COHN URI (IL)
LEVI YAIR (IL)
COHN URI (IL)
JPH06122996A | 1994-05-06 | |||
US5739692A | 1998-04-14 | |||
US20040248428A1 | 2004-12-09 |
WHAT IS CLAIMED IS:
1. A method for manufacturing an electrocoated medical device, the method comprising: providing a medical device; performing an efectrocoating process on said medical device; quality control testing said medical device during said electrocoating process, for obtaining at least one quality index value; and determining quality of said electrocoating process from said at least one quality index value.
2. The method of claim 1, wherein said performing said electrocoating process includes generating an electric potential difference and an electric current in a solution.
3. The method of claim 2, further including measuring said potential difference and said electric current, for obtaining measured values of said potential difference and values of said electric current.
4. The method of claim 3, further including processing said measured values of said potential difference and of said electric current to obtain a value of a coating process parameter.
5. The method of claim 4, wherein said determining said quality is performed by using said obtained value of said coating process parameter.
6. The method of claim 4, wherein said processing includes comparing said measured values of said potential difference and of said electric current at different times during said electrocoating process.
7. The method of claim 4, wherein said processing includes comparing said measured values of said potential difference and of said electric current at a time before said electrocoating process and at a time after said electrocoating process.
8. The method of claims 2 or 3, wherein said comparing said measured values includes obtaining a ratio between said measured values.
9. The method of any of claims 6 to 8, wherein said determining said quality includes comparing said obtained value of said coating process parameter with a predefined value.
10. The method of any of the preceding claims, wherein said electrocoating process includes using cyclic voltammetry for changing a potential difference between a working electrode and a counter electrode.
11. The method of any of the preceding claims, wherein said etectcocoating process includes using alternating-current voltammetry for changing a potential difference between a working electrode and a counter electrode.
12. The method of claim 1, wherein said quality control testing is performed according to an in-process mode, involving an in-process quality index.
13. The method of claim 12, wherein said electrocoating process includes operation of an electrochemical cell, such that said in-process quality index is a ratio between net charge flowing in said electrochemical cell at different cycles of cyclic voltammetry.
14. The method of claim 1, wherein said quality control testing is performed according to an out-of-process mode, involving an out-of-process quality index.
15. The method according to any of the preceding claims, wherein said electrocoating process comprises chronoamperometry (CA), chronocoulometry (CC), linear sweep voltammetry (LSV), cyclic voltammetry (CSV), alternating current voltammetry (ACV), voltammetry techniques with different pulse shapes, square wave voltammetry (SWV), differential pulse voltammetry (DPV), normal pulse voltammetry (NPV), AC impedance spectroscopy, chronopotentiometry, and cyclic chronopotentiometry.
16. The method of claim 11, wherein said working electrode comprises at least a portion of the medical device.
17. The method of claim 4, wherein value of said coating process parameter has a smaller variance than said measured values of said potential difference and of said electric current, wherein a variance of a value is measured in units of an average of a same value.
18. The method according to any of the preceding claims, wherein said electrocoating process includes coating the medical device with a diazonium salt.
19. The method of claim 18, wherein said coating is no more than 100 nm thick.
20. The method according to any of the preceding claims, wherein said coating is no more than 20 nm thick.
21. A method for quality control testing a coated medical device using an electrical cell, the method comprising: measuring at least one electrical parameter of the coated medical device inside the electrical cell, for forming at least one measured electrical parameter; obtaining at least one quality index value of the coated medical device from said at least one measured electrical parameter; and determining quality of the coated medical device from said at least one quality index value.
22. A method for setting process parameters for electrocoating a medical device, the method comprising: measuring at least one electrical parameter of the medical device inside an electrical ceil, for forming at least one measured electrical parameter; and electrocoating the medical device inside said electrical cell, based on said at least one measured electrical parameter.
23. A method for validating of a medical device electrocoating process, the method comprising: performing the electrocoating process on a medical device; quality control testing said medical device during said electrocoating process, for obtaining at least one quality index value; and determining quality and validity of said electrocoating process from said at least one quality index value.
24. A system for manufacturing an electrocoated medical device, the system comprising: an electrocoating cell, including electrodes, for electrocoating a medical device; a power source, for supplying power to said electrodes for effecting said electrocoating; and circuitry, for quality control testing said medical device subjected to said electrocoating, for obtaining at least one quality index value, and for determining quality of the electrocoated medical device from said at least one quality index value.
25. A holder for holding a medical device in a solution for electrocoating the medical device in a coating process, the holder comprising: an electrode lead connectable to a power source; and at least one electrically conductive support member for keeping the medical device in place during the coating process, said support member being in electrical contact with said electrode lead; wherein portions of said electrode lead other than said support members are electrically isolated from the solution.
26. The holder of claim 25, wherein said at least one support member has a conductive portion not contacting the medical device, and said conductive portion is small enough to have only a negligible effect on the coating process.
27. The holder of claims 25 or 26, configured to press against the medical device without causing a plastic deformation of the device. |
MANUFACTURING ELECTROCOATED MEDICAL DEVICES, AND QUALITY CONTROL
TESTING AND VALIDATING THEREOF
RELATED APPLICATIONS
This claims the benefit of priority of U.S. Prov. Pat. Appl. No. 61/006,375, filed Jan. 10,
2008, entitled εLECTROCOAT1NG APPRATUS, PROCESS, AND CONTROL THEREOF", and of U.S. Prov. Pat. Appl. No. 61/084,276, filed July 29, 2008, entitled "COATING MEDICAL
DEVICES". The contents of these documents are incorporated by reference as if fully set forth herein.
FIELD OF THE INVENTION The present invention, in some embodiments thereof, relates to manufacturing electrocoated medical devices, and more particularly, but not exclusively, to manufacturing electrocoated medical devices, and quality control testing and validating thereof. Some embodiments of the present invention relate to a method for manufacturing an electrocoated medical device; a method for quality control testing a coated medical device using an electrical cell; a method for setting process parameters for electrocoating a medical device; a method for validating a medical device electrocoating process; a system for manufacturing an electrocoated medical device (applicable for a single medical device, or for a plurality of medical devices); and a holder for holding a medical device in a solution for electrocoating the medical device in a coating process.
BACKGROUND OF THE INVENTION
Electrocoating of medical devices, such as stents, for example, with a thin layer of diazonium compound(s), is taught [1] by the same applicant/assignee as the present invention. There is teaching [2] of a method of monitoring and controlling the deposition of a metal or an alloy onto the surface of a substrate. The method includes measuring the electric potential between the substrate and a reference electrode during processing, and comparing this potential to a predetermined, target value. This predetermined target value is selected as an indicator of deposition of a layer that properly adheres to the substrate and is generally free of defects observed with conventional methods. There is teaching [3] of using cell voltage and current as a monitor to prevent electrochemical deposition tools from deplating wafers with no or poor metal seed coverage.
The contents of each of the preceding references is incorporated by reference as if fully set forth herein.
SUMMARY OF THE INVENTION
The present invention, in some embodiments thereof, relates to manufacturing electrocoated medical devices, and more particularly, but not exclusively, to manufacturing electrocoated medical devices, and quality control testing and validating thereof. Some embodiments of the present invention relate to a method for manufacturing an electrocoated medical device; a method for quality control testing a coated medical device using an electrical cell; a method for setting process parameters for electrocoating a medical device; a method for validating a medical device electrocoating process; a system for manufacturing an electrocoated medical device (applicable for a single medical device, or for a plurality of medical devices); and a holder for holding a medical device in a solution for electrocoating the medical device in a coating process.
The present invention, in some embodiments thereof, also concerns controlling the quality of electrocoating processes, where nanometric non-conducting layers are coated on conducting surfaces, particularly, conducting surfaces of medical devices. Thus, according to a main aspect of some embodiments of the present invention, there is provided a method for manufacturing an electrocoated medical device, the method comprising: providing a medical device; performing an electrocoating process on the medical device; quality control testing the medical device during the electrocoating process, for obtaining at least one quality index value; and determining quality of the electrocoating process from the at least one quality index value.
According to another main aspect of some embodiments of the present invention, there is provided a method for quality control testing a coated medical device using an electrical cell, the method comprising: measuring at least one electrical parameter of the coated medical device inside the e\ectπca\ cell, for forming at least one measured electrical parameter; obtaining at least one quality index value of the coated medical device from the at least one measured electrical parameter; and determining quality of the coated medical device from the at least one quality index value.
According to another main aspect of some embodiments of the present invention, there is provided a method for setting process parameters for electrocoating a medical device, the method comprising: measuring at least one electrical parameter of the medical device inside an electrical cell, for forming at least one measured electrical parameter; and electrocoating the medical device inside the electrical cell, based on the at least one measured electrical parameter.
According to another main aspect of some embodiments of the present invention, there is provided a method for validating a medical device electrocoating process, the method comprising: performing the electrocoating process on a medical device; quality control testing the medical device during the electrocoating process, for obtaining at least one quality index value; and determining quality and validity of the electrocoating process from the at least one quality index value.
According to another main aspect of some embodiments of the present invention, there is provided a system for manufacturing an electrocoated medical device, the system comprising: an electrocoating cell, including electrodes, for electrocoating a medical device; a power source, for supplying power to the electrodes for effecting the eiectrocoating., and circuitry, for quality control testing the medical device subjected to the electrocoating, for obtaining at least one quality index value, and for determining quality of the electrocoated medical device from the at least one quality index value.
According to another aspect of some embodiments of the present invention, there is provided a holder for holding a medical device in a solution for electrocoating the medical device in a coating process, the holder comprising: an electrode lead connectable to a power source; at least one electrically conductive support member for keeping the medical device in place during the coating process, the support member being in electrical contact with the electrode lead; wherein portions of the electrode lead other than the support members are electrically isolated from the solution. Some embodiments of the present invention are implemented by performing steps or procedures, and sub-steps or sub-procedures, in a manner selected from the group consisting of manually, semi-automatically, fully automatically, and a combination thereof, involving use and operation of system units, system sub-units, devices, assemblies, sub-assemblies, mechanisms, structures, components, and elements, and, peripheral equipment, utilities, accessories, and materials. Moreover, according to actual steps or procedures, sub-steps or sub-procedures, system units, system sub-units, devices, assemblies, sub-assemblies, mechanisms, structures, components, and elements, and, peripheral equipment, utilities, accessories, and materials, used for implementing a particular embodiment of the disclosed invention, the steps or procedures, and sub-steps or sub-procedures, are performed by using hardware, software, or/and an integrated combination thereof, and the system units, sub-units, devices, assemblies, sub-assemblies, mechanisms, structures, components, and elements, and, peripheral equipment, utilities, accessories, and materials, operate by using hardware, software, or/and an integrated combination thereof.
For example, software used, via an operating system, for implementing some embodiments of the present invention can include operatively interfaced, integrated, connected, or/and functioning written or/and printed data, in the form of software programs, software routines, software sub-routines, software symbolic languages, software code, software instructions or protocols, software algorithms, or a combination thereof. For example, hardware used for implementing some embodiments of the present invention can include operatively interfaced, integrated, connected, or/and functioning electrical, electronic or/and electromechanical system units, sub-units, devices, assemblies, sub-assemblies, mechanisms, structures, components, and elements, and, peripheral equipment, utilities, accessories, and materials, which may include one or more computer chips, integrated circuits, electronic circuits, electronic sub-circuits, hard-wired electrical circuits, or a combination thereof, involving digital
or/and analog operations. Some embodiments of the present invention can be implemented by using an integrated combination of the just described exemplary software and hardware.
In exemplary embodiments of the present invention, steps or procedures, and sub-steps or sub-procedures, can be performed by a data processor, such as a computing platform, for executing a plurality of instructions. Optionally, the data processor includes volatile memory for storing instructions or/and data, or/and includes non-volatile storage, for example, a magnetic hard-disk or/and removable media, for storing instructions or/and data. Optionally, exemplary embodiments of the present invention include a network connection. Optionally, exemplary embodiments of the present invention include a display device and a user input device, such as a keyboard or/and 'mouse'.
BRIEF DESCRIPTION OF THE DRAWINGS
Some embodiments of the present invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative description of some embodiments of the present invention. In this regard, the description taken together with the accompanying drawings make apparent to those skilled in the art how some embodiments of the present invention may be practiced.
