Inspections, Compliance, Enforcement, and Criminal Investigations
Arrow International, Inc. 03-Aug-05
Department of Health and Human Services
Public Health Service
August 3, 2005
RETURNED RECEIPT REQUESTED
Mr. Carl G. Anderson, Jr.
Chairman and Chief Executive Officer
Arrow International, Inc.
2400 Bernville Road
Reading, PA 19605
Dear Mr. Anderson:
During an inspection of your establishment located in San Antonio, Texas, on December 6 through 20, 20041 our investigators determined that your firm manufactures neonatal central catheters, umbilical vessel catheters, urinary drainage catheters, blood filters, and feeding tubes. These products are devices as defined by section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act). This letter addresses the violations of the Act and of FDA regulations that were noted at that inspection and the letters you have sent to FDA responding to the charges in the List of Inspectional Observations, Form FDA-483; which was issued at the close of the inspection.
The above-stated inspection revealed that your devices are adulterated and misbranded within the meaning of the Act. Your devices are adulterated within the meaning of Section 501(h) of the Act because the methods used in, or the facilities or controls used for the manufacturing, packing, storage, or installation are not in conformance with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) Regulation for medical devices, as specified in Title 21, Code of Federal Regulations (CFR), Part 820. Your devices are misbranded within the meaning of Section 502(t)(2) of the Act because your firm failed to submit reports of medical adverse events within the 30-day timeframe to FDA, as required by Section 5'19(a) of the Act and Title 21, Code of Federal Regulations (CFR), Part 803 .50. Your devices are also adulterated under Section 501(f)(1)(B) and misbranded under Section 502(o) of the Act because your firm failed to submit a 510(k) premarket notification for a change or modification in the device that could significantly affect the safety and effectiveness of the device, as required by Section 510(k) of the Act and Title 21, Code of Federal Regulations (CFR), Part 807.81.
Quality System Regulation
At the close of the inspection, your firm was issued a List of Inspectional Observations, Form FDA-483 (copy enclosed), which identified a number of significant QS Regulation violations including, but not limited to, the following:
1. Failure of the management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization, as required by 21 CFR 820.20 [FDA-483 Items 1 through 37]. For example, your firm's corporate management and local management failed to (a) conduct management reviews at defined intervals; (b) follow procedures for conducting quality audits; and (c) establish and maintain procedures for complaint handling, design controls, corrective and preventive actions, validating manufacturing processes, acceptance activities, environmental monitoring, purchasing controls, and document controls.
2. Failure to allocate necessary resources, including the assignment of trained personnel for management, performance of work, and assessment activities, as required by 21 CFR 820.20(b)(2) [FDA-483 Item 33(c)]. For example, the job position of quality manager was vacated in 8/04, and the job responsibilities associated with this job title have not been delegated to other employees.
3. Failure to establish and maintain procedures for receiving or reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a) [FDA- 83 Items 24 and 25]. For example:
a) 23 complaint records were not reviewed, evaluated, and the results of the evaluation are not documented, to determine whether an investigation is necessary. For example, Complaint #04D005 was not evaluated to determine if an investigation is necessary for the increase in the incidences of phlebitis in the leg for the period of December 2003 to April 2004 at a particular hospital; and
b) 10 complaints did not document an explanation of the reasons why these complaints are not reportable under the MDR regulation; and
c) 30 complaints were not processed in a uniform and timely manner, 2 complaints lacked the dates of receipt of the complaints, and 4 complaints did not have a complaint number to identify the documents associated with the complaints; and
4. Failure to establish and maintain procedures for the identification, documentation, validation or verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i) [FDA-483 Item 7]. For example, your firm increased the level of the barium sulfate in the medical grade tubing used to manufacture the Neo Picc 1.9 French Catheter without validating or verifying to determine the effects of this material change prior to the implementation.
