- Medinol Ltd.
- Issuing Office:
- Center for Devices and Radiological Health
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||10903 New Hampshire Avenue|
Silver Spring, MD 20993
JUL 29, 2014
VIA UNITED PARCEL SERVICE
Judith Richter, Ph.D.
Chief Executive Officer
Bech Tech Building
Har Hotzvim, P.O. Box 45026
Jerusalem, Israel 91450
Dear Dr. Richter:
During an inspection of your firm located in Jerusalem, Israel, on March 23, 2014, through March 27, 2014, investigators from the United States Food and Drug Administration (FDA) determined that your firm manufactures the Presillion Plus CoCr Stent and Delivery System. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), this product is a device because it is 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 any function of the body.
Our inspection revealed that the Presillion Plus CoCr Stent and Delivery System is 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. We received a response from Daniel P. Levy, Vice-President Quality, dated April 17, 2014, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which 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 develop, maintain, and implement written medical device reporting (MDR) procedures, as required by 21 CFR 803.17(a).
For example, after conducting a review of your firm’s MDR procedure, titled “Complaint Reporting to US,” (b)(4), Revision #5, Effective: November 14, 2013, the following deficiencies were noted:
a. Procedure (b)(4), Revision #5, does 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 omits the definitions of the terms “become aware,” and “caused or contributed,” found in 21 CFR 803.3, and the definition for the term “reasonably suggests,” found in 803.20(c)(1). The exclusion of the definitions of these terms from the procedure may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR 803.50(a).
b. Procedure (b)(4), Revision #5, does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the procedure does not include instructions for how to obtain and complete the FDA 3500A form.
2. Failure to submit a supplemental or follow-up report within one month of the day that your firm obtained information that it did not previously provide because it was not known or was not available when your firm submitted the initial report, as required by 21 CFR 803.56.
For example, the supplement MDR 9710284-2012-00001, received by FDA for Complaint PP128, which included the results of the investigation, was not submitted within one month of the day that your firm received information that was not available at the time the initial report was submitted.
3. Failure to report to us no later than 30 calendar days after the day that your firm received or otherwise became aware of information, from any source, that reasonably suggests that a device that it markets has malfunctioned and that this device or a similar device that your firm markets would be likely to cause or contribute to a death or serious injury if the malfunction were to recur, as required by 21 CFR 803.50(a)(2).
For example, on December 2, 2012, your firm became aware of information for complaint PP172 that reasonably suggests that your firm’s device malfunctioned during use. An MDR should have been submitted to FDA within the 30-day timeframe.
We reviewed your firm’s responses, dated April 17, 2014, and July 10, 2014, and conclude that they are not adequate. Your firm stated that it opened CAPA 874 to address the observation noted in the FDA 483. Your firm also submitted a revised version of its MDR procedure titled, “Complaint Reporting to US,” Reference (b)(4), Revision #6, Effective April 13, 2014. After conducting a review of your firm’s revised procedure, the following deficiencies are still noted:
1. Procedure (b)(4), Revision #6, does 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 omits the definitions of the terms “become aware,” and “caused or contributed,” found in 21 CFR 803.3, and the definition of the term “reasonably suggests,” found in 803.20(c)(1). The exclusion of the definitions for these terms from the procedure may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR 803.50(a).
2. Procedure (b)(4), Revision #6, does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the procedure does not include instructions for how to obtain and complete the FDA 3500A form.
The eMDR Final Rule requiring manufacturers and importers to submit electronic Medical Device Reports (eMDRs) to FDA was published on February 13, 2014. The requirements of this final rule will take effect on August 14, 2015. If your firm is not currently submitting reports electronically, we encourage you to visit the following web link for additional information about the electronic reporting requirements:
If your firm wishes to discuss MDR reportability criteria or to schedule further communications, it may contact the Reportability Review Team by email at ReportabilityReviewTeam@fda.hhs.gov
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 awarding of contracts.
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, as well as 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 actions (which must address systemic problems) 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. Your firm’s response should be comprehensive and address all violations included in this Warning Letter. Please provide a translation of documentation not in English to facilitate our review.
In addition, FDA has noted nonconformances with regards to section 501(h) of the Act, 21 U.S.C. § 351(h), which are deficiencies within your firm’s quality system pertaining to current good manufacturing practice requirements specified in the Quality System regulation found at 21 CFR Part 820. These nonconformities include, but are not limited to, the following:
1. Failure to establish and maintain procedures for implementing corrective and preventive actions, as required by 21 CFR 820.100. For example:
a. Your firm failed to establish and maintain procedures for analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and other potential causes of nonconforming product, or other quality problems, and to employ appropriate statistical methodology, where necessary, to detect recurring quality problems, as required by 21 CFR 820.100(a)(1).