In the drawings: FIG. 1 is a (block-type) flow diagram of an exemplary embodiment of a method for manufacturing an electrocoated medical device, and of a method for quality control testing thereof, in accordance with the present invention;
FIG. 2 is a block-type diagram of an exemplary embodiment of a method for quality control testing a coated (e.g., electrocoated) medical device, in accordance with the present invention;
FIG. 3 is a (block-type) flow diagram of an exemplary embodiment of a method for overall ('in-process' and 'out-of-process') quality control testing and validation of an electrocoating process, in accordance with the present invention;
FlG. 4 is a (block-type) flow diagram of an exemplary embodiment of a method for 'in- process 1 quality control testing, in accordance with the present invention;
FIG. 5 is a (block-type) flow diagram of an exemplary embodiment of a method for 'in- process' quality control testing and validation of an electrocoating process, in accordance with the present invention;
FIG. 6 is a schematic diagram illustrating an exemplary embodiment of an electrical (e.g., electrochemical - electrocoating) cell, in accordance with the present invention;
FIG. 7 is a (hatch-type) schematic diagram illustrating an exemplary embodiment of an electrical (e.g., electrochemical - electrocoating) cell, particularly showing a medical device (e.g., stent) holder, and wherein the working electrode is a medical device (e.g., stent) held with a metal 'wire' and centered in the cell, particularly suitable for medical device coating and
performing 'in-process' quality control testing and validation, in accorάance with the present invention;
FIG. 8 is a (hatch-type) schematic diagram illustrating an exemplary embodiment of an electrical (e.g., electrochemical - eiectrocoating) cell, particularly showing a medical device (e.g., stent) holder, and wherein the working electrode is a medical device (e.g., stent) held with a metal 'tube' and centered in the cell, particularly suitable for medical device coating and performing 'in-process' quality control testing and validation, in accordance with the present invention;
FlG. 9 is a (pictorial-type) schematic diagram illustrating an exemplary embodiment of a single-electrical (e.g., electrochemical - eiectrocoating) cell (i.e., single-cell) system, suitable for medical device coating and performing quality control testing and validation, in accordance with the present invention;
FIG. 10 is a (pictorial-type) schematic diagram illustrating an exemplary embodiment of a multi-electrical (e.g., electrochemical - eiectrocoating) cell (i.e., multi-cell) system, suitable for medical device coating anά performing quality control testing and validation, in accordance with the present invention;
FIG. 11 is a (block-type) flow diagram of an exemplary embodiment of a method for 'out- of-process' quality control testing, in accordance with the present invention;
FIG. 12 is a (block-type) flow diagram of an exemplary embodiment of a method for 'out- of-process' quality control testing and validation of an eiectrocoating process, in accordance with the present invention;
FIG. 13 is a photographic-schematic diagram illustrating an exemplary embodiment of an electrical (e.g., electrochemica!) cetf, particularly suitable for performing 'out-of-process' quality control testing, in accordance with the present invention; FIG. 14 is an exemplary graphical presentation of results obtained from making electrochemical measurements and evaluations on a (nano) coated medical device (e.g., stent) via performing cyclic voltammetry type of 'out-of-process' quality control testing (i.e., CV out), in accordance with some embodiments of the present invention;
FIG. 15 is an exemplary Nyquist plot graphical presentation of results obtained from making electrochemical measurements and evaluations on a (nano) coated medical device (e.g., stent) via performing electrochemical impedance spectroscopy (EIS) type of 'out-of-process' quality control testing (i.e., EIS out), suitable for determining capacity of the medical device (e.g., stent) coating, in accordance with some embodiments of the present invention;
FIG. 16 is an exemplary Bode plot graphical presentation of results obtained from making electrochemica) measurements and evaluations on a (nano) coated medical device (e.g., stent) via performing electrochemical impedance spectroscopy (ElS) type of 'out-of-process' quality control testing (i.e., ElS out), suitable for determining capacity of the medical device (e.g., stent) coating, in accordance with some embodiments of the present invention;
FIG. 17 is an exemplary Bode plot graphical presentation of results obtained from making electrochemical measurements and evaluations on a (nano) coated medical device (e.g., stent) via performing alternating current voltammetry (ACV) type of 'out-of-process 1 quality control testing (i.e., ACV out), suitable for determining double-layer capacity, C d |, of the medical device (e.g., stent) coating, in accordance with some embodiments of the present invention;
FIG. 18 is a (chart-type) diagram presenting exemplary 'acceptance / rejection' criteria for 'in-process' quality control testing, in accordance with some embodiments of the present invention;
FIG. 19 is a (chart-type) diagram presenting exemplary 'acceptance / rejection' criteria for 'out-of-process' quality control testing, in accordance with some embodiments of the present invention;
FIG. 20 is a schematic diagram illustrating an exemplary embodiment of an electrical (e.g., electrochemical - electrocoating) cell, including an exemplary embodiment of a medical device (e.g., stent) holder, and wherein the working electrode is a medical device (e.g., stent) held with a metal 'tube' and centered in the cell, suitable for suitable for medical device coating and performing 'in-process' quality control testing and validation, in accordance with some embodiments of the present invention; in accordance with the present invention;
FIG. 21 is a schematic diagram illustrating an exemplary embodiment of electrical connections in an electrical (e.g., electrochemical - electrocoating) cell, such as that illustrated in FIG. 20, in accordance with some embodiments of the present invention;
FIG. 22 is a (pictorial-type) schematic diagram illustrating an exemplary embodiment of a multi-electrical (e.g., electrochemical - electrocoating) cell (i.e., multi-cell) system, suitable for medical device coating and performing quality control testing and validation, in accordance with some embodiments of the present invention;
FIG. 23 is a (block-type) flow diagram of an example of a method for overall ('in-process' and 'out-of-process') quality control testing and validation of an electrocoating process, as implemented and illustratively described in Example 2, in accordance with some embodiments of the present invention; FIG. 24 is a (bar-graph) type graphical presentation of results obtained from making electrochemical measurements and evaluations, via performing alternating current voltammetry (ACV) type of 'out-of-process' quality control testing (i.e., ACV out), and validation, of (pre-coated, and post-coated) stents, as described in Example 2, in accordance with some embodiments of the present invention; FIG. 25 is a (bar-graph) type graphical presentation of results obtained from making electrochemical measurements and evaluations, via performing cyclic voltammetry type of 'out- of-process' quality control testing (i.e., CV out), and validation, of (pre-coated, and post-coated) stents, as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 26A is a 'computer display screen print 1 of results obtained from making electrochemical measurements and evaluations, via performing cyclic voltammetry type of 'out- of-process' quality control testing (i.e., CV out), and validation, of treated stents [Chi-square ranking (Weibull distribution)], as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 26B is a 'computer display screen print' of results obtained from making electrochemical measurements and evaluations, via performing cyclic voltammetry type of 'out- of-process' quality control testing (i.e., CV out), and validation, of control stents [Chi-square ranking (Normal distribution)], as described in Example 2, in accordance with some embodiments of the present invention,"
FIG. 27A is a 'computer display screen print' of results obtained from making electrochemical measurements and evaluations, via performing alternating current voltammetry
(ACV) type of 'out-of-process' quality control testing (i.e., ACV out), and validation, of treated stents [Chi-square ranking (Student's t distribution)], as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 27B is a 'computer display screen print' of results obtained from making electrochemical measurements and evaluations, via performing alternating current voltammetry
(ACV) type of Out-of-process' quality control testing (i.e., ACV out), and validation, of control stents [Chi-square ranking (Maximum Extreme distribution)], as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 28A is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of treated postcoated stents (Weibull distribution), as described in Example 2, in accordance with some embodiments of the present invention, ' FIG. 28B is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of control postcoated stents (Normal distribution), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 29A is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of treated postcoated stents (Normal distribution), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 29B is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of control postcoated stents (Normal distribution), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 3OA is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of
treated postcoated stents (Student's t distribution), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 3OB is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of control postcoated stents (Maximum Extreme distribution), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 31A is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of treated postcoated stents (Normal distribution), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 31B is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of control postcoated stents (Normal distribution), as described in Example 2, in accordance with some embodiments of the present invention; FIG. 32A is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index ranked distribution), as described in Example 2,_ in accordance with some embodiments of the present invention;
FIG. 32B is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index normal), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 33A is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index ranked distribution), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 33B is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index normal), as described in Example 2, in accordance with some embodiments of the present invention; FIG. 34A is a "computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index normal), as described in Example 2, in accordance with some embodiments of the present invention;
FIG. 34B is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index ranked distribution), as described in Example 2, in accordance with the present invention;
FIG. 35A is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index normal), as described in Example 2, in accordance with some embodiments of the present invention; and
FIG. 35B is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index ranked distribution), as described in Example 2, in accordance with some embodiments of the present invention.
DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
The present invention, in some embodiments thereof, relates to manufacturing electrocoated medical devices, and more particularly, but not exclusively, to manufacturing an electrocoated medical device, and quality control testing and validating thereof. Some embodiments of the present invention relate to a method for manufacturing an electrocoated medical device; a method for quality control testing a coated medical device using an electrical cell; a method for setting process parameters for electrocoating a medical device; a method for validating a medical device electrocoating process; a system for manufacturing an electrocoated medical device (applicable for a single medical device, or for a plurality of medical devices); and a holder for holding a medical device in a solution for electrocoating the medical device in a coating process.
The present invention, in some embodiments thereof, also concerns controlling the quality of electrocoating processes, where nanometric non-conducting layers are coated on conducting surfaces, particularly, conducting surfaces of medical devices. A main aspect of some embodiments of the present invention is provision of a method for manufacturing an electrocoated medical device, the method including the following main steps or procedures, and, components and functionalities thereof: (a) providing a medical device; (b) performing an electrocoating process on the medical device; (c) quality control testing the medical device during the electrocoating process, for obtaining at least one quality index value; and (d) determining quality of the electrocoating process from the at least one quality index value.
Another main aspect of some embodiments of the present invention is provision of a method for quality control testing a coated medical device using an electrical cell, the method including the following main steps or procedures, and, components and functionalities thereof: (a) measuring at least one electrical parameter of the coated medical device inside the electrical cell, for forming at least one measured electrical parameter; (b) obtaining at least one quality index value of the coated medical device from the at least one measured electrical parameter; and (c) determining quality of the coated medical device from the at least one quality index value. Another main aspect of some embodiments of the present invention is provision of a method for setting process parameters for electrocoating a medical device, the method including the following main steps or procedures, and, components and functionalities thereof: (a) measuring at least one electrical parameter of the medical device inside an electrical cell, for
forming at least one measured electrical parameter; and (b) electrocoating the medical device inside the electrical cell, based on the at least one measured electrical parameter.
Another main aspect of some embodiments of the present invention is provision of a method for validating a medical device electrocoating process, the method including the following main steps or procedures, and, components and functionalities thereof: (a) performing the electrocoating process on a medical device; (b) quality control testing the medical device during the electrocoating process, for obtaining at least one quality index value; and (c) determining quality and validity of the electrocoating process from the at least one quality index value. Another main aspect of some embodiments of the present invention is provision of a system for manufacturing an electrocoated medical device, the system including the following main components and functionalities thereof: (a) an electrocoating cell, including electrodes, for electrocoating a medical device; (b) a power source, for supplying power to the electrodes for effecting the electrocoating; and circuitry, for quality control testing the medical device subjected to the electrocoating, for obtaining at least one quality index value, and for determining quality of the electrocoated medical device from the at least one quality index value.
. Another main aspect of some embodiments of the present invention is provision of a holder for holding a medical device in a solution for electrocoating the medical device in a coating process, the holder including the following main components and functionalities thereof: (a) an electrode lead connectable to a power source; and (b) at least one electrically conductive support member for keeping the medical device in place during the coating process, the support member being in electrical contact with the electrode lead; wherein portions of the electrode lead other than the support members are electrically isolated from the solution.
Based on the preceding stated main aspects, some embodiments of the present invention include several special technical features, and, aspects of novelty and inventiveness over teachings in the relevant fields and arts of the present invention.
It is to be understood that the present invention is not limited in its application to the details of the order or sequence, and number, of steps or procedures, and sub-steps or sub-procedures, of operation or implementation of some embodiments of the method / process, or to the details of type, composition, construction, arrangement, order, and number, of the system units, system sub-units, devices, assemblies, sub-assemblies, mechanisms, structures, components, elements, and configurations, and, peripheral equipment, utilities, accessories, chemical reagents, and materials, of some embodiments set forth in the following illustrative description, accompanying drawings, and examples, unless otherwise specifically stated herein. For example, the following illustrative description refers to a stent as an exemplary medical device, in order to illustrate implementation of some embodiments of the present invention. Moreover, although illustrative description of the present invention is primarily focused on applications involving electrocoating of stents as an exemplary medical device, it is to be fully understood that the present invention is also applicable to other medical devices. Accordingly,
the present invention can be practiced or impiemented according to various other alternative embodiments and in various other alternative ways.
