Arrow = International, Inc., Warning Letter

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Department of Health and Human Services

Public Health Service
Food and Drug = Administration

PHILADELPHIA DISTRICT
900 U.S. Customhouse
2nd end = Chestnut=20 Streets
Philadelphia, PA 19106

Telephone: 215-597-4390

CORPORATE WARNING LETTER
08-PM-01 =

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

October 10, 2007

Philip B. Fleck, Interim President and Chief Executive Officer =
Arrow=20 International, Inc.
2400 Bernville Road
Reading, Pennsylvania = 19605

Dear Mr. Fleck:

During inspections of your facilities located in Everett, MA, on = January 17=20 through February 13, 2007, and Asheboro, NC, on January 8 through = February 13,=20 2007, investigators from the United States Food and Drug Administration = (FDA)=20 determined that your firm manufactures various devices, including = Intra-Aortic=20 Balloon (IAB) catheters, catheters intended for hemodialysis, central = venous,=20 cardiovascular, percutaneous, and epidural uses, and other devices. = Under=20 section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act, 21 = U.S.C.=20 321(h), these products are devices because they are intended for use in = the=20 diagnosis of disease or other conditions, or in the cure, mitigation, = treatment,=20 or prevention of disease, or are intended to affect the structure or any = function of the body.

These FDA inspections revealed significant regulatory problems = involving the=20 devices manufactured by your firm. It is imperative that you understand = the=20 serious nature of the deficiencies and the urgent need to promptly = implement=20 corrective actions that will effectively remedy the problems found. As = you are=20 aware, FDA issued to your corporation three (3) Warning Letters in 2005 = relating=20 to deficiencies we identified during inspections at three (3) separate = Arrow=20 International facilities. The first Warning Letter was issued on June 3, = 2005,=20 to your Mount Holly, NJ, facility. The second Warning Letter was issued = on June=20 16, 2005, to your Reading, PA, facility. The third Warning Letter was = issued on=20 August 3, 2005, to your San Antonio, TX, facility, which we now = understand is no=20 longer in operation. The Warning Letters identified systemic deviations = from the=20 Current Good Manufacturing Practice (CGMP) requirements set forth in = FDA's=20 Quality System (QS) regulation found at Title 21, Code of Federal = Regulations=20 (21 CFR), part 820.

Carl Anderson, past Chief Executive Officer for Arrow International, = Inc.=20 participated in a regulatory meeting with FDA's New Jersey District = Office on=20 November 29, 2006, to discuss continuing violations documented during = FDA's=20 inspection of your Mount Holly, NJ, facility in September 2006.

The purpose of this letter is to make sure you are aware of the = serious=20 nature of the problems we found during the facility inspections and to = remind=20 you of your responsibility to assure that all of your facilities = establish and=20 maintain a quality system that complies with the Act and all pertinent=20 regulations. Although your corporation has made some attempts to correct = the=20 identified deficiencies, these efforts to date have been inadequate as = evidenced=20 by the continuing violations at your facilities. If we continue to = observe=20 similar problems at the same or other Arrow International facilities, = you will=20 not receive any further warnings from our office prior to us taking = regulatory=20 action against your firm.

The above-referenced inspections revealed that your firm's devices = are=20 adulterated within the meaning of section 501(h) of the Act [21 U.S.C. = =A7351(h)],=20 in that the methods used in, or the facilities or controls used for, = their=20 manufacture, packing, storage, or installation are not in conformity = with the=20 CGMP requirements of the QS regulation at 21 CFR part 820. = Specifically,the=20 deficiencies found include the following, among others:

1. Failure to establish and maintain procedures for investigating = the cause=20 of nonconformities relating to product, processes, and the quality = system, as=20 required by 21 CFR 820.100(d)(2). For example, the Asheboro, NC, = facility did=20 not review the corrective action taken in response to reported = sterilizer=20 cycle deficiencies to ensure that appropriate action was taken. = Unscheduled=20 sterilizer maintenance was not evaluated to ensure repairs were timely = and=20 correct. Non-conformance [redacted] was written in = response=20 to a temperature over exposure of 48.1 degrees Celsius for 10 minutes = on=20 August 14, 2006 in cycle [redacted] in Sterilizer=20 [redacted]. The relay switch that controlled the = steam valve=20 on the sterilizer was replaced. No test runs were performed. = Subsequently,=20 cycle [redacted] was aborted due to high temperature = during=20 the exposure phase of [redacted] degrees Celsius. The = main=20 stem valve was found defective and replaced. Your Asheboro, NC, = facility=20 failed to ensure the initial action taken corrected the problem.

