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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Invatec S.p.A. 5/6/13

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 
10903 New Hampshire Avenue
White Oak Building 66
Silver Spring, MD 20993 

 

May 6, 2013
 WARNING LETTER
 
VIA UNITED PARCEL SERVICE
 
Mr. Omar Ishrak
Chairman & CEO
Medtronic, Inc.
710 Medtronic Parkway
Minneapolis, Minnesota 55432
 
Dear Mr. Ishrak:
 
During an inspection of your subsidiary firm Invatec S.p.A., located at Via Martiri della Liberta 7, Roncadelle (BS), Italy, on February 4, 2013, through February 7, 2013, an investigator from the United States Food and Drug Administration (FDA) determined that Invatec S.p.A. manufactures the Amphirion Plus Percutaneous Translumenal Angioplasty (PTA) Catheter and the Driver CE Catheter.  Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
 
This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
 
We received responses from Andrea Giarrizzo, Site Leader and Director of Operations, dated February 27, 2013, and April 3, 2013, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to Invatec S.p.A. We address this response below in relation to each of the noted violations. These violations include, but are not limited to, the following:
 
1. Failure to verify or validate corrective and preventive actions to ensure that those actions are effective and do not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, the Risk Assessment Environmental Controls July 2012 (Q1 FY2013) for the (b)(4) Assembly area shows that the Microbial Counts on Surfaces ((b)(4)) exceeded both Warning Limits ((b)(4))and Action Limits ((b)(4)), and the (b)(4) Assembly ((b)(4)) area shows that the Direct Contact and Hands values ((b)(4)) exceeded the Warning Limits ((b)(4)). Although the cleaning operators were notified of the nonconformance, and a commitment was made to retrain them on the controlled environment room procedures, and verification or validation of the corrective or preventive action to show effectiveness of the actions was not conducted.
 
The adequacy of your firm’s responses dated February 27, 2013, and April 3, 2013, cannot be determined at this time because this item was not addressed.
 
2. Failure to establish and maintain adequate procedures for validated processes to document the monitoring and control methods and data, the date performed, and, where appropriate, the individuals performing the process or the major equipment used, as required by 21 CFR 820.75(b)(2). For example, the Raw Data Sheet Forms for test numbers (b)(4) for lot numbers (b)(4), (b)(4), and (b)(4) did not indicate the test method used to perform the testing.
 
The adequacy of your firm’s responses dated February 27, 2013, and April 3, 2013, cannot be determined at this time because this item was not addressed.
 
3. Failure to establish and maintain adequate procedures for the identification, documentation, validation or, where appropriate, verification, review and approval of design changes prior to their implementation, as required by 21 CFR 820.30(i).  For example, the Design Change Procedure (Modifica di Prodotto/Processo, IST/03A/04.00.03-08) does not include requirements for the validation of design changes prior to implementation.
 
The adequacy of your firm’s responses dated February 27, 2013, and April 3, 2013, cannot be determined at this time. Your firm states that it will revise the instructions in the procedure Modifica Prodotto Processo (IST/03A/04.00.03-08, rev.9, June 13, 2012) and the Design Control Procedure (PRC/02/07.01.01, rev 8, October 13, 2012) to add the term “required” for validation or verification of a design change. Additionally, your firm stated that it will perform a retrospective review of design changes completed in the past (b)(4) related to products distributed in the U.S. market. None of the revised procedures or the retrospective review of design changes for the past (b)(4) was submitted with your firm’s responses.
 
4. Failure to validate computer software for its intended use according to an established protocol, as required by 21 CFR 820.70(i). For example, Section 7.3.5 of Invatec’s Process Validation Procedure (#PRC/04/07/.00.10), dated October 16, 2012, states,
 
“When the manufacturing or test equipment contains software or firmware that is used to operate the equipment, the software will be validated for its intended use per PRC/03A/06.00.01.”
 
