Inspections, Compliance, Enforcement, and Criminal Investigations

Arkray Factory, Inc. 3/4/15

  

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

Public Health Service
Food and Drug Administration
 10903 New Hampshire Avenue
Silver Spring, MD 20993

 

WARNING LETTER
MAR 4, 2015 
 
VIA UNITED PARCEL SERVICE
 
Mr. Masanori Hatta
President and Chief Executive Office
Arkray Factory, Inc.
1480 Koji
Konan-Cho, Koka-Shi
Shiga-Ken 520-3306, Japan
 
Dear Mr. Hatta:
 
During an inspection of your firm located in Shiga-Ken, Japanon October 6, 2014 through October 8, 2014, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Class II over the counter blood glucose monitoring devices, clinical HbA1c analyzers, and urinalysis reagent strips/analyzer systems.  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 to affect the structure or 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 requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
 
We received a response from Takeshi Matsuda, President and CEO, Arkray Inc. dated October 30, 2014 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
 
1.    Failure to ensure that all activities required under section 21 CFR 820.100, and their results are documented, as required by 21 CFR 820.100(b). For example, (b)(4) and corresponding CAPA report (b)(4), did not document all of the investigation activities as required by the firm’s CAPA procedure, Corrective Action and Preventive Action Procedure Document Number: (b)(4).  Mr. Kazayuki Yamaguchi, the firm’s Director of Quality Assurance, explained that, as part of the investigation for the opened CAPA, the firm had conducted a test of (b)(4) ReliOn blood glucose monitoring devices which were (b)(4).  Specifically, when the readings of the (b)(4) were requested by the investigator, it was noted that the (b)(4) used during the investigation were not recorded and that the firm had not investigated why all (b)(4).  Additionally, the cause of the (b)(4) ReliOn blood glucose monitoring devices was not determined and no corrective actions were identified during the investigation.
 
We reviewed your firm’s response and conclude that it is not adequate.  Your firm provided revised Corrective Action and Preventive Action Procedure Document Number: (b)(4) Revision No: 6 Effective dated: 10/27/2014, which states that the CAPA Board shall evaluate verification and validation of corrective and/or preventive action plan and effectiveness check plan, and determine if the actions have an adverse effect on finished products, as well as determine the acceptability of the corrective and/or preventive action plan. Your firm states that relevant individuals were trained on the new/revised procedures and provided Education and training implementation record (b)(4) Dated 10/27/2014. However, your firm has not provided evidence that a corrective action has been implemented to include a retrospective review of all CAPA records to ensure that all investigations have been adequately documented and that the corrections and corrective actions do not adversely affect the devices.  Your firm also has not provided evidence that the identified deficiency of (b)(4) has been adequately documented.  Additionally, your firm has not provided a description or evidence of implementation of a correction to the deficiency to include evidence that the results obtained during the (b)(4) were documented and that (b)(4) was revised to reflect the results. In addition, your firm did not provide evidence that the cause and the corrective actions for the (b)(4) reading ReliOn blood glucose monitoring devices were determined.  Evidence that a systemic corrective action was considered to include a retrospective review of all CAPAs to ensure CAPAs were completed as required was not provided.
 
2.    Failure to establish and maintain procedures for rework, to include retesting and reevaluation of the nonconforming product after rework, to ensure that the product meets its current approved specifications, as required by 21 CFR 820.90(b)(2). For example, the rework and acceptance activities were not fully documented in the Device History Records (DHRs) for two DHRs reviewed which involved rework. Specifically:
 
a.  During review of your firm’s nonconformance Handling Procedure Document Number: (b)(4) Revision: 1.2 Effective Date: 10/2/2014 and previous version Revision: 1.1 Effective Date 10/3/2011, noted in the Rework section (b)(4) on page 52 on 7/30/2013.  However, the DHR did not include the initial failed test results but only included the final test results performed on 7/31/2013.  The failure for the (b)(4) recorded in (b)(4) as well as the action to (b)(4) on 7/31/2013, however, the initial failure (b)(4) not recorded in the test records. 
 