2. Failure to establish and maintain procedures for identifying all = of the=20 actions needed to correct and prevent the recurrence of nonconforming = product=20 and other quality problems,as required by 21 CFR 820.100(a)(3). For = example,=20 the Asheboro, NC, facility did not implement corrective and preventive = actions=20 for the following:

a. Management did not implement corrective action for=20 previously-identified deficiencies between the = [redacted]=20 and [redacted] computer systems. Specifications and = part=20 numbers were incorrectly transferred when the facility went from the = [redacted] computer system to the=20 [redacted] computer system. Your Asheboro, NC, = facility had=20 604 non-conformances relating to graphic, specifications, and = inspection=20 criteria which more issued between May 1, 2006 and December 29, = 2006. This=20 facility submitted a CAPA Project Request for action to the Arrow = corporate=20 CAPA board in October 2006. However, the project request was denied = in=20 December 2006 and sent back to the Asheboro, NC, facility without = any=20 corrective action being taken at the corporate level.

b. The Asheboro, NC, facility initiated CAPA = [redacted]=20 for loose Y-connectors coming off the trays before or during the = packaging=20 processes. The corrective action was referred to Arrow corporate for = follow-up; however, no preventive/corrective action was implemented. = Additionally, the bioburden program was not updated to include the = Central=20 Venous Catheters (CVC)/Dialysis Large Bore Kits as a product family = as per=20 corporate memo addressed to [redacted] from=20 [redacted] dated July 11, 2006.

c. The Asheboro, NC, facility did not perform corrective actions = after=20 confirming complaint [redacted] dated June 4, 2006, = and MDR=20 [redacted] in which the user reported both ports of = a=20 Cannon hemodialysis catheter fragmented and migrated into a = patient's=20 pulmonary artery. The investigation by Arrow corporate concluded = that a=20 manufacturing error occurred during plastic welding of the distal = legs to=20 the main catheter body. The weld failed and caused serious injury to = the=20 patient. The corrective action indicated that the Asheboro, NC, = facility was=20 to assess corrective actions. The February 2007 FDA inspection = revealed that=20 your Asheboro, NC, facility was not aware of this complaint and that = corrective action was needed. As a result, there were no = improvements or=20 changes made to the welding process.

d. Your Asheboro, NC, facility received at least four (4) = complaints=20 [redacted] and [redacted] in 2006 = which=20 indicated that customers received hemodialysis catheters that were = blocked.=20 A manufacturing defect was confirmed in several returned samples. = The=20 complaints indicated that corrective action would include a 100% = check for=20 tip blockage with a gauging wire. There were no instructions or=20 documentation included in the firm's assembly procedure=20 [redacted] indicating that these corrective actions = have=20 been implemented: The current procedure, which was released in = October 2005,=20 did not include any updates or revisions to account for the 100% = inspection=20 of the catheter tips to check for excessive glue.

3. Failure to establish and maintain procedures for analyzing = processes,=20 work operations, concessions, quality audit reports, quality records, = service=20 records, complaints, returned product, and other sources of quality = data to=20 identify existing and potential causes of nonconforming product, or = other=20 quality problems, as required by 21 CFR 820.100(a)(1). For example: =

a. At your Asheboro, NC, facility, complaint = [redacted]=20 indicated that a Device History Record (DHR) review was performed in = response to a customer complaint of a blocked hemodialysis catheter. = The=20 complaint report indicates that your firm's review of the DHR did = not reveal=20 any abnormalities; however, during the February 2007 FDA inspection, = no=20 device history records were available for the lot at issue in this = complaint=20 (Lot # [redacted]) and the FDA Investigator noted = that the=20 subject lot number was not a valid number: There were numerous cases = of=20 incorrect information in the complaint handling system.

