removed from the outside surface of the stent to increase the microscopic surface area of the stent. The reason for this process is to allow a greater drug coating to be placed on the surface of the stent.

Figure 8: Swaging

The equipment involved in the swaging process consists of a swaging machine. The swage machine uses 3 cutters which spin around the outside of the stent. These cutters remove a very small amount of material to create very small flat spots on the stent. The equipment used is small and quite simple. This process is only necessary for Drug Eluted Stents. Annealing In the annealing process stents are placed in a heating chamber filled with an inert gas. They are heated for approximately 1 hour. The reason for this process is to grow the grain

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size of the stents to a specific length. The chamber is filled with inert gas to remove oxidation from the stents which may be caused by the cutting or fusing processes. The equipment used in annealing is a batch system with a series of ovens and the continuous system, with one oven. The stent undergoes a series of heat treatments at different temperatures. For the batch system a number of ovens are used. The batch is moved from one oven to the next. Each oven is at a different temperature, set specifically to the design requirements. Each oven has pumps which remove the air from inside them and refill them with an inert gas. For the continuous system one oven is used which has a conveyor belt which runs through it. The oven has different stages within it set at different temperatures. Nitrogen gas is pumped in the opposite direction of the conveyor belt along its entire length. This is done for the same reason as the batch oven system, which is to remove oxidation from the stents. The continuous system lends itself well to a high volume, continuous, automated system. It reduces the amount of handling of the stents between heat treatment stages and therefore reduces the risk of defects due to miss handling. The batch system has a smaller foot print but is a slower process and does not lend itself well to automation. However the batch system is more suited towards Arterial Products Ltd stent production due to the smaller foot print and the fact that the continuous system would be more suited to a higher production rate than they are considering. Chemical blasting This is a process used to remove both the oxide layer and the remelt resulting from the laser cutting. This is a high precision process. Chemical blasting treats all surfaces equally. 25

The equipment used in chemical blasting is quite simple, although it requires the storage of dangerous chemicals. The chemical is applied to the stent using a pump system or the stent may also be dipped in the chemical. It treats all areas, which is especially good in the treatment of stents due to their small features which can be hard to reach with micro blasting. With the use of the water guided laser cutting this process is generally not needed. Also with the fact that Arterial Products Ltd. has micro blasting facilities already available, the introduction of chemical blasting would be wasteful if they have the capacity in their existing micro blasting facilities. Basic micro abrasive blasting In this process the stent is fixed by custom holders which are controlled by the operator. Depending on the size of the stent, vision enhancements systems may be used. A blasting nozzle is pointed at the surface to be abraded and the operator uses a foot pedal to activate it. The air pressure and amount of abrasive used is monitored and automatically regulated. The blasting process must be very precise. If too much abrasion is used the joints of the stents will be weakened which can cause premature failure of the stent. This is often controlled by measuring the amount of material removed from the stent in thousandths of grams. A flow of clean dry air is mixed with a pure, uniform, abrasive media. An extraction system is used to remove the abrasive, from around the work piece. Various media and air pressure can be used depending on the attributes and specifications of the product. The equipment used for this process consists of an air pressurised system which is used to blast the stent with abrasive. The operation of it is described above. There must be very high control on the equipment used in this machine. If the micro blasting machine removes too much or too little material from the surface of the stent it could cause the failure of the stent and or complications after stent implantation. As said with chemical blasting the use of this process can be rendered unnecessary with the use of the water guided laser cutting machine. 26

