Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|10903 New Hampshire Avenue|
Silver Spring, MD 20993
September 16, 2013
VIA UNITED PARCEL SERVICE
Epflex Feinwerktechnik GmbH
Im Schwoellbogen 24
Dettingen An Der Erms
Dear Mr. Uihlein:
During an inspection of your firm located in Dettingen An Der Erms, Germany on June 10, 2013, through June 13, 2013, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures guidewire 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. We received a response from Jochen Kurz, dated June 28, 2013, 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 establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example:
A. The (b)(4) Class 8 cleanroom qualification failed on February 20, 2013, because the (b)(4). CAPA 029-13 was initiated on April 17, 2013, and the root cause was identified as the improper installation of (b)(4). Your firm retrospectively prepared an investigation document, dated June 12, 2013, that showed the investigation was conducted on March 2, 2013. Your firm initiated a corrective action to install (b)(4) with a longer stem to improve the (b)(4). The corrective action was completed on April 11, 2013. The verification of the corrective and preventive action (CAPA) was the requalification of the clean room on June 7, 2013.
The adequacy of your firm’s response cannot be determined at this time because corrective actions are in progress. Your firm initiated CAPA 08713 in response to the observation, created instructions describing actions to be taken in the event of cleanroom deviations, modified its CAPA procedure to include effectiveness testing, and trained employees on the new documents. Monitoring of the cleanroom (b)(4) integrity testing is ongoing. Please send us the results of your firm’s (b)(4) integrity testing.
B. Your firm did not analyze all sources of quality data to identify existing and potential causes of nonconforming product and other quality problems. Internal failures (production nonconformances), which were identified as a CAPA input, were not monitored or analyzed.
The adequacy of your firm’s response cannot be determined at this time because corrective actions are in progress. Your firm stated that it has done the following: initiated CAPA 08813 in response to the observation; revised the CAPA procedure to include internal failures as a CAPA input; revised forms for rework and special release to include a CAPA identification number; revised the Control and Process of Production procedure to require a CAPA if nonconformities are observed during in-process or final inspection; revised the Special Release procedure to require a CAPA for each special release; and trained your firm’s employees on the revised procedures.
Your firm is also establishing a system to monitor internal production failures to be implemented by December 31, 2014. Please send us documentation showing how your firm has verified the effectiveness of its internal production failure monitoring system
2. Failure to establish and maintain procedures to adequately control environmental conditions where these conditions could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(c). For example, after the Class 8 cleanroom failed requalification due to (b)(4) on February 20, 2013, production continued in the cleanroom until April 11, 2013, without your firm enacting additional environmental controls to ensure that bioburden did not reach unacceptable levels.
Your firm’s response to this observation appears to be adequate.
3. Failure to ensure, when 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 (b)(4) test method used to monitor the guidewire (b)(4) process has not been validated.
The adequacy of your firm’s response cannot be determined at this time because corrective actions are in progress. Your firm initiated CAPA 09213 in response to the observation. Your firm will validate the (b)(4) test method by December 31, 2013. Please send us your firm’s validation protocol, validation report, and data showing that its (b)(4) test method has been validated.
4. 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, nonconforming product is identified by a “(b)(4)” sheet that includes the (b)(4). The “(b)(4)” sheet is (b)(4) after the material disposition is decided.
The adequacy of your firm’s response cannot be determined at this time because corrective actions are in progress. Your firm initiated CAPA 09313 in response to this observation. The Control and Process of Production procedure, PB14, and Incoming Goods procedure, PB04, were modified to include each “(b)(4)” sheet with the production record instead of incoming goods records. Training documentation for both procedures was provided for affected personnel. Monitoring of the implementation of the changes is in process. Please provide us with documentation that your firm has verified that its CAPA was effective.
5. Failure to establish and maintain acceptance procedures to ensure that specified requirements for in-process product are met, as required by 21 CFR 820.80(c). For example, the (b)(4) process for Article number (b)(4) is verified by a (b)(4) test. The test is performed at the setup of the (b)(4) process and (b)(4) the process. The testing of Lot (b)(4) did not meet the testing requirement for the (b)(4) on (b)(4) of the tests performed during the process. The procedure instructs that test failures be included in the production order. These tests were not included in the batch record. There is no assurance that materials made during this process met the in-process dimension requirement.