b. The analysis of complaints at your Everett, MA, facility did = not=20 include an analysis by the IAB catheter lot number to determine = problems=20 with a particular lot. The printouts from the corporate Complaint = Management=20 System (CMS) included a field for lot number; however, the lot = number was=20 often recorded as either unknown or was listed as the sterilization = load=20 number which can include multiple lots of product. The spreadsheet = used=20 in-house for data analysis of complaints did not include a field for = lot=20 number. At least eight (8) of 24 complaints reviewed listed the=20 sterilization load number in the lot number field although the = catheter lot=20 number was determined. At least nine (9) of 24 complaints reviewed = listed=20 "Unknown" in the lot number field although the catheter lot number = was=20 determined.

4. Failure to establish and maintain procedures for submitting = relevant=20 information on identified quality problems, as well as corrective and=20 preventive actions, for management review, as required by 21 CFR=20 820.100(a)(7). For example, the management reviews at your Asheboro, = NC,=20 facility did not include non- conformances and quality data analysis = from all=20 sources, in that re-works, re-sterilizations, preventive maintenance=20 corrective actions and returned goods (sources of quality problems) = were not=20 addressed in management reviews.

5. Failure to establish and maintain acceptance procedures, where=20 appropriate, to ensure that specified requirements for in-process = product are=20 met, as required by 21 CFR 820.80(c). For example:

a. There was no required review of each lot of balloons by the = Quality=20 Assurance department prior to using the balloons in IA8 catheter=20 manufacturing at your Everett, MA, facility. The balloons are = critical=20 components of the catheters according to your Associate Quality=20 Assurance/Regulatory Affairs (QA/RA) Manager.

b. The DHR for catheter lot [redacted] showed 98 = balloons were wrapped on October 12, 2006, and that subsequently 99 = balloons=20 were heat treated (furl baked) on October 13, 2006. The quality = review of=20 the DHR was on October 13, 2006. There was no evidence that the = discrepancy=20 in the listed quantities was noted at your Everett, MA, facility.=20

6. Failure of the management representative to ensure quality = system=20 requirements are effectively established and effectively maintained = within the=20 organization, as required by 21 CFR 820.20(b)(3)(i). For example, = problems=20 were noted with quality assurance, documentation, process controls, = complaint=20 handling, data analysis, employee training, and equipment maintenance = at your=20 Everett, MA, facility that resulted in the development of the Process=20 Validation Remediation Project Summary (Summary). This Summary = described Arrow=20 International's reengineered Quality System which was implemented in = August=20 2006, and applies to all Arrow International manufacturing facilities. = On=20 February 8, 2007, the Management Representative stated that he had not = seen=20 the Summary prior to February 7, 2007. This Summary was sent to the = FDA with a=20 December 18, 2006, cover letter January 10, 2007, the Summary was sent = to two=20 employees who reported to the Management Representative at the = Everett, MA,=20 facility (the Plant Manager and the Quality Manager of = Instrumentation), but=20 apparently had not been provided to the Management Representative = himself.=20

7. Failure to establish and maintain procedures to ensure that all=20 purchased or otherwise received product and services conform to = specified=20 requirements, as required by 21 CFR 820.50. For example, your = Asheboro, NC,=20 facility receives many components, finished devices, and kits for = further=20 packaging and ethylene oxide (EO) sterilization from other Arrow = facilities.=20 There was no indication that the Asheboro, NC, facility has procedures = to=20 ensure that all materials received from your other facilities (Mt = Holly, NJ;=20 Reading, PA, Czech Republic; and Mexico) conform to specified = requirements.=20

8. Failure to develop, conduct, control, and monitor production = processes=20 to ensure that a device conforms to its specifications and failure to=20 establish and maintain process control procedures that describe any = process=20 controls necessary to ensure conformance to specifications, as = required by 21=20 CFR 820.70(a). For example:

a. For your Asheboro, NC, facility, their established procedure,=20 Operational Procedure for Product Sterilization, indicated that = Arrow=20 products can be re-sterilized up to two (2) times with minimal = limitations=20 and exceptions. Your firm does not have data and has not conducted = testing,=20 especially functionality testing, that shows the components in Arrow = kits=20 can be re-sterilized.

