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WO2009087637A2 - Fabrication de dispositifs médicaux revêtus par électrodéposition, et test de contrôle de qualité et validation de ceux-ci - Google Patents

Fabrication de dispositifs médicaux revêtus par électrodéposition, et test de contrôle de qualité et validation de ceux-ci Download PDF

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Publication number
WO2009087637A2
WO2009087637A2 PCT/IL2009/000040 IL2009000040W WO2009087637A2 WO 2009087637 A2 WO2009087637 A2 WO 2009087637A2 IL 2009000040 W IL2009000040 W IL 2009000040W WO 2009087637 A2 WO2009087637 A2 WO 2009087637A2
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WIPO (PCT)
Prior art keywords
medical device
electrocoating
quality
coating
quality control
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/IL2009/000040
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English (en)
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WO2009087637A3 (fr
Inventor
Yair Levi
Uri Cohn
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Elutex Ltd
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Elutex Ltd
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Publication date
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Publication of WO2009087637A2 publication Critical patent/WO2009087637A2/fr
Publication of WO2009087637A3 publication Critical patent/WO2009087637A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D13/00—Electrophoretic coating characterised by the process
    • C25D13/22—Servicing or operating apparatus or multistep processes

Definitions

  • 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.
  • 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.
  • 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.
  • a method for manufacturing an electrocoated medical device 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.
  • a method for quality control testing a coated medical device using an electrical cell comprising: measuring at least one electrical parameter of the coated medical device inside the e ⁇ ect ⁇ ca ⁇ 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.
  • a method for setting process parameters for electrocoating a medical device 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.
  • a method for validating a medical device electrocoating process 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.
  • a system for manufacturing an electrocoated medical device 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • exemplary embodiments of the present invention include a network connection.
  • exemplary embodiments of the present invention include a display device and a user input device, such as a keyboard or/and 'mouse'.
  • 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 accor ⁇ ance with the present invention;
  • an electrical e.g., electrochemical - electrocoating
  • 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;
  • an electrical e.g., electrochemical - eiectrocoating
  • 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
  • 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 an ⁇ performing quality control testing and validation, in accordance with the present invention
  • a multi-electrical (e.g., electrochemical - eiectrocoating) cell i.e., multi-cell) system, suitable for medical device coating an ⁇ 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
  • a (nano) coated medical device e.g., stent
  • CV out cyclic voltammetry type of 'out-of-process' quality control testing
  • 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;
  • EIS electrochemical impedance spectroscopy
  • 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;
  • ElS electrochemical impedance spectroscopy
  • 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
  • ACCV alternating current voltammetry
  • 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. 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-co
  • 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 'out-of-process' quality control testing
  • 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 Out-of-process' quality control testing
  • ACV out 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
  • 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.
  • 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.
  • a holder for holding a medical device in a solution for electrocoating the medical device in a coating process 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 'a', 'an', and 'the' 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.
  • 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.
  • the phrase 'a compound' may also refer to, and encompass, a plurality of compounds, or/and mixtures thereof.
  • the phrase 'a medical device' may also refer to, and encompass, a plurality of medical devices.
  • 'includes', 'including', 'has', 'having', 'comprises' and
  • 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 'quality control 1 can be defined in a variety of different ways and particular contexts of use and application.
  • the phrase 'quality control 1 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).
  • 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' 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/an ⁇ after, the product is subjected to a process (e.g., a medical device coating process or medical device electrocoating process).
  • a process e.g., a medical device coating process or medical device electrocoating process.
  • 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).
  • 'in-process quality control testing' 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.
  • a process e.g., a medical device coating process or medical device electrocoating process
  • phrases 'out-of-process quality control testing' 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.
  • a process e.g., a medical device coating process or medical device electrocoating process
  • the phrase 'out-of-process quality control testing 1 is also abbreviated, and sometimes referred to, as 'out-process 1 .
  • Validation' can be defined in a variety of different ways and particular contexts of use and application.
  • the terms Validation 1 , or 'validating 1 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).
  • a 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.
  • a medical device e.g., a stent
  • a process such as a medical device coating process or medical device electrocoating process, typically, in a commercial scale manufacturing environment.
  • 'validation', and 'validating 1 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.
  • a medical device e.g., a stent
  • a process such as a medical device coating process or medical device electrocoating process
  • 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'.
  • results, analyses, and conclusions, obtained from 'quality control' and 'quality control testing' can be used as the basis of 'validation' and Validating'.
  • 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' 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' 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 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.
  • dilicate means either of a plurality of things substantially alike and usually produced at the same time or by the same process.
  • 'about' refers to ⁇ 10 % of the stated numerical value.
  • 'room temperature' refers to a temperature in a range of between about 20 0 C and about 25 0 C.
  • 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.
  • 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'.
  • 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.
  • 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
  • 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 co ⁇ troffing 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.
  • 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.
  • an aspect of the invention concerns a system for coating medical devices, which is adapted for in situ evaluation of a quality index.
  • a coating system is made to coat simultaneously a lot of medical devices.
  • 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.
  • 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.
  • 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.
  • 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.