It is also to be understood that all technical and scientific words, terms, or/and phrases, used herein throughout the present disclosure have either the identical or similar meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise specifically defined or stated herein. Phraseology, terminology, and, notation, employed herein throughout the present disclosure are for the purpose of description and should not be regarded as limiting. For example, it is expected that during the life of a patent maturing from this application many relevant coating solutions and medical devices will be developed and the scope of the terms 'solution' and 'medical device' is intended to include all such new technologies a priori.
Moreover, all technical and scientific words, terms, or/and phrases, introduced, defined, described, referenced to, or/and exemplified, in the above Field and Background sections, are equally or similarly applicable in the illustrative description of the embodiments, examples, and appended claims, of the present invention.
Each of the following terms written in singular grammatical form: 'a', 'an', and 'the', as used herein, may also refer to, and encompass, a plurality of the stated entity or object, unless otherwise specifically defined or stated herein, or, unless the context clearly dictates otherwise. For example, the phrases: 'a unit', 'a device', 'an assembly', "a mechanism', 'a component', and 'an element', as used herein, may also refer to, and encompass, a plurality of units, a plurality of devices, a plurality of assemblies, a plurality of mechanisms, a plurality of components, and a plurality of elements, respectively. For example, the phrase 'a compound' may also refer to, and encompass, a plurality of compounds, or/and mixtures thereof. Also, for example, the phrase 'a medical device' may also refer to, and encompass, a plurality of medical devices. Each of the following terms: 'includes', 'including', 'has', 'having', 'comprises', and
'comprising', and, their linguistic / grammatical variants, derivatives, or/and conjugates, as used herein, means 'including, but not limited to'.
Each of the phrases 'consisting of and 'consists of, as used herein, means 'including and limited to'. The phrase 'consisting essentially of means that the stated method or process, step or procedure, sub-step or sub-procedure, system, system unit, system sub-unit, device, assembly, sub-assembly, mechanism, structure, component, element, composition or formulation, or, peripheral equipment, utility, accessory, or material, which is an entirety or part of an embodiment of the disclosed invention, or/and which is used for implementing an embodiment of the disclosed invention, may include at least one additional 'feature or item' being a step or procedure, sub-step or sub-procedure, system unit, system sub-unit, device, assembly, sub-assembly, mechanism, structure, component, or element, or, peripheral equipment, utility, accessory, or material, but only if each such additional 'feature or item' does not materially alter the basic novel
and inventive characteristics or special technical features, of each claimed entity (method, system, or device).
The phrase 'operatively connected 1 , as used herein, equivalents refers to the corresponding synonymous phrases Operatively joined', and Operatively attached', where the operative connection, operative joint, or operative attachment, is according to a physical, or/and electrical, or/and electronic, or/and mechanical, or/and electro-mechanical, manner or nature, involving various types and kinds of hardware or/and software equipment and components.
The phrase 'quality control', can be defined in a variety of different ways and particular contexts of use and application. For the purpose of illustratively describing exemplary embodiments of the present invention, as well as implementation thereof, the phrase 'quality control 1 , as used herein, refers to checking the relative quality of a (manufactured) product, such as a medical device (e.g., a stent), or to checking the relative quality of a process, such as a medical device coating process or medical device electrocoating process, typically, in a commercial scale manufacturing environment. Quality control is performed by testing (inspecting, analyzing) (periodically or randomly selected) samples of the (manufactured) product (e.g., medical device (e.g., stent)), before, during, or/and after, the product is subjected to a process (e.g., a medical device coating process or medical device electrocoating process). Quality control is used to ensure that (manufactured) products, such as manufactured coated medical devices (e.g., coated stents), are designed and produced (constructed) to meet or exceed pre-determined specific requirements or criteria (i.e., quality or quality control requirements or criteria).
The phrase 'quality control testing', as used herein, refers to the preceding stated testing (inspecting, analyzing) (periodically or randomly selected) samples of a (manufactured) product (e.g., medical device (e.g., stent)), before, during, or/anό after, the product is subjected to a process (e.g., a medical device coating process or medical device electrocoating process). Such quality control testing is used to ensure that (manufactured) products, such as manufactured coated medical devices (e.g., coated stents), are designed and produced (constructed) to meet or exceed pre-determined specific requirements or criteria (i.e., quality or quality control requirements or criteria). The phrase 'in-process quality control testing', as used herein, refers to the preceding stated testing (inspecting, analyzing) (periodically or randomly selected) samples of a (manufactured) product (e.g., medical device (e.g., stent)), which is specifically performed during (while) the product is being subjected to a process (e.g., a medical device coating process or medical device electrocoating process), i.e., 'in the process, or during (while) the process takes place. Herein, for brevity, the phrase 'in-process quality control testing', is also abbreviated, and sometimes referred to, as 'in-process'.
The phrase 'out-of-process quality control testing', as used herein, refers to the preceding stated testing (inspecting, analyzing) (periodically or randomly selected) samples of a (manufactured) product (e.g., medical device (e.g., stent)), which is specifically performed before
or after (following) the product is subjected to a process (e.g., a medical device coating process or medical device electrocoating process), i.e., 'out-of the process, or after (following) the process takes place. Herein, for brevity, the phrase 'out-of-process quality control testing 1 , is also abbreviated, and sometimes referred to, as 'out-process 1 . The terms Validation', or Validating 1 , can be defined in a variety of different ways and particular contexts of use and application. For the purpose of illustratively describing exemplary embodiments of the present invention, as well as implementation thereof, the terms Validation 1 , or 'validating 1 , as used herein, refer to a procedure, process, or action(s) taken, for finding, testing (checking), declaring, or establishing, of 'something' as being valid (i.e., accurate, true, correct), in particular, in accordance with pre-determined specific requirements or criteria (e.g., quality or quality control requirements or criteria). In the context of the present invention, that 'something' particularly refers herein to a (manufactured) product, such as a medical device (e.g., a stent), or to a process, such as a medical device coating process or medical device electrocoating process, typically, in a commercial scale manufacturing environment. The terms 'validation', and 'validating 1 , as used herein, implies that one is able to state or/and document, and therefore, to establish, that 'something', in particular, a (manufactured) product, such as a medical device (e.g., a stent), or a process, such as a medical device coating process or medical device electrocoating process, typically, in a commercial scale manufacturing environment, is valid (i.e., accurate, true, correct) or suited for its intended use. Clearly, in the context of embodiments of the present invention, and implementation thereof, aspects relating to the preceding defined 'quality control' and 'quality control testing 1 , are intimately inter-related to aspects of the preceding defined 'validation 1 and Validating'. For example, results, analyses, and conclusions, obtained from 'quality control' and 'quality control testing' can be used as the basis of 'validation' and Validating'. Moreover, for example, in a non-limiting general sense, without becoming overly involved with semantics or linguistics, aspects of 'quality control' and 'quality control testing' can be considered as being synonymous with, and equivalent to, aspects of 'validation' and 'validating'.
The phrase 'quality index', as used herein, refers to 'something' (e.g., property, characteristic, feature, parameter, or result) that serves to provide an indication or level of quality. The phrase 'quality index', as used herein, also refers to 'something' (e.g., property, characteristic, feature, parameter, or result) that serves to guide, point out, or otherwise facilitate reference, to an indication or level of quality. The phrase 'quality index value 1 , as used herein, refers to a (numerical) value or magnitude of the preceding defined 'quality index'. The phrases 'quality index' and 'quality index value' are used in the context of aspects of the above defined quality control, quality control testing, validation, and validating.
The term "duplicate" means either of a plurality of things substantially alike and usually produced at the same time or by the same process.
The term 'about', as used herein, refers to ± 10 % of the stated numerical value.
The phrase 'room temperature', as used herein, refers to a temperature in a range of between about 20 0 C and about 25 0 C.
Throughout the illustrative description of some embodiments, the examples, and the appended claims, of the present invention, a numerical value of a parameter, feature, object, or dimension, may be stated or described in terms of a numerical range format. It is to be fully understood that the stated numerical range format is provided for illustrating implementation of some embodiments of the present invention, and is not to be understood or construed as inflexibly limiting the scope of embodiments of the present invention.
Accordingly, a stated or described numerical range also refers to, and encompasses, all possible sub-ranges and individual numerical values (where a numerical value may be expressed as a whole, integral, or fractional number) within that stated or described numerical range. For example, a stated or described numerical range 'from 1 to 6' also refers to, and encompasses, all possible sub-ranges, such as 'from 1 to 3', 'from 1 to 4', 'from 1 to 5', 'from 2 to 4', 'from 2 to 6', 'from 3 to 6', etc., and individual numerical values, such as '1', '1.3', '2', '2.8', '3', '3.5', '4', '4.6', '5', '5.2', and '6', within the stated or described numerical range of 'from 1 to 6'. This applies regardless of the numerical breadth, extent, or size, of the stated or described numerical range.
Moreover, for stating or describing a numerical range, the phrase 'in a range of between about a first numerical value and about a second numerical value', is considered equivalent to, and meaning the same as, the phrase 'in a range of from about a first numerical value to about a second numerical value', and, thus, the two equivalents meaning phrases may be used interchangeably. For example, for stating or describing the numerical range of room temperature, the phrase 'room temperature refers to a temperature in a range of between about 20 0 C and about 25 0 C, is considered equivalent to, and meaning the same as, the phrase 'room temperature refers to a temperature in a range of from about 20 °C to about 25 0 C
Steps or procedures, sub-steps or sub-procedures, / and, equipment and materials, / system units, system sub-units, devices, assemblies, sub-assemblies, mechanisms, structures, components, elements, and configurations, and, peripheral equipment, utilities, accessories, chemical reagents, and materials, as well as operation and implementation, of exemplary embodiments, alternative embodiments, specific configurations, and, additional and optional aspects, characteristics, or features, thereof, according to the present invention, are better understood with reference to the following illustrative description and accompanying drawings. Throughout the following illustrative description and accompanying drawings, same reference notation and terminology (i.e., numbers, letters, or/and symbols), refer to same system units, system sub-units, devices, assemblies, sub-assemblies, mechanisms, structures, components, elements, and configurations, and, peripheral equipment, utilities, chemical reagents, accessories, and materials, components, elements, or/and parameters.
As stated hereinabove, the present invention, in some embodiments thereof, relates to manufacturing electrocoated medical devices, and quality control testing thereof. Some
embodiments of the present invention relate to a method for manufacturing an etectrocoated medical device; a method for quality control testing a coated medical device using an electrical cell; a method for setting process parameters for electrocoating a medical device; a method for validating a medical device efecfrocoating process; a system for manufacturing an electrocoated medical device (applicable for a single medical device, or for a plurality of medical devices); and a holder for holding a medical device in a solution for electrocoating the medical device in a coating process. The present invention, in some embodiments thereof, also concerns coπtroffing the quality of electrocoating processes, where nanometric non-conducting layers are coated on conducting surfaces, particularly, conducting surfaces of medical devices. One problem with monitoring electrochemical processes for generating nanometric coating is that due to the minute amounts of materials participating in a typical process, regularly measured variables, like voltage and current, are very small and may vary considerably in a hard to control manner. For example, allowed variance in thickness of different duplicates of a given medical device (e.g., stent) might cause very large differences in the current that is measured when the two duplicates are coated, even if all the coating conditions appear to be exactly the same.
Thus, an aspect of some embodiments of the invention concerns defining at least one 'quality index' that does not change considerably between coatings of different duplicates and is correlated with the quality of the obtained coating, or/and of the coating process. Another aspect of the invention concerns a system for coating medical devices, which is adapted for in situ evaluation of such a quality index.
It was found by the inventors, that one possible way of obtaining reliable quality indexes is by normalizing values obtained during a coating of a given duplicate with other values, obtained during the coating of the same duplicate. This way, the effect of differences between duplicates is reduced. For example, the position of a peak in a graph presenting the current measured at different times during a single coating process may be a more reliable quality index than the vafue of current at some predetermined time, say, 30 seconds after coating begins. Similarly, the ratio between different peaks obtained during the coating process may be a reliable quality index. Various quality indexes are described in detail below. As stated above, an aspect of the invention concerns a system for coating medical devices, which is adapted for in situ evaluation of a quality index.
In an exemplary embodiment, a coating system is made to coat simultaneously a lot of medical devices. Typically, the simultaneously coated devices are different duplicates of the same device. Each medical device that is coated by the system is electrified when held by a medical device holder in a bath of coating solution.
There is teaching [4] of a similar type of coating system in the same applicant/assignee previous patent application, incorporated herein by reference, in particular, therein, in the
description, along with reference to figures 14 - 16 thereof. Nevertheless, some embodiments of the present invention suggest some improvements to that coating system.
First, in some embodiments of the present invention, the solutions in the different cells are separate, and there is no fluid communication between them. This way, if one of the cells has a defected solution, this does not affect the other cells.
