•

~I DEPARTMENT OF HEALTH AND HUMAN SERVICE S

August 12, 2008

CERTIFIED MAILRETURN RECEIPT REQUESTE D

WARNING LETTERRef: KAN 2008-1 0

Mr. Richard J . Meelia, President/CEOMallinckrodt, Inc ., dba Covidien15 Hampshire StreetMansfield, MA 0204 8

Dear Mr. Meelia :

Food and Drug AdministrationKansas City DistrictSouthwest Region11630 W . Be StreetLenexa, Kansas 66214Telephone : (913) 752-2100

On March 11-13, 2008, Food and Drug Administration (FDA) investigators performed aninspection of your pharmaceutical manufacturing operation located at 2703 Wagner Place,Maryland Heights, Missouri . This inspection revealed serious deviations from the current GoodManufacturing Practice (CGMP) regulations, Title 21, Code of Federal Regulations, Parts 210and 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) ofthe Federal Food, Drug, and Cosmetic Act (the Act) (21 U .S.C. § 351(a)(2)(B)), which requiresthat 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 therequirements of the Act as to safety, and have the identity and strength, and meet the quality andpurity characteristics, which they purport or are represented to possess .

FDA's list of inspectional observations, also known as FDA Form 483, was issued to anddiscussed with Ms . Mitzi L . Pennington, Site Director, during a close-out meeting held on thefinal day of the inspection . A copy of the FDA Form 483 is enclo$ed 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 ; andJuly 24, 20008, respectively . We address these responses below, in relation to each of the notedviolations where appropriate .

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

1 . Failure to establish scientifically sound and appropriate specifications, standards andtest procedures designed to assure that drug products conform to appropriate standards ofidentity, strength, quality, and purity, as required by 21 CFR § 211 .160(b) . Specifically,your release limit for Molybdenum-99 breakthrough for Ultra-TechneKow DT E

bcc : FF (1946929); LF (35943); DDRF ; NNJ: FOI (thru RLL); HFC-210 (via e-mail) ; CDER(HFD-320): DKW

Warning Lette rMr. Richard J . MeeliaMallinckrodt, Inc ., dba CovidienAugust 12, 2008Page 2

(Technetium Tc 99m) Generator did not assure that the specification would be met a t(Reference : FDA 483 Observation 1 )

We have reviewed the written responses and we note that your revised Standard"Test Methodprocedure (STM240-018 now *indicates that the internal control limit will be related to actualbreakthrough values at as is consistent with your package insert and U .S.P.guidelines, i .e., not more than f Tc-99m at -administration .

This revised p ro cedure includes a calculation, usin;predict the ratio of Mo99 to Tc .99m atnot to exceed

Tc-99m value, tohis predicted calculated ratio is

f Tc99m . Please explain why you have chosen to set th elimit in this manner versus setting a maximum limit that cannot be exceeded at the time thesample is. taken and tested .

We acknowledge your intent to formally supplement your NDA for the specification and relatedprocedural 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 contro lsand tests, or examinations to be conducted on approp riate samples of-in-process materialsof each batch. Failure to establish control procedures to monitor the output and tovalidate thl performance of those manufactu ring processes that may be responsible forcausing variability in the characte ristics of in-process material and the drug product asrequired by 21 CFR § 211 .110(a) . (Reference : FDA 483 Observations 4 & 5)

Appropriate controls fo backwashing, column assembly, and column activation werenot established, validated, and monitored to assure that the molybdenum adsorbs and remainsadsorbed 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 incomponent quality and/or the manufacturing process appears to cause or contribute to the recentincreased number of molybdenum breakthrough complaints . The relationships between processand component parameters and product quality attributes must be understood in order toimplement effective controls to prevent drug product defects . We note that at the time ofinspection your firm had failed to study, among other things, the washing process. and particlesize, as well as how they impact product quality and function .

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

f

Warning LetterMr. Richard J . MeeliaMallinckrodt, Inc ., dba Covidien

August 12, 2008Page 3

3 . The quality control unit failed to meet the responsibility for approving or rejecting allprocedures or specifications impacting the identity, strength, quality, and purity of thedrug product as required by 21 CFR § 211 .22(c) .

Based upon the inspectional obse rvations and other information in the establishment inspectionreport (E1R), we have concluded that your Quality Control Unit (QCU) is not fulfilling itsobligations in some significant respects . For example, the QCU did not-

• Assure that the internal release s ecification for the Ultra-TechneKow Generators wasappropriate to meet the quality. Failure to have an appropriaterelease specification led to the release of two Generators (lots 881/895-6070 and881/895-7042) that exceeded their Molybdenum-99 specification at(Reference: FDA 483 Observation 1 )

■ Assure that preventive action steps and studies recommended as a result of themolybdenum 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 processvariables (e .g., time and flow rate for backwashing and particle size distributionof the washed JNJJJWd component attributes (e .g., particle size and content o f

were fully studied and controlled to assure product quality. (Reference : FDA483 Observation 5 )

■ Detect a discrepancy between a testing procedure (STM 240-018) and the procedure forevaluating out-of-specification results [Procedure 240-057] . (Reference : FDA 483Observation 2) .

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

The quality system estab lished by your QCU must be proactive in reviewing and re-evaluating,as necessary, the adequacy of specifications, qualification and validation studies and p roceduresthat assure product quality and process control at all stages of manufacturing. We note that yourfirm's QCU has failed to prevent the dist ribu tion of defective products in the past. In yourresponse, provide the steps you have taken to improve the effectiveness of your QCU and qualitysystems. .

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

Warning Lette r

Mr. Richard J . MeeliaMallinckrodt, Inc., dba Covidien

August 12, 2008Page 4

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

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

Additionally, FDA may withhold approval of requests for export certificates, or approval ofpending new dj-ug applications listing your facili ty as a manufacturer until the above violationsare corrected . A reinspection may be necessa ry.

Within fifteen working days of receipt of this letter, please . notify this office in writing ofadditional, specific steps that you have taken to correct violations . Include an explanation ofeach step being taken to prevent the recurrence of violations, as well as copies of relateddocumentation : If you cannot complete corrective action within fifteen Working days, state thereason for the delay and the time within which you will complete the correction . If you nolonger manufacture or market the iJltra-TechneKow DTE (Technetium Tc 99m) Generator, yourresponse should so indicate, including the reasons that, and the date on which,,you ceasedproduction. Your reply should be sent to Nadine Nanko Johnson, Compliance Officer, at theabove letterhead address .

Sincerely,

Jo/John W. ThorskyDistrict DirectorKansas City District

Enclosure -FDA Form 483

cc: Steve Hanley, President, ImagingMallinckrodt, Inc. dba Covidien2703 Wagner PlaceMaryland Heights, MO 63043-3421

s