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~ DEPARTMENT OF HEALTH & HUMAN SERVICE S~ New York District

Food & Drug Administration300 Pearl Street, Suite 100Buffalo, NY 14202

March 23, 2007

WARNING LETTER NYK 2007-11

CERTIFIED MAILRETURN RECEIPT REQUESTED

Roger L . HungerfordPresident/Owner/Chief Executive OfficerSigma International General Medical Apparatus, LLC711 Park AvenueMedina, NY 14103

Dear Mr. Hungerford :

During an inspection of your firm located in Medina, NY, on September 19 through October 18,2006, an Investigator from the United States Food and Drug Administration (FDA) determined thatyour firm manufactures software-controlled volumetric infusion pumps, model Sigma Spectrum IV(Spectrum), that includes a new Patient Controlled Analgesia/Patient Controlled Epidural Analgesia(PCA/PCEA) delivery mode and a Master Drug Library (MDL) software . Under section 201(h) ofthe Federal Food, Drug, and Cosmetic Act (the Act), 21 U .S.C. 321(h), these products are devicesbecause they are intended for use in the diagnosis of disease or other conditions or in the cure,mitigation, treatment, or prevention of disease, or are intended to affect the structure or any functionof the body.

This inspection revealed that these devices are adulterated within the meaning of section 501(h) ofthe Act [21 U.S.C. § 351(h)], in that the methods used in, or the facilities or controls used for, theirmanufacture, packing, storage, or installation are not in conformity with the Current GoodManufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title21, Code of Federal Regulations (CFR), Part 820 . We received your firm's response letters datedNovember 6, 2006, December 22, 2006 and February 16, 2007 ; from Colleen Dugan, Director ofQuality and Regulatory Affairs for your firm, concerning our investigator's observations noted on theForm FDA 483, Inspectional Observations, which was issued to your firm at the conclusion of theSeptember 2006 facility inspection . We address these responses below, in relation to each of the,noted violations . These violations include, but are not limited to, the following :

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1) Failure to establish and maintain procedures for the identification, documentation, validation, orwhere appropriate verification, review, and approval of design changes . before their

implementation, as required by 21 CFR 820.30(i). Specifically:

a) In June 2006, your firm recalled 2455 units of the Spectrum Infusion Pump due to severalevents where the pump tubing mis-loaded when it was installed by the end user . Severaldesign changes were made to the Spectrum Pump's hardware and software to better assist the

end user in installing the pump tubing. These design changes were incorporated into theblanket Engineering Change Notice (ECN # 15501) . This ECN contained several individualECNs to cover each change that was made to correct the tubing mis-loading problem .

However, the blanket ECN also included an individual ECN to implement the PCA/PCEAdelivery modes within the Spectrum pump . ECN# 15501 and all individual ECNs under thisblanket ECN were cleared for manufacturing on May 01, 2006 . However, our inspectionrevealed the software verification/validation for the pump operating software version 4 .00.04

and MDL software version 5, and the design of the hardware components associated with thePCA/PCEA module were not completed at the time the re-designed Spectrum pump was

released for manufacturing. Yet, ECN # 15501 was approved for manufacturing by yourfirm's Approval Committee (consisting of representatives from Engineering, Manufacturing,Quality Assurance and Purchasing), without ensuring that the appropriateverification/validation for the PCA/PCEA functions were completed . More significantly,257 units of the Spectrum pumps, manufactured between May 01, 2006, and June 26, 2006,were distributed into interstate commerce with an "enabled" version of this unvalidatedPCA/PCEA function as replacements for defective devices that were returned to SigmaInternational as a result of the June 2006 recall .

b) Your firm's procedure for Engineering Changes was not followed in that there was noEngineering Change Request (ECR) or Engineering Change Notice (ECN) for the designchange to the AC power cord adapter retainer bracket . There was no documentedverification or validation of this design change to establish the effectiveness of this correctiveaction.

c) One of the ECN's (ECN # 01306) associated with the Spectrum Infusion Pump required tthe pump be redesigned to accommodate tubing sets manufactured b} i~As part of this re-design, the CAM (a component . of the motor) and the pumping fingers

wereHowever, our inspection revealed that

the design validation and functional testing associ d with these changes were onlyperformed with the+~~ and not the Yet, ECN # 01306, whichwas approved on March 03, 2006, indicated that the Spectrum pump was calibrated for usewith the when in fact it was not completed. Also, theengineering testing for the flow rate decay (described above) relied on a I

but there is no documented specification for this offset .