When all the simultaneously coated devices are duplicates of each other, it is preferable to have all the medical devices electrified with the same electrification scheme, such that all the medical devices go under substantially the same coating process, although the processes in each of the cells may differ due to minute differences in the solution content or minute differences in the structure of the medical devices. As noted above, such differences may have a significant effect on the measured values of current and voltage, even when the differences are within tolerances that may be considered acceptable for other causes.
Preferably, the electrochemical characteristics of each of the medical devices are measured independently of the other medical devices, so as to allow running in-process quality tests to each of the medical devices independently of the others.
Second, in some embodiments of the invention, the holder holding the medical device in the electrochemical cell is made to meet two, generally contradicting, requirements: on the one hand, it should connect the medical device with the power input so as to allow the medical device electrification and coating; and on the other hand, it should have only minimal effect on the electrical current in the coating solution in any other way.
Furthermore, since a medical device portion that is touching the holder is blocked from the coating solution, it is preferable that the medical device holder holds the medical device at a minimal area, leaving a maximal surface area free to contact the coating solution. The latter requirement contradicts the requirement of reliable electrical contact Third, the medical device holder should hold the medical device softly enough as not to deform it irreversibly. This may be achieved rather easily with robust medical devices, for example, orthopedic nails, but becomes more difficult with more fragile medical devices, for example, stents. In some cases, this requirement also makes the reliable electrical contact hard to achieve. Thus, in accordance with some embodiments of the present invention, almost the entire body of the medical device holder is an electrical insulator, to minimize the electric interaction of the holder with the solution, and only a small portion of the medical device holder is electrically conducting. The conducting portion is small in comparison with the medical device to be coated, and optionally also in comparison with that part of the medical device that is being coated. For example, the medical device holder is designed such that all the electrically conducting area is used for supporting the medical device, such that all this area is blocked from direct contact with the coating solution, thus having only minimal interference with the electrochemical reaction in the cell.
The scope of implementation of some embodiments of the present invention is primarily focused toward application of a medical device in the form of a medical implant or medical implant component, for example, a stent, having a metal surface. In a non-limiting manner, the scope of implementation of some embodiments of the present invention clearly includes applications to various other medical devices (for example, in the form of a medical implant or medical implant component), which can have a metal surface, for example, a catheter, a balloon, a shunt, a valve, a pacemaker, a pulse generator, a cardiac defibrillator, a spinal stimulator, a brain stimulator, a sacral nerve stimulator, an inducer, a sensor, a seed, an anti- adhesion sheet, a prosthesis, a plate, a joint, a fin, a screw, a spike, a wire, a filament, a thread, an anchor, or a bone fixation element, among other exemplary medical devices.
Within the scope of some embodiments of the present invention, in a non-limiting manner, it is to be fully understood that a medical device may also generally correspond to, and be representative of, an entire or whole medical device, such as an entire or whole stent, or an entire or whole prosthesis, or, alternatively, an entire or whole part or component of a medical device, such as of a stent or a prosthesis.
For example, an exemplary part or component of a stent, is a metal wire, a metal filament, or a metal thread, or, alternatively, a metal film, a metal plating, or a metal coating, deposited upon at least a section of another non-metal or metal part or component of the stent. Accordingly, as an example, the medical device component can generally correspond to, and be generally representative of, at least a section of at least a metal wire, a metal filament, or a metal thread, of a stent, or, alternatively, at least a section of a metal film, a metal plating, or a metal coating, deposited upon at least a section of another non-metal or metal part or component of a stent.
For example, an exemplary part or component of a prosthesis, is a metal plate, a metal joint, a metal fin, a metal screw, a metal spike, a metal wire, a metal filament, a metal thread, a metal anchor, or another metallic bone fixation element, or, a metal film, a metal plating, or a metal coating, deposited upon at least a section of another non-metal or metal part or component of the prosthesis. Accordingly, as an example, the medical device component can generally correspond to, and be generally representative of, at least a section of at least a metal plate, a metal joint, a metal fin, a metal screw, a metal spike, a metal wire, a metal filament, a metal thread, a metal anchor, or another metallic bone fixation element, of a prosthesis, or alternatively, at least a section of at least a metal film, a metal plating, or a metal coating, deposited upon at least a section of another non-metal or metal part or component of a prosthesis. As stated hereinabove, a main aspect of some embodiments of the present invention is provision of a method for manufacturing an electrocoated medical device, the method including the following main steps or procedures, and, components and functionalities thereof: (a) providing a medical device; (b) performing an electrocoating process on the medical device; (c) quality control testing the medical device during the electrocoating process, for obtaining at least
one quality index value; and (d) determining quality of the electrocoating process from the at least one quality index value.
Coating (electrocoating) Process
Exemplary teachings of electrocoating medical devices, such as stents, with, for example, a thin layer of diazonium compound(s), is ϊaught [1, 5, 4, 6, 7, 8] by the same applicant/assignee as the present invention. The contents of these documents are incorporated by reference as if fully set forth herein.
Some optional coating processes are discussed hereinbelow in connection with action
102 (FIG. 1). In the present section, an exemplary coating process is described with more details.
For example, electrochemical reduction of diazonium salts on metal medical devices
(e.g., stents) in acetonitrile [ACN] + 0.1 M NBu 4 BF 4 [TBATFB] leads to the formation of organic electrocoat on the surface. Electrochemical reduction of diazonium salt with R = OCi 2 H 2S can be performed by cyclic voltammetry. Manufacturing of an electrocoated medical device (e.g., stent) can be performed by using an electrochemical cell, for example, as shown in FIGS. 6, 7, or 8, or a single-cell system, for example, as shown in FIG. 9, or a multi-celi system, for example, as shown in FIGS. 10 and
22. These systems are illustratively described in detail below.
As preparation for the electrocoating process, before coating, the medical device (for example, a stent, such as a metal alloy stent) is optionally weighted and cleaned. Weighting (for example, using a microgram balance) allows comparison of the device weight before and after the coating. A decrease in weight is optionally interpreted as an indication to a degradation of the medical device, for instance, due to exposure to a wrong (opposite in sign than required) potential difference. Cleaning is optionally by immersing in a solvent under ultrasound for 15 minutes, and drying with air or inert gas atmosphere. Suitable solvents depend on the substance making the medical device and of the substances to be removed by the cleaning. For example, to clean a stent made of Nitinol™ alloy, acetone or/and acetonitrile [ACN] is suitable.
Optionally, all substances and accessories are under inert environment, and the work is carried out with the electrocoating cell inside a glove box, in which nitrogen, argon, or/and other inert gas is circulated, for example, for at least 30 minutes before coating starts. This will enable coating under an inert environment, such that concentrations of possible impurities of active ingredients in the electrochemical solution will be less than, for example, about 5 - 10 ppm.
Optionally, the cleaning of the medical device and bubbling inert gas are conducted in a system comprising a plurality of electrocoating cells. Optionally, all the cells are under the same inert atmosphere. Alternatively, each cell has its own gas inlet and outlet, so as to control the atmosphere in each cell independently of the others (for example, as shown in FlG. 10).
The medical device, for instance, a stent made of Nitinol alloy, is inserted into an electrochemical cell (FIGS. 6, 7, or 8), and mounted on a working electrode by utilizing a holder that provides the stent minimal support, but good electrical contact. For example, the medical
device (e.g., stent) may be tied to the holder with a thin conducting wire, for example, a wire of 50 μm diameter. Optionally, the wire is made of the same substance, Nitinol alloy, as the medical device in the present example. Other holders, the use of which is more easily automated, are described below. Optionally, medical device (e.g., stent) mounting can be done automatically using a designated multiple electrocoating system.
Platinum foil or rounded net can be used as a counter electrode(s). Optionally, the reference electrode is inside the medical device (e.g., stent), optionally parallel to a longitudinal axis of the medical device (e.g., stent), optionally going along the longitudinal axis (for example, as shown in FIGS. 7 and 8). When the reference electrode is symmetrical in respect of the medical device, for instance, going inside the medical device and parallel to its axis, or surrounding the medical device, the obtained results represent the coating over the entire medical device (e.g., stent) without being biased to better represent device portions that are closer to the reference electrode.
Optionally, there is using reference electrode(s) of either Ag/AgBr, or Pt wire, both located in the middle of the cavity of the medical device (e.g., stent).
The cell is filled, optionally partly filled, with a coating solution comprising a supporting electrolyte (for example, 0.1 M, tetrabutylammonium tetrafluoroborate [TBATFB]) and with an amount of the species to be coating the device (hereinafter, 'active agent'), for example, 8 mM of a diazonoium salt [DS]. Ar gas is then bubbled into the electrolyte in order to ensure inert electrocoating conditions.
The OCP (open circuit potential) of the stent in the solution is measured using a potentiostat, and when the measured value stabilizes, the power is turned on to start electrocoating the medical device (e.g., stent). Exemplary coating conditions for a chromium cobalt [CrCo] stent is voltage scanning between 0 and -1.4V (vs. OCP) at a scan rate of 100 mV/sec for 30 cycles.
The electrocoating process is conducted using a potentiostat at any of the methods described hereinbelow, for instance, at cyclic voltammetry mode, galvanostatic mode (constant current), or potentiostatic (constant voltage) mode. The coated medical device (e.g., stent) is optionally rinsed in an ultrasonic cleaner in acetonitrile for 15 minutes in order to remove excess solution or excess solutes from the medical device (e.g., stent). Optionally, ultrasonic cleaning of the coated medical device (e.g., stent) can be done automatically using a designated multiple electrocoating system.
The preceding is an illustrative example of performing an electrocoating process on a medical device. In the following, there is an illustrative example of quality control testing the medical device during the electrocoating process. A main objective or goal of performing such quality control testing is for obtaining at least one quality index value, which can be used as a basis for determining quality of the electrocoating process from the at least one quality index value.
In addition to a main aspect of some embodiments of the present invention being provision of a method for manufacturing an electrocoated medical device, as stated hereinabove, another main aspect of some embodiments of the present invention is provision of a method for quality control testing a coated medical device using an electrical cell, the method including the following main steps or procedures, and, components and functionalities thereof:
(a) measuring at least one electrical parameter of the coated medical device inside the electrical cell, for forming at least one measured electrical parameter; (b) obtaining at least one quality index value of the coated medical device from the at least one measured electrical parameter; and (c) determining quality of the coated medical device from the at least one quality index value.
Quality Control Testing
Referring now to the drawings, FIG. 1 illustrates the actions taken in a method 100 according to an exemplary embodiment of the invention.
At 102, a medical device is coated. The thickness of the coating is preferably smaller than 1 μm, optionally smaller than about 100 nm, optionally about 20 nm or smaller, for example, between about 4 nm and about 10 nm.
The coating is preferably electrochemical, which means that it includes generating electric potential difference and electric current in a solution, such that charged species in the solution stick to the medical device (e.g., stent) so as to coat the medical device. Examples of such coating techniques include: Chroπoamperometry (CA), chronocoulometcy (CC), linear sweep voltammetry (LSV), cyclic voltammetry (CSV), alternating current voltammetry (ACV), voltammetry techniques with different pulse shapes, especially square wave voltammetry
(SVW), differential pulse voltammetry (DPV) or normal pulse voltammetry (NPV), AC impedance spectroscopy, chronopotentiometry and cyclic chronopotentiometry can be used as electrochemical detection methods.
In the present application mainly cyclic voltammetry (CV) and AC voltammetry (alternating voltammetry, ACV) are referred in detail, however, in some embodiments of the invention, other coating techniques are applied and controlled.
At 104, the potential difference V and the current / are measured and recorded. Optionally, a potential difference is applied between a working electrode, which comprises the medical device, and a counter electrode. In some embodiments, platinum foil or platinum rounded net are used as a counter electrode. Optionally, the voltage V is measured between the working electrode and a reference electrode. The reference electrode is a calomel electrode, a sliver/silver bromide/silver chloride electrode, or other reference electrode known in the art as such. The current / is optionally measured between the working electrode and the reference electrode (see also FIG. 21).
At 106, measured values of the potential difference and current are processed to obtain a value of a quality index.
As stated hereinabove, the phrase 'quality index', as used herein, refers to 'something' (e.g., property, characteristic, feature, parameter, or result) that serves to provide an indication or level of quality. The phrase 'quality index', as used herein, also refers to 'something' (e.g., property, characteristic, feature, parameter, or result) that serves to guide, point out, or otherwise facilitate reference, to an indication or level of quality. The phrase 'quality index value', as used herein, refers to a (numerical) value or magnitude of the preceding defined 'quality index 1 . The phrases 'quality index' and 'quality index value' are herein used in the context of aspects of quality control, quality control testing, validation, and validating.