i. Your firm re-sterilized a lot of epidural catheterization = kits that=20 contain syringes (Lot [redacted] Two (2) = complaints were=20 received from the field for condensation in the syringe=20 [redacted] and a leaking syringe=20 [redacted]. Your Asheboro, NC, facility did not = perform=20 functional testing on the re-sterilized kits.

ii. Lot [redacted] was re-sterilized. No = functional=20 testing was done post-sterilization.

iii. Lot [redacted] was re-sterilized. No = functional=20 testing was performed post-sterilization.

b. The viscosity measurement was not compared to the Dipping=20 Configuration Matrix for the balloon type, as required by procedure=20 #[redacted] "Texin Bladder Dipping Procedure" for = your=20 Everett, MA, facility. The matrix was left out of Revision 6 of the = updated=20 procedure in December 2006. There was no Dipping Configuration = Matrix within=20 the dipping room on January 19, 2007, during the 2007 FDA = inspection.=20

9. Failure to review, evaluate and investigate a complaint = involving the=20 possible failure of a device, labeling, or packaging to meet any of = its=20 specifications, as required by 21 CFR 820.198(c). For example:

a. The complaint investigations were not carried out to the = degree=20 necessary to draw conclusions as to the validity and cause of = complaints at=20 your Asheboro, NC, facility. For example,

i. A failure investigation and follow-up have not been = initiated in=20 response to a report that a catheter ([redacted])=20 migrated from the femoral vein into a patient's pulmonary = artery=20 after the catheter body detached at the hub = [redacted]=20 dated October 10, 2006; [redacted] The patient = expired as=20 a result of blood pressure and other issues. Complaint records = indicated=20 that a comprehensive investigation could not be completed since = the sample=20 was not available for review. The hospital system pulled all of = the=20 subject lot from ten (10) hospitals and your Asheboro, NC, = facility=20 replaced the customer's product at no charge. At the time of = inspection,=20 one hundred and twelve (112) unopened kits were in quarantine in = the=20 re-packaging area of the firm and could have been used for = purposes of=20 evaluating the subject lot.

ii. At least six (6) complaint incidents indicating "patient = vessel=20 perforation" with multi lumen Percutaneous Sheath Introducer kits = were=20 documented on August 26, 2005 for one (1) hospital. Each of the = six (6)=20 scenarios were different; however, there was no documented = investigation=20 into these incidents or documentation of any follow-up with the=20 hospital.

b. At your Everett, MA, facility at least eight (8) complaint=20 investigation records [redacted] showed no review = by either=20 Engineering or Research & Development (R&D) although the = root causes=20 of the complaints were reported as either unconfirmed or = undetermined. In=20 many cases the products at issue in the complaints were returned for = evaluation. The initial evaluation, including the decision to have=20 Engineering or R&D review the complaint, in each case was made = by the QA=20 Technical Support Specialist.

10. Failure to promptly review, evaluate, and investigate a = complaint that=20 represents an event which must be reported to FDA under part 803 and=20 maintained in a separate portion of the complaint files or otherwise = clearly=20 identified, as required by 21 CFR 820.198(d). For example, the MDR=20 determinations and complaint evaluations were not promptly reviewed or = evaluated for several complaints at your Asheboro, NC, facility, = including:=20 (1) [redacted], Spring Wire Guide Deformed, Reported: = February 20, 2006, MDR Evaluation: January 9, 2007, Status: Closed = June 20,=20 2006, and (2) [redacted] Blocked Catheter, Reported: = March=20 17, 2006, MDR Evaluation: January 9, 2007, Status: Open.