Regarding the PCA/PCEA function, your firm's November 6 response states that SigmaInternational conducted a recall in October 2006, during which your firm's representatives

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visited each consignee that received the defective devices, and "disabled" the PCA/PCEAfunctions through the factory menus in the pumps' software . Your firm's recall action indicatesthat a total of 257 devices were released into interstate commerce and that of those 257 units,only 25 devices remained in interstate commerce with the PCA/PCEA function enabled .Records reviewed during our inspection of your facility revealed that a total of ~weremanufactured between May 01, 2006, and June 26, 2006 . Of these ~ units remained 'in-house an were introduced into interstate commerce . We are unaware of the dispositionof the hich remained in-house, whether the PCA/PCEA function has been disabledin these devices, and whether the devices were distributed .

Your firm's response also states that the hardware required to operate the PCA/PCEA functionswas not released to consignees. This hardware would be required in order to successfully operatethe PCA/PCEA function . Additionally, your firm stated that the PCA/PCEA function wasdisabled in all Spectrum pumps manufactured after June 30, 2006 . However, these correctionsdo not detract from the observation that the "unvalidated" PCA/PCEA module was released aspart of a validated finished product . Your November 6 response stated that the Engineering

Change Procedure, Standard Operating Procedure (SOP)11010, for Engineering Changes wouldbe updated . Your February 16 response stated that this activity was still in progress . Theseresponses are not adequate. Please provide a timeline detailing when these corrective actionswill be completed and provide us a copy of the Engineering Change Procedure upon its

completion .

Regarding the ECN for the AC power cord adapter retainer bracket, your firm states in theNovember 6 response that Sigma International routinely includes many ECRs into a single ECN .However, the particular ECR or ECN for this change was not completed . Your firm promised toupdate your SOP 11010, Engineering Change Procedure to clarify the ECN / ECR process, yetyour firm still has not completed the ECN/ECR for the changes to the AC power cord adapterretainer bracket . Your February 16 response states that this activity is still ongoing . Yourresponse is not adequate . Please provide documentation to show that the change to the ACpower cord adapter retainer bracket has been completed for this device.

In addition, your firm's response regarding the CAM and pumping finger re-design is notadequate . Your February 16 response states that CAPA 26012 has been completed . However,your firm has not provided any documentation (i .e. testing protocols, validation reports, summaryreports, etc .) to show the tests that were performed, whether they were successfully completed,and how any errors that might have occurred during the testing were addressed . Please providesuch documentation with your response to this letter. Regarding the lack of documentation ofyour firm's specification for the calibration offset used in the flow rate decay testing, your firm'sNovember 6 response stated that the testing " . . .will be repeated to remove the test anomaliesobserved in the data set associated with the pump that exhibited the flow rate error for the 96 ffihour . . ." Your firm's response also stated that the calibration offset feature shall be documentedthrough hardware/software verification and validation activities . Your firm's response is notadequate because it does not specify why your firm is repeating testing to "remove test

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anomalies." Any change to design specifications must be controlled through your firm's design

control procedures and protocols .

2) Failure to establish and maintain procedures for validating the device design, including softwarevalidation as part of the design validation, as required by 21 CFR 820 .30(g). Specifically :

a) There was no documented verification or validation testing of the PCA/PCEA delivery modesoftware that was integrated into the Spectrum operating software version 4 .00.04. Thisversion is the first version of Spectrum pump software that contained the PCA / PCEA

delivery mode ..b) Validation of MDL software for Sigma Spectrum pumps was either not performed or it was

incomplete. For example,• STP 35700-009, Rev. G - Your firm presented this Software Test Protocol (STP) to

support the validation of the MDL software version 2 .00.0009. However, the documentdid not specify that version 2 .00.0009 was the version being tested .

• STP 35700-009, Rev . K - Your firm presented this Software Test Protocol (STP) tosupport the validation of the MDL software version 2 .0.2-0002 . However, there was notest data or engineering report to show the actual results of the validation.

• STP 35700-009, Rev . L, M, Q - Your firm presented these Software Test Protocols(STP) to support the validation of MDL software versions 4 .00.02, 5 .0 .0.25 and 5 .0.2,

respectively. With regard to Rev . L, there is no test data or engineering report to show

the actual results of the validation.• Additionally, in all software versions above, two tests to support the "library download

deployment and download validation", which were consistently performed in validationof previous iterations of the MDL, were excluded from these protocols . Your firm hasnot provided any justification as to why these tests were removed from the protocol .Failure to validate the data integrity of the MDL library is especially crucial for versions5 .0 .0.25 and 5 .0.2, which supports the unvalidated PCA/PCEA delivery modules .

c) Testing was not performed to verify or validate that newer versions of the MDL couldsuccessfully import the drug library data from older versions of the software . For example,in June 2006 your firm recalled several lots of the Spectrum Infusion Pump to correct atubing mis-loading problem. As part of the factory upgrade, your firm updated each recalleddevice's operating software to the latest version (Version 4 .00.04). The MDL that

corresponds with Spectrum operating software 4 .00.04 was MDL version 5 .0 .0 .25 . SigmaInternational's engineers stated that MDL software and data files can be migrated into themost current version of the MDL that is installed on any particular device . However, yourfirm has not validated that this migration can be performed successfully, withoutcompromising the integrity of the data that is transferred from older MDLs to newer MDLs .