The inspection revealed that the following software-controlled manufacturing equipment used to process the Amphirion Plus PTA Catheter was never validated:
 
·   (b)(4)
·   (b)(4)
·   (b)(4)
·   (b)(4)
·   (b)(4)
·   (b)(4)
·   (b)(4)
 
The adequacy of your firm’s response dated February 23, 2013, cannot be determined at this time. Your firm states that, after the close of the inspection, Invatec performed a review of all Amphirion Plus software validation requirements and confirmed that these activities were conducted in accordance with the General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 11, 2002, and that your firm conducted (b)(4), and other tests. Neither the results of the software validation requirements, nor the results of the (b)(4), were submitted to FDA for review.
 
Invatec also:
 
1. Promised to revise its Process Validation Procedure (PRC/04/07.00.10, revision 2, 16 Oct. 2012) to include reference to Convalida dei Process Control System Procedure (PRC/o3A/06.00.02, rev 6, 16 Apr. 2012);
2. Promised to train personnel involved in Process Validation;
3. Promised to conduct a retrospective assessment of all activities used for the risk assessment of Amphirion Plus in relation to compliance with Convalida dei Process Control System Procedure;
4. Promised to revise the conclusions associated with the Amphirion Plus Convalida dei Process Control System risk assessment documentation, where required, as output of Action #1.3.
 
Your firm’s response dated April 3, 2013, states that your firm has completed revision of its Process Validation Procedure, completed training of personnel in the revised validation procedure, completed a retrospective assessment of all activities used for risk assessment of the Amphirion Plus PTA Catheter, and revised the conclusions associated with the Amphirion Plus PTA Catheter Convalida dei Process Control System Procedure. However, documentation or evidence of the corrections, corrective actions, revised procedures, retrospective assessment of risk, and revisions of your firm’s conclusions has not been provided to FDA for review.
 
5. Failure to establish and maintain adequate calibration procedures to include specific directions and limits for accuracy and precision, as required by 21 CFR 820.72(b). For example, the acceptance limits for the calibration of the (b)(4) were not defined.  
 
The adequacy of your firm’s responses dated February 27, 2013, and April 3, 2013, cannot be determined at this time because this item was not addressed.
 
Our inspection also revealed that your firm’s devices are misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the Amphirion Plus PTCA Catheter and the Driver CE Catheter that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 806 – Medical Devices; Reports of Corrections and Removals.  Significant violations include, but are not limited to, the following:
 
1. Failure to submit a written report to FDA of any correction or removal of a device initiated to remedy a violation of the Act caused by the device that may present a risk to health, as required by 21 CFR 806.10(a)(2). For example, on March 4, 2009, your firm recalled 279 Diver CE Catheters due to (b)(4). This change in the (b)(4).
 
The adequacy of your firm’s responses dated February 27, 2013, and April 3, 2013, cannot be determined at this time because this item was not addressed.
 
2. Failure to submit a written report to FDA of any correction or removal of a device within 10 working days of initiating the correction or removal, as required by 21 CFR 806.10(b). For example, a written report of the recall for the Diver CE Catheter was not submitted to FDA within 10 working days of initiating that correction or removal.
 
The adequacy of your firm’s responses dated February 27, 2013, and April 3, 2013, cannot be determined at this time because this item was not addressed.
 
Given the serious nature of the violations of the Act, the Amphirion Plus PTA Catheters and the Diver CE PTA Catheters manufactured by your firm are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. § 381(a), in that they appear to be adulterated.  As a result, FDA is taking steps to refuse entry of these devices into the United States, known as “detention without physical examination,” until these violations are corrected. In order to remove these devices from detention, your firm should provide a written response to this Warning Letter as described below and correct the violations described in this letter. We will notify you if your firm’s response appears to be adequate, and we may need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made.
 
U.S. federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts.  Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected.  Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected. 

Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, including an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again.  Include documentation of the corrections and/or corrective action (including any systemic corrective actions) that your firm has taken.  If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities.  If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed.  Please provide a translation of documentation not in English to facilitate our review.

 
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Operations Branch, White Oak Building 66, Rm 2609, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #395615 when replying. If you have any questions about the contents of this letter, please contact: Daniel G. Walter at (301) 796-5587 or FAX (301) 847-8138.
 
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility.  It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA.  The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems.  Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance. 
 
 
Sincerely yours,
/S/                                                           
Steven D. Silverman
Director
Office of Compliance
Center for Devices and
Radiological Health