For example, a review of five CAPA records (b)(4) found all of the investigations were conducted at the complaint level and none of them included corrective actions.
b. Your firm failed to verify or validate corrective and preventive actions to ensure that such actions are effective and do not adversely affect the finished device, as required by 21 CFR 820.100(a)(4).
For example, your firm failed to verify or validate the effectiveness of its corrective and preventive actions for the following eight CAPAs that were reviewed during the inspection:(b)(4).
c. Failure to ensure that all activities and their results required by 21 CFR 820.100(a), are documented, as required by 21 CFR 820.100(b). For example:
- The CAPA Record Form (b)(4)], Handling of Corrective/Preventive Actions, contains sections for recording root cause determination, risk assessment, corrective/preventive action plans, CAPA follow up, CAPA verification, and CAPA closure; however, the CAPA record forms for at least five CAPAs ((b)(4)) were incomplete in that they contained sections that were either crossed through or left blank.
- CAPA (b)(4), relating to bioburden monitoring levels exceeding action limits, was closed as being effective on February 13, 2014; however, the training for corrective actions was not completed until March 18, 2014, more than one month later.
The adequacy of your firm’s responses, dated April 17, 2014, and July 10, 2014, to this item cannot be determined at this time because documentation of training on the revised procedures, and corrective actions, was not provided.
2. Your firm failed to establish and maintain procedures to adequately control environmental conditions, and to ensure that these activities are documented and reviewed, as required by 21 CFR 820.70(c).
For example, the bacterial action limits were exceeded for “(b)(4)”, and for “(b)(4)”; however, the corrective actions required by Section 126.96.36.199 of the Environmental Monitoring SOP (b)(4), Revision 0, June 5, 2013) were not conducted or documented.
Your firm’s responses, dated April 17, 2014, and July 10, 2014, are inadequate because this item was not addressed.
3. Your firm failed to ensure, where the results of a process cannot be fully verified by subsequent inspection and test, that the process shall be validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75(a).
For example, the original Test Protocol dated August 7, 2014, (b)(4) for increasing the tip bond strength of the NIRxcell Catheter, called for testing to be conducted in (b)(4). There was no documentation showing that a revised protocol was approved prior to the testing and there was no statistical rationale for (b)(4). The Test Report dated February 10, 2014, (b)(4) indicated the parameters of the test groups had been changed and (b)(4) had been added.
The adequacy of your firm’s responses dated April 17, 2014, and July 10, 2014, cannot be determined at this time. Although your firm updated its Process Validation SOP (b)(4) to include the requirement that each study be conducted according to an approved protocol, we have not received documentation of training on the revised procedure or a retrospective review of all process improvements, protocols, and reports for the last two years in order to verify that studies were documented properly and that protocol deviations were justified.
4. Your firm failed to establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50.
For example, Section 6.3.1 of the procedure for Audit of Suppliers (b)(4) requires the audit of Critical Type 1 suppliers within 12 months from the date of their approval as a Critical Type 1 supplier. There was no documentation to show that finished devices manufactured from raw materials provided by Critical Type 1 suppliers were successfully audited prior to commercial distribution of product.
The adequacy of your firm’s responses, dated April 17, 2014, and July 10, 2014, cannot be determined at this time because documentation of training on the revised procedures has not been received.
5. Your firm failed to establish and maintain procedures for acceptance of incoming product, and to document the acceptance or rejection, as required by 21 CFR 820.80(b). For example:
a. The incoming acceptance activities for three lots of sterilization pouches reviewed, as documented on Form (b)(4), Incoming Inspection of Sterilization Pouch, effective March 12, 2008, failed to document the equipment number used to conduct the seal peel test; and
b. Section 6.4.2. of your firm’s procedure for Statistical Techniques ((b)(4), effective May 2012) permits (b)(4) size if an inspection attribute is defined as characterization data and if an explanation is provided of the manufacturing conditions that warrant the (b)(4). The (b)(4)
The adequacy of your firm’s responses, dated April 17, 2014, and July 10, 2014, cannot be determined at this time because CAPA (b)(4) remains open; action items were expected to be completed May 1, 2014; however, , documentation for the reduced sample size was not provided.
Your firm’s response to this letter should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Inspection and Support Branch (FISB), White Oak Building 66, Rm 2609, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to the Unique Identification Number CMS #434410when replying. If you have any questions about the contents of this letter, please contact: Daniel G. Walter, Chief, Foreign Enforcement Devices Branch at (301) 796-5587 or FAX (301) 847-8139.
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
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