Inspections, Compliance, Enforcement, and Criminal Investigations
Fisioline s.r.l. 3/5/13
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|10903 New Hampshire A\ienue|
White Oak Building 66
Silver Spring. MD 20993
March 5, 2013
VIA UNITED PARCEL SERVICE
Co-Owner, General Director
Borgata Molino, 29
Verduno, Italy 12060
Dear Mr. Battogliotti:
During an inspection of your firm located in Verduno, Italy on October 29, 2012, through November 1, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Lumix 2 and Lumix 3 laser devices. 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. Your firm’s response dated November 19, 2012, to the Form FDA 483 (FDA 483) was not reviewed because it was not received within fifteen business days of issuance of the FDA 483. We received your response on November 29, 2012. The response may be evaluated along with any other written material provided in response to the violations cited in this Warning Letter. These violations include, but are not limited to, the following:
1. Failure to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a). For example, your firm’s “PSI Nonconforming product management” procedure, which contains complaint handling procedures in Section 4.5 “Nonconformities at customer’s premises,” does not include a requirement that ensures all complaints are evaluated to determine whether the complaint should be filed as a Medical Device Report (MDR). None of the complaint records reviewed contained evidence of an evaluation to determine if an MDR was required.
2. Failure to review and evaluate all complaints to determine whether an investigation is necessary and when no investigation is made, the manufacturer shall maintain a record that includes the reason no investigation was made and the name of the individual responsible for the decision not to investigate, as required by 21 CFR 820.198(b). For example, the “PSI Nonconforming product management” procedure, which contains complaint handling procedures in Section 4.5 “Nonconformities at customer’s premises,” does not include requirements that ensure records for complaints where no investigation was made include the reason why and the name of the individual responsible for the decision not to investigate. None of the complaint records reviewed contained these required elements.
3. Failure to maintain a record of the investigation by the formally designated unit identified in paragraph (a) of 21 CFR 820.198 when an investigation is made under this section, as required by 21 CFR 820.198(e). For example, the “PSI Nonconforming product management” procedure, which contains complaint handling procedures in Section 4.5 “Nonconformities at customer’s premises,” does not include requirements which ensure all required data elements, including the dates and results of the investigations and any replies to the complainants, are included in the complaint records when investigations are conducted. None of the complaint records reviewed contained these required elements.
4. Failure to validate computer software for its intended use according to an established protocol when computers or automated data processing systems are used as part of production or the quality system, as required by 21 CFR 820.70(i). For example, the software developed by your firm to record, evaluate, investigate, correct and repair incoming technical assistance calls, complaints, and service records was implemented in the first part of October 2012, and has not been validated. No validation documentation was available for an established protocol, any testing data, or a finished report for the validation of this system. Mr. Lucca Ferrua, the Assistant Manager, indicated that your firm had not validated the software system.
5. Failure to establish and maintain procedures for validating the device design, as required by 21 CFR 820.30(g). For example, the design validation procedures outlined in “PP1 Design and Development” do not include:
a) requirements which ensure that protocols with acceptance criteria are established prior to the performance of validation activities; and
b) requirements which ensure that the results of design validation, including the identification of the design, the methods, and the measuring equipment used, are documented and filed in the design history file.
Software validation documentation for a new user interface on an existing laser model did not document the above information.
6. Failure to establish and maintain procedures for verifying the device design to confirm that the design output meets design input requirements, as required by 21 CFR 820.30(f). For example, the design verification procedures outlined in the procedure titled, “PP1 Design and Development,” do not include requirements which ensure that protocols with acceptance criteria are established prior to the performance of verification activities, nor does the procedure include requirements which ensure that the results of design verification, including identification of the design, the methods, and the measuring equipment used, are documented and filed in the design history file.
7. Failure to establish and maintain procedures to ensure that formal 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 procedure titled, “PP1, Design and Development,” Rev 1.3, dated October 2012, describes the implementation of design and development processes, but does not include requirements which ensure that all individuals with responsibility for the design stage being reviewed be in attendance, as well as an individuals without responsibility for the design stage being reviewed, and any specialists if necessary. The procedure does not include requirements to specifically indicate when design reviews were required to be held. Mr. Alberto Bergesio, Engineer and Manager of Quality Assurance and Research and Development, stated that there was no individual in attendance at any of the review meetings who did not have direct responsibility for the design stage being reviewed since the firm was not aware of this requirement.
8. Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, the corrective and preventive action procedure titled, “Improvement,” Chapter 7 of PP8 Quality Management System procedure Rev. 0.9, has the following incomplete or missing requirements:
a) missing and incomplete requirements in Section 7.1, “Scope:” addressing the analysis of sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, and does not identify all sources of potential causes of nonconforming product or other quality data sources in the procedure;
b) no requirements for verifying or validating corrective or preventive actions prior to implementation, to ensure the actions do not adversely affect the devices;
c) missing requirement for assurance that all required activities are to be documented; and
d) no requirements for investigating the cause of nonconformities relating to processes, products, and the quality system.
