March 23, 2007 WARNING LETTER NYK

Transcription

1 ~ ~ -3 ~, ~ DEPARTMENT OF HEALTH & HUMAN SERVICE S ~ New York District March 23, 2007 WARNING LETTER NYK Food & Drug Administration 300 Pearl Street, Suite 100 Buffalo, NY CERTIFIED MAIL RETURN RECEIPT REQUESTED Roger L. Hungerford President/Owner/Chief Executive Officer Sigma International General Medical Apparatus, LLC 711 Park Avenue Medina, NY 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 that your 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) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h), these products are devices because 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 function of the body. This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act [21 U.S.C. 351(h)], in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. We received your firm's response letters dated November 6, 2006, December 22, 2006 and February 16, 2007 ; from Colleen Dugan, Director of Quality and Regulatory Affairs for your firm, concerning our investigator's observations noted on the Form FDA 483, Inspectional Observations, which was issued to your firm at the conclusion of the September 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 : 1

2 1) Failure to establish and maintain procedures for the identification, documentation, validation, or where appropriate verification, review, and approval of design changes. before their implementation, as required by 21 CFR (i). Specifically: a) In June 2006, your firm recalled 2455 units of the Spectrum Infusion Pump due to several events where the pump tubing mis-loaded when it was installed by the end user. Several design 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 the blanket Engineering Change Notice (ECN # 15501). This ECN contained several individual ECNs 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/PCEA delivery modes within the Spectrum pump. ECN# and all individual ECNs under this blanket ECN were cleared for manufacturing on May 01, However, our inspection revealed the software verification/validation for the pump operating software version and MDL software version 5, and the design of the hardware components associated with the PCA/PCEA module were not completed at the time the re-designed Spectrum pump was released for manufacturing. Yet, ECN # was approved for manufacturing by your firm's Approval Committee (consisting of representatives from Engineering, Manufacturing, Quality Assurance and Purchasing), without ensuring that the appropriate verification/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 unvalidated PCA/PCEA function as replacements for defective devices that were returned to Sigma International as a result of the June 2006 recall. b) Your firm's procedure for Engineering Changes was not followed in that there was no Engineering Change Request (ECR) or Engineering Change Notice (ECN) for the design change to the AC power cord adapter retainer bracket. There was no documented verification or validation of this design change to establish the effectiveness of this corrective action. c) One of the ECN's (ECN # 01306) associated with the Spectrum Infusion Pump required t the 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 were However, our inspection revealed that the design validation and functional testing associ d with these changes were only performed with the+~~ and not the Yet, ECN # 01306, which was approved on March 03, 2006, indicated that the Spectrum pump was calibrated for use with the when in fact it was not completed. Also, the engineering 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 Sigma International conducted a recall in October 2006, during which your firm's representatives 2

3 visited each consignee that received the defective devices, and "disabled" the PCA/PCEA functions through the factory menus in the pumps' software. Your firm's recall action indicates that 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 ~were manufactured between May 01, 2006, and June 26, Of these ~ units remained ' in-house an were introduced into interstate commerce. We are unaware of the disposition of the hich remained in-house, whether the PCA/PCEA function has been disabled in these devices, and whether the devices were distributed. Your firm's response also states that the hardware required to operate the PCA/PCEA functions was not released to consignees. This hardware would be required in order to successfully operate the PCA/PCEA function. Additionally, your firm stated that the PCA/PCEA function was disabled in all Spectrum pumps manufactured after June 30, However, these corrections do not detract from the observation that the "unvalidated" PCA/PCEA module was released as part of a validated finished product. Your November 6 response stated that the Engineering Change Procedure, Standard Operating Procedure (SOP)11010, for Engineering Changes would be updated. Your February 16 response stated that this activity was still in progress. These responses are not adequate. Please provide a timeline detailing when these corrective actions will 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 the November 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 to update your SOP 11010, Engineering Change Procedure to clarify the ECN / ECR process, yet your firm still has not completed the ECN/ECR for the changes to the AC power cord adapter retainer bracket. Your February 16 response states that this activity is still ongoing. Your response is not adequate. Please provide documentation to show that the change to the AC power 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 not adequate. Your February 16 response states that CAPA has been completed. However, your firm has not provided any documentation (i.e. testing protocols, validation reports, summary reports, 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 provide such documentation with your response to this letter. Regarding the lack of documentation of your firm's specification for the calibration offset used in the flow rate decay testing, your firm's November 6 response stated that the testing "...will be repeated to remove the test anomalies observed in the data set associated with the pump that exhibited the flow rate error for the 96 ffi hour..." Your firm's response also stated that the calibration offset feature shall be documented through hardware/software verification and validation activities. Your firm's response is not adequate because it does not specify why your firm is repeating testing to "remove test 3