The adequacy of your firm’s response cannot be determined at this time because corrective actions are in progress. Your firm initiated CAPA 09113 in response to this observation. Your firm provided the test records showing the remainder of the lot met test requirements. Your firm has modified Instruction QAA00020, Measuring with (b)(4) to document the disposition of the parts last manufactured when an out of specification test occurs. Training was provided to employees in the (b)(4) department to print out and save each test report that is out of specification. A written rationale why the (b)(4) process cannot be validated was provided. Your firm is in the process of validating the (b)(4) test process and validation should be completed by December 31, 2013.
6. 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, Special Releases did not always justify the rationale for acceptance of the product or the component.
a. Special Release (b)(4) identified that the (b)(4) requirement of the guidewire was not met. The (b)(4) for the product is not to exceed (b)(4). The product was found to have an (b)(4) of (b)(4). There was no basis for the decision that the nonconformance did not affect product functionality.
b. Article number (b)(4) of the guidewire, which did not meet the acceptance criteria, was released under Special Release (b)(4). The rationale for the acceptance stated that there was no acceptance criteria identified on the drawing, so the (b)(4) should be applied. However, there was a (b)(4) specified on the drawing.
c. Not all finished device testing for “(b)(4)” of Lot (b)(4) (Article number (b)(4)) met the dimensional requirement. The batch was given a Special Release. The Special Release did not include a rationale for accepting this nonconformance.
The adequacy of your firm’s response cannot be determined at this time because corrective actions are in progress. Your firm initiated CAPA 08913 in response to the observation, revised its Special Release procedure to include a justification for the special release, and provided training to affected personnel. Your firm will perform a systemic corrective action by reviewing special releases for the last (b)(4) to determine if they comply with the revised procedure and open additional CAPAs if necessary.
7. Failure to review, evaluate, and investigate any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications, as required by 820.198(c). For example, complaint 38-12 describes a (b)(4). Your firm did not investigate this complaint. There was no attempt to obtain information on the (b)(4). Your firm received correspondence from the customer that it had received high quantities of damaged guidewire products and pictures were provided.
Your firm’s response to this observation appears to be adequate. Your firm initiated CAPA 08613 in response to this observation. Your firm reported that it did not receive any further information from the customer so an investigation could be initiated. Your firm modified its process instruction to obtain detailed information on the complaint, including whether a patient was affected by an Epflex product. Training records were also provided.
8. Failure to maintain device history records (DHRs) and failure to establish and maintain procedures to ensure that DHRs for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the Device Master Record (DMR) and the requirements of 21 CFR 820, as required by 21 CFR 820.184. For example, DHRs for Article (b)(4) did not include verification that (b)(4). Also, the DHRs do not always include representative product labeling. For example, DHRs for Lots (b)(4) and (b)(4) of Article number (b)(4) did not include documentation of product labels.
Your firm’s response to this observation appears to be adequate. Your firm initiated CAPAs 09013 and 09413 in response to this observation, revised procedures, and provided training to affected personnel.
9. Failure to establish and maintain a design history file (DHF) for each type of device, as required by 21 CFR 820.30(j). For example, Epflex has a premarket notification for a guidewire product that was preliminarily identified with 510(k) number K130854. Your firm does not have a DHF for the guidewire product.
The adequacy of your firm’s response cannot be determined at this time because corrective actions are in progress. Your firm initiated CAPA 09613 in response to this observation. Your firm stated that the guidewire products, which were the subject of 510(k) K130854, were developed prior to the company registering with the FDA. Your firm stated that a retrospective DHF would be created by December 31, 2013.
In addition, under section 510 of the Act,21 U.S.C. § 360, manufacturers of medical devices are required to annually register with the FDA. In September 2007, section 510 of the Act was amended by the Food and Drug Administration Amendments Act of 2007 (Pub. L. 110-85) to require domestic and foreign device establishments to submit their annual establishment registration and device listing information to FDA by electronic means [section 510(p) of the Act (21 U.S.C. § 360(p))] during the period beginning October 1st and ending December 31st of each year.
Our records indicate that your firm has not fulfilled annual registration and listing requirements for fiscal year 2013 because your firm’s guidewire devices have not been listed. Therefore these devices are misbranded within the meaning of section 502(o) of the Act, 21 U.S.C. § 352(0), in that the devices were manufactured, prepared, propagated, compounded, or processed in an establishment not duly registered under section 510 of the Act and were not included in a list required by section 510(j) of the Act, 21 U.S.C. § 360(j).
The 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 #409621 when replying. If you have any questions about the contents of this letter, please contact: LaShanda Long, Chief, General Surgery Devices Branch at (301) 796-5465or (301) 847-8137.
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