b.  Mr. Ryulchi Sasaki, your firm’s Deputy Director of Quality Assurance Management Representative Appointee, and Mr. Kazuyuki Yamaguchi, your firm’s Director of Quality Assurance and Deputy Director for Corporate Quality explained that the Nonconformity record (b)(4) opened 4/23/2014, documents the issue discovered by (b)(4). The rework was not adequately documented in the DHR as required.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided (b)(4) which clarifies the procedure to address reworking of non-conforming (b)(4) which defines procedure for handling of samples collected or testing/inspection purposes during rework activities.  Your firm states that all relevant personnel and departments have been trained on the new/revised procedures and provided training records indicating this. Your firm also provided revised (b)(4) and DHR format for instrument products to ensure the background of rework and reconciliation of reworked quantity are addressed, and to check the (b)(4) during rework activities.  Your firm states that all personnel in relevant departments have been trained on the revised procedures and DHR format and provided training records to this effect (b)(4). Your firm states that since implementation of the new procedures, there have been no cases of rework; therefore, past rework (b)(4) 10/21/2014).  Your firm provided Attachment 2-2-4 Cover Sheet of (b)(4) identified in item 1 above.  Your firm provided Attachment 2-1-4-1 Document (b)(4) as evidence of the correction for the deficiency outlined in item 2 above. However, your firm did not provide a description and evidence of implementation of a correction to include the requirement for retesting and reevaluation of nonconforming product after rework to be included in the procedures for evaluating nonconforming product. Additionally, your firm has not provided evidence that a retrospective review was performed of all DHRs to ensure that all rework and reevaluation activities were fully and adequately documented as required in the DHR.
 
3.    Failure to maintain a record of the investigation, when an investigation is made under section 21 CFR 820.198, by the formally designated unit identified in paragraph (a) of 21 CFR 820.198, as required by 21 CFR 820.198(e).  For example, the Complaint Handling Procedure, Document No: (b)(4), Revision 12.1, Effective date: 10/1/2014, regarding investigation results does not include requirements to ensure that the dates of the firm’s investigations are recorded. The 10 complaints sampled during the inspection did not include several required elements as indicated in 21 CFR 820.198(e). Specifically:
 
a.  Complaint #M5010162 involving (b)(4), did not have the report date accurately recorded in the Complaint form as evidenced by the associated emails in the original record. Emails provided by Mr. Genta Tanaka, your firm’s Manager of the Safety Management Team Quality Division, indicate the actual receipt date of the complaint was 03/08/2013, but 03/09/2013 was documented on the complaint form.  (b)(4) details section of the form included required questions to be answered; however, the listed questions were deleted from the complaint form.
 
b.  The complaint from a hospital in Australia involved instances where the test results from the HbA1c analyzer would be assigned to the wrong patient after a (b)(4) occurred.  The complaint record does include an MDR evaluation form but inaccurately records that the device or a similar device is sold in the US.  The MDR evaluation tree indicates the event was not reported to the US because it was deemed not an unreasonable risk to health.  Your firm stated this MDR evaluation tree was not completed accurately and should have indicated the device was not sold in the US.  In addition, the dates of the investigations required (b)(4) were not recorded nor were the investigation results and attachments identified as required by the procedure yet many emails with investigation activities were attached.
 
c.  Complaint #s M5100355, R5110050, M5110297, R5100349, M5100308, M5100311, M5100505, M5100449, M5100504, and R5100255 all lacked required elements, such as dates of investigation, contact information of the complainant, and dates and results of the investigations.
 
We reviewed your firm’s response and conclude that it is not adequate. The response did not address the items outlined in this deficiency as it was not listed on the FDA 483 as an observation.  
 
4.    Failure to establish and maintain procedures to control labeling activities, as required by 21 CFR 820.120.  For example, the firm’s labeling procedures, Labeling Control Procedures Document Number (b)(4), Revision A, Effective Date: 10/25/2011, does not include adequate requirements which ensure that (1) the release of labeling is appropriately documented in the DHR; (2) labeling and packaging operations are controlled to prevent labeling mix-ups; and (3) copies of the primary identification labels are retained in the DHR for the blood glucose monitor devices. Specifically, it was noted that the work instructions included in the Labeling Control Procedure D-Working Instruction Document No: (b)(4), Revision No: A, Effective Date 10/25/2011, does not include requirements to ensure that the label review and approval is recorded in the DHR and signed by the individuals performing the check and the approval of the labels.  The work instruction does not include any requirements to prevent-mix ups such as accounting for labels that are applied/scrapped/retained in the DHR and there is no reconciliation process to ensure all defective labels and printed labels are accounted for. Additionally, only a copy of a (b)(4).  No copies of the primary identification labels actually applied or the instructions for use inserted with the units were included in the DHR.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided revised Label Control Procedure (Device) Document No: (b)(4) Revision No: B, Effective date 10/27/2014.  The procedure describes the process used to ensure that labels are appropriately accounted for and documented in the DHR. Specifically, (b)(4) describes the responsible party that should check the details and approve the labeling issuance instruction. The document further states the procedure used for preparation of serial labels in the event of defective labels and storage of the label in the DHR.  The procedure also provides specific instructions for retaining the first and last label for glucose monitor devices in the DHR.  (b)(4) of the procedure provides instruction for controlling the number of labels used to include the number of initially issued labels, re-issued labels, labels used and defective labels.  Your firm states that since revision of the procedure, you have utilized the performance of the past nonconformity handling activities to ensure that the revised procedure, Label Issuance instruction form (b)(4), is properly applied.  However, your firm did not provide evidence that a correction and corrective action were implemented to include evidence that the primary identification label and labeling used for (b)(4) documented in the DHR, evidence that a retrospective review of all primary identification labels and labeling for each lot, unit, or batch was completed to ensure they were documented in the DHR as required, and evidence that employees were trained on the revised procedures.  In addition, your firm did not provide evidence that a systemic corrective action was considered to include a retrospective review of all DHRs to ensure all information was included as required.
 
