| Public Health Service Food and Drug Administration |
10903 New Hampshire Avenue |
Department of Health and Human ServicesWARNING LETTER
OCT 1 2010
VIA UPS EXPRESS
Bruno Thevenet
President
Biotech International
305, Allées de Craponne
13300 Salon de Provence
France
Dear Mr. Thevenet:
During an inspection of your firm located in Salon de Provence, France, on May 31, 2010, through June 3, 2010, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the Cross.Bone bone void filler device and Omnitech and Easylock Osteosystem bone fixation plates. 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 are intended 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 (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (C.F.R.), Part 820. We received responses from you dated June 29, 2010, June 30, 2010, July 12, 2010, and July 19, 2010. However, these were not considered for review because they were not received within fifteen days of the close of inspection. The violations found at your firm include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, the firm's procedure, Amelioration Continue (Continuous Improvement), P3/4, dated June 9, 2005, does not include requirements for analyzing sources of quality data (other than complaints) to identify existing and potential causes of nonconforming product, or other quality problems. Nor does the procedure require documentation of the verification/validation of corrective and preventive actions to ensure that such action is effective and does not adversely affect the finished devices.
2. Failure to document activities required under 21 CFR 820.100, Corrective and preventive action, and their results as required by 21 CFR 820.100(b). For example:
a. Records of corrective action associated with Nonconforming Report FNC # (b)(4), involving barcode label errors for implantable devices and instruments, contain no documentation of the investigation, the proposed corrections and corrective actions, or corrective action validation activities to ensure the action was effective and did not adversely affect the finished device.
b. Records of corrective action associated with Nonconforming Report FNC # (b)(4) involving cannulated screws where a wire was unable to pass through the screw contain no documentation of the investigation, the proposed corrections and corrective actions, or corrective action validation activities to ensure the action was effective and did not adversely affect the finished device.
3. Failure to establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a). For example, (b)(4) individual devices that did not meet specified requirements and were returned in association with confirmed complaints FNC (b)(4), FNC (b)(4) were not identified as nonconforming product. (b)(4) of the returned nonconforming devices were retained in packages labeled with different batch and/or part numbers while (b)(4) nonconforming device was retained in a package with the correct lot number and part number which made it appear to be a conforming device. None of the retained packages for these returned devices nor the devices themselves were identified as nonconforming product.
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, the change in data transfer for part/lot information for a new client in the firm's software barcode reader process was not validated prior to implementation. This resulted in incorrect barcode labels for implantable devices being shipped to the customer as identified in nonconforming report, FNC # (b)(4).
5. Failure to establish and maintain adequate procedures to ensure complaints are evaluated to determine whether the complaint represents an event which is required to be reported to FDA under part 803 of this chapter, Medical Device Reporting, as required by 21 CFR 820.198(a)(3). For example, the firm's procedure, Amelioration Continue (Continuous Improvement) P3/4, dated June 9, 2005, does not ensure that oral complaints received from foreign countries involving products also distributed to the U.S. are documented upon receipt and evaluated by a formally designated unit to determine whether the complaint represents an event which is required to be reported to FDA under 21 CFR 803.
6. 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:
a. Amelioration Continue (Continuous Improvement) P3/4 dated June 9, 2005, requires Form E16 be completed for each nonconformance that is identified as a complaint. Each section on the form is to be completed, dated and initialed by the responsible individual completing that section. Three nonconformance forms reviewed (FNC # (b)(4), # (b)(4), # (b)(4) did not contain the required initials of the responsible individual and one FNC # (b)(4) did not include the required date for the implementation of the immediate corrective actions. All three of the E16 forms had been reviewed, signed and closed by the quality department representative.
b. For one nonconformance form reviewed (dated 30/10/2009), no FNC number had been assigned to the complaint as per procedure, Amelioration Continue (Continuous Improvement) P3/4 dated June 9, 2005, even though the investigation had been conducted and decisions were made regarding the immediate corrective action. This nonconformance form was also not signed or dated by the quality department representative.