Regarding validation of the MDL software, your November 6 response states that the correctiveactions for these observations have been completed, and specifies implementation of EngineeringTest Procedure (ETP) 35700-071, Rev . A, signed October 10, 2006. Your firm's response tothese observations appears to be adequate, but will be evaluated further during a future

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inspection of your facility.

Regarding the compatibility of newer versions of the MDL software with older versions, yourfirm's November 6, December 22, and February 16 responses are not adequate . The responsesstate that the corrective action for this observation has been completed . Specifically, accordingto ETP 35700-071, the following test was successfully completed without failures : ImportingDrug Libraries from MDL v2 .0.0-0002 to MDL v4. 00. 02 to MDL v5.0.0.25, MDL 5. 0.1 to v5 .0.2.However, based upon our review, it appears that your firm's tests only verify that any givenversion of the MDL would successfully import software and data files from its immediatepredecessor . The tests do not show that newer versions of the MDL can successfully importsoftware and data files from all older versions of the software. For example, your firm's testsmight have shown that MDL Version 5 .0.2 (the most current version) can successfully importdata files from MDL Version 5 .0.1 . However, your firm's tests do not show that data from otherprevious versions (such as Versions 2 .0.0-0002, 4 .00.02 and 5 .0.0.25) can be successfullyimported into Version 5 .0.2. Additionally, as data from each previous version of the MDL isimported into a newer version, your firm's tests do not verify the data's integrity after theimporting process. Please provide documentation that demonstrates that each time a new versionof the MDL software is introduced, it is fully compatible with EACH of the previous versions ofthis software. Please provide documentation to show that when data files are transferred fromolder versions of the MDL to newer versions, they can be fully interpreted by the new MDLsoftware .

3) Failure to establish and maintain procedures to ensure that the device design is correctlytranslated into production specifications, as required by 21 CFR 820 .30(h) . Specifically, SOP11125, Design Transfer Procedure states that the application of this procedure is intended to beongoing. The procedure states that as the design of Sigma International's devices evolves andvalidation is proven to. be successful, the design team will translate the design into productionspecifications . Yet, your firm failed to maintain DMRs for your MDL software, released units ofthe Spectrum Infusion Pump into interstate commerce with unvalidated software, and releasedversions of the Spectrum Pump software with a PCA/PCEA function

Your firm's November 6 response states that the MDL process and other software processes willbe evaluated to determine the gaps relating to production specifications that resulted from thepoor design transfer. Your February 16 response states that manufacturing work instructions,control, labeling, packaging, device history and distribution instructions were updated andimplemented . That response also states that the design transfer process was verified andvalidated. Your response to this observation appears to be adequate and will be evaluated furtherat a future inspection of your facility .

4) Failure to establish and maintain procedures for analyzing processes, quality records, servicerecords, complaints, returned product and other sources of quality data to identify existing andpotential causes of nonconforming product, or other quality problems, as required by 21 CFR

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820.100(a)(1). For example, during our inspection of your firm's facility we discovered thatthere were several Spectrum Infusion Pumps in which the 1/0 PC board had failed . When yourfirm queried the electronic CAPA system containing customer complaints and product repairsusing the part number for the 1/0 PC board,ssociated with failures of theI/O PC board in the pump were found to have occurred between January 2006 and September2006. However, onlywere actually reported as a nonconformance on yourNonconformance Report (NCR) . The SOP 11057, Nonconformance Procedure, defines a"nonconformance" as "a departure from the requirements designated in the specification,drawing or other approved descriptive documents ." This SOP also indicates that not allcomplaints and repairs are reportable nonconformances . Yet, our assessment of the 10complaints/repairs that your firm did not consider to be nonconformances, revealed that eachresulted in a failure of the 1/0 PC board. Please explain why NCRs were not issued for these 10complaints, when the root cause for each was identical to other complaints for which NCRs wereissued.

Additionally, regarding your Model 8000 infusion pumps, our investigator identified that manyof these pumps failed in-process and final checks for flow calibration, and that several deviceswere reprocessed multiple times . Although the multiple nonconformances may be indicative ofproblems with your firm's flow calibration process, your firm has not initiated any corrective andpreventive action (CAPA) to investigate this trend .

