Inspections, Compliance, Enforcement, and Criminal Investigations
BTS S.p.A. 5/10/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|10903 New Hampshire Avenue|
Silver Spring, MD 20993-0002
MAY 10, 2012
VIA UNITED PARCEL SERVICE
Mr. Bruno Ros, CEO
via Della Croce Rossa 11
Dear Mr. Ros:
During an inspection of your firm located in Padova, Italy, on January 30, 2012 through February 02, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the FreeEMG and PocketEMG. 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 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 a response from you dated February 14, 2012, concerning our investigator's observations noted on the Form FDA 483 (FDA 483), List of lnspectional Observations, that was issued to your firm. 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 establish and maintain adequate procedures for validating the device design. The results of the design validation, including identification of the design, methods, the date, and the individuals performing the validation, shall be documented in the Design History File (DHF), as required by 21 CFR 820.30(g).
For example: the DHF for the FreeEMG 300 (FreeEMG) design project included the following hardware testing protocols in the validation, verification, and testing section:
A. ERMT1-00571-06 SENSE (b)(4)
B. ERMT1-00572-02 FSEWGN (b)(4)
C. ERMT1-00636-02 (b)(4)
D. ERMT1-00872-00 (b)(4)
However, no reports in the DHF included evidence to indicate that the validation protocols were followed, the validation testing was actually performed on a FreeEMG device, the dates of validation testing, who was responsible for performing the testing, and whether or not the results of the validation testing met the specifications outlined in ERMT1-00872-00 and other testing protocols.
We reviewed your firm's response and conclude that it is not adequate. In the response to this observation, your firm re-performed the aforementioned tests for the FreeEMG. A result report was submitted as evidence showing that the hardware validation protocols have been followed and that the specifications defined in the test protocols were met. The new report included identification of the design, method, the date, and the individuals who performed the validation. However, the evidence provided by your firm did not indicate that a systemic corrective action was considered (e.g., conducting a review of other products distributed to the United States to ensure that similar issues have not occurred or will be corrected).
2. Failure to establish and maintain adequate procedures to ensure that format documented reviews of the design results are planned and conducted at appropriate stages of the device's design development, as required by 21 CFR 820.30(e).
For example: the FreeEMG design plan, dated March 10, 2010, does not define the appropriate stages of the design process at which design reviews will be conducted. Also, according to your firm's project manager, design reviews were conducted approximately every 2 weeks for the design project. However, the design reviews were not documented.
We reviewed your firm's response and conclude that it is not adequate. Your firm amended its design project EQSGQ-00300-06 PROC R&D for the FreeEMG device to include design review requirements. Additionally, evidence was provided to show that the design review dated February 7, 2012, was performed for the final stage of the device design, as required by the new design review procedure. However, the evidence provided by your firm did not indicate that a systemic corrective action was considered (e.g., conducting a review of other products distributed to the United States to ensure that similar issues have not occurred or will be corrected).
3. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit. Such procedures shall ensure that complaints are evaluated to determine whether the complaint represents an event that is required to be reported to FDA under 21 CFR 803, Medical Device Reporting(MDR), as required by 21 CFR 820.198(a)(3).
For example: section 6 of your firm's Non-conformity, Complaint, and Corrective and Preventive Action procedure requires that non-conformances from complaints be evaluated for MDR reportability. However, your firm's PROC HelpDesk procedure, which is used for processing complaints in your firm's database, does not require that complaints be evaluated for potential medical device reporting. Additionally, complaint records reviewed (e.g., 869, 826, and 833) did not contain evidence to indicate that each complaint was evaluated to determine whether it represented an event which is required to be reported to FDA as a MDR.
We reviewed your firm's response and conclude that it is not adequate. In the response to the observation, your firm revised and modified its Nonconformity and PROC HelpDesk procedures. The Help Desk data base has been modified in order to provide evidence and records of performing a determination of whether or not the complaint is required to be reported to the FDA as a MDR. Evidence of the revised procedures, EQSGQ-00308-06 PROC Non conformities corrective and preventive actions, and EQSGQ-00868-08 PROC HelpDesk (Help Desk Procedure), were provided. Your firm also provided an example of a new complaint case (Help Desk Ticket #2158) that verified MDR review implementation. However, your firm did not provide evidence to indicate that applicable employees were trained on the new procedures. Also, evidence that your firm performed a review of past complaint cases for potential MDR reportability was not submitted.
4. Failure to establish and maintain procedures for acceptance activities, including inspections, tests, or other verification activities, as required by 21 CFR 820.80(a).
For example: as a part of the (b)(4), a visual inspection of the probes is conducted for your firm's FreeEMG Device. However, upon request for review, your firm did not provide the visual inspection testing procedure or the acceptance criteria. Your firm's project manager stated that your firm would create a procedure for conducting the visual inspection.
Your firm 's response dated February 14, 2012, is not adequate. Your firm altered its hardware test procedures for (b)(4) sensors to include an inspection section. However, your firm did not provide evidence to indicate that applicable employees were trained on the new procedures. Also, your firm did not provide evidence to indicate that it performed a review of probe historical visual inspection records to ensure that specifications were met. Your firm also did not provide evidence that it conducted a review to ensure that all other inspection tests used for the FreeEMG device had procedures. Additionally, your firm did not provide evidence to indicate that a systemic corrective action was considered (e.g., review records of other products manufactured to ensure that all acceptance tests have procedures).
5. Failure to establish and maintain adequate procedures to control all documents that are required by 21 CFR 820. All obsolete documents shall be promptly removed from all points of use or otherwise prevented from unintended use, as required by 21 CFR 820.40(a).
For example: (b)(4) is the software version currently used for the FreeEMG and it is maintained within a folder on your firm's computer system. However, it was observed that the previous versions of this software were not removed from the same electronic folder, were still marked as released, were still available for use, and were not marked as obsolete.