7. Sampling plans are not based on a valid statistical rationale as required by CFR 820.250(b). For example:
a. During finished device acceptance activities, (b)(4) sampled and tested for each lot regardless of the number of devices contained within the lot. The finished device testing of the cannulated screwdriver with the screw to ensure the two devices meet specifications and permit wire access through both is conducted on one device per lot as indicated in the Device History Record for part number (b)(4), Lot (b)(4). A nonconformance report FNC # (b)(4) documents a customer could not insert a wire through the screwdriver while connected to the screw for product from the aforementioned part and lot number. No statistical rationale for this sampling plan was documented.
b. Incoming acceptance records contained within the Design History File for Project 08/03 (the development of a bone cutter device used in percutaneous foot surgery) document two out of (b)(4) devices from Lot (b)(4) were measured to ensure the prototypes met drawing specifications. No statistical rationale for this sampling plan was documented.
8. Failure to establish and maintain adequate procedures for supplier data that clearly describe or reference the specified requirements for purchased or otherwise received product and services, as required by 21 CFR 820.50(b). For example, during a review of the supplier monitoring records for a critical parts supplier, no record was available for the evaluation of the supplier for the fiscal year 2008-2009. An annual evaluation is required by the firm's purchasing procedure, Achat, P5/4, dated June 6, 2009.
9. Failure to establish and maintain adequate procedures to ensure that all inspection, measuring, and test equipment is suitable for its intended purposes and is capable of producing valid results, as required by 21 CFR 820.72(a). For example:
a. The firm's calibration control procedure titled Maitrise du contrôle et des ICME I20/1, dated February 2, 2009, requires instruments to be calibrated (b)(4). During a review of calibration records for calibrated digital measuring instruments, two digital calipers (Serial Numbers (b)(4) and (b)(4) were recognized as not having been calibrated within the specified (b)(4) timeframe. Both instruments are used in final acceptance testing of orthopedic implants.
b. There were no documented calibration results (e.g. Certificate of Calibration) for a digital caliper used to conduct final inspection testing of orthopedic implants.
10. Failure to establish and maintain adequate procedures to control all documents including provisions to ensure obsolete documents are promptly removed from all points of use or otherwise prevented from unintended use as required by 21 CFR 820.40(a). For example, the Design History File for Project 08/03 (the development of a bone cutter device used in percutaneous foot surgery) included results of (b)(4) testing conducted by surgeons on May 16, 2009 and recorded on an obsolete version of Form E75. The results were recorded using Prototype Test Report Form E75/3 dated February 20, 2006. The current version of the form at that time was Form E75/5 dated April 16, 2009.
11. Failure to establish and maintain adequate 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 Design History File for Project 08/03 (the development of a bone cutter device used in percutaneous foot surgery) does not document the results and individuals performing the design review entitled “Direction Validation.”
Our inspection also revealed that your Cross.Bone bone void filler devices and Omnitech and Easylock Osteosystem bone fixation plate 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 device that is required by or under section 519 of the Act, 21 U.S.C. 360i, and 21 C.F.R. Part 803 - Medical Device Reporting (MDR) regulation. Significant deviations include, but are not limited to, the following:
Failure to develop, maintain, and implement written MDR procedures, as required by 21 CFR 803.17, Medical Device Reporting. Specifically, you do not have written MDR procedures that outline the necessary steps to be taken for complaints with MDR Reportable events to ensure such events are reported to FDA.
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action, which may include detaining your devices without physical examination upon entry into the United States until the corrections are completed. Section 801(a) of the Act (21 U.S.C. § 381(a)) Also, U.S. federal agencies are advised of the issuance of all 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 (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. If the documentation is not in English, please provide a translation to facilitate our review.
Your response should be sent to:
Matthew Krueger
Chief
Orthopedics and Physical
Medicine Devices Branch
Office of Compliance
Center for Devices and
Radiological Health
WO 66, Room 3676
10903 New Hampshire Avenue
Silver Spring, MD 20903-0002
If you have any questions about the content of this letter please contact: Amy Skrzypchak at phone number (301) 796-5613 or amy.skrzypchak@fda.hhs.gov.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.
Sincerely yours,
/s/
Steven D. Silverman
Director
Office of Compliance
Center for Devices and
Radiological Health
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