4 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 software validation as part of the design validation, as required by 21 CFR (g). Specifically : a) There was no documented verification or validation testing of the PCA/PCEA delivery mode software that was integrated into the Spectrum operating software version This version 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 , Rev. G - Your firm presented this Software Test Protocol (STP) to support the validation of the MDL software version However, the document did not specify that version was the version being tested. STP , Rev. K - Your firm presented this Software Test Protocol (STP) to support the validation of the MDL software version However, there was no test data or engineering report to show the actual results of the validation. STP , Rev. L, M, Q - Your firm presented these Software Test Protocols (STP) to support the validation of MDL software versions , 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 validation of previous iterations of the MDL, were excluded from these protocols. Your firm has not 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 versions 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 could successfully 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 a tubing mis-loading problem. As part of the factory upgrade, your firm updated each recalled device's operating software to the latest version (Version ). The MDL that corresponds with Spectrum operating software was MDL version Sigma International's engineers stated that MDL software and data files can be migrated into the most current version of the MDL that is installed on any particular device. However, your firm has not validated that this migration can be performed successfully, without compromising 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 corrective actions for these observations have been completed, and specifies implementation of Engineering Test Procedure (ETP) , Rev. A, signed October 10, Your firm's response to these observations appears to be adequate, but will be evaluated further during a future 4

5 inspection of your facility. Regarding the compatibility of newer versions of the MDL software with older versions, your firm's November 6, December 22, and February 16 responses are not adequate. The responses state that the corrective action for this observation has been completed. Specifically, according to ETP , the following test was successfully completed without failures : Importing Drug Libraries from MDL v to MDL v to MDL v , MDL to v However, based upon our review, it appears that your firm's tests only verify that any given version of the MDL would successfully import software and data files from its immediate predecessor. The tests do not show that newer versions of the MDL can successfully import software and data files from all older versions of the software. For example, your firm's tests might have shown that MDL Version (the most current version) can successfully import data files from MDL Version However, your firm's tests do not show that data from other previous versions (such as Versions , and ) can be successfully imported into Version Additionally, as data from each previous version of the MDL is imported into a newer version, your firm's tests do not verify the data's integrity after the importing process. Please provide documentation that demonstrates that each time a new version of the MDL software is introduced, it is fully compatible with EACH of the previous versions of this software. Please provide documentation to show that when data files are transferred from older versions of the MDL to newer versions, they can be fully interpreted by the new MDL software. 3) Failure to establish and maintain procedures to ensure that the device design is correctly translated into production specifications, as required by 21 CFR (h). Specifically, SOP 11125, Design Transfer Procedure states that the application of this procedure is intended to be ongoing. The procedure states that as the design of Sigma International's devices evolves and validation is proven to. be successful, the design team will translate the design into production specifications. Yet, your firm failed to maintain DMRs for your MDL software, released units of the Spectrum Infusion Pump into interstate commerce with unvalidated software, and released versions 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 will be evaluated to determine the gaps relating to production specifications that resulted from the poor design transfer. Your February 16 response states that manufacturing work instructions, control, labeling, packaging, device history and distribution instructions were updated and implemented. That response also states that the design transfer process was verified and validated. Your response to this observation appears to be adequate and will be evaluated further at a future inspection of your facility. 4) Failure to establish and maintain procedures for analyzing processes, quality records, service records, complaints, returned product and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, as required by 21 CFR 5