We reviewed your firm's response and conclude that it is not adequate. In the response to the observation. your firm provided a print screen showing the change so that previous software revisions are marked as obsolete and are made inaccessible. However, evidence that your firm reviewed other files to ensure that obsolete procedures were removed was not provided. Evidence that your firm updated procedures to ensure that obsolete documents were not made available was not provided. Also, your firm did not provide evidence to indicate that a systemic corrective action was considered (e.g., implementing a correction to prevent future occurrences and/or the use of obsolete documents for other products manufactured).
6. Failure to establish and maintain adequate procedures to ensure that Device History Records (DHRs) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the Device Master Record (DMR) and the requirements of Part 820, as required by 21 CFR 820.184.
A. According to the DMR document, (b)(4) document ID: ERFNC-00734-00, dated September 15, 2009, 27 components are to be included in the finished device. However, device history records (e.g., 0311 -0066, 0311 -0071, 0711 -0081 , and 1011-0111) for the FreeEMG device did not include evidence to indicate that all of the final components listed in ERFNC-00734-00 were assembled into the final device. Examples of missing components include: (b)(4)
B. DHRs for the FreeEMG device contain a System Test Suite that includes testing of devices at frequencies ranging from 1 kHz to 4 kHz. However, DHR's 0311-0071, 0711-0081, and 1011-011 did not include evidence to indicate that all of the tests for the System Test Suite were completed. The forms indicate that the devices passed; however, there was no explanation about why certain tests were not performed. According to your firm, the tests were skipped to save time in the testing process.
We reviewed your firm's response and conclude that it is not adequate. A copy of the revised procedure; ERMTI-00354-06 (b)(4) Procedure; including test report template was provided. However, your firm did not provide evidence to indicate that applicable employees were trained on the new procedures. Also, evidence that your firm considered and/or conducted a review of DHRs for other devices manufactured was not provided.
7. Failure to establish adequate procedures for quality audits and to conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system. Quality audits shall be conducted by individuals who do not have direct responsibility for the matters being audited, as required by 21 CFR 820.22.
For example: section 2 of your firm's internal audit procedure (EQSGQ-00307-04, dated October 13, 2010) requires that internal audits are to be conducted by someone who is not responsible for the areas being audited. However, your firm's November 23 - 30, 2011, internal audit report indicated that the quality and regulatory affairs manager, who is responsible for implementing the quality management system and internal quality auditing, conducted an audit of the quality manual (section 4.2.2) and verified that the internal audit was performed in accordance with your firm 's 2011 audit plan (section 8.2.2).
Your firm's response to this observation appears to be adequate. A retrospective quality audit review was performed over section 4.2.2, quality manual, and section 8.2.2, internal audit, by (b)(4) - project manager, an individual who does not have direct responsibility for the matters being audited. The review was performed retrospectively for years 2010 to 2012. The result report of the review was provided as evidence of correction implementation.
8. Failure to establish adequate procedures for identifying training needs, ensuring that all personnel are trained to adequately perform their assigned responsibilities, and documenting training, as required by 21 CFR 820.25(b).
For example: section 5 of your firm's employee training procedure, EOSG0-00298-004, dated October 7, 2010, requires that areas of training be identified in the annual training plan. The employee training plan for 2011 identified eleven training needs for the year. However, upon request, your firm could not provide documentation to verify that the training needs identified for 2011 were met. Your firm stated that it did not have the resources to send its employees to the desired trainings for 2011 and, therefore, the trainings were not conducted.
We reviewed your firm's response and conclude that it is not adequate. Your firm modified its Resource Management procedure clarifying the difference between training needs that are required and training opportunities that are optional. The revised plan with the training needs and the training opportunities for 2011 and 2012 was provided. However. documents supporting completion of training were not provided and your firm did not provide evidence to indicate that applicable employees were trained on the new procedure.
Our inspection also revealed that your firm's FreeEMG and PocketEMG 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 device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 - Medical Device Reporting. Significant violations include, but are not limited to, the following: failure to develop, maintain, and implement written MDR procedures, as required by 21 CFR 803.17. For example: During the inspection, your firm acknowledged that it did not have a written MDR procedure.
The response dated February 14, 2012, is not adequate. Your firm submitted an MDR procedure. A review of your firm 's MDR procedure, EQSGQ-01023-00 (b)(4), was conducted. The procedure fails to meet the requirements of 21 CFR 803.17. The following issues were noted:
1. EQSGQ-01 023-00 fails to establish internal systems that provide for timely and effective identification, communication. and evaluation of events that may be subject to MDR requirements. For example, to facilitate the correct interpretation of reportable events and to assure the quality of MDR submissions (b)(4).
2. EQSGQ-01 023-00 fails to establish internal systems that provide for timely transmission of complete medical device reports to FDA. For example, the procedure does not include the address identifying where MDR reports should be submitted. The address for MDR submission is: FDA, CDRH, Medical Device Reporting, P.O. Box 3002, Rockville, MD 20847-3002.
Please note that EQSGQ-01023-00 includes references to baseline reports. Baseline reports are no longer required and all references to a Baseline Report should be removed from EQSGQ-01023-00 (see: 73 Federal Register Notice 53686, dated September 17, 2008).
If your firm wishes to submit MDR reports via electronic submission it can follow the directions stated at the following URL:
If your firm wishes to discuss MDR re portability criteria or to schedule further communications, it may contact the MDR Policy Branch at 301 -796-6670 or by email at MDRPolicy@fda.hhs.gov.
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# 274316 when replying. If you have any questions about the contents of this letter, please contact: Charles Cathlin at 301-796-5540 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 lnspectional 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.
Steven D. Silverman
Office of Compliance
Center for Devices and