The quality index is preferably selected to be repeatable, and at the same time, correlated with coating quality. In this context, 'repeatable 1 means that in measurements made on a large number of duplicate devices (for example, 20, 50, or 1000 devices) the standard deviation among the quality index values is much smaller than the standard deviation of voltage and current (normalized to the average voltage and current, and if the quality index value is not dimensionless, the quality index value standard deviation is normalized to the average quality index value).
Optionally, processing the measured values includes mathematical manipulations on values measured at different stages of the coating process. Optionally, the different stages are before coating and after coating. Alternatively, at least one of the stages is during coating.
For example, the current measured at some well defined period during the coating process is divided by the current measured at some other well defined period during the same coating process.
Optionally, when the coating involves cyclic voltammetry, the current measured during one cycles is integrated over the cycle's period to obtain a first charge unit; the current measured during another cycles is integrated over the other cycle's period to obtain a second charge unit; and the first and second charge units are compared to obtain a quality index.
A comparison is optionally by way of subtraction, such that the comparison results in an index having dimensions; in this case, dimensions of charge. Alternatively, a comparison is by way of division, such that the comparison results in a dimensionless index.
Additional examples of quality indexes are discussed below. Optionally, the value of the quality index has a smaller normalized standard deviation than the value of each of the voltage and current, used for evaluating the quality index.
At 108, the quality of the monitored coating is determined responsive to the obtained value of the quality index. Optionally, this is done by comparing the obtained value with a predetermined quality interval, as discussed below, under the heading "Exemplary 'acceptance / rejection' criteria for passing in-process and out-of-process quality control tests". Quality Control Testing Modes (in-process testing and out-of-process testing) Reference is made to FIG. 2 and FIG. 3.
Coating parameters are determined using both in-process, and out-of-process types or modes of evaluations. In-process measurements are recorded automatically during the
electrocoating process, results are compared to calibrated control standards. In-process testing is performed for all manufactured coated medical devices (e.g., stents). In contrast, out-of- process evaluations are performed only on a fraction of the manufactured coated medical devices (e.g., stents), for example, for about 1/1000 medical devices (e.g., stents), via statistical sampling, and the results are compared to calibrated control standards. Electrochemical out-of- process evaluation is performed using a designated electrical cell (e.g., the same as, or different than, the electrocoating cell). Other successive out-of-process evaluations are performed externally to the medical device coating (electrocoating) process.
FIG. 2 is a block-diagram of an exemplary a quality control method 200 according to an embodiments of the invention.
Quality control method 200 has two main parts, each of which can be applied independently of the other. So there are, in fact, two independent methods: out of process quality control 200A, and in-process quality control 200B.
Optionally, at 200C, a final quality is determined for a coating responsive to out-of process evaluation 200A and in process evaluation 200B. Optionally, some deviations from a quality interval in one of the processes may be 'forgiven' if the coating quality index falls within a high quality inteFval of the other.
Optionally, each and every (uncoated, coated) medical device undergoes in-process quality control testing. Optionally, only a sample of the (uncoated, coated) medical devices undergoes out-of process quality control testing. Optionally, if a medical device fails the out-of-process quality control test after standing the in-process quality control test, then, the entire batch is discarded. Optionally, in such a case, all the (uncoated, coated) medical devices in the same batch go through out-of-process quality control testing. in-process quality control testing
Reference is made to FIG. 4 and FIG. 5.
FIG. 4 is a flowchart of actions taken in an exemplary in-process quality control 200B 1 taken during a coating process according to an embodiment of the invention.
At 202B 1 an electrochemical characteristic of the device is measured and recorded at a first predetermined time during the coating process. Optionally, the directly measured parameters are time, current, and voltage. The predetermined time is optionally a certain number of seconds from the beginning of the coating. Optionally, the predetermined time is the time at which a peak is observed in the value of a parameter directly measured during the coating, for example, current or voltage. Optionally, the predetermined time is the time at which a certain cycle takes place, for example, the first CV cycle. Other examples include: the time at which solvent redox occurs, a cycle where a minimal peak current differential exists, and a cycle where the current time derivative is the closest to a predetermined value.
At 204B, the same characteristic is measured and recorded at a second predetermined time.
At 206B, the two recordings are processed to obtain a quality index. At 210B, a quality of the coated device is determined based on the quality index, optionally, by comparison with a given quality interval.
In exemplary methods of in-process quality control, differences or ratios between electrochemical characteristics of the device at different coating stages are compared. In one example, the electrical resistance of the device 10 seconds after some predetermined time is compared to the electrical resistance of the same device after additional 100 seconds of coating, and the ratio between the two provides a quality index. At another example, the electrical resistance of the device at a first predetermined time is compared to the electrical resistance of the same device at a second predetermined time, and the ratio between the two provides a quality index. The electrical resistance of the medical device is optionally evaluated in methods, which as such are known in the art, for instance, methods based on current/voltage relationships found in cyclic voltammetry. Similarly, quality indexes can be determined by comparing the device capacitance, or any other value obtaining by integrating or differentiating one of current, voltage, or time in respect of the other.
Additionally, alternatively, or independently from comparing electrochemical characteristics at different coating stages, one or more characteristic is looked for, and if not found, the device fails the quality test. For example, in some embodiments, a device that is coated under conditions of cyclic changes in voltage fails the in-process quality test if the first cycle does not contain a clear peak, that is, a voltage value, at which the absolute value of the current is maximal. Quality indexes which are not based on comparison but on a single event may be defined also for out-of-process quality control. Quality indexes for in-process quality control testing
An exemplary in-process quality index is the ratio between net charge flowing in the cell at different cycles of cyclic voltammetry.
Optionally, the charge flowing in one of the first cycles is compared with the charge flowing in one of the later cycles, for example, the 30 th cycle.
Optionally, the later cycle is determined by the difference between the peak current measured in two successive cycles. In an exemplary embodiment, when this current difference is below some predetermined threshold (for instance, 10 pico amperes) the cycle is considered appropriate for comparison with the first cycle. Optionally, if the threshold current is not achieved within a predetermined interval of number of cycles (for instance, between cycle No. 25 and cycle No. 35) the coated device fails the quality test in respect of this quality index. In-process quality control testing - procedures, equipment reagents Measurements are conducted during medical device (e.g., stent) manufacturing, by utilizing an electrochemical cell, for example, as shown in FIGS. 6, 7, and 8, or by using a single- cell system or a multi-cell system, for example, as shown in FIGS. 9 and 10, respectively. Electrocoating Process
Electrocoating is performed using either of the following electrochemical methods: cyclic voltammetry (CV-In), glavanistatic (GaMn) [constant current process], or potentistatic (Poten-in) [constant voltage process].
Examples
(1) Cyclic voltammetrv (CV-In)
Solution: 8mM active ingredient (e.g., diazonium salt) in acetonitrile + 0.1 M NBu 4 BF 4 .
Electrochemical cell
A suitable electrochemical cell is a cylindrical three electrode cell (for example, as shown in FIGS. 6, 7, and 8). The counter electrode is a circular Pt foil, and the reference electrode is a Ag/AgBr rod, while the working electrode is a metal medical device (e.g., stent) wrapped with a metal (e.g., stainless steel) wire (e.g., FIG. 7) or tube (e.g., FIG. 8) and centered in the cell.
Experimental setup and procedure Repetitive potential cycles, cyclic voltammetric current-potential curve for different cycle number between OCP and 5OmV negative to the reduction peak of the diazonuim salt and back
(e.g., for a specific ingredient).
Results
The organic layer obtained by the reduction of diazonium (example of an active electrocoating ingredient) salts reduces the reduction peak current. By integration of the CV curve, one can estimate the charge that passes in this process. This can provide information about the organic layer capacitance and thickness.
(2) Analytic Cyclic Voltammetrv. In-process (CV In) Precoat analysis, and postcoat analysis The 'blocking behavior' of a modified metal medical device (e.g., stent) can be investigated by cyclic voltammetry (CV) in the presence of a ferrocene, or any other, reduction/oxidation (redox) couple.
Method
CV measurements for the unmodified medical devices (e.g., stents) before and after the electrocoating process in the electrocoating electrolyte.
Solution
8 mM diazonium (as an exemplary active electrocoating ingredient) salts in CAN + 0.1 M
TBATFB and 2mM ferrocene.
Electrochemical cell A suitable electrochemical cell is a cylindrical three electrode cell (for example, as shown in FIGS. 6, 7, and 8). The counter electrode is a circular Pt foil, and the reference electrode is a Ag/AgBr rod, while the working electrode is a metal medical device (e.g., stent) wrapped with a metal (e.g., stainless steel) wire (e.g., FIG. 7) or tube (e.g., FIG. 8) and centered in the cell.
Experiment setup and procedure
After installing the electrochemical cell, the electrocoating process begins. Results
This measurement result can be presented in the format of a cyclic voltammogram. A reversible peak should appear.
Out-of-process quality control testing
Reference is made to FIG. 11, and to FIG. 12.
FIG. 1 is a flowchart of actions taken in an exemplary out-of-process quality control 200A. At 202A, corresponding to a (pre-coating) out-of-process testing, electrochemical characteristics of the bare medical device are first compared with a standard. The standard is optionally based on values of the same characteristics measured for a large number of bare medical devices, which after being coated, proved to coat well.
In one embodiment, the value used for evaluating a bare medical device (e.g., stent) is the peak value in a first CV cycle, carried out in a standard, non-coating solution. Optionally, the non-coating solution comprises 5mM Fe(CN) 6 3" ; 5mM Fe(CN) 6 4" ; AND 0.1 M KCI, adjusted to pH7 by phosphate buffer. In this example, when the medical device is a stent, the quality interval is a peak in the current value obtained with voltage of between -0.8V and -1.0V.
At 204A, a bare medical device, having electrochemical characteristics that deviate from the quality interval, is discarded without coating.
When out-of-process quality control 200A is used to control the coating of a plurality of medical devices, a discarded medical device is optionally replaced with another duplicate medical device. Alternatively, the discarded medical device is not replaced, and the cell that was initially designated for coating the discarded medical device is not used in this run of the coating process.
At 206A, the medical device is coated, optionally, with application of in-process quality control testing, as described above with reference to FIG. 4.
At 208A, electrochemical characteristics of the coated medical device are compared with those of the bare medical device, as measured at 202A, to obtain a quality index and a value thereof.
At 210A, the quality of the coated medical device is determined based on the obtained quality index value, optionally, by comparing the quality index value to a predefined interval or range of quality index values (i.e., quality index interval or range). Quality indexes for out-of-process quality control testing An exemplary out-of-process quality index is the ratio between current measured with a coated medical device (e.g., stent) in a test solution at a certain voltage, and current measured with the bare medical device (e.g., stent) (before coating) at the same voltage. All the other parameters, for instance, the cell geometry and the test solution are the same.
One preferred index is the ration between pre-coating and post-coating current at the maximal voltage value at which components of the test solution do not undergo redox reaction. This point is preferred because the large voltage allows good signal to noise ratio, and that all the signal is from the medical device (and not from reactions in the solution). Generally, when currents are compared, the smaller is the post-coating current in relation to the pre-coating current, the better is the coating.
For example, alternating-current voltammetry (ACV) and cyclic voltammetry (CV) are suitable for indirect measurement of the electrical resistance and capacitance of the medical device, thus sensitive to the existence of an insulating layer adsorbed on a conductive layer of the medical device.
Out-of-proceβs quality control testing - procedures, equipment, reagents
The process requires the replacement of the organic coating solvent with an aqueous base solvent containing non-active reduction couple that enable the estimation coating effectiveness. (A) Electrochemical Evaluations
Out-of-process quality control testing, via electrochemical evaluations, is performed by utilizing any of various different types of analytical techniques. Exemplary electrochemical evaluation types of analytical techniques are: (1) cyclic voltammetry, (2) capacitance, (3) linear polarization, (4) electrochemical impedance spectroscopy, and (5) alternating current voltammetry, each of which is described hereinbelow. (1 ) Cyclic Voltammetry , Out-of-process (CV out)
The 'blocking behavior' of a modified metal medical device (e.g., stent) can be investigated by cyclic voltammetry (CV) in the presence of a ferri/ferrlcyanide, or any other, reduction/oxidation (redox) couple. Method
CV measurements for the diazonium (as an exemplary active electrocoating ingredient) coated 316L (e.g., for a specific ingredient) metal medical devices (e.g., stents), and as a control, received medical device (e.g., stents) and electro-polished medical devices (e.g., stents) are tested. Solution
5 mM Fe(CN) 6 3 V 5 mM Fe(CN) 6 4" /0.1 M KCI, adjusted to pH 7 by phosphate buffer. Electrochemical cell
A designated electrical cell (e.g., the same as, or different than, the electrocoating cell) is used. For example, with reference to FIG. 13, the measurements are made using a calomel electrode as a reference electrode (RE), included in an electrochemical cell using a salt bridge with a capillary in the center of the medical device (e.g., stent). Platinum wire with 25mm 2 surface area can be used as a counter electrode (CE). Half of the medical device (e.g., stent) is immersed in the electrolyte which is used as the working electrode (WE). Experiment setup and procedure
After installing the electrochemical cell, there is scanning from OCP to -0.7V vs. OCP, and back to 0.7V vs. OCP (e.g., for a specific ingredient). Results
This measurement result can be presented in the format of a cyclic voltammogram, for example, as shown in FIG. 14.