5.    Failure to establish calibration procedures that include specific directions and limits for accuracy and precision, as required by 21 CFR 820.72(b). Specifically, the firm’s Calibration Procedure Document No: (b)(4), Revision 1.0, Effective Date10/01/2014, does not include adequate requirements for the in house calibration (b)(4) the acceptable ranges are defined.  Mr. Kazuyuki Yamaguchi, your firm’s Director of Quality Assurance, confirmed that your firm’s calibration procedure does not identify the acceptable range for the in house calibration checks.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided revised Calibration procedures (Device Manufacturing) Document Number: (b)(4), Revision 2.0, Effective date 10/27/2014.  The document includes, (b)(4), clarified instructions indicating the defined acceptable ranges for measuring equipment subject to calibration.  The procedures also include the number of calibration points, effective period, and if the calibration is a primary (outside site) or secondary calibration (in-house).  (b)(4) includes the procedures used for handling calibration non-conformance.  Your firm states that they have revised the Calibration Record Form to include a place to fill in the acceptable ranges. Your firm provided Attachment (b)(4) example as evidence of implementation of the revised Calibration record.  Your firm states that personnel of relevant departments have been trained on the new procedures and provided (b)(4) Education and Training Implementation Record Dated 10/27/2014, as evidence.  Your firm provided (b)(4) which your firm states it retrospectively reviewed the records for the past (b)(4) calibration records for measuring equipment with unclear acceptable range of calibration, to check whether they conform to the clarified acceptable ranges included in the revised procedures.  Your firm states that as a result of reviewing the past (b)(4) calibration records for subject measuring equipment, all were found to meet the standard as outlined in the revised procedures.  However, your firm did not provide evidence that it implemented a corrective action to include a retrospective review of all calibration results to ensure they met acceptable ranges as defined.
 
6.    Failure to establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirement s and to determine the effectiveness of the quality system, as required by 21 CFR 820.22.  Specifically, the firm’s Internal Quality Audit Procedure Document No: (b)(4) (multiple revisions reviewed) does not include adequate requirements which ensure all applicable FDA regulations are covered during internal audits.  Additionally, a discrepancy between the imbedded English translations of the frequency of audits which states (b)(4) that internal audits shall be implemented at least (b)(4) and the Japanese version which states the internal audit shall be implemented (b)(4).  Review of the audit schedules for Fiscal Year 2012 and 2013 noted that (b)(4) audits were conducted within (b)(4) year timeframe; the audit of the Research and Development Company was conducted (b)(4) while the audit of the Servicing Company was conducted (b)(4).
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided revised Internal Quality Audit Procedure Document No (b)(4) Revision 5.0.  The revised procedure includes in Section (b)(4) a clearly defined timeframe (b)(4) requirement for conducting internal audits to reconcile the discrepancy observed during the inspection.  Additionally, (b)(4) refers auditors to a table titled “(b)(4)” that includes all applicable regulations and the divisions that are subject to comply with the requirements.  Your firm provided revised forms for the Internal audit plan ((b)(4) Rev 5) and report (b)(4) to identify which requirements should be checked in which department.  Your firm states that the audit intervals have been clearly defined and are easily known by looking at the revised Master Schedule.  Your firm states that all internal quality auditors as well as the members of the internal quality audit control departments have been trained on the revised procedures and provided (b)(4) as evidence of the training.  However, your firm has not provided evidence that internal audits were conducted as required by the revised audit procedure.  In addition, your firm did not provide evidence that it completed a retrospective review of procedures to ensure they met regulatory requirements as a corrective action to this deficiency.
 
