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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Mallinckrodt Inc., dba Covidien 12-Aug-08

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration


Kansas City District
Southwest Region
11630 W. Be Street
Lenexa, Kansas 66214
Telephone: (913) 752-2100


August 12, 2008



Ref: KAN 2008-10

Mr. Richard J. Meelia, President/CEO
Mallinckrodt, Inc., dba Covidien
15 Hampshire Street
Mansfield, MA 02048

Dear Mr. Meelia:

On March 11-13, 2008, Food and Drug Administration (FDA) investigators performed an inspection of your pharmaceutical manufacturing operation located at 2703 Wagner Place, Maryland Heights, Missouri. This inspection revealed serious deviations from the current Good Manufacturing Practice (CGMP) regulations, Title 21, Code of Federal Regulations, Parts 210 and 211 (21 CFR 210 and 211). These deviations cause your Ultra-TechneKow DTE (Technetium Tc 99m) Generator to be adulterated within the meaning of Section 501 (a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 351(a)(2)(B)), which requires that the methods used in, or the facilities or controls used for, the manufacture, processing, packing, or holding of drugs conform with CGMP to assure that such drugs meet the requirements of the Act as to safety, and have the identity and strength, and meet the quality and purity characteristics, which they purport or are represented to possess.

FDA's list of inspectional observations, also known as FDA Form 483, was issued to and discussed with Ms. Mitzi L. Pennington, Site Director, during a close-out meeting held on the final day of the inspection. A copy of the FDA Form 483 is enclosed for your information. Dirk E. Stevens, Ph.D., Vice President, Quality, at the manufacturing site (Maryland Heights, MO) responded to the FDA Form 483 in three letters: dated April 3, 2008; May 9, 2008; and July 24, 20008, respectively. We address these responses below, in relation to each of the noted violations where appropriate.

Deviations observed during the establishment inspection include, but are not limited to the following:

1. Failure to establish scientifically sound and appropriate specifications, standards and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity, as required by 21 CFR § 211.160(b). Specifically, your release limit for Molybdenum-99 breakthrough for Ultra-TechneKow DTE (Technetium Tc99m) Generator did not assure that the specification would be met at (b)(4) (Reference: FDA 483 Observation 1)

We have reviewed the written responses and we note that your revised Standard Test Method procedure (STM240-018 now indicates that the internal control limit will be related to actual breakthrough values at (b)(4) as is consistent with your package insert and U.S.P. guidelines, i.e., not more than (b)(4) of Tc-99m at administration.

This revised procedure includes a calculation, using an (b)(4) Tc-99m value, to predict the ratio of Mo99 to Tc99m at (b)(4). This predicted calculated ratio is not to exceed (b)(4) of Tc99m. Please explain why you have chosen to set the limit in this manner versus setting a maximum limit that cannot be exceeded at the time the sample is taken and tested.

We acknowledge your intent to formally supplement your NDA for the specification and related procedural changes. Please provide the status of that activity in your response to this letter.

2. Failure to establish and follow written procedures that describe the in-process controls and tests, or examinations to be conducted on appropriate samples of-in-process materials of each batch. Failure to establish control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product as required by 21 CFR § 211.110(a). (Reference: FDA 483 Observations 4 & 5)

Appropriate controls for (b)(4) backwashing, column assembly, and column activation were not established, validated, and monitored to assure that the molybdenum adsorbs and remains adsorbed to the column. Failure of the molybdenum to remain adsorbed to the column can lead to the molybdenum breakthrough defect.

Although the DTE Generator is not a new product or process, new unexplained variability in component quality and/or the manufacturing process appears to cause or contribute to the recent increased number of molybdenum breakthrough complaints. The relationships between process and component parameters and product quality attributes must be understood in order to implement effective controls to prevent drug product defects. We note that at the time of inspection your firm had failed to study, among other things, the washing process and particle size, as well as how they impact product quality and function.

We acknowledge the written responses indicating that your firm is continuing to investigate the factors that affect molybdenum adsorption onto the column . We also acknowledge receipt of your firm's root cause investigation including corrective and preventive actions taken.

3. The quality control unit failed to meet the responsibility for approving or rejecting all procedures or specifications impacting the identity, strength, quality, and purity of the drug product as required by 21 CFR § 211.22(c).

Based upon the inspectional observations and other information in the establishment inspection report (E1R), we have concluded that your Quality Control Unit (QCU) is not fulfilling its obligations in some significant respects. For example, the QCU did not:

•Assure that the internal release specification for the Ultra-TechneKow Generators was appropriate to meet the (b)(4) quality. Failure to have an appropriate release specification led to the release of two Generators (lots 881/895-6070 and 881/895-7042) that exceeded their Molybdenum-99 specification at (b)(4) (Reference: FDA 483 Observation 1)
•Assure that preventive action steps and studies recommended as a result of the molybdenum breakthrough investigation were completed in a timely manner. (Reference: FDA 483 Observation 3)
•Assure that validation of the manufacturing process was complete, i.e., all key process variables (e.g., time and flow rate for backwashing (b)(4) and particle size distribution of the washed (b)(4) and component attributes (e.g., particle size and (b)(4) content of were fully studied and controlled to assure product quality. (Reference: FDA 483 Observation 5)
•Detect a discrepancy between a testing procedure (STM 240-018) and the procedure for evaluating out-of-specification results [Procedure 240-057]. (Reference: FDA 483 Observation 2)

While your investigation into the cause of the increased incidents of Molybdenum breakthrough was initiated in 2007, follow up on the issues listed above did not occur until our FDA representatives inspected your facility in March 2008.

The quality system established by your QCU must be proactive in reviewing and re-evaluating, as necessary, the adequacy of specifications, qualification and validation studies and procedures that assure product quality and process control at all stages of manufacturing. We note that your firm's QCU has failed to prevent the distribution of defective products in the past. In your response, provide the steps you have taken to improve the effectiveness of your QCU and quality systems.

The issues and violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.

Our inspectors made similar observations in other product areas during previous inspections at your facility. As management, it is your responsibility to assure that deviations corrected in one product system or area are also corrected in other product systems or areas of this facility, as well as within any other facilities under your control to assure compliance with the provisions of the Act and all applicable regulations.

You should take prompt action to correct the violations cited in this letter . Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure, and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.

Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications listing your facility as a manufacturer until the above violations are corrected. A reinspection may be necessary.

Within fifteen working days of receipt of this letter, please notify this office in writing of additional, specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. If you no longer manufacture or market the Ultra-TechneKow DTE (Technetium Tc 99m) Generator, your response should so indicate, including the reasons that, and the date on which, you ceased production. Your reply should be sent to Nadine Nanko Johnson, Compliance Officer, at the above letterhead address.



John W. Thorsky
District Director
Kansas City District


Enclosure - FDA Form 483

cc: Steve Hanley, President, Imaging
Mallinckrodt, Inc. dba Covidien
2703 Wagner Place
Maryland Heights, MO 63043-3421