(2) Capacitance (Cap-out)
Capacitance was measured using CV. In this case, there is scanning through a potential range that has no oxidation or reduction peaks {from 0±300 mV}. The CV is recorded at different scan rates, for example, (10, 50, 100, 500) mV/sec. For example, this test can be performed in a 100 ml aqueous solution of 0.1 M phosphate buffer, pH7, upon immersion.
Method
CV measurements for the electrocoated medical devices (e.g., stents) and as a control, as received stents and electro-polished stents were used (ex. For a specific ingredient).
Solution Phosphate buffer, pH 7, with or without ferri/ferrlcyanide redox couple or any other couple.
Electrochemical cell
A designated electrical cell (e.g., the same as, or different than, the electrocoating cell) is used (for example, as shown in FIG. 13), the measurements are made using a calomel electrode as a reference electrode (RE), included in an electrochemical cell using a salt bridge with a capillary in the center of the medical device (e.g., stent). Platinum wire with 25mm 2 surface area can be used as a counter electrode (CE). Half of the medical device (e.g., stent) is immersed in the electrolyte which is used as the working electrode (WE).
Experiment setup and procedure After installing the electrochemical cell, there is scanning through a potential range that has no oxidation or reduction peaks {from 0+300 mV}. The CV is recorded at different scan rates, for example, (10, 50, 100, 500) mV/sec.
Results
The profile obtained is typically box shaped. As the scanning rate is increased, the following change is to be observed:
I=Cv, i- amper, C- faraday, v- volt/sec
By plotting I vs. v, one can generate the capacitance as the curve slope. The process commences without delay (the medical device (e.g., stent) does not arrive at its OCP (open circle potential). The capacitance value changes in accordance to coating thickness/source. Measurement time of these procedures is typically only about 1 minute.
(3) Linear Polarization, Out process (LP out)
Linear Polarization (LP) technique is used in the electrochemical evaluation of the preparation for electrocoating and the diazonium electrocoating. In this method one could measure the polarization resistance (R p ) and the corrosion current (I corτ ) of the medical device (e.g., stent). Method
Linear Polarization (LP) technique for the electrocoated stents. Control is either non- treated stents or electro-polished stents (ex. For a specific ingredient). Solution
Phosphate buffer, pH 7, with or without femVferrlcyanide redox couple or any other couple.
Electrochemical cell
A designated electrical cell (e.g., the same as, or different than, the electrocoating cell) is used (for example, as shown in FIG. 13), the measurements are made using a calomel electrode as a reference electrode (RE), included in an electrochemical cell using a salt bridge with a capillary in the center of the medical device (e.g., stent). Platinum wire with 25mm z surface area can be used as a counter electrode (CE). Half of the medical device (e.g., stent) is immersed in the electrolyte which is used as the working electrode (WE). Experiment setup and procedure
After installing the electrochemical cell, after the electrode is allowed to equilibrate for 10 min, there is scanning through a potential range around the OCP (+ 0.1V) with a scan rate of 0.1 mV. Results
High resistance and low corrosion current compared to non-coated medical devices (e.g., stents) is observed. This is indicative of an organic layer on the medical device (e.g., stent) surface. The limitation of this technique is that it provides comparative results, but does not indicate the quality of the coating. (4) Electrochemical Impedance Spectroscopy (EIS out)
E(S generated quantitative data that relates to the quality of a coating on a metal substrate. EIS is a very sensitive detector of the condition of a coated metal, so the EIS response can be used to indicate changes in the coating long before any visible damage occurs. From this measurement, the capacity of the coating can be evaluated and the relative dielectric constant and the thickness of the coating can be evaluated. One can also measure the polarization resistance. Method EIS measurements for the electrocoated medical devices (e.g., stents) and as a control, standard non-treated medical devices (e.g., stents) and electro-polished medical devices (e.g., stents) are used. Solution
5 mM Fe(CN) 6 3 V 5 mM Fe(CN) 6 4 VdM KCI, adjusted to pH 7 with phosphate buffer.
Electrochemical cell
A designated electrical cell (e.g., the same as, or different than, the electrocoating cell) is used (for example, as shown in FIG. 13), the measurements are made using a calomel electrode as a reference electrode (RE), included in an electrochemical cell using a salt bridge with a capillary in the center of the medical device (e.g., stent). Platinum wire with 25mm 2 surface area can be used as a counter electrode (CE). Half of the medical device (e.g., stent) is immersed in the electrolyte which is used as the working electrode (WE).
Experiment setup and procedure
After installing the electrochemical cell, it is required to wait until the open circuit potential (OCP) stabilizes, afterwards the initial potential is set to the OCP value. Impedance spectroscopy is scanned from 100KHz to ImHz with 3 measures per frequencies, with an amplitude set to 5mV (Faradic current).
Results
Results of the above analysis can be presented in a Nyquist plot (e.g., FIG. 15), and a Bode plot (e.g., FIG. 16), and from this data the coating polarization resistance difference between modified and unmodified medical device (e.g., stent) can be determined, and thus, the frequency of the maximum difference between the two can also be determined. Then, using this constant frequency, the capacity of the coating can be measured.
(5) Alternating Current Voltammetry (ACV out) Double-layer capacity, C d |, is measured in a 100 ml aqueous solution of 0.1 IVl phosphate buffer, pH7. After the electrode is allowed to equilibrate for 10 min, an ac voltage of
25 mV peak to peak and 100, 300, 600, 900 Hz is superimposed on the dc potential (0 - 0.3V versus SCE [standard calomel electrode]), and the real and imaginary parts of the ac current are detected with CHI potentiostat. Method
ACV measurements for the electrocoated stents and as a control, non-treated standard medical devices (e.g., stents), and electro-polished medical devices (e.g., stents) are used.
Solution
Phosphate buffer, pH 7, with or without ferri/ferrlcyanide redox couple or any other couple.
Electrochemical cell
A designated electrical cell (e.g., the same as, or different than, the electrocoating cell) is used (for example, as shown in FIG. 13), the measurements are made using a calomel electrode as a reference electrode (RE), included in an electrochemical cell using a salt bridge with a capillary in the center of the medical device (e.g., stent). Platinum wire with 25mm 2 surface area can be used as a counter electrode (CE). Half of the medical device (e.g., stent) is immersed in the electrolyte which is used as the working electrode (WE).
Experiment setup and procedure
After installing the electrochemical eel ) , an ac voltage of 25 mV peak to peak amplitude and 100, 300, 600, 900 Hz, is superimposed on the dc [direct current DC] potential (0 - 0.2 V versus SCE), 25 mV step size. Results While inserting a coated electrode into an electrolyte we generated a double layer, the behavior is similar to that of a capacitor, and this is referred as Helmholtz model. In accordance to this model, the capacitance of the capacitor is represented by the following equation:
d εo = dielectric constant, ε r = constant, A = electrode area, d = coating thickness (average distance between opposite charges, Q), where
Q = CD(δV) δV = potential difference on capacitor surface.
(i) First, there is generating a potential on the surface (no electron movement), for instance, -1 volt, where this process charges the surface.
(ii) Second, there is changing the potential difference, δV, and checking how the charge changes accordingly on the surface. For example, changing the potential difference, δV, by about 50 mv, where there is an aryl coating, or an oxide coating, will strongly influence the value of 1 Cf", and therefore, also the value of C. In such a case, a constant potential on the electrode is used, accompanied by a sinusoidal wave of about 25 mv, and a frequency between 100 - 1000 Hz. The working operation is done at a fixed frequency, and for an ideal plate capacitor, a linear relationship of voltage (V) directly proportional to capacitance (C) is obtained (for example, as shown in FIG.
17). Measurement is conducted in aqueous solution, since in an organic medium the dielectric constant is low.
Expected value of capacitance (C), prior to coating: 10 - 50 μF/cm 2 (stainless steel).
Expected value of capacitance (C), after coating: < 1 μF/cm2.
(B) Physical Evaluations
Out-of-process quality control testing, via physical evaluations, is performed by utilizing any of various different types of analytical techniques. Exemplary physical evaluation types of analytical techniques are: (1) auger electron spectroscopy (AES), (2) X-ray photoelectron spectroscopy (XPS), (3) scanning electron microscopy (SEM), and (4) energy dispersive spectroscopy (EDS), each of which is described hereinbelow. Any of these techniques can be used to evaluate the preparation for the electrocoating process. (1 ) Auger Electron Spectroscopy (AES-out) Analysis
Instrument
VG Scientific Microlab 350 Scanning Auger Microscope, using the following exemplary settings:
Primary Electron Beam: 10.0 keV, 60 nA
Ar Ion Beam: 4.0 keV Sputtering Rate calibrated with a 20 nm thick SiO 2 standard.
Procedure
Analysis is performed in accordance with SEMATECH SEMASPEC Test Method for AES Analysis Standard 91060573B-STD.
Elemental composition of the surfaces is determined by survey scans. Atomic concentrations are calculated using elemental sensitivity factors, without applying any standardization procedure. Depth profiles of relevant elements are acquired in the alternate sputtering mode, using a beam of Ar + ions. Sputtering depths are reported as Si oxide equivalent. By using the Auger depth profiles, the oxide layer thickness is estimated as the depth at which the oxygen signal in the atomic concentration profile decreases to half its maximum value.
(2) X-ray Photoelectron Spectroscopy (XPS-out) Analysis Instrument
VG Scientific Sigma Probe, using the following exemplary settings: X-ray source: monochromatic Al Ka, 1486.6eV. X-ray beam size: 150 μm.
Procedure
Analysis is performed in accordance with SEMATECH SEMASPEC Test Method for XPS Analysis Standard 90120403BB-STD. For surface analysis, samples are irradiated with monochromatic X-rays. Survey spectra are recorded with a pass energy of 100 eV, from which the surface chemical composition is determined. Survey scans are presented as plots of the number of electrons measured as a function of binding energy. High energy resolution measurements can be performed with a pass energy of 50 eV. Core level binding energies of the different peaks can be normalized by setting the binding energy for the C1s at 284.6 eV.
Elemental composition of the surface is determined by a survey scan. Atomic concentration is calculated using elemental sensitivity factors, without applying any standardization procedure. Data analysis can be performed using the Sigma Probe Advantage software.
(3) Scanning Electron Microscopy (SEM-oυt) and Energy Dispersive Spectroscopy (EDS- out) The method is based on FEI low-vacuum scanning electron microscope Quanta
200(FEI, USA) and EDS Oxford Instruments energy-dispersive spectrometer INCA, attached to SEM Quanta 200.
This method is used to perform image analysis of the surface of the medical device (e.g., stent), and to compare the medical devices (e.g., stents) that undergo a preparation for
electrocoating (e.g., surface cleaning pre-treatment) and the medical devices (e.g., stents) that are either bare or coated. EDS analysis is used to determine the contaminations in the composition.
(4) Atomic Force Microscopy (AFM-out) AFIVl is used in order to determine medical device (e.g., stent) surface roughness, or/and capacitance, or/and conductivity, for standard non-treated medical devices (e.g., stents), compared to pretreated and electrocoated medical devices (e.g., stents). Measurements can be used for determining and analyzing the effect of the roughness in the diazonium electrocoating process. 'Acceptance / Rejection' criteria for 'passing / failing' in-process and out-of-process quality control testing
For the in-process and out-of-process quality control testing, each quality index is associated with a quality interval. Reference is made to FIGS. 18 and 19, which show 'acceptance / rejection' criteria for in-process quality control testing and out-of-process quality control testing, respectively.
In some embodiments, if a quality index lies outside the quality interval associated therewith, the medical device fails the quality test.
Optionally, more than one quality index is defined for evaluating the quality of a single coating. In some embodiments, the coated medical device passes a quality test only if each of the quality indexes is within the quality interval associated therewith. In some other options, the coated medical device passes a quality test only if a minimal number of quality indexes lie within their corresponding quality intervals. Other options are also available, as known in the art of quality control.
Optionally, there are several quality intervals for the same index. For instance, if a coated medical device is suitable for several uses, each requiring a different coating quality, different quality intervals for the same quality index may be defined, each interval reflecting the quality required for a different use of the coated medical device. In such a case, a medical device may pass the quality control test for one use, and not for another.