Polishing This is a final surface finishing process used in stent manufacturing. The industry standard is electro polishing (an electrically driven process). Electro-polishing creates a high chrome surface finish. The object to be polished is placed on an anode bar which is lowered into a number of chemical baths. Material comes out of the solution in the chemical baths and is attracted to the surface due to the electrical current supplied. The material reforms on the surface to create a coating on the object. The object is then passed through a passivation stage in nitric acid to remove any ions and prevent rust forming. The equipment used in electro polishing has a large foot print due to the number of tanks used in the two stages of the process. The storage of the various chemicals is another associated issue and cost. Along with the cost of the power consumed during the process. The quality of the finish is of a high quality. More recently, chemical processes have been used. The basic principal behind chemical polishing is an object is placed in a bath of acid. A typical mixture used is phosphoric acid (80%), nitric acid (4%) and water (16%) at approx 35 C. The main advantages of chemical polishing are that it reduces the outlay in the plant due to less tanks and fixtures along with the reduction in electrical powers supply. The purpose of all these surface finishing processes are to improve the surface finish so as to reduce and eliminate surface defects and to produce a stent that has improved corrosion resistance and fatigue life. Stent Crimping Stent crimping is a process whereby the stent is crimped over its balloon delivery system. The balloon is place inside the stent and the stent is then reduced in diameter by a crimping machine. The purpose of this is so that the stent may be delivered to the

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affected area with the balloon in it. The balloon may then be inflated to expand the stent to its desired size. The equipment used here is pretty standard and very simple. It has a small foot print and is high automatable. Coating There are various coating methods, each with specific characteristics, which may be chosen when considering stent manufacture. Dipping The stent is dipped in a bath of liquid to form the coating. When the stent is removed a film is left on the surface as a solid. The equipment used in dipping is very simple and is as described above. It allows for batch coating as all stents can be coating at the same time thus reducing time of coating. Any coating that can be liquefied and re-solidified can be used. Spraying The coating is applied via a spraying gun. It sticks to the surface of the stent to create a thin film of the coating. Spraying is a simple process which requires simple equipment. It uses a pressurised air system and a spray gun device which uses the pressure of the air to spray the coating on the stent. The use of spray for a stent coating may not be very suitable due to the small features of the stent which may be hard to reach with spray. It requires that the stent or the spray gun can move during coating to reach the various parts of the stent. As with dipping any coating that can be liquefied and re-solidified can be used.

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Physical vapour deposition (PVD) The material to be used as the coating is a substrate and the stents act as the cathode target. The power supply creates plasma between the substrate holder and the target. Material is transferred from the substrate to the target via this method. This creates a thin film on the surface of the stent.

Figure 9: Physical Vapour Deposition From figure 9 above the outlay of the equipment used is clear. The foot print of the PVD machine would be reasonable large. It requires a large amount of power which increases the cost of the stent coating. PVD is also preformed in a vacuum which also increases the equipment required and the cost. Almost any type of inorganic coating can be used as well as some kinds of organic coatings. Chemical vapour deposition (CVD) CVD is be defined as the atomistic deposition of solid material onto a substrate from the vapour / gas phase, brought about by thermally induced chemical reactions. CVD creates a thin film coating on the surface. The equipment required for CVD is complex, has a large footprint and is totally unsuitable for Arterial Products Ltd stent manufacturing. The running cost and setup cost are far too great. CVD is also a very slow and non-automatable process. CVD coatings are usually only a few microns thick and are generally deposited at fairly slow rates, usually of the order of a few hundred microns per hour. 29

5.0 Manufacturing Procedure

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5.1 Evaluation of Manufacturing Procedure and Production Line Setup

Medtronic is one of the leading manufacturers of coronary stents worldwide and would therefore be one of Arterial Products main competitors in this area. Consequently, it is beneficial to examine and evaluate their production process with a view to incorporating some of their methods into the companys production procedure. According to the latest available information, Medtronic use the wire/ring construction method (see Section 4.3). The figure below is a schematic of the process used by Medtronic in the manufacture of stents as of 2004.