11. Failure to perform design validation under defined operating = conditions=20 on initial production units, lots, or batches, or their equivalents = and to=20 ensure that devices conform to defined user needs and intended uses = and=20 include testing of production units under actual or simulated use = conditions,=20 as required by 21 CFR 820.30(g). For example:

a. Validation was not conducted prior to implementing Engineering = Change=20 Order (ECO) [redacted] in August 2003 at your = Everett, MA,=20 facility. [redacted] added the = [redacted]=20 Procedure to the LWS (Light Wave Sensor) or Fiber Optic Sensor = catheters.=20 Performance testing was conducted on only three (3) catheters and = five (5)=20 sensors. As a result of higher yield losses (due to low pressure = readings=20 found during manufacturing after the [redacted]. = Process=20 was removed from the manufacturing process for LWS catheters in = October=20 2004.

b. There were no manufacturing design validation records for the = balloons=20 or catheters used to verify the new 35cc balloon size introduced in = 2004 at=20 your Everett, MA, facility. The Product Design Verification Report,=20 [redacted], was approved in August 2004. =

12. Failure to establish procedures for identifying training needs, = ensure=20 that all personnel are trained to adequately perform their assigned=20 responsibilities, and document training, as required by 21 CFR = 820.25(b). For=20 example:

a. Training records for a sterilizer operator and packager were = requested=20 at your Asheboro, NC, facility during the 2007 FDA inspection. Out = of five=20 (5) training records requested for the sterilizer operator, only two = (2)=20 were available. Two (2) training records were requested for the = packager and=20 only one (1) record was available.

b. A number of documents were collected demonstrating that = employees were=20 not adequately trained, at your Everett, MA, facility:

i. The IAB Manufacturing Technician who prepared dipping = solutions for=20 balloons and cleans the mixing tanks, said there was no procedure = for=20 cleaning the mixing tanks for the dipping solution. Process = Specification=20 [redacted] "Urethane Solution-Mixing" did in fact = include=20 instructions for cleaning the dip circuit between polyurethane = mixes.

ii. An IAB Manufacturing Technician who was hired in April of = 2001 did=20 not receive GMP training until 2006.

iii. Affected = employees were=20 not trained on Procedure [redacted] = "Environmental"=20 Monitoring Viable Counts Revision 8, which was effective from = February=20 2003 until July 2003.

iv. All seven (7) employee training records reviewed had = incomplete=20 training requirements. According to procedure #CHR-001. "Training=20 Administration, Documentation, and Recordkeeping Procedure," your = firm has=20 30 days to complete the training. One training requirement was = over six=20 (6) months late.

13. Failure to establish, procedures for and conduct quality audits = to=20 assure that the quality system is in compliance with the established = quality=20 system requirements and to determine the effectiveness of the quality = system,=20 including reaudits of deficient matters, as required by 21 CFR 820.22. = For=20 example:

a. Your Asheboro, NC, facility did not perform quality audits = with=20 sufficient frequency to identify and correct deficiencies within the = quality=20 system as evidenced by the multiple observations noted during the = February=20 2007 FDA inspection.

b. Your Asheboro, NC, facility did not re-audit deficient areas=20 identified during quality audits and did not monitor corrective = action for=20 effectiveness. The established procedure, Internal Audit System, = indicated=20 non-conformances were entered into the non-conformance system and = then, the=20 audit was closed. There was no verification of corrective action, = preventive=20 measures, or of a re-audit of the deficient areas.

14. Failure to validate computer software for its intended use = according to=20 an established protocol when computers or automated data processing = systems=20 are used as part of production or the quality system; as required by = 21 CFR=20 820.70(i). For example:

a. Your Everett, MA, facility had a validation deficiency that = was=20 identified during the February 2007 FDA inspection. The Post = Sterilization=20 Functional Release Testing [redacted] software=20 [redacted] was not validated which has been in use = since=20 October 2002. The [redacted] Testing software is = used to=20 conduct post-sterilization functional testing of the IAB catheters. =

b. For yours, Asheboro, NC, facility, the [redacted]=20 Training Database software validation used to document = employee=20 training was deficient in that the test scripts were not available = to show=20 the execution of the software validation protocol. It appears that = at least=20 five (5) tests specified in the. approved protocol were not = performed.=20