In some embodiments, the quality intervals are determined by comparing quality index values with quality evaluations done on the same duplicates with state of the art methods. For example, when the coating is for releasing drug, drug release profile of different duplicates is measured, and compared with values of a quality index. The quality interval is optionally defined such that the medical devices having the quality index within this interval are reliably predicted to provide satisfactory drug release profile. Another way to define a quality interval is in a relative manner, that is, that in a batch or any other large number of duplicates, an average quality index is defined, and the quality interval is defined as a limit to an allowed deviation from this average. Optionally, the allowed deviation is expressed in units of a standard deviation, for example, a quality interval may be defined as the interval between x o -2σ and x o +2σ, where X 0 is the average index, and σ is the standard
deviation. When this method is applied to large enough a number of medical devices (typically, at least 1000), about 5 % of the medical devices may be expected to be outside the quality interval. In some embodiments, the large number of medical devices, for which X 0 and σ are determined, are medical devices that were all coated simultaneously, in a multi-cell system (for example, as shown in FIGS. 10 and 22.
As stated hereinabove, another main aspect of some embodiments of the present invention is provision of a method for setting process parameters for electrocoating a medical device, the method including the following main steps or procedures, and, components and functionalities thereof: (a) measuring at least one electrical parameter of the medical device inside an electrical cell, for forming at least one measured electrical parameter; and (b) electrocoating the medical device inside the electrical cell, based on the at least one measured electrical parameter.
In some embodiments of the method, step (a) measuring at least one electrical parameter of the medical device inside an electrical cell, for forming at least one measured electrical parameter, is performed by using any of the above illustratively described electrochemical types of in-process quality control testing or/and out-of-process quality control testing. Based on the at least one measured ejectrical parameter obtained from step (a), then, step (b) is performed, for electrocoating the medical device inside the electrical cell.
In addition to the hereinabove illustratively described main aspects of some embodiments of the present invention, as stated hereinabove, another main aspect of some embodiments of the present invention is provision of a method for validating a medical device electrocoating process, the method including the following main steps or procedures, and, components and functionalities thereof: (a) performing the electrocoating process on a medical device; (b) quality control testing the medical device during the eiectrocoating process, for obtaining at least one quality index value; and (c) determining quality and validity of the electrocoating process from the at least one quality index value.
In some embodiments of the method, step (b) quality control testing the medical device during the electrocoating process, for obtaining at least one quality index value, is performed by using any of the above illustratively described types of in-process quality control testing or/and out-of-process quality control testing. Based on the at least one quality index value obtained from step (b), then, step (c) is performed, for determining quality and validity of the electrocoating process. For example, in some embodiments of this method, there is performing various types of mathematical and statistical analyses, for example, either involving or based on the well known types of six sigma (6 sigma) levels of quality and validation. Electrical (electrochemical) cells, for performing the coating process, and for performing in-process or/and out-of-process quality control testing
Reference is made to FIG. 20, a schematic illustration of an electrical cell 300, which is configured as an electrochemical cell, according to an embodiment of the invention.
Cell 300 comprises a container 305 for coating solution 310. Container 305 optionally has a port 315, useful for letting solution 310 into container 305, before a coating process begins and out thereof, for replacing a solution. Optionally, the solution is replaced after every predetermined number of coating processes, for instance, after each time a medical device (e.g., a stent) 325 is coated, the solution is replaced. Optionally, port 315 is also useful for bubbling inert gas into solution 310, from a gas source (not shown). Optionally, there is a separate gas inlet. Optionally, there is also a gas outlet, open to the glove box.
Three electrodes are shown in FIG. 20: reference electrode 312; counter electrode 316; and working electrode 320. Electrical connection between the electrodes, appropriate for CV is shown in FIG. 21, a schematic illustration of the electrical connections in an electrochemical type of electrical cell according to an embodiment of the invention. Working electrode 320 and counter electrode 315 are connected to two poles of a potentiometer (not shown) and reference electrode 312 is connected to the third pole. The voltage is optionally measured with voltmeter
405; and the current is optionally measured with current-meter 410. In some embodiments, meter 410 is a microampermeter, suitable for providing accurate current readings in the range of between 10 micro-amp and 300 micro-amp, which is the typical range of currents obtained in coating processes according to embodiments of the invention.
Electricity is applied to the (target) working electrode 320, as follows. By sweeping the potential from zero to -1.5 V vs. reference electrode 312, a reduction potential that is applied on counter electrode 315 supplies a current that produces a potential difference which causes electrocoating of medical device 325 (e.g., a stent).
Working electrode 320 comprises an electrical lead 322 having an electrical insulation 324; a medical device (e.g., a stent) 325; and supports 330 and 332.
Supports 330 and 332 are just large enough to press against device 325 so as to hold the device at place without deforming the device.
At least one of supports 330 and 332 is in electrical communication with lead 322, such that medical device (e.g., a stent) 325 becomes electrically a part of working electrode 320. Electrical insulation 324 insulates solution 310 from any part of lead 322.
This arrangement of one or more supports, that at least one of which electrically connects the medical device being coated with the lead of the working electrode is one way to meet the two, generally contradicting, requirements discussed above. It allows connecting medical device (e.g., a stent) 325 with the power input while having only minimal effect on the electrical current in coating solution 310 other than by contacting medical device (e.g., a stent) 325. In the embodiment shown, portions of medical device (e.g., a stent) 325 that touch supports 330 and 332 do not contact coating solution 310, and therefore not coated. Therefore, it is preferred to have supports 330 and 332 as small as possible, to minimize the area that is not coated.
Based on this arrangement of one or more supports, for example two supports 330 and 332, as stated hereinabove, another main aspect of some embodiments of the present invention is provision of a holder for holding a medical device in a solution for electrocoating the medical device in a coating process, the holder including the following main components and functionalities thereof: (a) an electrode lead connectable to a power source; and (b) at least one electrically conductive support member for keeping the medical device in place during the coating process, the support member being in electrical contact with the electrode lead; wherein portions of the electrode lead other than the support members are electrically isolated from the solution. Supports 330 and 332 hold medical device (stent) 325 softly, ensuring that the medical device (stent) does not deform.
In an embodiment of the invention, insulation 324 is formed over lead 322 in a deposition process (for instance, vapor deposition of Teflon), with portions of lead 322 masked so as not to coat these portions with the insulator. Supports 330 and 332 are electrically connected to the lead through the portions that were masked during the deposition process.
Also shown in FIG. 20 are pillars 340, standing outside container 305, and cover 345, which has -protrusions suitable for snugly receiving therein the upper tips of pillars 340.
Optionally, (as indicated by the dashed line 318) counter electrode 316 is integral with cover 345, and is designed to be placed perpendicularly to the solution upper surface when pillars 340 are all the way inside the protrusions.
As stated hereinabove, another main aspect of some embodiments of the present invention is provision of a system for manufacturing an electrocoated medical device, the system including the following main components and functionalities thereof: (a) an electrocoating cell, including electrodes, for electrocoating a medical device; (b) a power source, for supplying power to the electrodes for effecting the electrocoating; and circuitry, for quality control testing the medical device subjected to the electrocoating, for obtaining at least one quality index value, and for determining quality of the electrocoated medical device from the at least one quality index value.
FIG. 22 is a pictorial representation of a multi-cell coating system 500, according to an embodiment of the invention.
System 500 is shown to include a base, with a plurality of containers 305 mounted thereon. Each container 305 has electrodes as shown in FIGS. 20 and 21, except for a working electrode.
Working electrodes 320 with their holders (345) are mounted on a system cover 505. When cover 505 is put on base 502, the working electrodes 320 enter container 305 and form a plurality of cells, each substantially identical to cell 300 of FIG. 20. In system 500, pillars 340 are optionally omitted, and accordingly, not shown.
The arrows in FlG. 22 show how cover 505 can fit onto the containers 305 and removed therefrom. in system 500, the solutions in each of the different containers 305 is separate from the solution in the other containers 305, and there is no fluid communication between them, so if one of the cells has a defected solution, this does not affect the other cells.
For example, the electrochemical characteristics of each of the medical devices coated simultaneously in system 500 are measured independently of the other medical devices, so as to allow running quality control tests to each of the medical devices independently of the others.
EXAMPLES
Selected embodiments of the present invention, including novel and inventive aspects, characteristics, special technical features, and advantages thereof, as illustratively described hereinabove, and as claimed in the claims section hereinbelow, are exemplified and have experimental support in the following examples, which are not intended to be limiting.
EXAMPLE 1
Example 1 is an exemplary manufacturing of an eiectrocoated medical device, and quality control testing and validating thereof.
Materials, Methods, and Results
All substances and accessories were inserted prior to work into an inert environment, using a designated glove box, in which N 2 1 or Ar was circulated for at least 30 min to ensure inert environment.
A stent made of metal alloy was inserted into an electrochemical cell, and was mounted on the working electrode by utilizing a holder made of identical metal alloy.
Platinum foil was used as a counter electrode. Reference electrode/s was either Ag/AgBr, or silver wire, located in the electrochemical cell with close vicinity to the working electrode (stent).
Aragon gas was then bubbled into the electrolyte in order to ensure inert electrocoating conditions.
Stent CV pre in ferric/ferricyanide solution was measured via oxidation-reduction until its value stabilizes using a potensiostat. The measurement peak value was then recorded for future process reference.
Stent ACV pre in ferric/ferricyanide solution was measured until its value stabilizes using a potensiostat. The measurement current value was then recorded for future process reference.
Supporting electrolyte solution (TBATFB 0.1M) with an amount of active agent (diazonoium salt, 8 mM) replaced prior solution and added into the electrochemical cell.
Electrocoating process was conducted using a potensiostat with cyclic voltammetry, at potentio-static (constant voltage) mode and the following parameters were measured: > If in the first coating cycle the voltogram derivative equals 0 ± 0.1.
> and/or the ratio between the integral at the first cycle and the 30 th cycle equals 20 ± 8. and/or the ratio between the integral at the 2 nd cycle and cycle 30 equals 6 + 3.
> then, the stent passes the quality test. If none of the above occur, the stent fails.
Stent CV pσst in ferric/ferricyanide solution replacing the electrocoating solution was measured via oxidation-reduction until its value stabilizes using a potensiostat. The measurement peak value was then recorded and compared against CV results. The device
CV re passes the quality test if — > 1 ; Otherwise, the device fails the quality test.
^- V post
Stent ACV t in ferric/ferricyanide solution was measured until its value stabilizes using a potensiostat. The measurement current value was then recorded was then recorded and
ACV compared against ACV pre results. If — > 1 then the stent passes the quality test,
^' post otherwise, the stent fails the quality test.
The stent was finally rinsed in an ultrasonic cleaner in acetonitrile for 15 min in order to remove non-grafted/ non electrocoated substances. Coating parameters were determined using in- process evaluations.
In-process measurements were recorded automatically during the electrocoating process; and the results obtained from each of the coated stents were compared to calibrated control standards. Some out-of-process evaluations were conducted only on a fraction of the manufactured stents, roughly 1/1000 stents statistically sample, and the results obtained from each of the sampled stents were compared to calibrated control standards.
1. In some cases, other successive out process evaluations were done externally to the process such as:
Coating validation The predictive value of a quality index is optionally evaluated by correlating results of X- ray Photon Spectroscopy (XPS) analysis, with results of the quality index. Optionally, the medical device (stent) is subjected to XPS analysis after 'coating' without an active ingredient, after a full coating process with active ingredient, and after the coating process, but before the measurements were made in the ferric/ferricyanide solution.
Another optional validation process is based on correlating between quality index value and drug release profile. In this option, stents of each of the above-mentioned . groups (control, coated, coated and measured in ferric/ferricyanide solution) are spray coated with polymer and drug and incubated to measure drug release and weight loss profile, for example, 1 , 3, 5, 7, 10 ,15 days after coating.
EXAMPLE 2
MATERIALS AND METHODS
Materials
All chemicals were used as received unless otherwise stated.
CrCo (L605) stents LOT NO. (STI Laser Industries, Israel), were electrocoated with Diazonium salts C 8 H 9 N 2 OBF 4 (DS-04), Ci 8 H 29 N 2 OBF 4 (DS-06, NT-3-32 ) - Elutex LTD. in-house synthesis. Electrochemical procedures were conducted using Platinum wire and Platinum foil ( counter electrode), Holand-Moran Ltd., Israel [Catalog #Z730107], Ag wire (AgBr reference electrode), Holand-Moran Ltd., Israel [Catalog #Z730204], HBR vail cat no. Acetonitryl 99.9%, water <10ppm, Extra Dry, Holland-Moran, Israel [Catalog #326810010], Tetrabutylammonium tetrafluoroborate (TBATFB), Aldrich, Israel, [Catalog # 217964], Ferrocen 98%, Sigma-aldrich, Israel [Catalog # F408J , Potassium Chloride, AR, Gadot, Israel [catalog* P-L60066474J ferri .pH =7 was kept using phosphate buffer, pH= 7. Phosphate buffer was prepared from sodium phosphate monobasic monohydride (Mallinckrodt AR ® 7892 V10606 (ACS) and disodium hydrogen phosphate dodecahydrate (Acros Organics, lot A0249582). Cleaning the stents in ACN bio fab.
