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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Enforcement Actions

Abbott Laboratories, Inc. 30-Jan-02

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration

Denver District Office

Building 20 - Denver Federal Center

P.O. Box 25087

Denver, Colorado 802250087

TELEPHONE: 303-236-3000

January 30, 2002

WARNING LETTER

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

Ref. # - DEN-02-10

Mr. Miles White

Chairman and Chief Executive Officer

Abbott Laboratories, Inc.

100 Abbott Park Road

Abbott Park, Illinois 60064-3500

Dear Mr. White:

An inspection of your firm located at 4455 Atherton Drive, Salt Lake City, Utah was conducted between November 5 - 20, 2001, by Investigators Nicholas R. Nance and Ricki A. Chase-Off. This inspection determined that your firm manufactures sterile and non-sterile critical-care catheters, monitoring systems, auto-transfusion and infusion accessories, and custom surgical kits. These catheters, monitoring systems, and accessories are devices as defined by Section 201(h) of the Federal Food, Drug and Cosmetic Act (the Act).

The inspection revealed that these devices are adulterated within the meaning of Section 501(h) of the Act, in that the methods used in, or the facilities or controls used for manufacturing, packing, storage, or installation are not in conformance with the Quality System/Good Manufacturing Practice (QS/GMP) for Medical Devices Regulation, as specified in Title 21, Code of Federal Regulations (21 CFR), Part 820. The deviations are as follows:

Failure to establish CAPA procedures that assure all relevant information on identified quality problems, as well as corrective and preventive actions, are submitted for management review, as required by 21 CFR 820.100(a)(7). F or example, procedures do not assure that all sources of quality data are identified, reviewed, tracked or trended. Such sources of product non-conformance/quality data include production travelers, Device History Records (DHR), and Quality Tracking Reports.

Failure to establish and maintain procedures for corrective and preventive actions (CAPA) to include requirements to assure corrective actions are implemented and changes in methods and procedures to correct and prevent identified quality problems are recorded, as required by 21 CFR 820.100(a)(5). F or example, your CAPA procedure does not provide specific guidelines/timeframes in which corrective action reports (CAPARs) are to be closed. Several CAPARs were found to be open over a year after they had been initiated. Also, although your firm instituted corrective actions in May 2000 to eliminate/minimize catheter balloon failures, our inspection found that this change was not implemented in all catheters approved under this design control project manufactured since that time. There was no justification as to why this change was not incorporated in all devices.

Failure to establish adequate CAPA procedures in that your procedures lack verification or validation to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). F or example, there is no evidence that CAPAR #[redacted], initiated to correct catheter balloon bursts and tears, was evaluated for efficacy. Complaints of balloon failures continue to be received.

Failure to establish and conduct adequate 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. Your firm manufactured and distributed Thennodilution (TD) catheters with new design changes even though all aspects of design controls had not been approved and finalized. For example, lot #[redacted] was the first-lot-to-stock to be manufactured incorporating new design changes. Production of this lot began on February 10, 2000, and was released for distribution on April 27, 2000. The design transfer was partially signed and approved May 4, 2000, after release of this lot. The design inputs and design validation were not finalized until April 25, 2000, and the design history file was not signed and approved until November 20, 200l.

Failure to control nonconforming product to assure that it is identified, evaluated, segregated and disposed of according to procedures, as required by 21 CFR 820.90(a), and failure to establish and maintain adequate written procedures for rework, to include re-testing and re-evaluation of the nonconforming product after rework, to ensure that the product meets its current approved specifications, as required by 21 CFR 820.90(b). F or example, the disposition of in-process scrap or rejected material noted on Restrictions and DHRs is not always noted. Complaints alleging heparin occlusion occurred in several lots of catheters that had been previously re-worked for occlusions and subsequently distributed.

Failure to establish and maintain written procedures for changes to a specification, method, process, or procedure and to verify or validate that change before implementation, as required by 21 CFR 820.70(b). For example, there is no evidence that the rework procedure for TD catheters involving the balloon removal and reapplication, de-heparinization and re-heparinization, has been validated. Records documenting the " [redacted] procedure show inconsistencies from the protocol.

The protocol stated that the validation lot was to be lot # [redacted]. However, the validation summary page indicates that lot # [redacted] was used to complete the testing. Records from the DHR for lot #[redacted] indicate that it was scrapped in total due to extrusion problems. Records for lot [redacted] show that it was released for distribution on April l8, 2000.

Documentation is inadequate to indicate which lot was used for validation and testing. This discrepancy was not detected by your company upon review of the validation, prior to its release.

Failure to establish sampling plans based on a valid statistical rationale and to ensure that

sampling methods are adequate for their intended use, as required by 21 CFR 820.250(b). For example, our inspection revealed that in-process sampling data is recorded on the Quality Tracking Records. There is no evidence of the statistical rationale used for this sampling. Also, procedures require that all catheters are tested for resistance and conductivity; however, only the test results from the first twenty catheters manufactured per lot each day are maintained in the DHR. There is no rationale for this practice.