Figure 10 Process Flow Chart Wire/Ring In the pre-processing stage rough cobalt chrome alloy rings are tumbled to smooth the edges in a controlled process which ensures uniform mass and dimensions of the rings. The rings are then loaded onto a plastic rod, presumably manually, and transferred to the forming machine. The rings are then sent, individually, through the forming machine which uses dies to press them into a zigzag pattern. The resultant product is then dumped into a bucket and sent to the loading station. 31

At the loading station, the rings are loaded onto a tungsten rod one-by-one and, once the appropriate number of rings has been loaded, the rod is passed to the fusing machine. The fusing machine automatically moves and rotates the stent to the general location where the stent must be fused and a worker, operating a laser welding machine, fuses the appropriate joints together. At this point, the first formal inspection takes place. It involves looking for geometric anomalies and poorly fused joints. Defective stents are discarded and all other stents move to the swaging stage. Swaging (see Section 4.3) is the process of removing material from the stents in order to increase its surface area. This allows the drug coating to have a greater effect. It is done by placing the stents on a mandrel and passing them through a series of dies. There are 8 swaging stations in the production line. The stents are collected after this process and transferred in batches of 200 to the synergy stage.

Figure 11: Swaging Synergy refers to a cleaning solution which is used to clean the stents. The 200 stent batch is split into lots of 50 and each lot is passed through the four successive stages in the cleaning process.

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The cleaned stents are then loaded onto tungsten rod trees and annealed in batches. This grows the grain size of the stents to a specific level. Annealing is a time consuming process taking 90 minutes to complete including loading and unloading. There are 4 annealing ovens in the production line but there is a problem with queues forming at this stage of the process. In the electro-polishing stage batches of stents, which are manually loaded onto an anode fixture, are lowered into heated chemical baths and then sent through a passivation stage to remove ions and prevent rust before being unloaded and placed in a tray for final inspection. There are 5 electro-polishing stations in the production line. Human inspectors inspect each stent under a microscope for an average of 3.7 seconds. The most expensive stages in the process are fusion followed by final inspection. The final inspection is not only time consuming and non-value added, but also prone to human error. In terms of technology, some of the processes outlined above are dated. Pre-processing, forming, loading and fusion are time consuming, labour intensive processes which could all realistically be replaced by laser cutting in Arterial Products production procedure. Laser cutting cycle times are around 4 to 5 minutes so significant savings could be made by pursuing this option. Laser cutting technology can achieve better accuracy also and can be automated which reduces labour costs and improves the repeatability and uniformity of the product. However a micro abrasive blasting procedure is required following laser cutting to remove remelt and any oxidation. This process is likely to have a similar cycle time to laser cutting depending on what laser cutting technology was used. Another point which must be taken into consideration is the fact that this plant produces 3000 stents per day over a 16 hour period whereas Arterial Products Ltd envisage an initial production figure of 10000 per year eventually rising to 20000 per year. On the presumption that the factory would operate for 250 days of the year, these figures 33

represent production levels of 40 and 80 stents per day respectively. Therefore, while it would be feasible to use a similar layout and system to Medtronics, the scale would be much smaller and only a single line would be necessary. Taking a cycle time of six minutes for both the laser cutting and the microblasting processes (including time taken to transfer to the next station), maximum production of 80 stents per day could be met in an 8 hour day using one laser cutting and one microblasting machine and queuing or idle time would not be an issue in this part of the process. The annealing process takes 90 minutes. Theoretically, during this time, 15 stents would have been cut, micro blasted and swaged. This means that, in order to avoid a bottleneck, an annealing oven capable of annealing at least 15 stents at a time would be required. However, while this would easily achieve the targeted starting production level of 40 stents per day, a problem would occur if production went above 75 stents per day. In this case a slightly larger oven would be needed. If a larger oven was purchased straight away higher capital and running costs would be incurred and the oven would not be used to its full capacity until production went above 75 stents per day. If a smaller oven was purchased at first, an upgrade would almost certainly be required in the next 10 years. Durney (1984) suggests an electropolishing time of 4 to 5 minutes for stainless steel which indicates that a single electropolishing setup, similar to that of Medtronics but much smaller, would fulfil the required production levels and keep a continuous flow in the production line. A cleaning procedure similar to Medtronics Synergy process would also have to be incorporated into Arterials production setup. This would, of course, also be on a much smaller scale than Medtronics setup. With regard to final inspection, an automated system would be the preferred option as this would minimize errors and would probably reduce costs also, depending on the type of system being chosen. Tolerances of stents are in the range of 5m. This is achievable using laser cutting technology with Synova claiming precision levels of 3microns from its Laser Micro34

