Inspections, Compliance, Enforcement, and Criminal Investigations

Shima Laboratories Co., Ltd. 3/21/14

  

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 21, 2014

Masakatsu Hashimoto, Ph.D.
President & CEO
SHIMA Laboratories Co., Ltd
1-16-4, Maeno-Cho,
Itabashi-Ku, Tokyo, 174-0063 Japan
 
Dear Dr. Hashimoto:
 
During an inspection of your firm located in ltabashi-Ku, Tokyo, Japan on September 30, 2013 through October 3, 2013, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures K-Assay D-Dimer, K-Assay D-Dimer Calibrator, Models KAI 090, KAJ-091 C. 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 Dr. Masakatsu Hashimoto, President and CEO, dated October 24, 2013 concerning our investigator's observations noted on the Form FDA 483 (FDA 483), List of lnspectional Observations that 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 establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30(a)(1).
 
For example: your firm has yet to subject the K-Assay D-Dimer lmmunoturbidmetric Assay and K-Assay D-Dimer lmmunoturbidmetric Calibrator (cleared under 510(k) #K030687) through the design control process in order to ensure that specified design requirements are met. Your firm's Director, Board Member, and Top Management, Mr. Masahiro Baba, confirmed and stated that your firm has not conducted design controls for the D-Dimer lmmunoturbidmetric Assay and Calibrator.
 
We reviewed your firm's response and conclude that it is not adequate. Your firm provided no documentation of staff training on the revised SOP. Also, documentation of completing the design controls for the K-Assay D-Dimer lmmunoturbidmetric Assay and Calibrator was not provided pending completion of the design control process of the K-Assay and controls after the 8 week period from the inspection date. Finally, your firm did not provide documentation supporting that a comprehensive retrospective assessment was conducted in conjunction with the above corrective actions to determine if your firm had other products that needed to be subjected to design controls.
 
2.    Failure to establish and maintain procedures for implementing corrective and preventive action that shall include a requirement for analyzing processes, work operations, concessions, quality audit reports, 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 820.100(a)(1).
 
For example: your firm's Corrective and Preventive Action (CAPA) Procedure, Document #17, version 12.0, requires that a CAPA be initiated (as necessary) based on the results of the data analysis. However, your firm has yet to identify the quality data sources to be analyzed, using the appropriate statistical methodology where necessary, to detect recurring quality problems. Your firm's Director, Board Member, and Top Management, Mr. Masahiro Baba, confirmed that your firm has yet to identify the quality data sources to be analyzed.
 
We reviewed your firm's response and conclude that it is not adequate. Your firm did not provide documentation of staff training on the revised SOP. In addition, your firm did not provide documentation supporting that a comprehensive retrospective assessment was conducted in conjunction with the above corrective actions to ensure that all data sources were analyzed to identify existing or potential causes of nonconforming product
 
3.    Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test, that the process shall be validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75(a).
 
For example: Your firm currently uses the (b)(4) that is used to manufacture the D-Dimer lmmunoturbidmetric Assay once (b)(4) added. However, your firm's (b)(4) has yet to be validated. Your firm's Director, Board Member, and Top Management, Mr. Masahiro Baba, confirmed that your firm has not validated the (b)(4).
 
We reviewed your firm's response and conclude that it is not adequate. Documentation of the results of the validation activities was not provided pending completion of the validation process after the 24 week period from the inspection date. In addition, your firm has not ensured that future processes will be validated as appropriate. Finally, your firm has not provided evidence that it has performed a comprehensive retrospective assessment of all processes to ensure that all processes requiring validation have actually been validated.
 
4.    Failure to develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications, as required by 21 CFR 820.70(a).
 
For example: your firm's Product Standard Specifications for the D-Dimer Product, Document (b)(4), version 8.0, states that once the (b)(4) portion of the procedure. Your firm's Director, Board Member, and Top Management, Mr. Masahiro Baba agreed that the procedure lacks specific instructions for the (b)(4)
 
We reviewed your firm's response and conclude that it is not adequate. Your firm did not demonstrate full implementation of the new document to include training records of the individuals to be trained on the procedure. In addition, your firm did not provide documentation supporting that a comprehensive retrospective assessment of other products was conducted in conjunction with the above corrective actions to ensure that production processes were conducted, controlled, and monitored to ensure products met specifications.
 