5) Failure to establish and maintain procedures for investigating the cause of nonconformitiesrelating to product, processes and the quality system, as required by 21 CFR 820 . 1 00(a)(2) . Forexample, our investigator identified NCR 16525 (Date : February 27, 2006), which described theroot cause for the UO PC board failure on the Spectrum Infusion Pump # 60091 as "UO PCBfailures where component level failure could not be identified at incoming evaluation ."Similarly, the root cause in NCR 23126 (Date : August 14, 2006) states that "UO failed toinitialize IrDA port, specific component not identified ." On your NCR form, there is a space toenter a "Reason Code", in addition to stating the root cause for a nonconformance . In bothexamples cited above, the reason code was entered ; however, the SOP 11057, NonconformanceProcedure, does not provide any definition for these "Reason Codes ." There was no furtheranalysis attached to the NCR's to explain the reason for the 1/0 PC board failures. We alsonoted that other codes such as the "Symptom Code" and the "Disposition Code", which wereidentified on your NCR form, were not defined in SOP 11057 .

Your November 6, December 22 and February 16 responses state that SOP 11057 has beenupdated to clarify the NCR process, trending effectiveness and coding. These responses are notadequate in that you still have not identified the reason for the UO PC board failures . Pleaseprovide copies of any additional testing that your firm performed regarding the I/O PC boardsfailures .

6) Failure to establish and maintain procedures for verifying or validating the corrective andpreventive action to ensure that such action is effective and does not adversely affect the firiished

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device, as required by 21 CFR 820.100(a)(4) . For example, NCR 16525 (Date: February 27,2006), states that the corrective action to the I/O PCB failures was to "replace the UO with thecurrent revision." Similarly, NCR 23126 (Date : August 14, 2006) states that the correctiveaction to the I/O PCB failure w as to "replace [the] 1/0 PCB." There was no documentation toshow that verification or validation of this corrective action w as effective in eliminating the I/OPC board failure in current and future devices, and that this corrective action did not have anadverse affect on the finished device .

Additionally, during the inspection, our investigator identi fied NCR 18118 (Date: May 18, 2006)which showed an increase in production battery failures for the Spectrum Infusion Pump, and thetendency for these batteries to only charge to 83% of their capacity. Your firm stated that "someof the batteries coming from the supplier had incompatible voltages when mated together for thebattery packs." Sigma's vendor advised that there might have been an "electrostatic discharge(ESD) on the bench tops where the batteries were manufactured ." These statements of root causewere entered into your firm's electronic CAPA system. Yet, the system does not indicate whichlot or serial numbers of batteries were affected and how many units of the . Spectrum pump(which have already been introduced into interstate commerce) were affected by this problem.During the inspection, your firm stated that, since identifying the battery discharge problem, yourfirm has implemented 100% inspection of all lots of ba tteries that Sigma receives from thevendor, and that your firm continues to monitor in-process ba ttery charging data for any failures .However, there is no documentation of any verification/validation efforts to support these

corrective actions . It is notewo rthy that during our inspection, our investigator identifiedComplaint # IM (Dated: July 31, 2006) which showed a battery charging problem which hadnot yet been entered into your firm's CAPA system.

This same deficiency was previously identified on the May 05, 2004, FDA 483 issued to yourfirm at the conclusion of the Ap ri l/May 2004 inspection .

Regarding the I/O PC board failures, your firm's November 6 response states that your firm isreplacing the current `llWinished Boards" with new " oards." The responsealso states "to date, there have been 3 failures to these new oards ." However, theresponse does not indicate whether Sigma has performed any verification or validation into theeffectiveness of these new boards even though your firm has commenced installing the

AWjolMoards into new Spectrum pumps . Your February 16 response states that this correctiveaction is still ongoirig. Your responses are not adequate . Please provide copies of the specificverification or validation tests and data that support the conclusions that thoardsare an effective solution to the Spectrum Infusion Pump I/O PC board failure problem .

Regarding the battery failures in the Spectrum Infusion Pumps, please provide copies of theverification/validation tests that were performed to suppo rt your firm's corrective actions . Also,please provide specific information indicating when the battery charging problem was firstidentified, how many units of your products have been affected by this problem, how m any unitsare still in interstate commerce, how many complaints Sigma received regarding this problem,

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and whether these problems have been reported to the FDA.

7) Failure to validate computer software for its intended use according to an established protocol,when computers or automated data processing systems are used as part of production or thequality system, as required by 21 CFR 820 .70(i) . Specifically, your firm has not performed anyvalidation for the automated process of programming the Spectrum pump's operating softwareand MDL software onto its PC boards. This process is defined in SOP 11004, I/O and ProcessBoard Programming, SIGMA Model 35700 . Also, there is no validation for thprogram. This software s used to program the Spectrumpump's microprocessor control, operating software and Master Drug Library onto its PC boards .Furthermore, there is no qualification of the essential hardware utilized in this process, such asthe sed to transfer operating and MDL software to thepumps, and the

on* used to store andtransfer various versions of the MDL and files specific to each hospital . Qualification . of thisequipment is crucial to your software validation process, which assures that your firm cansuccessfully transfer the operating and MDL software to the Spectrum infusion pump .