6 (a)(1). For example, during our inspection of your firm's facility we discovered that there were several Spectrum Infusion Pumps in which the 1/0 PC board had failed. When your firm queried the electronic CAPA system containing customer complaints and product repairs using the part number for the 1/0 PC board,ssociated with failures of the I/O PC board in the pump were found to have occurred between January 2006 and September However,onlywere actually reported as a nonconformance on your Nonconformance 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 all complaints and repairs are reportable nonconformances. Yet, our assessment of the 10 complaints/repairs that your firm did not consider to be nonconformances, revealed that each resulted in a failure of the 1/0 PC board. Please explain why NCRs were not issued for these 10 complaints, when the root cause for each was identical to other complaints for which NCRs were issued. Additionally, regarding your Model 8000 infusion pumps, our investigator identified that many of these pumps failed in-process and final checks for flow calibration, and that several devices were reprocessed multiple times. Although the multiple nonconformances may be indicative of problems with your firm's flow calibration process, your firm has not initiated any corrective and preventive action (CAPA) to investigate this trend. 5) Failure to establish and maintain procedures for investigating the cause of nonconformities relating to product, processes and the quality system, as required by 21 CFR (a)(2). For example, our investigator identified NCR (Date : February 27, 2006), which described the root cause for the UO PC board failure on the Spectrum Infusion Pump # as "UO PCB failures where component level failure could not be identified at incoming evaluation." Similarly, the root cause in NCR (Date : August 14, 2006) states that "UO failed to initialize IrDA port, specific component not identified." On your NCR form, there is a space to enter a "Reason Code", in addition to stating the root cause for a nonconformance. In both examples cited above, the reason code was entered ; however, the SOP 11057, Nonconformance Procedure, does not provide any definition for these "Reason Codes." There was no further analysis attached to the NCR's to explain the reason for the 1/0 PC board failures. We also noted that other codes such as the "Symptom Code" and the "Disposition Code", which were identified on your NCR form, were not defined in SOP Your November 6, December 22 and February 16 responses state that SOP has been updated to clarify the NCR process, trending effectiveness and coding. These responses are not adequate in that you still have not identified the reason for the UO PC board failures. Please provide copies of any additional testing that your firm performed regarding the I/O PC boards failures. 6) Failure to establish and maintain procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the firiished 6

7 device, as required by 21 CFR (a)(4). For example, NCR (Date: February 27, 2006), states that the corrective action to the I/O PCB failures was to "replace the UO with the current revision." Similarly, NCR (Date: August 14, 2006) states that the corrective action to the I/O PCB failure w as to "replace [the] 1/0 PCB." There was no documentation to show that verification or validation of this corrective action w as effective in eliminating the I/O PC board failure in current and future devices, and that this corrective action did not have an adverse affect on the finished device. Additionally, during the inspection, our investigator identi fied NCR (Date: May 18, 2006) which showed an increase in production battery failures for the Spectrum Infusion Pump, and the tendency for these batteries to only charge to 83% of their capacity. Your firm stated that "some of the batteries coming from the supplier had incompatible voltages when mated together for the battery 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 cause were entered into your firm's electronic CAPA system. Yet, the system does not indicate which lot 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, your firm has implemented 100% inspection of all lots of ba tteries that Sigma receives from the vendor, 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 identified Complaint # IM (Dated: July 31, 2006) which showed a battery charging problem which had not yet been entered into your firm's CAPA system. This same deficiency was previously identified on the May 05, 2004, FDA 483 issued to your firm at the conclusion of the April/May 2004 inspection. Regarding the I/O PC board failures, your firm's November 6 response states that your firm is replacing the current `llwinished Boards" with new " oards." The response also states "to date, there have been 3 failures to these new oards." However, the response does not indicate whether Sigma has performed any verification or validation into the effectiveness of these new boards even though your firm has commenced installing the jolmoards into new Spectrum pumps. Your AW February 16 response states that this corrective action is still ongoirig. Your responses are not adequate. Please provide copies of the specific verification or validation tests and data that support the conclusions that thoards are 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 the verification/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 first identified, how many units of your products have been affected by this problem, how m any units are still in interstate commerce, how m an y complaints Sigma received regarding this problem, 7