Methods
1. Electrochemical Methods: 1.1 sonication - cleaning method
Prior and in the end of the electrocoating process, the CrCo (L605) stents were cleaned to remove impurities from the surface. Stents were placed in a 4 ml glass Vail with 1 ml of ACN . vail placed in an ultra sonic cleaner for 15 minutes. Electrochemical process and measurements were conducted using Bio-Logic SA VSP potentiostat (USA).
1.2 Cyclic Voltammetry in process (CV-in) Potentiostat: Bio-Logic SA VSP potentiostat.
Electrocoating the stent with basecoat: 3 electrodes cylindrical cell was used, with stent as working electrode (hold by CrCo (L605) wire), Pt foil as counter electrode and Ag/AgBr as a reference electrode.
DS06, NT-3-32 was weighted into 5 lots of 45 mg each. 5 Vails with DS and 5 empty vails (control group) were place in a -20C refrigerator. 8 mM solution of the DS06 was prepared in ultra dry acetoneitrile (<10ppm water) containing 0.1M TBATFB. Electrocoating process was conducted under N 2 atmosphere inside a glove box and inside each cell Ar gas was bubbled to avoid O 2 . Ag/AgBr wire was used as reference electrode (RE). Reduction of diazonium salt was conducted by scanning from a potential of OV to (-1.6)V Vs. RE and back, at scan rate of 100 mV/second. The scan was repeated 30 cycles, obtaining an organic layer on the stent surface, followed by a decrease in current density, meaning blocking behavior of the electrode (stent).
.1.3 Cyclic Voltammetry out process (CV-out) Potentiostat: CH630B, CH Instruments, USA.
The blocking behavior of the modified CrCo (L605) stent comparing to non modified stents was investigated by cyclic voltammetry (CV) in the presence of the Fe(CN) 6 3" (ferri) outside the glove box. A 5 mM Fe(CN) 6 3 YO.1 M KCI solution, adjusted to pH 7 by phosphate buffer was prepared. Calomel (SCE) as reference electrode and Pt wire (25mm 2 ) as counter electrode, were used in the electrochemical cell. Measurement was conducted by scanning from 0.3V to -0.8V and back Vs. SCE, 1 cycle, at 100 mV/sec. The voltammogram obtained showed low current densities, in contrast with non coated stent.
1.4 Alternating Current Voltammetry (ACV out): Potentiostat: CH630B, CH Instruments, USA.
Blocking behavior of the modified stent was also investigated by its double-layer capacity, C dl , in a 25 ml of A 5 mM Fe(CN) 6 3 VO.1 M KCI solution, adjusted to pH 7 by phosphate buffer, outside the glove box. AC voltage was applied with amplitude of 25 mV at 50Hz in addition to the DC potential (0.5-1.5V versus SCE), detecting the real and the imaginary parts of the AC current. Calomel (SCE) as reference electrode and Pt wire (25mm 2 ) as counter electrode was used. The insertion of a coated electrode into the electrolyte generated a double layer with a similar behavior to that of a capacitor.
1.5 Weight (internal)
Instrument: Mettler Toledo MX5 (d=1μg).
Stents were weighted before electrochemical procedure for identification.
Quality Control Testing and Validation Procedure
FIG. 23 shows the procedure used for performing the method of ('in-process' and Out- of-process') quality control testing and validation of the electrocoating process of Example 2.
1.2 Validation parameters
1.2.1 Stents sample name: Cr_V_stent number 1-50. e.g Cr__V_1, Cr_V_2... etc.
1.2.2 Number of replicates and experimental groups : 50 CrCo (L605) stents in 2 groups; 25 stents for the treated group (DS06 coated) and 25 stents for the control group (pseudo electrocoationg - no DS)
1.2.3 Time table: all lots went to validation procedure at the working day.
1.2.4 Procedure order: validation procedure started for Lot A by alphabetic order to Lot E. for each Lot stent went under all EC methods by the order of numbers starting from 1 to 10.
RESULTS
ACV out - Alternating Current Voltammetry results
FIG. 24 shows the ACV-out results in graph for pre coating analysis (50 bare CrCo stents), post coating -treated group (25 DS06 coated CrCo stents) and control group (25 bare CrCo stents - after Electrocoating without DS). All values were taken at a constant potential of 0.1V.
CV out - Cyclic Voltammetry out process results
Table 2: CV-out results for pre coating analysis (bare CrCo stent), post coating treated group (DS06 coated CrCo stent) and control group (bare CrCo stent - after Electrocoating without DS). All values were taken at a constant potential of -0.8V.
FIG. 25 shows the CV-out results in graph for pre coating analysis (50 bare CrCo stents), post coating treated group (25 DS06 coated CrCo stents) and control group (25 bare CrCo stents - after Electrocoating without DS). All values were taken at a constant potential of -0.8V.
CV - in process results
Epeak [V] lpeak [mA] Charge [mQ]
Overall average -1.08 + 0.05 -0.19 ± 0.02 -5.72 ± 0.53
Table 3: Cyclic voltammetry - in process Average Epeak, Ipeak, and total charge values for 25 DS06, NT-3-32 coated stent.
Discussion & analysis of the results: Validation and quality assurance goal was set to conform with 6 sigma yield. Therefore a quantitive analysis was made using rhe "Crystal ball®" statistical SW. The analysis was conducted according to the functional steps described hereunder:
1. using the chi-square ranking method a probability distribution of the following test data was fitted (Anderson-darting and Kofmogorov-Smirnov ranking method were also used for reference):
> FIG. 26A: CV out process of control stents results was ranked to best fit the normal distribution as shown. FIG. 26A is a 'computer display screen print' of results obtained from making electrochemical measurements and evaluations, via performing cyclic voltammetry type of 'out-of-process' quality control testing (i.e., CV out), and validation, of treated stents [Chi-square ranking (Weibull distribution)].
> FIG. 26B: ACV out process of treated stents results was ranked to best fit the student's t distribution as shown. FIG. 26B is a 'computer display screen print' of results obtained from making electrochemical measurements and evaluations, via performing cyclic voltammetry type of 'out-of-process' quality control testing (i.e., CV out), and validation, of control stents [Chi-square ranking (Normal distribution)].
> FIG. 27A: ACV out process of control stents results was ranked to best fit the maximum extreme distribution as shown. FIG. 27A is a 'computer display screen print' of results obtained from making electrochemical measurements and evaluations, via performing
alternating current voltammetry (ACV) type of 'out-of-process' quality control testing (i.e., ACV out), and validation, of treated stents [Chi-square ranking (Student's t distribution)]. > FIG. 27B: ACV out process of control stents results was ranked to best fit the maximum extreme distribution as shown. FIG. 27B is a 'computer display screen print' of results obtained from making electrochemical measurements and evaluations, via performing alternating current voltammetry (ACV) type of 'out-of-process' quality control testing (i.e., ACV out), and validation, of control stents [Chi-square ranking (Maximum Extreme distribution)]. 2. As reference to the distribution ranking a manual fitting to a normal distribution was predefined and used on test results: a. CV out process of treated stents results was fitted to normal distribution. b. CV out process of controlled stents results was fitted to normal distribution. c. ACV out process of treated stents results was fitted to normal distribution. d. ACV out process of controlled stents results was fitted to normal distribution. 3. In accordance with electrochemical theory the working electrode was blocked during the process, hence the process indexes:
CVI > χ
5. Shown in FIGS. 28A, 28B, 29A, 29B, 3OA, 3OB, 31 A, and 31 B, are the simulated test results for both CV and ACV types of quality control testing and validation.
FlG. 28A is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of treated postcoated stents (Weibull distribution). FIG. 28B is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of control postcoated stents (Normal distribution).
FIG. 29A is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of treated postcoated stents (Normal distribution). FIG. 29B is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of control postcoated stents (Normal distribution).
FIG. 3OA is a 'computer display screen print 1 of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of
treated postcoated stents (Student's t distribution). FIG. 3OB is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of control postcoated stents (Maximum Extreme distribution).; FIG. 31A is a 'computer display screen print 1 of results obtained from simulation of
(alternating current voltammetry) ACV out-of-process quality control testing, and validation, of treated postcoated stents (Normal distribution). FIG. 31 B is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of control postcoated stents (Normal distribution).
6. Additional simulation results are presented in FIGS. 32A, 32B, 33A, and 33B.
FIG. 32A is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index ranked distribution). FIG. 32B is a 'computer display screen print' of results obtained from simulation of
(cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index normal).
FIG. 33A is a 'computer display screen print' of results obtained from simulation of
(alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index ranked distribution). FIG. 33B is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index normal).
7. It can be noted that not all ACVIs and CVIs are above 1 as expected and those ratios bellow 1 are nonconforming stents.
8. Magnitude evaluation of the nonconforming stents can be acquired by evaluating the cumulative probability function, as shown in FIGS. 34A, 34B, 35A, and 35B.
FIG. 34A is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index normal). FIG. 34B is a 'computer display screen print' of results obtained from simulation of (cyclic voltammetry) CV out-of-process quality control testing, and validation, of stents (index ranked distribution). The results obtained and presented in FIG. 34B shows that the CVI value being bellow 1 occurred only 0.37 % of the time. FIG. 35A is a 'computer display screen print' of results obtained from simulation of
(alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index normal). FIG. 35B is a 'computer display screen print' of results obtained from simulation of (alternating current voltammetry) ACV out-of-process quality control testing, and validation, of stents (index ranked distribution). The results obtained and presented in FIG. 35B shows that the ACVI value being bellow 1 occurred only 3.36 % of the time.
9. Analyzing the simulation results as shown in FIGS. 34A, 34B, 35A, and 35B demonstrated that while using ranking methods to establish process behavior:
• The intersecting set of the treated and control stent groups when using CVI is 0. 37%. • The intersecting set of the treated and control stent groups when using ACVI is
3.36%. While assuming normal distribution behavior of test results:
• The intersecting set of the treated and control stent groups when using CVI is 1.84%. • The intersecting set of the treated and control stent groups when using ACVI is
2.53%.
10. Since both CV and ACV methods are applied during the overall quality control and validation method, the number of defects per million stents batch size were evaluated as follows:
\M ■ 0.31% • 2.53% < defects __ per _million < \MλM% - 3.36% 93 < defects _ per _ million < 618
Summary and recommendations:
11. The above results demonstrate that the electrocoating current validation process allows for a replicable and stable manufacturing. 12. To achieve 6 sigma yield we should concentrate on a CVl * ACVl target value of
0.0006% focusing mainly on the reduction of ACVI or developing a different analysis method. 13. Evaluating process noise factors and control parameters will allow us to decrease manufacturing variance and meeting that goal. A more robust electrocoating cell and a detailed noise factor analysis will enable us to decrease those parameters.
In view of the above, it is clearly apparent that some embodiments of the present invention successfully address and overcome at least some of the various shortcomings and limitations, and widen the scope, of teachings in the relevant field(s) and art(s) of the present invention. Moreover, some of the embodiments of the are readily commercially applicable to a variety of different industries.
It is expected that during the life of a patent maturing from this application many relevant coating solutions and medical devices will be developed and the scope of the terms 'solution' and 'medical device' is intended to include all such new technologies a priori.
It is to be fully understood that certain aspects, characteristics, and features, of the present invention, which are illustratively described and presented in the context or format of a
plurality of separate embodiments, may also be illustratively described and presented in any suitable combination or sub-combination in the context or format of a single embodiment. Conversely, various aspects, characteristics, and features, of the present invention, which are illustratively described and presented in combination or sub-combination in the context or format of a single embodiment, may also be illustratively described and presented in the context or format of a plurality of separate embodiments.
Although the invention has been illustratively described and presented by way of specific embodiments, and examples thereof, it is evident that many alternatives, modifications, and variations, thereof, will be apparent to those skilled in the art. Accordingly, it is intended that all such alternatives, modifications, and variations, fall within, and are encompassed by, the scope of the appended claims.
All patents, patent applications, and publications, cited or referred to in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual patent, patent application, or publication, was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this specification shall not be construed or understood as an admission that such reference represents or corresponds to prior art of the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.
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