Jet technology (see Section 4.2). In the micro abrasive blasting procedure, abrasives in the range of 17.5-25 microns are generally used. Wise et al. (2000) states that the initial raw material should have a surface roughness of less than 1m and that electropolishing reduces this to below 0.05m. Stents are also required to meet strict biocompatibility standards in order to reduce the risk of medical complications arising from the implanting of a stent. Biocompatibility is normally achieved by coating the stent with a biocompatible material such as gold or phosphorylcholine.

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5.2 Critical issues that may cause Disruptions

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Annealing oven A time plan needs to be implemented with rigid scheduling for the annealing oven. If the oven were to stop operating, the down time would have serious adverse effects such as a high backlog occurring.

Inspection A highly skilled operator is necessary for this process. Human error in this process can account for serious complications and damage to the companys reputation if a batch of unsuitable stents were released to the general public.

Production Line There is a high dependence on the production lime to operate efficiently. If the line breaks down there is no back-up and all manufacturing of the stents ceases.

Micro-blasting If this process is not highly controlled and too much material is removed from the stent it can lead to premature failure of the stent. This consequence can then cause major complications. On the other side, if not enough material is removed all defects present in the stent will not be removed. If the laser operates efficiently the microblasting process is not wholly required thus reducing this critical issue

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6.0 Automation Evaluation

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On request of Arterial Products Ltd. the use of automation technology that may be applied to processes examined is evaluated. There are four key areas listed below where automation solutions may be applied to stent production processes. Each area is evaluated in detail with reasoning for automation provided. 1. Reduction of Manual Handling. 2. Move from Batch to a more or fully continuous process. 3. Synova Laser Micro-Jet or Fiber laser cutter. 4. Integration of more specialized machines for each process and Robotic arms as a method of transportation between each process.

1. Reduction of Manual Handling Reasons

The use of manual handling increases the risk of possible damage occurring to the stents during the manufacturing process because of human error. The utilization of highly calibrated machines and tools speeds up the process to a significant extent when compared to manual work carried out by employees. As a result of the previous point there is an increased controllability and consistency built into the manufacturing process as a whole. Future implementations that are being considered to decrease a process time can be easier calculated and finer limits can be set when human factors can be ruled out. During Inspection- If the amount of manual handling down the line to this point can be decreased, the level of inspection to be carried out will be reduced as the error rate of each machine is prior knowledge.

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2. Move from Batch to a more or fully continuous process Reasons

A batch type manufacturing process in this case is directly related to point

1. Manual handling gives rise to work being done in portions rather than a quick changeover into the next step, as the Stents need to be loaded and unloaded onto the transporting vessel to change process

Change over to each process is time consuming; Non-value added and Current manufacturing procedures in stent production are of a batch

leads to human error. process type. After each stage which causes considerable amount of work being carried out on the stent, an inspection and quality assurance stage is necessary. One such reason for this is that the US FDA has laid down a protocol for maintaining correct tolerances on surface finishes on the stent. The introduction of drug eluting stents in 2003 has made this necessary. The result of this is the previous allowable tolerances of 15% have been dropped to 6 - 8%. Leading on to companies reducing the strut dimensions from about 110 m to as little as 60 m. To achieve these radical requirements it has been said that, "In the long

term, the current semi-industrial approach involving multiple manual operations and open loop, batch-oriented quality assurance procedures will have to be replaced by a monolithic, IT-based total quality management system involving fully automated and controlled process chains from tube to stent without any manual interference,"

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Figure 13: Showing real size of actual stent and the challenge facing laser cutting.

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3. Synova Laser Micro-Jet or Fiber laser cutter- Reasons

For the purpose of automation of the manufacturing process only Laser Micro-Jet cutting has been considered as its advantages weigh considerably higher than those associated with the Fiber Laser cutters on offer.