8 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 the quality system, as required by 21 CFR (i). Specifically, your firm has not performed any validation for the automated process of programming the Spectrum pump's operating software and MDL software onto its PC boards. This process is defined in SOP 11004, I/O and Process Board Programming, SIGMA Model Also, there is no validation for th program. This software s used to program the Spectrum pump'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 as the sed to transfer operating and MDL software to the pumps, and the on* used to store and transfer various versions of the MDL and files specific to each hospital. Qualification. of this equipment is crucial to your software validation process, which assures that your firm can successfully 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 systems will be validated, and that CAPA will track the completion of these activities. Your February 16 response states that validation of the process board programming is complete and has been documented in ETP Yet, elsewhere in this response, you state that the validation of the48100program is still ongoing. You also state that the "...purpose of the ~rogram is for software development." However, durin the September/October 2006 inspection, your firm told our investigators that the ~was used to program the MDL software onto the PC boards. Furthermore, your February 16 response states that the validation activities for the hardware components are still ongoing. Yet, your firm continues to manufacture the Spectrum Infusion Pumps using this unvalidated process. For this reason, your firm's responses are not adequate. Please provide a timeline which identifies when these validation activities will be completed. 8) Failure to establish and maintain procedures for changes to a specification, method, process or procedure, as required by 21 CFR (b). Specifically, SOP 11140, Deviation Report Instruction, Revision C, requires that when your firm initiates a Deviation Report, employees must "record a complete and thorough explanation of why the product is deviating from the specification." Yet, when our investigator assessed the Deviation Log, there were entries that did not contain any reason for the deviation from specification. Also, the SOP is unclear as to the type of "specification" that the product is deviating from. If the product is deviating from its Design Specifications, then the changes must be evaluated through the appropriate Design Control process. This SOP also states that for each deviation, employees will "Record a complete and thorough explanation of why the deviation can be accepted." Our assessment of the Deviation Log showed that the entries did not contain any explanation of why the deviations were accepted. Additionally, the SOP does not clarify the disposition or status of product that has deviated from the specification. Furthermore, the SOP states that "repeated utilization of an 8

9 established deviation report shall be limited to QM with tension allowable for a maximum of 4~ However, the SOP is not clear as to the final disposition of the deviation and subsequent corrective action after the Deviation Report expires. This same deficiency was previously identified on the FDA 483 issued to your firm May 05, 2004 at the conclusion of the April/May 2004 inspection. Your firm's November 6 response states that the Deviation Report Instructions will be reviewed and updated to clarify process flow and approval for deviations. Your February 16 response states that SOP 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 Manufacturing Work Instructions..." Your firm's responses are inadequate. Please provide a list of the outstanding deviation reports that were reviewed, and their current status. Please explain whether the affected product is put into an "in-process hold" or "quarantine" status, while the Deviation Report is being approved, or whether it is immediately "fixed" in-line and released for distribution. Please explain how the deviation will be incorporated into the design of the product once the Deviation Report timeframe expires. This observation was originally on an FDA 483 issued 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 Deviation Report Instruction procedure. As of the latest inspection of your facility, your firm has failed to demonstrate 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 specified requirements, as required by 21 CFR (a). Specifically, there is no established rework procedure for Spectrum Infusion Pumps being upgraded to new hardware and/or new software as a 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 Restock to reflect how to define and document rework and repair. Your firm's response appears to be adequate 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 Specifically, your firm does not have a DMR for the MDL software that contains or identifies the location of all device and software specifications ; installation, maintenance and servicing procedures ; packaging and labeling specifications and procedures ; production process specifications and procedures ; and quality assurance procedures and specifications. Your firm's December 22 response stated SOP has been revised, and that a DMR for the MDL software has been created. Your February 16 response states that this activity is "Inprocess." Yet, your firm continues to manufacture the Spectrum Infusion Pump without a DMR in place. Your responses to this observation are not adequate. The purpose of the DMR is to document the performance and configuration characteristics for the device, so that these 9

10 activities can be controlled. Currently, the Spectrum Infusion Pump and the MDL software are undergoing changes that need to be documented in the DMRs for these devices. Please explain how your firm can assure that the devices you manufacture meet all of their pre-defined specifications 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 documents that 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) for each batch, lot or unit are maintained to demonstrate that the device is manufactured in accordance with DMR and the.qs regulation, and failure to maintain DHRs for each batch, lot, or unit, as required by 21 CFR For example, during the inspection, your firm told our investigator that the DHR for the Spectrum pump Model usually includes the following datasheets : Inspection Check List (ICL) 35700, ICL 35703, Inspection Test Procedure 35700, and Calibration Test Procedure However, your firm did not establish and maintain a procedure that assures the device is manufactured in accordance with the DMR. Additionally, our inspection revealed that your firm has never maintained a DHR for any version or lot, batch, or unit of the MDL software that was released for manufacturing. During the inspection our investigator was told that DHR's for the MDL software would be developed from data collected by the sales force, which will identify which version of the MDL software was provided to each customer. A DHR is intended to provide objective evidence that each device lot, batch, or unit of your firm's devices meet the requirements stated in each respective device's DMR. Your firm's November 6 response states that "An SOP for the Device History Record requirements 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. The response clarifies that the date of manufacturing, quantity manufactured, quantity released, and other metrics will be part of the DHR. This response appears to be adequate and will be further investigated at a future inspection of your facility. Please provide a timeline that indicates when the DHR's for the MDL software will be completed. 12) Failure to establish and maintain procedures to control labeling activities, as required by 21 CFR Specifically, there were no procedures to control labeling inspection, storage, and operations 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 labeling requirements. The response also states that CAPA # will track the completion of this activity. 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 10