15. Failure to establish and maintain procedures to ensure that = sampling=20 methods are adequate for their intended use, to ensure,that when = changes occur=20 the sampling plans are reviewed, and that sampling plans are written = based on=20 a valid statistical rationale, as required by 21 CFR 820.250(b): For = example:=20

a. Your Asheboro, NC, facility did not have a robust endotoxin = testing=20 program for Central Venous Catheters (CVC) kits; CVC/Dialysis = Large-bore=20 ChlorPrep Drape Chlorhexidine (CDC) kits, epidural kits, and = Percutaneous=20 Sheath Introducer kits which are all labeled "non-pyrogenic." Of=20 approximately 30 sterilizer loads per week, only three (3) 10 tests = were=20 performed on a weekly basis. Statistical techniques were not used = for=20 control purposes where statistical techniques were applicable.

b. For your Everett, MA, facility, post-sterilization functional = testing=20 after the rework of catheter [redacted] was not = conducted=20 on a sample from the same lot, but rather on a sample from a = different=20 catheter lot in the same sterilization load. That test resulted in = the=20 functional release of product from lot [redacted] = which was=20 subsequently shipped to customers. Lot [redacted] = had been=20 reworked due to a previous failed post-sterilization functional = check that=20 identified a hole in the catheter.

16. Failure to establish and maintain procedures to control all = documents,=20 as required by 21 CFR 820.40. For example, the following deficiencies = were=20 identified for your Everett, MA, facility.

a. The released updated revision #2 of procedure=20 [redacted] "Drying Procedure for=20 [redacted] Pellets" actually contained a different=20 procedure (Urethane Mixing Solution, SOP = [redacted]. This=20 was not noted by any of the six (6) approving officials on December = 19-20,=20 2006, or during employee training on the updated procedure on = January 9,=20 2007.

b. The released updated revision #6 of procedure=20 [redacted] Texin Bladder Dipping Procedure" was = missing the=20 Dipping Configuration Matrix which was included in the red-lined = version in=20 the Engineering Change Order. This was not noted by any of the six = (6)=20 approving officials on December 19-20, 2006, or during the employee = training=20 on the updated procedure on January 5 and 9, 2007.=20

You should take prompt action to correct the violations addressed in = this=20 letter. Failure to promptly correct these violations may result in = regulatory=20 action being initiated by the Food and Drug Administration without = further=20 notice. These actions include, but are not limited to, seizure, = injunction,=20 and/or civil money penalties. Also, federal agencies are advised of the = issuance=20 of all Warning Letters about devices so that they may take this = information into=20 account when considering the award of contracts. Additionally, premarket = approval applications for Class III devices to which the Quality System=20 regulation deviations are reasonably related will not be approved until = the=20 violations have been corrected. Requests for Certificates to Foreign = Governments=20 will not be granted until the violations related to the subject devices = have=20 been corrected.

Please notify this office in writing within fifteen (15) working days = from=20 the date you receive this letter of the specific steps you have taken to = correct=20 the noted violations, including an explanation of how you plan to = prevent these=20 violations, or similar violations, from occurring again. Include = documentation=20 of the corrective action you have taken. If your planned corrections = will occur=20 over time, please include a timetable for implementation of those = corrections.=20 If corrective action cannot be completed within 15 working days, state = the=20 reason for the delay and the time within which the corrections will be=20 completed.

This letter is not intended to be an all-inclusive list of the = violations at=20 your facility. It is your responsibility to ensure compliance with = applicable=20 laws and regulations administered by FDA. The specific violations noted = in this=20 letter and in the Inspectional Observations, Form FDA 483s, issued at = the=20 closeout of the referenced inspections may be symptomatic of serious = problems in=20 your firm's manufacturing and quality assurance systems. You should = investigate=20 and determine the causes of the violations, and take prompt actions to = correct=20 the violations and to bring your products into compliance.

