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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Spes Medica Srl 1/23/13


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 


January 23, 2013
Mr. Giuseppe Mafrici
Chief Executive Officer
Spes Medica Srl
Via Casaregis, 44/1
16129 Genova, Italy
 Dear Mr. Mafrici:
During an inspection of your firm located in Battipaglia, Italy, on October 1, 2012, through October 4, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Electromyography Needles.  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 November 1, 2012, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional 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 the identification, documentation, validation or, where appropriate, verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i). 
For example: Your firm's design change practices that are covered under the Design and Development procedure (QAP 20.1) do not include requirements for validation or, where appropriate, verification of the design change prior to its approval and implementation.
We reviewed your firm’s response and conclude that it is not adequate. Your firm modified QAP 20.1 by adding a clause that any modification must be verified and/or validated and approved before any design change implementation. Furthermore, the form used for design changes (QPFM 004) was updated by adding columns to specify or refer to the change verification and validation done before implementation of the change. However, your firm did not perform personnel training to ensure correct implementation of the added requirements. Additionally, your firm did not perform a retrospective review to ensure that all devices manufactured are in compliance with the new procedure.
2.    Failure to maintain device master records (DMRs) for each type of device that shall include, or refer to, the location of device specifications including appropriate drawings, composition, formulation, component specifications, and software specifications; production process specifications, including the appropriate equipment specifications, production methods, production procedures, and production environment specifications; quality assurance procedures and specifications, including acceptance criteria and the quality assurance equipment to be used; packaging and labeling specifications, including methods and processes used; and installation, maintenance, and servicing procedures and methods, as required by 21 CFR 820.181. 
For example: Your firm does not have a DMR for the needles used for electromyography.
We reviewed your firm’s response and conclude that it is not adequate. Your firm produced a DMR document referencing the requirements under 21 CFR 820.181. However, the DMR document does not specify the exact location or document number for the supporting documents or references. Additionally, your firm did not perform a retrospective review to ensure DMRs are maintained for all devices manufactured.
3.    Failure to establish and maintain procedures to adequately control environmental conditions that could reasonably be expected to have an adverse effect on product quality. Environmental control systems shall be periodically inspected to verify that the system, including necessary equipment, is adequate and functioning properly. These activities shall be documented and reviewed, as required by 21 CFR 820.70(c). 
For example:
a)    Your firm's Environmental Control and Equipment Maintenance procedure (QAP 09.1) requires a stop in production, cleaning of the clean room environment, and new samples for microbiological analysis when the specification is exceeded. However, results of surface microbiological monitoring were found to be (b)(4) in May, 2012 (specification is (b)(4)). Your firm did not stop production, perform cleaning, or analyze new samples of the clean room environment when the results exceeded the specification limit.
b)    The clean room environment is monitored on a daily basis for pressure, relative humidity, and temperature. Several out‑of‑specification results were noted with no corrective follow-up activities documented by your firm. Further, your firm's Environmental Control and Equipment Maintenance procedure (QAP 09.1) does not address how these out-of-control clean room systems are to be documented and/or addressed by your firm.
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided a letter from the laboratory ((b)(4)) explaining that the out-of-specification surface microbiological test result was mistakenly reported for the supporting (b)(4). A bio-burden test ((b)(4)) was performed to show a level of (b)(4) that reflects historical data. Your firm performed a new analysis of the clean room, which shows values within the established specifications. Spes Medica created a new revision of the Environmental Control Procedure (QAP 09.1) to clarify the limits and the sampling points. Your firm developed form "QPFM 0928 - Control of Overpressure, Temperature, Relative Humidity," which clarifies the specifications. Your firm started providing training on the new form. However, your firm did not perform a retrospective review of current or past reports to ensure that all out-of-specification results are captured. Additionally, an English translation of the QAP 09.1 was not provided.
4.    Failure to document all activities required under 21 CFR 820.100 (corrective and preventive action), and their results, as required by 21 CFR 820.100(b). 
For example: Documentation of the investigations conducted was not maintained by your firm for all opened corrective and preventive actions (CAPAs). Specifically, investigation documentation for (b)(4), (b)(4), and (b)(4) were not available during the investigation.
We reviewed your firm’s response and conclude that it is not adequate. Your firm updated the QAP 13.1 (System Non Conformities/Corrective and Preventive Actions) procedure to include analysis requirements to identify existing and potential causes of non-conformities and other quality problems, and documentation requirements to ensure that investigations conducted are maintained and attached to the CAPAs opened. However, your firm did not perform a retrospective review of the current or past CAPAs to ensure that all CAPAs are in compliance with the new procedure. Additionally, your firm did not provide training to ensure correct implementation of the new procedure. 
5.    Failure to establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities, including the date and individuals performing the maintenance activities, shall be documented, as required by 21 CFR 820.70(g)(1). 
For example: There is no maintenance schedule for the (b)(4) used in production of the needles for electromyography. Additionally, maintenance is scheduled on a (b)(4) basis for the (b)(4) and (b)(4) machines. However, several examples of missing maintenance activities were noted with no rationale for the missing documentation, as provided below:
  • (b)(4) Machine - weekly maintenance was not conducted on the following dates: (b)(4).
  • (b)(4) Machine – weekly maintenance was not conducted on the following dates: (b)(4).
We reviewed your firm’s response and conclude that it is not adequate. Your firm established a maintenance form for the (b)(4) tools (QPFM 092-27). Your firm explained that the missing maintenance documentation corresponded to periods when the machine was nonfunctional. The person in charge of maintenance activities was trained on the maintenance documentation requirements. However your firm did not perform a review to ensure that all maintenance activities are in compliance for all equipment used in production of the devices. 
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 DMR and the requirements of 21 CFR 820.184. The DHR shall include, or refer to the location of, the primary identification label and labeling used for each production unit, as required by 21 CFR 820.184(e). 
For example: Five of ten DHR’s reviewed for the electromyography needles did not include the primary identification label that included DHR Lot Numbers (b)(4).
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided training on DHR requirements. However your firm did not provide the missing identification labels for the five DHRs or perform a retrospective review of the DHRs of devices to ensure compliance with the requirements. Additionally, your firm did not establish adequate systemic measures to prevent recurrence of the violation. 
7.    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 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: Your firm's Audit Management procedure (QAP 23.1) requires the auditor to have independence from the area being audited. However, the Quality Manager, whose responsibilities include management of the CAPA and customer complaint systems, conducted the quality audits that covered CAPA and the customer complaint systems in (b)(4) and (b)(4)
Your firm’s response to this observation appears to be adequate. Your firm stated that the Quality Audit plan for (b)(4) was checked and promises to ensure that all areas will be correctly audited as planned.
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 # 391578 when replying. If you have any questions about the contents of this letter, please contact: Tanisha Hithe at 301-796-5524 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,
Steven D. Silverman
Office of Compliance
Center for Devices and
     Radiological Health