The above identified deviations are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that each of your facilities is in compliance with all requirements of the Federal regulations. The specific violations noted in this letter and in the Form FDA-483 issued at the conclusion of the inspection (a copy of which is included for your information) may be symptomatic of serious underlying problems in your establishment?s quality system. You are responsible for investigating and determining the causes of the violations identified by the FDA. You also must promptly initiate permanent corrective and preventive action to your Quality System at this and at all your other locations. Continued distribution of violative devices may result in regulatory action without further notice. These actions include, but are not limited to seizure, injunction, and/or civil penalties.

Federal agencies are advised of the issuance of all warning letters regarding medical devices so that they may take this information into account when considering the award of contracts.

We are in receipt of your correspondence dated December 11,200l in response to the FDA 483 issued at the end of the November 5 - 20th inspection. With regards to your response, we have the following comments:

Observation 1 - You must assure that you are capturing, tracking and trending all sources of quality data and not just the specific items noted in our observations. The fact that there is evidence of continuing defects found after you have instituted corrective actions is indicative that the systems in place are inadequate to identify the source of these problems (i.e., balloon failures and heparin occlusions).

Observation 2 - Regarding your proposed changes to the CAPA procedures, your response does not indicate how the effectiveness of a corrective action will be determined and defined. Besides defining effectiveness, your procedures need to also state the time period over which corrective actions will be tracked, prior to their implementation.

Observation 3 - Your response appears adequate; however, you must assure the implementation of your corrective actions. The adequacy will be evaluated at the next inspection of your facility.

Observation 4 - We disagree with your response regarding design controls. Although your response refers to the lay-flat design change as a product improvement initiative, documentation noted throughout the design history file for this change indicate that the purpose was to make the tip diameter smaller, thus minimizing the likelihood of being caught on the introducer or contamination sheath. The sole purpose of this change was to minimize or eliminate balloon tears and damage and is therefore a corrective action.

Although your response states that design validation was established based on design verification data, the Design Validation Checklist in the Design History File indicated that design validation was based on the process validation of the lay-flat tip. There is no indication that Design Validation was based on the first-lot-to-stock, or on any other verification data.

Observation 5 - When our investigators asked why the design change was not applied to all TD catheters approved under the design control project, they were given two different explanations: Mr. Gilbreath, Engineering Manager stated that tooling issues somehow prevented implementation, and Mr. Cole Tims, Plant Quality Assurance Manager, attributed it to "low throughput," that is, Abbott was limited in its ability to manufacture these catheters. Mr. Tims stated that the new design was not to be manufactured on the remaining lists until new equipment was purchased to increase production. The document provided with your response was never supplied to our investigators or discussed at the close-out of the inspection. Nevertheless, it is essential that if your firm determines that a design change is warranted, the decision to implement or not to implement must be made using a risk-based assessment. That is, a risk-based assessment of the impact on patients? health should be performed prior to determining whether or not to implement the change.

Observation 6 - Your response appears adequate; however, we would like to remind you that you need to assure all BOPs define the methods for rework and that all steps taken are properly validated. The rationale for any decision not to validate rework on an EPWO must be also documented. Although your response indicated that all rework procedures were validated, our inspection found no evidence of the validation of the rework for ink removal and partial heparinization of TD catheters.

Observations 7 and 8 - Your responses appear adequate; however, you must assure the

implementation of your corrective actions. The adequacy will be evaluated at the next inspection of your facility.

Observation 9 - In response to the observation of lack of validation of the re-work of TD

catheters, your response states that validation was supported by document [redacted]".

Our review indicates that this document is the protocol used for the validation, but is not the actual validation results. We also note that this protocol is dated 1993; you must assure that any process changes which may have occurred since 1993 have been

addressed in order to assure re-validation is not necessary. Although your response states that the BOP for the Opticath catheter rework is appropriate for the TD catheters, our inspection revealed that your firm was only using part of this BOP for the rework. There is no justification for the partial use of the BOP in the addendum to the validation that your firm wrote on December 10, 200l.

Regarding validation [redacted used to support the rework of lots [redacted] and [redacted] our investigators reviewed Restriction [redacted], dated September 19, 2000. The restriction stated that the purpose was "to re-work this lot ([redacted] ) for a second sterilization the catheters need to be re-ballooned and re-heptined. The re-heparinization process needs to be validated. As a result test report [redacted])([redacted] will be run in parallel with the re-work of this lot of product." The EPWO, with re-work instructions, was dated September 27, 2000; however the validation (test report [redacted]) shows it originated December 4, 2000. Furthermore, the records for the lot indicate it was reworked and released to the sterilizer on December 6, 2000. This lot was not

received back until December 9, 2000, whereas the validation is signed off on December 7, 2000, before the product completed sterilization and before you could assure the process was indeed successful. This lot was later the subject of at least one complaint of heparin occlusion (PER # [redacted]).

You should notify this office in writing within 15 working days of receipt of this letter, of any additional steps you have taken to correct the noted violations, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time frame within which the correction will be completed.

Your reply should be sent to the Food and Drug Administration, Denver District Office, P.O. Box 25087, Denver, CO 80225-008, Attention: Regina A. Barrell, Compliance Officer. If you have any further questions, please feel free to contact Ms. Barrel1 at (303) 236-3043.

Sincerely,

B. Belinda Collins

Acting District Director