Response to FDA 483 Observations

We acknowledge the receipt of the responses from Arrow International, = Inc.,=20 Reading, PA, which address the two Form FDA 483s that were issued to = management=20 at the Everett, MA and Asheboro, NC facilities on February 13, 2007. = Your firm's=20 first response, dated March 7, 2007, was signed by Carl G. Anderson, = Jr., former=20 Chairman and CEO. The second response, dated June 27, 2007, was signed = by you.=20 We have reviewed these responses and the commitment to take corrective = action=20 that was made by Your firm during the November 2006 regulatory meeting. = However,=20 your firm's efforts to date have failed to achieve the necessary = systemic=20 approach to comprehensively address the noted violations. In your = corporate=20 responses dated, March 7 and June 27, 2007, your firm describes your = corporate=20 wide "Project Operational Excellence" program, initiated at Arrow = International=20 in January 2005, in which your firm created a new Quality Management = System for=20 all of your manufacturing facilities, including the Everett, MA, and = Asheboro,=20 NC, facilities. The responses also indicated that the "...implementation = of the=20 new Quality Management System is complete and has been operating since = September=20 2006." However; during the inspections at your Everett, MA, and = Asheboro, NC,=20 facilities we observed significant violations from the Quality System=20 regulation, as described above.

Complaint Handling

We understand from your responses that you will be modifying the = complaint=20 handling SOP and providing updates to the handling and investigation of=20 complaint reports. You stated that an improved complaint database called = [redacted] is on schedule for implementation on October = 27,=20 2007. In your Everett, MA, June 27, 2007, response you stated that your = review=20 of the April and May 2007 complaints identified a 50% failure rate based = mostly=20 on clerical errors. This significant failure rate occurred even after = you=20 revised the SOP and retrained the personnel. Your corrective actions to = date=20 appear ineffective in addressing the complaint handling issues and will = require=20 immediate action.

Training

Your corporate response indicates that training databases are being = improved,=20 a project team is being formed, and a "project plan is being developed = to=20 continually improve the corporate training system." In most of your = responses,=20 you either created procedures or revised existing procedures to include = training=20 with deadline dates. We would like immediate assurance that your = personnel are=20 trained and competent to perform their duties. As such, you need to = address your=20 training issues immediately. Your response should include a description = of the=20 steps you are taking, corporate-wide, to address these serious training=20 violations.

Sterilization

Your Asheboro, NC facility = referenced=20 compliance standard ISO [redacted] for sterilization = operations=20 in the June 27, 2007 response. This standard indicates the minimum = parameters=20 that should be monitored and the list includes, "Time, temperature, and = pressure=20 changes in the chamber and evidence that the gaseous sterilant has been = added to=20 the chamber." This is something that is ordinarily established during=20 validation, which was not completed for your Asheboro, NC facility.=20 Additionally, it was unclear in your response if endotoxin testing would = be=20 performed on each lot of product for each sterilization load. The USP = requires=20 endotoxin testing on each sterilizer load if you are claiming the = products are=20 non-pyrogenic. In the corporate June 27, 2007, response to validating = the=20 [redacted] software, you indicated the=20 [redacted] software was tested and updated but did not = indicate=20 that the system was validated.

Quality management problems, corrective action and preventive action, = complaint handling, and training issues were previously brought to your = firm's=20 attention in two (2) Warning Letters that were issued on June 16, 2005, = and=20 August 3, 2005. Additionally, your corporate-wide "Project Operational=20 Excellence" program has had more than two (2) years to implement an = effective=20 CAPA program that would review, evaluate, correct, and prevent this type = of=20 problem from recurring. These recurring, serious deficiencies with your=20 corporate quality management operations are significant. Changes made to = your=20 corporate quality system as detailed in your recent responses to these = FDA 483s=20 have failed to adequately correct these systemic quality problems, and = assure=20 that an effective quality system is currently in place. As such, we will = need to=20 verify implementation of your promised corrections, proposed plans, and=20 revised/new procedures through reinspections. We are aware that your = proposed=20 plans arid revised/new procedures covered many areas of the Quality = System,=20 including document controls, management, DHRs, audits, = production/process=20 controls, and validation. The violations included in this Warning Letter = and=20 discussed above are significant deficiencies that warrant your immediate = attention to assure an effective quality system.

Your response to this letter and any questions you may have should be = sent to=20 William J. Forman, Compliance Officer, Food and Drug Administration, 2nd = &=20 Chestnut Streets, Room 900, Philadelphia, Pennsylvania 19106.

Sincerely yours,

/S/

Thomas D. Gardine
District Director Director. =
Philadelphia=20 District Office

/S/

Timothy A. Ulatowski
Director
Office of Compliance
Center = for=20 Devices and
Radiological Health

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FDA/Freedom=20 of Information

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