5. Failure to establish and maintain procedures for validating the device design to ensure that the device conforms to user needs and intended uses and include design testing under actual or simulated user conditions, as required by 21 CFR 820.30(g) [FDA-483 Item 14]. For example, your firm's test protocol and results failed to explain or demonstrate:
a) how your use of the [redacted] French catheters simulates the neonate vein; and
b) how the increase of the radiopaque barium sulfate in the medical grade tubing used to manufacture the Neo Picc 1.9 French (Fr.) Catheter meets user needs and intended uses; and
c) how a testing period of [redacted] simulates the intended use of the Neo Picc 1.9 Fr. Catheter as a long-term catheter in the neonate vein. Your firm documented that the testing period of [redacted] was used to establish the catheter's flow rate and not the long-term use of the catheter; and
d) how the use of [redacted] fluid to the [redacted], Fr. catheter, which is used to simulate the neonate vein, simulates the actual use of the 1.9 Fr. catheter in a neonate vein.
6. Failure to establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30(a) [FDA-483 Items 7, 8, 9, 10, 11, and 12]. For example:
a) Your firm failed to update, complete, and approve the design development plan of the Neo Picc 1.9 Fr. catheters that describes or references the design development activities; and
b) Your firm failed to establish and maintain procedures to ensure that the design requirements relating to the above-referenced material change in the medical grade tubing of the Neo Picc 1.9 Fr. Catheter were met; and
c) Your firm's design procedures for design inputs for the Neo Picc 1.9 Fr. Catheter do not include a mechanism for addressing incomplete, ambiguous, or conflicting requirements; and
d) Your firm's design procedures for the Neo Picc 1.9 Fr. Catheter do not define the essential design outputs; and
e) Your firm's design history file does not include or reference the Phase IV design review minutes, detailed device design, and device drawings for the Neo Picc 1.9 Fr. Catheter.
7. Failure to adequately validate manufacturing processes with a high degree of assurance and approve them according to established procedures to ensure that product specifications can be consistently met, as required by 21 CFR 820.75(a) (FDA-483 Item 15). For example;
a) Your firm has not validated the molding process used in the manufacture of various sizes of the Umbilical Vessel Catheter, Urinary Drainage Catheter, Neo Picc Central Catheter, and Feeding Tubes. A review of the 33 device history records revealed numerous product non-conformances due to molding contamination or incomplete molding;and
b) Your firm has not validated the bonding [redacted] process used in the manufacture of various sizes of the Single Lumen Polyurethane Umbilical Catheter.
8. Failure to analyze processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, as required by 21 CFR 820.100(a)(1) [FDA-483 Items 19 and 20] . For example:
a) Your firm's corrective and preventive action procedures do not define which sources of quality data should be analyzed, or when the data should be analyzed; and
b) Your firm has not analyzed the data included in the nonconforming material reports (NCMR), inspection results (receiving, in-process, and finished product), quality audits, and returned product. For example, a review of 85 of the 87 device history records for the Neo Picc 1.9 French Kits with Break Away Needle Introducer and Introducer Sheath, and Neo Picc 1.9 French Silicone Catheters, and 5 device history records for the Dual Lumen Silicone Umbilical Vessel Catheters, Silicone Feeding Tubes, and Micron Blood Filters revealed production rejects or non-conformances that have not been analyzed.
9. Failure to implement and record changes in methods and procedures needed to correct and prevent identified quality problems, as required by 21 CFR 820.100(a)(5) [FDA-483 Item 21]. For example:
a) Deficiencies that are similar or in addition to deficiencies in management responsibility and management reviews that your firm previously identified, corrected, and verified were observed uncorrected at the time of our inspection; and
b) Your firm's corrective actions to address deficiencies in your firm's purchasing controls, lack of component specifications, and lack of supplier qualifications had not been fully implemented at the time of our inspection; and
c) The [redacted] bonding process has not been validated; and
d) Your firm's bioburden testing procedures, implementation dated 10/24/03, require that the acceptable bioburden level will be re-established [redacted] after the initial level is established. At the time of our inspection, your firm's initial product bioburden levels have not been established.