Your firm's November 6 response states that all computers or automated data processing systemswill be validated, and that CAPA 26009 will track the completion of these activities . YourFebruary 16 response states that validation of the process board programming is complete andhas been documented in ETP 35700-97 . Yet, elsewhere in this response, you state that thevalidation of the48100program is still ongoing . You also state that the " . . .purpose of the~rogram is for software development ." However, durin the September/October 2006inspection, your firm told our investigators that the ~was used to program theMDL software onto the PC boards. Furthermore, your February 16 response states that thevalidation activities for the hardware components are still ongoing. Yet, your firm continues tomanufacture the Spectrum Infusion Pumps using this unvalidated process . For this reason, yourfirm's responses are not adequate . Please provide a timeline which identifies when thesevalidation activities will be completed .

8) Failure to establish and maintain procedures for changes to a specification, method, process orprocedure, as required by 21 CFR 820 .70(b) . Specifically, SOP 11140, Deviation ReportInstruction, Revision C, requires that when your firm initiates a Deviation Report, employeesmust "record a complete and thorough explanation of why the product is deviating from thespecification." Yet, when our investigator assessed the Deviation Log, there were entries that didnot contain any reason for the deviation from specification . Also, the SOP is unclear as to thetype of "specification" that the product is deviating from . If the product is deviating from itsDesign Specifications, then the changes must be evaluated through the appropriate DesignControl process . This SOP also states that for each deviation, employees will "Record acomplete and thorough explanation of why the deviation can be accepted ." Our assessment ofthe Deviation Log showed that the entries did not contain any explanation of why the deviationswere accepted . Additionally, the SOP does not clarify the disposition or status of product thathas deviated from the specification. Furthermore, the SOP states that "repeated utilization of an

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established deviation report shall be limited to QM with tension allowablefor a maximum of 4~ However, the SOP is not clear as to the final disposition of thedeviation and subsequent corrective action after the Deviation Report expires . This samedeficiency was previously identified on the FDA 483 issued to your firm May 05, 2004 at theconclusion of the April/May 2004 inspection.

Your firm's November 6 response states that the Deviation Report Instructions will be reviewedand updated to clarify process flow and approval for deviations . Your February 16 responsestates that SOP 11140 was reviewed, rewritten, and implemented. This response also states that" . . .all open deviations have been reviewed for compliance to this new procedure . . .," and that" . . .deviations outstanding are being addressed by incorporating processes into ManufacturingWork Instructions . . ." Your firm's responses are inadequate . Please provide a list of theoutstanding deviation reports that were reviewed, and their current status . Please explainwhether the affected product is put into an "in-process hold" or "quarantine" status, while theDeviation Report is being approved, or whether it is immediately "fixed" in-line and released fordistribution. Please explain how the deviation will be incorporated into the design of the productonce the Deviation Report timeframe expires . This observation was originally on an FDA 483issued to your firm at the end of the April/May 2004, inspection . In your firm's May 18, 2004,response to that FDA 483, your firm promised to correct the deficiencies in your DeviationReport Instruction procedure. As of the latest inspection of your facility, your firm has failed todemonstrate that the changes that were implemented, if any, were effective .

9) Failure to establish and maintain procedures to control product that does not conform to specifiedrequirements, as required by 21 CFR 820.90(a) . Specifically, there is no established reworkprocedure for Spectrum Infusion Pumps being upgraded to new hardware and/or new software asa result of engineering changes and/or correction and removal activities .

Your firm's November 6 response stated that your firm will review and update SOP 11060,Manufacturing Work Instructions and SOP 11061, Establishing Pumps to Reconditioned Restockto reflect how to define and document rework and repair . Your firm's response appears to beadequate and will be evaluated further at a future inspection of your facility .

10) Failure to maintain device master records (DMR's), as required by 21 CFR 820 .181 .Specifically, your firm does not have a DMR for the MDL software that contains or identifies thelocation of all device and software specifications ; installation, maintenance and servicingprocedures ; packaging and labeling specifications and procedures ; production processspecifications and procedures ; and quality assurance procedures and specifications .

Your firm's December 22 response stated SOP 11016 has been revised, and that a DMR for theMDL software has been created . Your February 16 response states that this activity is "In-process." Yet, your firm continues to manufacture the Spectrum Infusion Pump without a DMRin place . Your responses to this observation are not adequate . The purpose of the DMR is todocument the performance and configuration characteristics for the device, so that these

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activities can be controlled . Currently, the Spectrum Infusion Pump and the MDL software areundergoing changes that need to be documented in the DMRs for these devices . Please explainhow your firm can assure that the devices you manufacture meet all of their pre-definedspecifications and characteristics, when the procedure for the DMR has not been established yet .Please provide copies of the revised SOP 11016, Device Master Record and a list of documentsthat will be included in the DMR for the MDL software .