11 when this corrective action will be completed. 13) Failure to store labeling in a manner that provides proper identification and is designed to prevent mixups, as required by 21 CFR (c). Specifically, as a result of your firm's lack of labeling control, an incorrect electronic version of the MDL software User's Guide (Revision A) was stored with the MDL software version The correct version of the user's guide to accompany MDL software version was Version C. End users at your firm's consignees were incorrectly issued Spectrum Infusion Pumps with Revision A of the User's Guide, which did not contain the new procedures for loading the MDL data file into the Spectrum pump. This procedure 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 corrective action associated with Observation 14 of the FDA-483. Based on our evaluation of these responses 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 to show how your firm will segregate labeling to prevent future mixups and a timeline detailing when this corrective action will be completed. 14) Failure to review for adequacy, and approve prior to issuance, all documents established to meet the requirements of the QS regulation, as required by 21 CFR (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 intended to identify revision codes associated with components of the Spectrum Infusion Pump. Instead, DOC was issued to production without any specific revision codes. The Production Supervisor created his own revision codes for the Spectrum pump components, which he handwrote onto a copy of document DOC Subsequently, he photocopied his revision code list and distributed it to production and repair personnel, who utilized and referenced these codes in official test records, and check lists for the Spectrum pump. The Production Manager continued to maintain the revision code list. Your firm has yet to update DOC to reflect the current revision codes that Sigma International uses. Sigma International's personnel continue to use modified versions of official forms to document testing that is performed on the Spectrum Infusion Pumps. b) The procedures titled Spectrum Drug Library Update and Spectrum Flash Download System have not been approved. In addition, although the procedures do not include the dates when these procedures were created, and the dates when they were implemented, your Repair Technicians and Programmers continue to use them to download Master Drug Libraries to your Spectrum Infusion Pumps. c) The Engineering Report ER , Software Build Tracking List, Master DrugLibrary, SIGMA Model Spectrum was reviewed and approved on July 26, The purpose of this document is to provide a description of the software detail that has been added to each labeled version of the Sigma MDL application. This document captures the software revision history from March 2005 through June However, your firm's records indicate that the MDL software has been in production since as early as December Changes to 11

12 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, the Spectrum Drug Library Update and the Spectrum Flash Download System, your firm's November 6 response states that these documents have been updated as part of ER This corrective action appears to be adequate and will be evaluated further at a future inspection of your facility. Regarding the Revision Code Sheet, your firm's November 6 response stated that the procedure DOC 11088, Revision Code Sheet, SIGMA Model Spectrum Infusion Pump is currently being revised. 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 action will be completed. Also, please clarify whether this unapproved document is being utilized as part of your current manufacturing process. Please indicate how your process will capture the information 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 when the change became effective, as required by 21 CFR (b). Specifically, there are no records of 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 each document. This document did not show the history of changes to any Operator Manuals issued before Rev. H (December 08, 2005). The revision history for the Service Manual only documents changes made in May 2006 for Revision E (The current revision for the Operator Manual and the Service Manual is Revision K). Your December 22 and February 16 responses indicate that your firm updated the revision history for the Operator and Service Manuals. This response appears to be adequate, but will be evaluated further at a future inspection of your facility. 16) Failure to provide adequate resources, including the assignment of trained personnel, for performing management, performance of work, and assessment activities, including internal quality audits, as required by 21 CFR (b)(2). Specifically, your firm created a new Director of Regulatory Affairs/Quality Assurance position which was filled on September 20, Prior to creating this position, the quality organization was a one person unit consisting of a Manager of Regulatory Affairs/Quality Assurance. It is evident based on the inspectional observations, that Sigma's quality organization cannot adequately satisfy the quality requirements as stated within the QS regulation. Your firm's November 6 and December 22 responses state that the Regulatory Affairs / Quality Assurance department has been expanded to include a Director of Quality and Regulatory, a Quality Supervisor, and a Quality Engineer. This response is not adequate in that you have not provided any job descriptions for the new job functions. Also, it is not clear how the Regulatory 12