10. Failure to establish and maintain procedures to control product that does not conform to specified requirements and to address the identification, documentation, evaluation, segregation, and disposition of nonconforming product, as required by 21 CFR 820.90(a) [FDA-483 Items 22 and 23]. For example:
a) Between the dates of 9/24/03 and 12/6/04, your firm did not hold the [redacted] QARB (Quality Assurance Review Board) meetings, as required by your firm's procedures, to review the NCMR reports and make a decision concerning the disposition of the nonconforming products; and
b) Your firm has not reviewed the NCMR reports for the purpose of identifying trends of the non-conformances as required by your corrective action procedures; and
c) You did not document the disposition of non-conforming product identified in the 9 of the 54 NCMR reports, initiated between 1/5/04 and 12/8/04.
11. Failure to establish and maintain procedures for acceptance or rejection of incoming product, and to include documentation of the results of acceptance or rejection, as required by 21 CFR 820.80(b) [FDA-483 Items 28 and 30]. For example:
a) One of the eleven receiving inspection reports documented that the outer diameter of the Neo Picc catheters was accepted outside the approved specification range; and
b) Test records for job number 03298-C in laboratory notebook #03-002 are missing the test results for the length of the cut tubing for sample #17 through 32, the pass/fail results for the molding inspections for sample #32 through 50, and the results for the length of the trirnming/hubbing test for all 50 samples.
12. Failure to establish and maintain procedures for acceptance or rejection of finished device production runs, lots, or batches, and to ensure that finished devices are not released for distribution until all the activities in the device master record are completed and documented, as required by 21 CFR 820.80(d) and (e) [FDA-483 Items 27 and 29]. For example: (a) 21 of the 43 sterile load and pyrogen test records lacked signatures or forms required by your procedures; and (b) 14 of 79 device history records lacked required signatures, the-number of -units accepted, the pyrogen laboratory number; and the rejection summary.
13. Failure to establish and maintain procedures to ensure that device history records for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record, as required by 21 CFR 820.184 [FDA-483 Item 26]. For example, your firm's inspection procedures used in the inspection of the radiopaque tubin do not specify the methods for recording the inspection test results of the [redacted].
14. Failure to establish and maintain procedures to control a11 documents, as required by 21 CFR 820.40 [FDA-483 Items 31 and 32]. For example:
a) Your firm indicated that the CAPA records, initiated between 1/1/03 and 12/6/04, were missing and that your firm was unable to locate 12 records of engineering change order (ECO) at the time of our inspection; and
b) A number of the procedures relating to the sterilization process, validation of manufacturing process, process controls for sterilizer load, design control, device master record, and raw material specifications were not identified as obsolete documents; and
c) 83 of the 225 engineering change orders lacked the required records or information (e.g., description and impacts of changes, inventory disposition, review by responsible individuals, completion of the review checklist, current documents requiring a change, draft new documents incorporating a change, revision number and implementation date of the final documents).
15. Failure to establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, and to include evaluation of suppliers, contractors, and consultants, as required by 21 CFR 820.50 [FDA-483 Items 33 and 34]. For example:
a) Your firm failed to select the required number of suppliers for on-site audits as required by your audit procedures; and
b) No [redacted] QARB (Quality Assurance Review Board) meeting, as required by your procedures, was held in June, September, October, November, and December 2004, to evaluate your firm's suppliers quality performance and select the specific suppliers for audits; and
c) Some of your firm's suppliers were accepted on the basis of having their International Standard Organization (ISO) certifications without conducting further evaluation.
16. Failure to establish and maintain procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities, and to document employee training, as required by 21 CFR 820.25(b) [FDA-483 Items 16 and 17]. For example, your firm's training procedures do not identify specific training requirements for the following job descriptions: Quality inspector, assembler, molding operator, packager, material handling operator, facility maintenance, and purchasing personnel.