  • the medical device holder 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
  • 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.
  • 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.
  • 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.
  • a medical device in the form of a medical implant or medical implant component, for example, a stent, having a metal surface.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Exemplary teachings of electrocoating medical devices, such as stents, with, for example, a thin layer of diazonium compound(s), is ⁇ aught [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.
  • FIG. 1 An exemplary coating process is described with more details.
  • Manufacturing of an electrocoated medical device 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
  • the medical device for example, a stent, such as a metal alloy stent
  • Weighting 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 NitinolTM alloy, acetone or/and acetonitrile [ACN] is suitable.
  • 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.
  • nitrogen, argon, or/and other inert gas is circulated, for example, for at least 30 minutes before coating starts.
  • the cleaning of the medical device and bubbling inert gas are conducted in a system comprising a plurality of electrocoating cells.
  • all the cells are under the same inert atmosphere.
  • 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.
  • the medical device e.g., stent
  • the medical device may be tied to the holder with a thin conducting wire, for example, a wire of 50 ⁇ m diameter.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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].
  • 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].
  • 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
  • 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).
  • 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
  • the coated medical device 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).
  • ultrasonic cleaning of the coated medical device e.g., stent
  • the preceding is an illustrative example of performing an electrocoating process on a medical device.
  • 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.
  • 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:
  • FIG. 1 illustrates the actions taken in a method 100 according to an exemplary embodiment of the invention.
  • a medical device is coated.
  • the thickness of the coating is preferably smaller than 1 ⁇ m, 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.
  • coating techniques include: Chro ⁇ oamperometry (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
  • NPV normal pulse voltammetry
  • AC impedance spectroscopy chronopotentiometry and cyclic chronopotentiometry can be used as electrochemical detection methods.
  • 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.
  • the potential difference V and the current / are measured and recorded.
  • a potential difference is applied between a working electrode, which comprises the medical device, and a counter electrode.
  • platinum foil or platinum rounded net are used as a counter electrode.
  • 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).
  • measured values of the potential difference and current are processed to obtain a value of a quality index.
  • the phrase 'quality index' 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' 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' 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.
  • '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).
  • processing the measured values includes mathematical manipulations on values measured at different stages of the coating process.
  • the different stages are before coating and after coating.
  • at least one of the stages is during coating.
  • 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.
  • 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.
  • a comparison is by way of division, such that the comparison results in a dimensionless index.
  • 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.
  • the quality of the monitored coating is determined responsive to the obtained value of the quality index.
  • 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
  • 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).
  • 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.
  • a final quality is determined for a coating responsive to out-of process evaluation 200A and in process evaluation 200B.
  • 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.
  • each and every (uncoated, coated) medical device undergoes in-process quality control testing.
  • only a sample of the (uncoated, coated) medical devices undergoes out-of process quality control testing.
  • 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.
  • all the (uncoated, coated) medical devices in the same batch go through out-of-process quality control testing.
  • FIG. 4 and FIG. 5 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.
  • an electrochemical characteristic of the device is measured and recorded at a first predetermined time during the coating process.
  • 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.
  • 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.
  • 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.
  • the same characteristic is measured and recorded at a second predetermined time.
  • the two recordings are processed to obtain a quality index.
  • a quality of the coated device is determined based on the quality index, optionally, by comparison with a given quality interval.
  • differences or ratios between electrochemical characteristics of the device at different coating stages are compared.
  • 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.
  • 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.
  • 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.
  • one or more characteristic is looked for, and if not found, the device fails the quality test.
  • 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.
  • 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.
  • the later cycle is determined by the difference between the peak current measured in two successive cycles.
  • this current difference is below some predetermined threshold (for instance, 10 pico amperes) the cycle is considered appropriate for comparison with the first cycle.
  • 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.
  • 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.
  • 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].
  • CV-In cyclic voltammetry
  • GaMn glavanistatic
  • Poten-in potentistatic
  • 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
  • the reference electrode is a Ag/AgBr rod
  • 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.
  • the organic layer obtained by the reduction of diazonium (example of an active electrocoating ingredient) salts reduces the reduction peak current.
  • the CV curve 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.
  • 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
  • the reference electrode is a Ag/AgBr rod
  • 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.
  • This measurement result can be presented in the format of a cyclic voltammogram. A reversible peak should appear.
  • FIG. 1 is a flowchart of actions taken in an exemplary out-of-process quality control 200A.
  • 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.
  • the value used for evaluating a bare medical device is the peak value in a first CV cycle, carried out in a standard, non-coating solution.
  • 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.
  • the quality interval is a peak in the current value obtained with voltage of between -0.8V and -1.0V.
  • a bare medical device having electrochemical characteristics that deviate from the quality interval, is discarded without coating.
  • out-of-process quality control 200A 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.
  • the medical device is coated, optionally, with application of in-process quality control testing, as described above with reference to FIG. 4.
  • 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.
  • 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.
  • 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-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.