11) Failure to establish and maintain procedures to ensure that device history records (DHR's) foreach batch, lot or unit are maintained to demonstrate that the device is manufactured inaccordance with DMR and the .QS regulation, and failure to maintain DHRs for each batch, lot,or unit, as required by 21 CFR 820 .184 .

For example, during the inspection, your firm told our investigator that the DHR for theSpectrum pump Model 35700 usually includes the following datasheets : Inspection Check List(ICL) 35700, ICL 35703, Inspection Test Procedure 35700, and Calibration Test Procedure35703-002 . However, your firm did not establish and maintain a procedure that assures thedevice is manufactured in accordance with the DMR. Additionally, our inspection revealed thatyour firm has never maintained a DHR for any version or lot, batch, or unit of the MDL softwarethat was released for manufacturing .

During the inspection our investigator was told that DHR's for the MDL software would bedeveloped from data collected by the sales force, which will identify which version of the MDLsoftware was provided to each customer. A DHR is intended to provide objective evidence thateach device lot, batch, or unit of your firm's devices meet the requirements stated in eachrespective device's DMR .

Your firm's November 6 response states that "An SOP for the Device History Recordrequirements will be written to outline the requirements for all devices and software records . . ."Your February 16 response provides a detailed list of documents to be included in the DHR . Theresponse clarifies that the date of manufacturing, quantity manufactured, quantity released, andother metrics will be part of the DHR . This response appears to be adequate and will be furtherinvestigated at a future inspection of your facility . Please provide a timeline that indicates whenthe DHR's for the MDL software will be completed .

12) Failure to establish and maintain procedures to control labeling activities, as required by 21 CFR820.120. Specifically, there were no procedures to control labeling inspection, storage, andoperations for the Sigma Spectrum MDL software CD for end users and electronic User's Guide,or for the Sigma Spectrum volumetric infusion pump Service Manual and Operator's Manual .

Your firm's November 6 response states that you will write labeling SOPs that outline labelingrequirements. The response also states that CAPA # 26008 will track the completion of thisactivity. Your firm's February 16 response states that this corrective action is still ongoing.Your firm's responses to this observation are inadequate . Please provide a timeline detailing

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when this corrective action will be completed .

13) Failure to store labeling in a manner that provides proper identification and is designed toprevent mixups, as required by 21 CFR 820 .120(c). Specifically, as a result of your firm's lackof labeling control, an incorrect electronic version of the MDL software User's Guide (RevisionA) was stored with the MDL software version 4 .00.02. The correct version of the user's guide toaccompany MDL software version 4 .00.02 was Version C . End users at your firm's consigneeswere incorrectly issued Spectrum Infusion Pumps with Revision A of the User's Guide, whichdid not contain the new procedures for loading the MDL data file into the Spectrum pump . Thisprocedure is essential to operating the MDL with the Spectrum Infusion Pump .

Your firm's November 6 and February 16 responses to this deviation reference the correctiveaction associated with Observation 14 of the FDA-483 . Based on our evaluation of theseresponses to Observation 14, it appears that the procedures for labeling are still being developed .Your firm's response to this observation is also inadequate . Please provide documentation toshow how your firm will segregate labeling to prevent future mixups and a timeline detailingwhen this corrective action will be completed .

14) Failure to review for adequacy, and approve prior to issuance, all documents established to meetthe requirements of the QS regulation, as required by 21 CFR 820 .40(a). For example :a) The production procedure DOC 11088, Revision Code Sheet, SIGMA Model Spectrum

Infusion Pump, Revision B, which was approved and issued on April 13, 2005, was intendedto identify revision codes associated with components of the Spectrum Infusion Pump .Instead, DOC 11088 was issued to production without any specific revision codes . TheProduction Supervisor created his own revision codes for the Spectrum pump components,which he handwrote onto a copy of document DOC 11088 . Subsequently, he photocopiedhis revision code list and distributed it to production and repair personnel, who utilized andreferenced these codes in official test records, and check lists for the Spectrum pump . TheProduction Manager continued to maintain the revision code list . Your firm has yet toupdate DOC 11088 to reflect the current revision codes that Sigma International uses . SigmaInternational's personnel continue to use modified versions of official forms to documenttesting that is performed on the Spectrum Infusion Pumps .

b) The procedures titled Spectrum Drug Library Update and Spectrum Flash Download Systemhave not been approved. In addition, although the procedures do not include the dates whenthese procedures were created, and the dates when they were implemented, your RepairTechnicians and Programmers continue to use them to download Master Drug Libraries toyour Spectrum Infusion Pumps .

c) The Engineering Report ER35700-068, Software Build Tracking List, Master DrugLibrary,SIGMA Model Spectrum was reviewed and approved on July 26, 2006 . The purpose of thisdocument is to provide a description of the software detail that has been added to eachlabeled version of the Sigma MDL application . This document captures the softwarerevision history from March 2005 through June 2006 . However, your firm's records indicatethat the MDL software has been in production since as early as December 2004 . Changes to

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the MDL between December 2004 and March 2005 do not appear to have been documented .