Medical Device Reporting Regulation
Additionally, the above-stated inspection revealed that your devices are misbranded under section 502(t)(2) of the Act, in that your firm failed or refused to furnish any material or information required by or under section 519 respecting the device and 21 CFR Part 803, Medical Device Reporting (MDR) regulation. Specifically, you failed to submit an MDR report to FDA after receiving information which reasonably suggested that one of your commercially distributed devices may have caused or contributed to a death. For example,
1. Failure to file a report of death, serious injury, or malfunction to FDA within 30 calendar days from becoming aware of a reportable event, as required by 21 CFR 803.50 [FDA-483 Item 3]. For example, as noted in the June 16, 2005 warning letter FDA sent to your firm, 3 medical adverse events were not submitted to FDA until 1O/27/04, 83 days late.
MDR 1649393-2004-00003 was 10 days late. Your firm's 3500A report does not match the information in the complaint file for MDR 1649393-2004-00003. Please explain this discrepancy.
2. Failure to establish and maintain MDR event files which contain or include all adverse event information in the possession of the reporting entity, including documentation of the deliberations and decision making process used to determine if an event was or was not reportable, as required by 21 CFR 803.18(b)(1) [FDA-483 Items 4 and-5]: For example,
a) 12 of the 30 complaints were assigned an MDR number but did not have an MDR event file;
b) 4 MDR event files do not contain or reference all medical adverse event information.
Premarket Notification and Product Recall
As noted in the warning letter FDA sent to your firm on June 16, 2005, your firm implemented a material change to the Neo Picc 1.9 Fr. Catheter (percutaneous inserted central venous catheter) by increasing the level of barium sulfate in order to optimize its radiopacity. We consider this a significant change that may affect the safety specifications of the device, and therefore, require a 510(k) submission for the material change. See 21 CFR 807.81(a)(3)(i).
As noted in the June 16, 2005 warning letter, because~you have not submitted a 510(k) for the material change, marketing your devices is in violation of the law. In legal terms, the product is adulterated under section 501(f)(1)(B) and misbranded under section 502(o) of the Act. Until you submit a section 510(k) premarket notification and, FDA reviews it and notifies you that- you may market your devices, your devices are adulterated under the Act because you do not have an approved premarket approval application that shows your devices are safe and effective. Your devices are also misbranded under the Act because you did not submit a section 510(k) premarket notification which shows that your devices are substantially equivalent to other devices that are legally marketed.
Arrow International's Response
We acknowledge receiving your firm's letters, dated January 24, 2005, February 14, 2005 and March 15, 2005 in response to the Form FDA-483 issued to your firm at the conclusion of our last inspection. Your firm's responses are inadequate in that your firm has not outlined the timeframes and specific corrective action steps which will correct and verify the underlying GMP system issues identified in the FDA-483 and this warning letter and implemented a corporate-wide corrective plan for all of your firm's facilities in the U.S. and Mexico.
We acknowledge receiving your June 22, 2005 letter to Mr. Michael Chappell, Director of the Dallas District Office regarding your second supplemental response to the form FDA 483 issued to Arrow International Inc., San Antonio, Texas, on December 20, 2004. We are evaluating your response and will inform you of our results at a later date.
We acknowledge receiving your Root Cause Analysis for the NeoPICC 1.9 Fr. Catheter dated July 20, 2005. We are evaluating your report and will inform you of our results at a later date.
Responding to This Letter
This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure adherence to each requirement of the Act and the regulations. The specific violations noted in this letter and in the Form FDA-483 may be symptomatic of other serious underlying problems in your firm's manufacturing and quality assurance systems. 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.
You should take prompt action to correct these violations. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil penalties.
Please notify this office in writing within 15 working days of receipt of this letter of the specific steps you have taken, or will take to identify and correct the noted violations, including (1) the timeframes within which the corrections will be completed, (2) any documentation indicating the corrections have been achieved, and (3) an explanation of each step being taken to identify and make corrections to any underlying systems problems necessary to ensure that similar violations will not recur.
Your response should be sent to Thao Ta, Compliance Officer, DAL-DO, Food and Drug Administration, HFR-SW140, 4040 N Central, Dallas, TX. 75240.
If you have any questions about the contents of this letter please contact Thao Ta, at 214-253-5217 and FAX # 214-253-5314.
Michael A. Cha
Dallas District Director