5.     Failure to maintain complaint files and establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).
 
For example: Your firm's Quality Information Processing (or Complaint Handling) Procedure, document #19, version 2.0, does not require complaints to be evaluated to determine whether the complaint should be filed as a Medical Device Report (MDR) to the FDA. Complaints #012012-13 dated 5/17/2012 and #19-5 dated 11/29/2007 lacked MDR evaluation. Your firm's Director, Board Member, and Top Management, Mr. Masahiro Baba, confirmed and stated that the current complaint handling procedure does not require complaints to be evaluated for MDR reportability.
 
We reviewed your firm's response and conclude that it is not adequate. Your firm did not provide documentation of staff training on the revised SOP. In addition, your firm did not provide documentation supporting that a comprehensive retrospective assessment was conducted to determine if there were other historical complaints in addition to Complaints #012012-13 and #19-5 that should have been evaluated to determine whether the complaint should be filed as a Medical Device Report (MDR) to the FDA.
 
6.    Failure of management with executive responsibility to review the suitability and effectiveness of the quality system at defined intervals and with sufficient frequency according to established procedures to ensure that the quality system satisfies the requirements of this part and the manufacturer's established quality policy and objectives, as required by 21 CFR 820.20(c).
 
For example: There is no documented evidence showing that your firm's executive management attended the monthly meetings according to the meeting agendas from January, April, and August 2013. Your firm's Director, Board Member, and Top Management, Mr. Masahiro Baba, stated that the firm is not documenting the individuals who are attending the management review meetings.
 
We reviewed your firm's response and conclude that it is not adequate. Your firm did not provide documentation of completed reviews by management for January, April and August as a correction to the deficiency. Also, your firm did not demonstrate full implementation of the new document to include training records of the individuals to be trained on the procedure. Finally, your firm did not provide documentation supporting that a comprehensive retrospective review of all management review meetings to ensure all required attendees completed the management reviews.
 
Our inspection (also) revealed that your firm's K-Assay D-Dimer, K-Assay D-Dimer Calibrator, Models KAI 090, KAJ-091 C are 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 respecting the device 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 violations include, but are not limited to, the following:
 
Failure to develop, maintain, and implement written Medical Device Reporting (MDR) procedures, as required by 21 CFR 803.17.
 
For example: Your firm has yet to establish a Medical Device Reporting procedure. Your firm's Director, Board Member, and Top Management, Mr. Masahiro Baba, stated that this facility has yet to establish a written MDR procedure.
 
We reviewed your firm's response and conclude that it is not adequate. Your firm developed a written MDR procedure titled, "SOP of Medical Device Reporting Procedure Document #82, version 1, effective October 11 , 2013."
 
After reviewing SOP#82, version 1, the following issues were noted:
(1)  SOP#82, version 1 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 definitions for the terms "reasonably known" and "reasonably suggests," found respectively in 21 CFR 803.50(b) and 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).
 
(2)  SOP#82, version 1 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.
 
(3)  SOP#82, version 1 does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the following are not addressed:
 
a.  Instructions for how to obtain the FDA 3500A form. The procedure references an incorrect link to obtain the FDA 3500A form. The correct link is to obtain the FDA 3500A form is http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM/048334.pdf
 
b.  Although the procedure includes references to 30 day reports, it does not specify calendar days.
 
If your firm wishes to submit MDR reports via electronic submission it can follow the directions stated at the following URL: http://www.fda.gov/Forlndustry/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. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices 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.
 
Your firm's response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Operations Branch, White Oak Building 66, Rm 2622, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #418378 when replying. If you have any questions about the contents of this letter, please contact: Joshua Levin at 301-796-6695.
 
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 lnspectional 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 InVitro Diagnostics and
    Radiological Health
Center for Devices and
    Radiological Health

Page Last Updated: 04/14/2017
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