Regarding the Software Build Tracking List, Master Drug Library, SIGMA Model Spectrum, theSpectrum Drug Library Update and the Spectrum Flash Download System, your firm'sNovember 6 response states that these documents have been updated as part of ER35700-068 .This corrective action appears to be adequate and will be evaluated further at a future inspectionof your facility.

Regarding the Revision Code Sheet, your firm's November 6 response stated that the procedureDOC 11088, Revision Code Sheet, SIGMA Model Spectrum Infusion Pump is currently beingrevised. Your February 16 response states that the Revision Code Sheet is still being updated.This response is not adequate . Please provide a timeline detailing when this corrective actionwill be completed. Also, please clarify whether this unapproved document is being utilized aspart of your current manufacturing process. Please indicate how your process will capture theinformation that was originally conveyed through the Revision Code Sheet.

15) Failure to maintain records of changes to documents that include a description of the change,identification of affected documents, signature of approving individual, approval date and whenthe change became effective, as required by 21 CFR 820.40(b). Specifically, there are no recordsof the changes made to the Operator or Service Manuals for the Spectrum Infusion Pump .During the inspection, your firm performed an ad-hoc survey to document the history of eachdocument . This document did not show the history of changes to any Operator Manuals issuedbefore Rev. H (December 08, 2005) . The revision history for the Service Manual onlydocuments changes made in May 2006 for Revision E (The current revision for the OperatorManual and the Service Manual is Revision K) .

Your December 22 and February 16 responses indicate that your firm updated the revisionhistory for the Operator and Service Manuals . This response appears to be adequate, but will beevaluated further at a future inspection of your facility .

16) Failure to provide adequate resources, including the assignment of trained personnel, forperforming management, performance of work, and assessment activities, including internalquality audits, as required by 21 CFR 820 .20(b)(2) . Specifically, your firm created a newDirector of Regulatory Affairs/Quality Assurance position which was filled on September 20,2006. Prior to creating this position, the quality organization was a one person unit consisting ofa Manager of Regulatory Affairs/Quality Assurance. It is evident based on the inspectionalobservations, that Sigma's quality organization cannot adequately satisfy the qualityrequirements as stated within the QS regulation .

Your firm's November 6 and December 22 responses state that the Regulatory Affairs / QualityAssurance department has been expanded to include a Director of Quality and Regulatory, aQuality Supervisor, and a Quality Engineer . This response is not adequate in that you have notprovided any job descriptions for the new job functions . Also, it is not clear how the Regulatory

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Affairs/Quality Assurance department is aligned in Sigma's overall corporate organization .Please provide job descriptions for each position in your Regulatory Affairs/Quality Assurancedepartment, and an organizational chart of your entire company .

Also, we note that in your February 16 response, you state that your firm is still in the process ofhiring a software engineer and an electrical engineer . Yet, the response states that the correctiveaction for this deviation has been completed. Please explain how you have determined that thiscorrective action has been completed, when it appears that your firm is still hiring additionalpersonnel to address the deficiencies identified to you by the FDA .

17) Failure to establish procedures for identifying training needs and ensure that all personnel aretrained to adequately perform their assigned responsibilities, and failure to document thistraining, as required by 21 CFR 820 .25(b) . For example, there is no training record for theProduction Supervisor who has trained the current production staff to program the Spectrum UOPC boards. During the inspection, our investigator was told the Production Supervisor wastrained by engineers . However, your firm could not identify when the Production Supervisor wastrained or by whom.

Your firm's November 6 response states that SOP 11090, Employee Training will be reviewedand updated to improve employee training, and that employees' training files will be reviewedand updated with new training if gaps in training exist . Your firm's response appears to beadequate, but will be evaluated further during a future inspection of your facility .

18) Failure of management with executive responsibility to ensure that the established quality policyis understood, implemented, and maintained at all levels of the organization, as required by 21CFR 820.20(a) . Specifically, your firm's Quality Policy states that "SIGMA International'sTeam is dedicated to providing safe and reliable medical products and services to ourcustomers ." The Quality Policy also commits to " . . .maintaining compliance with all applicablestatutory and regulatory requirements . . ." However, the numerous deviations from the QSregulation that were observed during the FDA's September/October 2006 inspection of thefacility and noted on the FDA 483 issued to your firm on October 18, 2006, indicate your firm'smanagement has not ensured that all levels of your organization understand and implement theQuality Policy.

