Inspections, Compliance, Enforcement, and Criminal Investigations
Gambro Dasco S.p.A. Bloodline Division 7/2/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|Center for Devices and
9200 Corporate Blvd
Rockville, MD 20850
July 2, 2009
VIA FEDERAL EXPRESS
Mr. Ezio Nicola
Gambro Daseo S.p.A. Bloodline Division
Via Modenese, 66
Dear Mr. Nicola:
During an inspection of your firm located in Medolla, Italy on February 9, 2009, through February 14, 2009, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures products including the Gambro Cartridge Tubing Set and Phoenix Dialysis Machine. 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 (CFR), Part 820. We received responses from Javad Seyedzadeh, Senior Vice President Gambro Quality Assurance & Regulatory Affairs, dated February 27, 2009, March 27, 2009, March 30, 2009, and April 1,2009, concerning our investigator's observations noted on the Form FDA 483, List of Inspectional Observations that was issued to you. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
Failure to establish and maintain adequate procedures for implementing corrective and preventive action. The procedures shall include requirements for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4).
For example (b)(4), testing of (b)(4) for analysis of (b)(4) into (b)(4) into (b)(4), a corrective action described in (b)(4) dated (b)(4) is not adequately implemented. It is evident from the document (b)(4) dated that you did not conduct (b)(4) testing and analysis of (b)(4) during injection mold (b)(4), as is required by (b)(4).
We have reviewed your responses, dated February 27, 2009, March 27, 2009, March 30, 2009, and April 1,2009, and have concluded that they are inadequate. You have not provided evidence of adequate implementation of measurements of process indicators; including abnormal (b)(4) in injection molded (b)(4) as described in (b)(4) dated (b)(4). The procedures for injection mold Performance Qualification described in (b)(4) dated included in your response, do not include (b)(4) testing and analysis. Also, procedures for injection mold Operational Qualification only include (b)(4) and do not adequately describe the expected result from destructive testing or when such testing is applicable.
Moreover, your (b)(4), response is unclear. in that the Performance Qualification Protocol template (b)(4) in dated (b)(4) includes references to but no reference to injection molding. Also, (b)(4), docs not contain any entries under (b)(4).
Our inspection also revealed that your 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 CFR Part 803 - Medical Device Reporting (MDR) regulation. Significant deviations include, but are not limited to, the following:
1. Failure to report to the FDA no later than 30 calendar days after the day that you received or otherwise become aware of information, from any source. that reasonably suggests that a device that you market may have caused or contributed to a death, as required by 21 CFR Part 803.50(a)(1).
For example. your firm failed to submit an MDR report to the FDA for Complaint (b)(6), that involved a Phoenix device that may have caused or contributed to a patient death from mechanical hemolysis. "Lab work [upon admission to the ER following dialysis treatment] confirmed the patient had hemolysis and pancytopenia. The patient was empirically treated with antibiotics. Blood, urine and stool cultures were negative for a myriad of tests including bacterial and viral conditions. Patient was transfused with a total of 6 units of packed red blood cells and continued to hemolyze throughout hospitalization. Patient's medical course and blood dyscrasia began to improve and on hospital day twelve, patient developed PEA [Pulseless Electrical Activity] with an unsuccessful resuscitation."
The information in the complaint file indicates that your firm was in possession of information that reasonably suggests that one of your marketed devices may have caused or contributed to a patient death. Your firm failed to submit this report to FDA.
2. Failure to report to the FDA no later than 30 calendar days after the day that you received or otherwise become aware of information, from any source, that reasonably suggests that a device that you market may have caused or contributed to a serious injury, as required by 21 CFR Part 803.50(a)(1).
For example, your firm failed to submit an MDR report to the FDA for Complaint (b)(6), that involved a Phoenix machine that may have caused or contributed to a serious injury. Your firm became aware of this complaint on (b)(4). During the event described in this complaint. following a low pressure reading, the patient complained of nausea and the patient's blood pressure dropped to 65/38. A drop in the patient's blood pressure to 65/38 is a life threatening event. This event meets the threshold of a serious injury and requires the submission of an MDR.
The information in the complaint file indicates that your firm was in possession of information that reasonably suggests that one of your marketed devices may have caused or contributed to a serious injury to the patient. Your firm failed to submit this report to FDA.
During the inspection, the following issues were also noted and discussed with management, and should also be addressed by your firm:
1. Your firm failed to provide documentation demonstrating an evaluation of the suitability of the pin gauge for the purpose of determining the presence of flash and evidence of the capability of the pin gauge to produce valid results. Your firm also failed to provide an analysis of the deflection of thin flash and pin insertion force. This concern was discussed with Mr. Ezio Nicola at the conclusion of the inspection, and you promised to correct this. We have reviewed your responses, dated February 27, 2009, March 27, 2009, March 30, 2009, and April 1,2009, and have concluded that they are inadequate as they contained no evidence of any action to address this Issue.
2. Your firm failed to provide documentation providing the rationale for the use of acceptance sampling (Acceptable Quality Level (AQL)) in the production of dialyzer connectors, including documentation addressing the risk of the acceptance of a bad lot. This concern was discussed with Mr. Javad Seyedzadeh, (b)(6) at the conclusion of the inspection. We have reviewed your responses, dated February 27, 2009; March 27, 2009; March 30, 2009; and April 1, 2009, and have concluded that they are inadequate. While your February 27, 2009. response states that (b)(4) you have provided no documentation describing those revised criteria, and have provided no documentation evidencing implementation of such criteria.
3. Your firm failed to consider moldmakers of injection molds as suppliers and failed to exercise appropriate purchasing controls over moldmakers. During the inspection, (b)(6), Process/Product QA Manager - Bloodline, provided evidence that your firm's procedure for supplier qualification and evaluation was updated to include consultants and moldmakers. We have reviewed your responses, dated February 27, 2009, March 27, 2009, March 30, 2009, and April 1, 2009, and have concluded that they are inadequate as they contained no documentation demonstrating that these updated procedures have been implemented and maintained.
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: Paul F. Tilton, Branch Chief, 9200 Corporate Boulevard, Rockville, Maryland 20850, USA. If you have any questions about the content of this letter please contact Mr. Tilton at (301) 796-5770.
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, 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.
Office of Compliance
Center for Devices and