Review of (b)(4) Corrective Action record, CAPA No. (b)(4), related to a U.S. marketed device, the Lumix 3 Ultra/Plus, did not reveal any of the required information as described above.
9. Failure to establish and maintain procedures that define the responsibility for review and the authority for the disposition of nonconforming product, as required by 21 CFR 820.90(b)(1). For example, the “PS1 Nonconforming product management” procedure does not contain the following elements:
a) requirements which ensure that the disposition of nonconforming products is documented in the nonconformance records; and
b) requirements that ensure that reworked product is documented in the Device History Record (DHR).
(b)(4) out of (b)(4) nonconformance records reviewed by the investigator did not record disposition of the nonconforming component or device, and (b)(4) out of (b)(4) records, where an action was taken to correct the problem, did not record the corrective action in the Device History Record for the device involved.
10. Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a). For example, the calibration procedures in Section 7 of “PP4 Production” procedure, Rev. 0.9, dated September 2012, does not include requirements for specifying the calibration timeframes for primary measuring equipment devices used in the calibration of measuring equipment which is used in production testing of in-process and finished devices.
11. Failure to document equipment identification, calibration dates, the individual performing each calibration, and the next calibration date, as required by 21 CFR 820.72(b)(2). For example, the investigator noted that during review of the calibration records for the primary measuring equipment, the correct identification of the unit was not identified on the calibration certificates. Additionally, the identification of the measuring equipment calibrated in-house was not identified on the in-house calibration records.
12. Failure to document acceptance activities, as required by 21 CFR 820.80(e). For example, the measuring equipment used during in-process and finished device testing is not identified in the acceptance records. (b)(4) of the (b)(4) device history records reviewed by the investigator included any documentation of the measuring equipment used during acceptance testing.
13. Failure to establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements, to determine the effectiveness of the quality system, and to ensure that corrective actions, including a reaudit of deficient matters, shall be taken when necessary, as required by 21 CFR 820.22. For example, Chapter 3 titled, “Internal Audits” of the “Quality Management System” “PP8, Rev 0.9, dated September 2012, describes documentation of nonconformances found during the audit, but does not include requirements to ensure that re-audits are conducted when necessary.
Our inspection also revealed that your devicesare misbranded under section 502(t)(2) of the Act 21 USC 352 (t)(2), in that your firm failed or refused to furnish material or information respecting the devices that is required by or under section 519 of the Act, 21 USC 360i, and 21 CFR Part 803 – Medical Device Reporting (MDR) Regulation. Significant deviations include, but are not limited to:
1. Failure of your firm to develop, maintain and implement written MDR procedures, as required by 21 CFR 803.17. For example, in the December 18, 2012, response to the FDA 483, your firm submitted an English version of its revised procedure titled Operating Instruction OI: Recall of medical devices and notification of accidents to the competent authorities, Rev. 2.4 of November 2012. The following issues were noted:
a) The proceduredoes not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements. For example, the procedure includes definitions from 21 CFR 803.3, for “MDR reportable event” and “serious injury.” To facilitate the correct interpretation of reportable events and to assure the quality of MDR submissions, the procedure should also include definitions based on 21 CFR 803.3 for the terms “become aware,” “caused or contributed,” “malfunction,” and definitions for the terms “reasonably known” and “reasonably suggests,” found respectively in 21 CFR 803.50(b) and 803.20(c)(1).
b) The procedure does not establish internal systems that provide for a standardized review process to determine when an event meets the criteria for reporting under this part. For example:
i. There are no instructions for how your firm will evaluate information about an event to make MDR reportability determinations in a timely manner.
ii. The procedure, as written does not specify who makes the decision for reporting events to FDA.
c) The procedure does not establish internal systems that provide for timely transmission of complete medical device reports. For example, the following are not addressed:
i. Instructions for how to complete and obtain the FDA 3500A form.
ii. The procedure does not include the address for where to submit MDR reports: FDA, CDRH, Medical Device Reporting, P.O. Box 3002, Rockville, MD 20847-3002.
iii. The circumstances under which your firm must submit initial, supplemental, or follow-up reports and the requirements for such reports.
d) The procedure does not describe how your firm will address documentation and record-keeping requirements, including:
i. Information that was evaluated to determine if an event was reportable.
ii. Documentation of the deliberations and decision-making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable.
iii. Systems that ensure access to information that facilitates timely follow-up and inspection by FDA.
If your firmwishes to submit MDR reports via electronic submission it can follow the directions stated at the following URL:
If your firm wishes to discuss MDR reportability criteria, it may contact the Reportability Review Team by email at: ReportabilityReviewTeam@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 #392908 when replying. If you have any questions about the contents of this letter, please contact: Matthew Krueger at (301) 796-5585 or by fax at (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.
Steven D. Silverman
Office of Compliance
Center for Devices and