  • a modified metal medical device e.g., stent
  • CV cyclic voltammetry
  • ferri/ferrlcyanide or any other, reduction/oxidation (redox) couple.
  • Electrochemical cell 5 mM Fe(CN) 6 3 V 5 mM Fe(CN) 6 4" /0.1 M KCI, adjusted to pH 7 by phosphate buffer.
  • a designated electrical cell (e.g., the same as, or different than, the electrocoating cell) is used.
  • 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).
  • CE counter electrode
  • Half of the medical device e.g., stent
  • WE working electrode
  • This measurement result can be presented in the format of a cyclic voltammogram, for example, as shown in FIG. 14.
  • 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.
  • a designated electrical cell e.g., the same as, or different than, the electrocoating cell
  • 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
  • WE working electrode
  • the profile obtained is typically box shaped. As the scanning rate is increased, the following change is to be observed:
  • Linear Polarization (LP) technique for the electrocoated stents. Control is either non- treated stents or electro-polished stents (ex. For a specific ingredient).
  • Phosphate buffer pH 7, with or without femVferrlcyanide redox couple or any other couple.
  • 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).
  • RE reference electrode
  • CE counter electrode
  • WE working electrode
  • EIS 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.
  • Electrochemical cell 5 mM Fe(CN) 6 3 V 5 mM Fe(CN) 6 4 VdM KCI, adjusted to pH 7 with phosphate buffer.
  • a designated electrical cell e.g., the same as, or different than, the electrocoating cell
  • 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
  • WE working electrode
  • OCP open circuit potential
  • 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.
  • a Nyquist plot e.g., FIG. 15
  • Bode plot e.g., FIG. 16
  • 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
  • Phosphate buffer pH 7, with or without ferri/ferrlcyanide redox couple or any other couple.
  • a designated electrical cell e.g., the same as, or different than, the electrocoating cell
  • 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
  • WE working electrode
  • 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.
  • AES-out Auger Electron Spectroscopy
  • Ar Ion Beam 4.0 keV Sputtering Rate calibrated with a 20 nm thick SiO 2 standard.
  • 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.
  • VG Scientific Sigma Probe using the following exemplary settings: X-ray source: monochromatic Al Ka, 1486.6eV. X-ray beam size: 150 ⁇ m.
  • 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.
  • 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.
  • a preparation for electrocoating e.g., surface cleaning pre-treatment
  • EDS analysis is used to determine the contaminations in the composition.
  • AFIVl Atomic Force Microscopy
  • medical device e.g., stent
  • surface roughness or/and capacitance, or/and conductivity
  • 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
  • each quality index is associated with a quality interval.
  • FIGS. 18 and 19 show 'acceptance / rejection' criteria for in-process quality control testing and out-of-process quality control testing, respectively.
  • the medical device fails the quality test if a quality index lies outside the quality interval associated therewith.
  • more than one quality index is defined for evaluating the quality of a single coating.
  • 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.
  • 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.
  • a medical device may pass the quality control test for one use, and not for another.
  • 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.
  • 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 -2 ⁇ and x o +2 ⁇ , where X 0 is the average index, and ⁇ is the standard deviation.
  • a quality interval may be defined as the interval between x o -2 ⁇ and x o +2 ⁇ , where X 0 is the average index, and ⁇ is the standard deviation.
  • X 0 is the average index
  • ⁇ is the standard deviation.
  • 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.
  • the large number of medical devices, for which X 0 and ⁇ are determined are medical devices that were all coated simultaneously, in a multi-cell system (for example, as shown in FIGS. 10 and 22.
  • 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.
  • 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.
  • 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.
  • 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.
  • step (c) is performed, for determining quality and validity of the electrocoating process.
  • 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
  • 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.
  • 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.
  • port 315 is also useful for bubbling inert gas into solution 310, from a gas source (not shown).
  • there is also a gas outlet open to the glove box.
  • FIG. 20 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
  • 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.
  • 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.
  • a medical device e.g., a stent
  • 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.
  • medical device e.g., a stent
  • 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.
  • medical device e.g., a stent
  • 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.
  • 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.
  • 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.
  • pillars 340 standing outside container 305, and cover 345, which has -protrusions suitable for snugly receiving therein the upper tips of pillars 340.
  • 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.
  • 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.
  • the working electrodes 320 enter container 305 and form a plurality of cells, each substantially identical to cell 300 of FIG. 20.
  • 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.
  • 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.
  • 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.
  • Example 1 is an exemplary manufacturing of an eiectrocoated medical device, and quality control testing and validating thereof.
  • 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.
  • 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.
  • the stent passes the quality test. If none of the above occur, the stent fails.
  • CV re passes the quality test if — > 1 ; Otherwise, the device 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.
  • 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.
  • the medical device 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.
  • stents of each of the above-mentioned . groups control, coated, coated and measured in ferric/ferricyanide solution
  • 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.
  • Electrochemical Methods 1.1 sonication - cleaning method
  • the CrCo (L605) stents 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • Tabte 1 ACV-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 0.1V.
  • 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.
  • 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.
  • Table 3 Cyclic voltammetry - in process Average Epeak, Ipeak, and total charge values for 25 DS06, NT-3-32 coated stent.
  • 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)].
  • 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
  • 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)].
  • CVI > ⁇ were defined as the forecast target, when the index value drops bellow 1 an intersection set exist and stent coating can not be determined. 4. According to the above a "Monte Carlo" simulation was conducted to repeat 10,000 trials calculating the probability distribution function to both ACVI and CVI, thus simulating 10,000 additional tests.
  • 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
  • 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).
  • 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
  • FIG. 33A is a 'computer display screen print' of results obtained from simulation of
  • 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).
  • 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
  • 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:

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Abstract

L'invention porte sur un procédé de fabrication d'un dispositif médical revêtu pas électrodéposition; sur un procédé de test de contrôle de qualité d'un dispositif médical revêtu par utilisation d'une pile électrique; sur un procédé de réglage de paramètres de traitement de revêtement par électrodéposition d'un dispositif médical; sur un procédé de validation d'un traitement de revêtement par électrodéposition de dispositif médical; sur un système de fabrication d'un dispositif médical revêtu par électrodéposition (applicable à un seul dispositif médical, ou à une pluralité de dispositifs médicaux); et sur un dispositif de support destiné à maintenir un dispositif médical dans une solution pour un revêtement par électrodéposition du dispositif médical lors d'un traitement de revêtement.
PCT/IL2009/000040 2008-01-10 2009-01-11 Fabrication de dispositifs médicaux revêtus par électrodéposition, et test de contrôle de qualité et validation de ceux-ci Ceased WO2009087637A2 (fr)

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US5739692A (en) * 1995-11-08 1998-04-14 E. I. Du Pont De Nemours And Company Device for monitoring voltage and amperage on an article being passed through an electrocoating bath
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CN116912243B (zh) * 2023-09-12 2023-11-21 吉林大学第一医院 一种用于医疗用管的涂层质量检测方法及系统

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