We reviewed your firm’s response and conclude that it is not adequate in that it did not address this observation.
 
Our inspection also revealed that the Glucose test systemdevicesare misbranded under Section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information regarding the devices that is required by or under Section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 - Medical Device Reporting. Significant deviations include, but are not limited to:
 
Failure to adequately develop, maintain and implement written MDR procedures, as required by 21 CFR 803.17. For example, after reviewing your firm’s MDR procedure titled “Medical Device Reporting Procedure (US),” Rev. New, dated May 30, 2013, the following issues were noted:
 
a.  The procedure does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements. For example:
  • There are no definitions of what your firm will consider to be a reportable event under 21 CFR Part 803. The exclusion of definitions from 21 CFR 803.3 for the terms “become aware,” “caused or contributed,” “malfunction,” “MDR reportable event,” and “serious injury,” and the definition for the term “reasonably suggests,” found in 803.20(c)(1) may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR 803.50(a).
b.  The procedure does not establish internal systems that provide for a standardized review process to determine when an event meets the criteria for reporting under this part. For example:
 
1.    There are no instructions for conducting a complete investigation of each event and evaluating the cause of the event.
 
2.    The procedure, as written does not specify who makes the decision for reporting events to FDA. 
 
3.    There are no instructions for how your firm will evaluate information about an event to make MDR reportability determinations in a timely manner.
 
c.  The procedure does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the following is not addressed:
  • Instructions for how to obtain the FDA 3500A form.
d.  The procedure does not describe how your firm will address documentation and record-keeping requirements, including:
 
1.    Documentation of adverse event related information maintained as MDR event files.
 
2.    Information that was evaluated to determine if an event was reportable.
 
3.    Documentation of the deliberations and decision-making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable.
 
4.    Systems that ensure access to information that facilitates timely follow-up and inspection by FDA.
 
The adequacy of your firm’s response dated October 30, 2014 cannot be determined at this time. Your firm submitted a revised MDR procedure titled Medical Device Reporting Procedure, (b)(4), Rev. 1.0,dated October 22, 2014. After reviewing the revised MDR procedure, (b)(4), Rev. 1.0, the following was still noted:
 
a.  The procedure does not establish internal systems that provide for timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements. For example:
  • The procedure omits the definition for the term “reasonably suggests,” found in 803.20(c)(1). The exclusion of the definition for this term from the procedure may lead your firm to make an incorrect reportability decision when evaluating a complaint that may meet the criteria for reporting under 21 CFR 803.50(a). 
b.  The procedure does not establish internal systems that provide for a standardized review process to determine when an event meets the criteria for reporting under this part. For example:
  • There are no instructions for conducting a complete investigation of each event and evaluating the cause of the event.
c.  The procedure does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the following is not addressed:
  • Instructions for how to obtain the FDA 3500A form.
d.  The procedure does not describe how your firm will address documentation and record-keeping requirements, including:
 
1.    Documentation of adverse event related information maintained as MDR event files.
 
2.    Information that was evaluated to determine if an event was reportable.
 
3.    Documentation of the deliberations and decision-making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable.
 
4.    Systems that ensure access to information that facilitates timely follow-up and inspection by FDA.
 
The eMDR Final Rule requiring manufacturers and importers to submit electronic Medical Device Reports (eMDRs) to FDA was published on February 13, 2014.  The requirements of this final rule will take effect on August 14, 2015.  If your firm is not currently submitting reports electronically, we encourage you to visit the following web link for additional information about the electronic reporting requirements: http://www.fda.gov/ForIndustry/FDAeSubmitter/ucm107903.htm
 
If your firm wishes to discuss MDR reportability criteria or to schedule further communications, it may contact the Reportability Review Team by email at ReportabilityReviewTeam@fda.hhs.gov
 
U.S. federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts.  Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. 
 
Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, including an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again.  Include documentation of the corrections and/or corrective action (which must address systemic problems) that your firm has taken.  If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities.  If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed.  Please provide a translation of documentation not in English to facilitate our review. We will notify you regarding the adequacy of your firm’s response(s) and the need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made.
 
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Inspections Support Branch, White Oak Building 66, Rm 2622, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case 446565 when replying. If you have any questions about the contents of this letter, please contact James Woods at 301-796-6225.
 
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility.  It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA.  The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems.  Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance. 
 
 
Sincerely yours,
/S/                                                           
Alberto Gutierrez
Director
Office of In Vitro Diagnostics and
    Radiological Health
Center for Devices and
    Radiological Health

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