Your firm's November 6 response acknowledges that "Management with executiveresponsibility has not understood the quality system requirements to the level necessary to insurecompliance." As part of its corrective action, your firm proposed to review and update yourquality manual and quality policy, and to implement annual GMP training for all employees andmanagement. Your February 16 response states that the Quality Manual has been rewritten, theQuality Policy has been reviewed, and that all employees received GMP training on January 7,2007. The February 16 response also states that testing was conducted to determine theeffectiveness of the GMP training . Your responses are not adequate in that no specificinformation regarding the proposed GMP training was provided . Please identify the curriculum

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that was followed in the GMP training, the qualifications ofpersonnel who provided the training,the tests that were performed to determine the effectiveness of the GMP training, and the resultsof those tests .

Our inspection also revealed that your Spectrum Pump with the Patient Controlled Analgesia/PatientControlled Epidural Analgesia (PCA/PCEA) delivery modes is adulterated within the meaning ofsection 501(f)(1)(B) of the Act [21 U.S.C . § 351(f)(1)(B)], because it is a class III device undersection 513(f) of the Act [21 U .S.C. § 360c(f)] and does not have an approved application forpremarket approval in effect pursuant to section 515(a) of the Act [21 U.S.C. § 360e(a)], or anapproved application for an investigational device exemption under section 520(g) [21 U .S .C. §360j(g)] . Additionally, this device is misbranded within the meaning of section 502(o) of the Act[21 U.S.C . § 352(o)], because a notice or other information respecting the new PCA/PCEA deliverymodes in the Spectrum Pump was not provided to the FDA as required by section 510(k) [21 U .S .C .§ 3 60(k)] and agency regulations at 21 CFR 807 .81(a)(3) . The Center for Devices and RadiologicalHealth (CDRH), Office of Device Evaluation, reviewed your June 28, 2006, letter which stated thatthe PCA/PCEA delivery modes were included as part of the original 510(k) (K042121). During ateleconference held on July 14, 2006, and again in a letter dated July 28, 2006, CDRH informed youthat the PCA/PCEA delivery modes in the Spectrum Pump are considered to represent a". . .significant change or modification of the design, components . . . or intended use of the device . . .",and thus required anew 510(k) submission . In your December 22 response your firm stateddl"

You should take prompt action to correct the violations addressed in this letter. Failure to promptlycorrect the violations may result in regulatory action being initiated by the Food and DrugAdministration without further notice . These actions include, but are not limited to, seizure,injunction, and/or civil money penalties . Also, federal agencies are advised of the issuance of allWarning Letters about devices so that they may take this information into account when consideringthe award of contracts . Additionally, pre-market approval applications for Class III devices to whichthe QS regulation deviations are reasonably related will not be approved until the violations have beencorrected . Requests for Certificates to Foreign Governments will not be granted until the violationsrelated to the subject devices have been corrected .

Regarding your November 6, December 22, and February 17 responses, we believe that the generaltimelines identified by your firm for performing corrective actions do not reflect the urgent nature ofthe observations that our Investigator noted during the FDA inspection . Moreover, your firm statesthat only "Priority 1" action items pose "a possible health risk ." "Priority 2" and "Priority 3" actionsare deemed by your firm to pose "no health risk ." We believe that your firm's repeated failure tocomply with the QS regulation substantially increases the risk your devices pose to the patients whouse them.

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Please notify this office in writing within fifteen (15) working days from the date you receive thisletter of the specific steps you have taken to correct the noted violations, including an explanation ofhow you plan to prevent the violation, or similar violations, from occurring again . Include

documentation of the corrective action you have taken . If your planned corrections will occur overtime, please include a timetable for implementation of those corrections . If corrective action cannotbe completed within 15 working days, state the reason for the delay and the timeframe within whichthe corrections will be completed .

Your firm's response should be sent to FDA Compliance Officer James M . Kewley at the above

address. If you have any questions about the content of this letter please contact Mr . Kewley at (716)

541-0328 .

Finally, you should know that this letter is not intended to be an all-inclusive list of the violations atyour facility . It is your responsibility to ensure compliance with applicable laws and regulationsadministered by FDA. The specific violations noted in this letter, and in the InspectionalObservations, Form FDA 483 (FDA 483) issued at the closeout of the inspection, may besymptomatic of serious problems in your firm's manufacturing and quality assurance systems . Youshould investigate and determine the causes of the violations, and take prompt actions to correct theviolations and bring your products into compliance .

Sincerely,

Otto D. VitilloDistrict DirectorNew York District

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