Higher cutting speeds exhibited than conventional Nd: YAG lasers. Excellent tolerances and surface finishes giving narrow parallel cuts to the range of 28 to 60 m No thermal damage or material transformation due to a pulsed laser system refracted through a water jet. This provides immediate cooling to the heat affected zone (HAZ). No re-melt inside tubes resulting in very little or no micro-blasting being needed; which is an unwanted process that can cause stress to the struts, causing weakening and failure.

Very low running costs and no tool wear which can to production line downtime which is an unwanted occurrence. Constant repeatable results are seen to be provided. Any cutting geometry is possible on the Stent

Figure 14: Cutting with water jet guided laser 42

4. Integration of more specialized machines for each process and Robotic arms

as a method of transportation between each process Reasons The use of a conveyer-belt furnace to replace the batch annealing ovens.

This is the first step in moving the whole manufacturing process from a batch type into a continuous one. Currently, process operations require approximately 1.5 hours loading, annealing, and unloading. So only a certain number of stents per batch can be processed. With the conveyor oven system, there are various temperature zones through which stents travel to achieve desired annealing effects. Thus saving any downtime on letting ovens cool and be reheated for every batch. Automated optical inspection unit.

As the tolerances of strut thickness are being diminished (As it stands the current minimum coating thickness on DES is 60 nm), the time allocated to manual inspection of stents is ever increasing. This issue is a critical one in reducing overall production times of individual stents. Thus, the need for a 100% automated optical inspection station is becoming ever greater. At present however, there is no manufacturer of an all in one integrated system that would be needed for the optical inspections required. This is soon to change with developments in the biomedical industry being so fast-paced.

Finally the 3rd method to fully bring the company up to 100% automated

production levels and thus a fully continuous production line is the introduction of Robotic Handling, conveying systems and feedback loops providing a continual information feed. By the introduction of these units, the leading time for single unit outputs is only limited by the time involved in each individual process. Below, it is set out, an envisaged process for robotic handling which could be deployed step by step for the simple manufacturing process

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Also, it is clear to see that the introduction of automated systems brings with it a very high level of information availability which can be sent forward and backwards between station to provide higher productivity, higher through-put and significantly lower production cost. This can be seen in Figure 15 below:

Figure 15: Mesh Belt Annealing Oven

Figure 16: The optical inspection plant and the heat treatment unit are further decisive building blocks for a future fully automated stent production chain

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Figure 17: Automated processing chain for stent production

Figure 18: Stent Automation (1) Stent is placed on the annealing belt furnace after laser cutting has taken place. (2) Robot arm picks up annealed stent from conveyor belt; base rotates all arms to next station (3) Robot arm dips stent in chemical bath to electropolish surface; base rotates to next station

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(4) Robot arm dips stent in chemical bath to remove oxidation from surface; base rotates to next station (5) Robot arm holds and rotates stent in front of photo sensitive screen and light for light refraction analysis (inspect for geometric and surface errors); base rotates to next station (6) Robot arm holds and rotates stent in front of chemical detector to inspect for contamination; base rotates to next station (7) Robot drops stent into tray for post final-inspection steps; base rotates back to station (2) to repeat process As the confidence of Arterial Products Ltd. grows in the future and stent production levels become too high for the batch production system which we have recommended, it is felt by our team that these automation solutions outlined above would be a welcomed implementation to the manufacturing facility and also that the immediate cost of plant will be more than compensated for by its high level of flexibility, productivity and controllability in the long-term. However, it is a concern to us that the purchase of new equipment is capital intensive and the payback period is yet to be calculated because secrecy of production methods within the 4 big stent manufacturing companies is valued by them. As such, no figures were available on production times or machine costs. This hinders any recommendations that can be made on the feasibility of introduction of these automated solutions. If implementation of suggested automation solutions is carried out, the team feels that it would be beneficial to carry out the introduction of the machinery in parallel with the current processes, this would show any bugs that could arise and cause minimum disruption to output during the phase in period.