13 Affairs/Quality Assurance department is aligned in Sigma's overall corporate organization. Please provide job descriptions for each position in your Regulatory Affairs/Quality Assurance department, 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 of hiring a software engineer and an electrical engineer. Yet, the response states that the corrective action for this deviation has been completed. Please explain how you have determined that this corrective action has been completed, when it appears that your firm is still hiring additional personnel to address the deficiencies identified to you by the FDA. 17) Failure to establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities, and failure to document this training, as required by 21 CFR (b). For example, there is no training record for the Production Supervisor who has trained the current production staff to program the Spectrum UO PC boards. During the inspection, our investigator was told the Production Supervisor was trained by engineers. However, your firm could not identify when the Production Supervisor was trained or by whom. Your firm's November 6 response states that SOP 11090, Employee Training will be reviewed and updated to improve employee training, and that employees' training files will be reviewed and updated with new training if gaps in training exist. Your firm's response appears to be adequate, 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 policy is understood, implemented, and maintained at all levels of the organization, as required by 21 CFR (a). Specifically, your firm's Quality Policy states that "SIGMA International's Team is dedicated to providing safe and reliable medical products and services to our customers." The Quality Policy also commits to "...maintaining compliance with all applicable statutory and regulatory requirements..." However, the numerous deviations from the QS regulation that were observed during the FDA's September/October 2006 inspection of the facility and noted on the FDA 483 issued to your firm on October 18, 2006, indicate your firm's management has not ensured that all levels of your organization understand and implement the Quality Policy. Your firm's November 6 response acknowledges that "Management with executive responsibility has not understood the quality system requirements to the level necessary to insure compliance." As part of its corrective action, your firm proposed to review and update your quality manual and quality policy, and to implement annual GMP training for all employees and management. Your February 16 response states that the Quality Manual has been rewritten, the Quality Policy has been reviewed, and that all employees received GMP training on January 7, The February 16 response also states that testing was conducted to determine the effectiveness of the GMP training. Your responses are not adequate in that no specific information regarding the proposed GMP training was provided. Please identify the curriculum 13

14 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 results of those tests. Our inspection also revealed that your Spectrum Pump with the Patient Controlled Analgesia/Patient Controlled Epidural Analgesia (PCA/PCEA) delivery modes is adulterated within the meaning of section 501(f)(1)(B) of the Act [21 U.S.C. 351(f)(1)(B)], because it is a class III device under section 513(f) of the Act [21 U.S.C. 360c(f)] and does not have an approved application for premarket approval in effect pursuant to section 515(a) of the Act [21 U.S.C. 360e(a)], or an approved 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 delivery modes 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 (a)(3). The Center for Devices and Radiological Health (CDRH), Office of Device Evaluation, reviewed your June 28, 2006, letter which stated that the PCA/PCEA delivery modes were included as part of the original 510(k) (K042121). During a teleconference held on July 14, 2006, and again in a letter dated July 28, 2006, CDRH informed you that 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 promptly correct the violations may result in regulatory action being initiated by the Food and Drug Administration 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 all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, pre-market approval applications for Class III devices to which the QS regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected. Regarding your November 6, December 22, and February 17 responses, we believe that the general timelines identified by your firm for performing corrective actions do not reflect the urgent nature of the observations that our Investigator noted during the FDA inspection. Moreover, your firm states that only "Priority 1" action items pose "a possible health risk." "Priority 2" and "Priority 3" actions are deemed by your firm to pose "no health risk." We believe that your firm's repeated failure to comply with the QS regulation substantially increases the risk your devices pose to the patients who use them. 14

15 Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how 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 over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the timeframe within which the 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) Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter, and in the Inspectional Observations, Form FDA 483 (FDA 483) issued at the closeout of the inspection, may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring your products into compliance. Sincerely, Otto D. Vitillo District Director New York District 15