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It would be envisaged that each piece of equipment be installed in phases if at all possible so that the level of overlap of errors is completely minimised. When that specific piece of equipment is running error free then attention can be focused to the next piece. A high level of project management would be necessary during this time so that all parameters can be tested.

7.0 Proposal for Arterial Products Ltd

From the research outlined above, it is recommended that Arterial Products purchase one Micro Laser-jet machine to perform the laser cutting as this would achieve the highest accuracy and would reduce the amount of micro-blasting required. It is at the forefront of current laser cutting technology so it is therefore envisaged that this process would not need to be replaced or upgraded in the near future. Microblasting will directly follow the laser cutting procedure in the production line. One microblasting machine has been deemed suitable to meet targeted production levels. The design choice for the stent has yet to be finalized, however, if a drug eluting stent is chosen, a swaging machine is recommended. As stated previously, this would increase the surface area of the stent and thus allow a greater drug coating to be placed on the stent. If a non-drug eluting stent is chosen, this process is not necessary. Inspection is an important process to consider as some of the pieces would not need to be put through the microblasting process once they come out of the Laser Micro-Jet process. For this reason an inspection station after the Laser Micro-Jet station is recommended. 47

A cleaning process similar to Medtronics must be undertaken on the stents to meet manufacturing standards. Annealing is required to grow the grain size and achieve the desired physical properties. A small annealing oven with a capacity of around 15 stents is the recommended choice. This would meet production levels until production goes above 75 at which point a larger oven would have to be purchased. A single electro-polishing machine should be placed in the production line following the annealing phase. The recommended coating process is PVD as this would facilitate more control and easier automation. The final inspection will be a human inspection carried out with the use of microscopes. Although automated inspection is more reliable and accurate, production levels are quite low so the cost of an automated inspection unit would outweigh its benefits. Due to the small batch numbers coming through the system, human inspectors would not be time consuming and so it would be the most viable way to inspect the pieces. If a large expansion was going to be considered automated inspection systems could be brought in to cope at one or more of the inspection points depending on the numbers of pieces being brought through the system at the time. Finally a crimping machine is required at the end of the production line to produce the finished product. By including a finishing process the value is increased in the stent.

Regarding these choices, several observations can be made.

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As initial production volumes are low Arterial Products Ltd. would not need to engage in a large expansion of the factory area. This means that the capital cost of the manufacturing would be limited to the costs of the machines and the training costs for people to operate each machine. If Arterial Products Ltd. does decide to expand to 20,000 units, the line can easily be upgraded to cater for this with the purchase of only a few machines since many of the machines could be up-scaled to cater for an increased amount of pieces. This would mean that a smaller capital investment would be needed to upscale. Its also worth noting that there would be less capital costs associated with training and maintenance costs as workers would be familiar with the machines already. Another observation made is that the production line for coronary stents could be joined onto the other lines for the catheters and angioplasty balloons. This means that finished products could be sent out at the end of the line which would add value onto the pieces and so increase profits for the company. In regards to the capital cost, the cost the company would have to incur is at the high end as all the machines would have to be bought new as there is very minimal crossover between the manufacturing processes the company engages in. This also means that maintenance technicians and operators would need to be newly trained for the new machines. In regards the competition angle, the company has a distinct advantage because of its reputation for high quality products already established in the medical industry. As the company begins to expand, more R&D needs to be focused into the finishing and coating areas as this is where the future of stent manufacture is leading towards. As Arterial Products Ltd. are already heavily involved in the biomedical industry this area is one where they will most likely flourish in and its growth needs to be promoted.

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7.1 Proposal Summary

Figure 19: Proposal - Decision Chart Tube mesh:

Forefront of Stent production. Ring fusion uncontrolled, accuracy levels lower. Tubular steel can then be cut with laser methods, so it is the process of choice.

Micro Laser-Jet:

Higher cutting speeds. Greater accuracy. Minimizes post processing due to the fact that the heat affected zone is greatly reduced.

Batch:

Suitable for small production numbers. Low cost. Simple.

Manual: 50

Suitable for low production volumes. Low cost. Already possessed by Arterial Products Ltd. Cheap.

Micro-Blasting:

Electro-Polishing:

Excellent light reflection. Clarity for inspection. Surface retains the true grain structure and properties of the bulk metal. Exhibits Stress-relieving properties of the surface.

Bare-Metal Stent:

Great starting point for Arterial Products Ltd. Popular. Ability to fully assemble in-house.

PVD:

High level of controlability unlike dipping and spraying. Cheaper than CVD. Simpler than CVD.

Manual Inspection: At the moment, consistent automated testing machines that can carry out the variety of optical tests needed are very costly and time consuming.

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8.0 Appendix
8.1 Glossary 8.2 Calculations

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8.1 Glossary
Anti-coagulant a medicine that prevents or retards the clotting of blood Anti- platelet - a member of a class of pharmaceuticals that decreases platelet aggregation and inhibits thrombus formation Angioplasty an operation to repair a damaged blood vessel or unblock a coronary artery Catheter a thin flexible tube inserted into the body to permit introduction or withdrawal of fluids or to keep the passageway open Hemorrhage - bleeding: the flow of blood from a ruptured blood vessel Lesion - any localized abnormal structural change in a body part Neointima - The scar tissue made up of cells and cell secretions that often forms as a result of vessel injury following angioplasty or stent placement as part of the natural healing process Occlusion closure or blockage (as of a blood vessel) Restinosis The renarrowing of an artery in the same location of a previous treatment Stent A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open Strut - brace consisting of a bar or rod used to resist longitudinal compression

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Thrombosis - the formation or presence of a thrombus (a clot of coagulated blood attached at the site of its formation) in a blood vessel

8.2 Calculations
Current production rates of catheters for angioplasties = 25,000 per annum. Stent production = 25,000 x 40% = 10,000 per annum

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9.0 References
Step by Step through Cardiac Catheterization and Angioplasty Irish Heart Foundation Patient Information Publication 2005, available from www.irishheart.ie Recommendations on stent manufacture, implantation and utilization Balcon, Beyar et al. European Heart Journal (1997) 18, 15361547 Use of Fiber Lasers for Micro Cutting Applications in the Medical Device Industry Kleine, Whitney and Watkins, 21st International Congress on Applications of Lasers and Electro-Optics, Scottsdale, October 14-17, 2002 (ICALEO 2002) Damage-Free Cutting of Stents with SYNOVA Laser-Microjet Application Note No. 111, Synova S.A., available from www.synova.ch

Improvement of Medtronic Stent Manufacturing Process ME317 Design for Manufacturability Winter/Spring 2004 Product Development Report Design Division, Department of Mechanical Engineering Stanford University, Stanford, CA 94305 Recommendations on stent manufacture, implantation and utilization, R. Balcon, R. Beyar, S. Chierchia, I. De Scheerder, P. G. Hugenholtz, F. Kiemeneij, B. Meier, J. Meyer, J. P. Monassier and W. Wijns for the Study Group of the Working Group on Coronary Circulation Automating Stent Production, One Step at a Time, Klaus Vollrath 2007 Medical Product Manufacturing News Jan/Feb edition Y Kobayashi, F Wong (2004) ME317 Design for Manufacturability Winter/Spring 2004 Product Development Report D.L. Wise et al.(2000) Biomaterials and Engineering Devices Human Application, Vol.2, New Jersey, Humana Press Inc. L Durney (1984), Electroplating Engineering Handbook, 4th Ed.,London , Chapman and Hall http://www.photonics.com/, Fibre lasers used in Medical stent manufacturing, Date retrieved: 16/10/2009 Precise thin metal cutting using the Laser MicroJet Dr A. Pauchard1Synova SA, Ecublens, Switzerland

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