Inspections, Compliance, Enforcement, and Criminal Investigations

INCYTO CO., LTD. 9/8/16

  

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
SEP 8, 2016 
 
VIA UNITED PARCEL SERVICE
 
Mr. Shane Cho, CEO
Incyto Co., Ltd.
112 Seonggeo-gil
Seonggeo-eup, Seobuk-gu,
Cheonan-si
Chungnam-do, 331-836
Republic of Korea
 
Dear Mr. Cho:
 
During an inspection of your firm located in Chungnam-do, Republic of Koreaon March 28, 2016 through March 31, 2016, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures several Class I devices, Incyto C-Chip-disposable hemocytometers.  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 you dated April 20, 2016 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 establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a).
 
For example: During the inspection, four CAPA’s were reviewed and revealed they lack details about the investigations conducted and effectiveness checks conducted as specifically evidenced by:
 
1.    CAPA C5-9, dated 06/24/2015, related to liquid injection failure, does not include the investigation details, evidence that the information was disseminated to those affected, and the effectiveness date.
 
2.    CAPA C5-8, dated 06/24/2015, related to defects on the C-Chip device surface, does not include investigation details and the effectiveness date.
 
3.    CAPA C4-11, dated 06/12/2014, related to equipment not having verification or validation, does not include investigation details or evidence that an effectiveness check was completed as required.
 
4.    CAPA C5-01, dated 05/24/2015, related to a nonconformity with the C- Chip packaging, does not include an effectiveness plan.
 
We reviewed your firm’s response and conclude that it is not adequate.  Your firm did not provide evidence of corrective actions nor did it provide the required revisions to the CAPAs (C5-9, C5-8, C4-11 and C5-01) reviewed during the inspection.  The CAPA revisions that your firm needed to provide include the missing investigation details and the relative required effectiveness checks, plans, dates and actions to each respective CAPA.  The corrective actions included evidence of revisions to CAPAs C5-9 and C5-8 as these documents were missing investigative details along with the required effectiveness checks.  However, your firm did not provide evidence of a revised procedure—i.e. it did not outline revisions to the CAPA requirements.  The revised procedure should include details of the investigation, effectiveness checks and dates; it should also include quality product validation and verification activities.  In addition, evidence of notifications of the relevant production staff involved in the investigation was not provided as part of the revised CAPAs.  Your firm also did not provide a plan or evidence that it conducted a systemic corrective action to include a retrospective review of all CAPAs to ensure CAPAs were completed as required.
 
2.    Failure to ensure all complaints are evaluated to determine whether the complaint represents an event which is required to be reported to FDA under part 803 of this chapter, Medical Device Reporting, as required by 21 CFR 820.198(a)(3).
 
For example: Your firm did not evaluate five Incyto C-Chip complaints to determine MDR reportability.  You confirmed that Incyto did not conduct an MDR determination for the complaints.  Specifically, five complaints: CP15-01 dated 05/22/2015, CP13-05 dated 10/23/2013, CP13-04 dated 03/14/2013, CP12-02 dated 04/02/2012, and CP11-01 dated 05/17/2011, were not evaluated to determine whether the complaints were MDR reportable events as outlined in your Quality Manual QM-01 section 7.2.2(c).
 
We reviewed your firm’s response and conclude that it is not adequate.  You indicate that, as part of corrective actions, the firm amended procedures in the Quality Manual QM-01 section 7.2.2(c) and Customer Complaint Handling SOP OP-710. This included the evaluation of an MDR reportable event along with reforming the customer complaint report, F710-02 in order to insert items of the related evaluation. However, your firm did not provide evidence of what revisions (English translation) were outlined in OP-710 and to form F710-02. Your firm did not provide evidence of verification of the effectiveness and implementation of the corrective actions outlined in QM-01, Sec 7.2.2(c), OP-710 and in form F710-02. Also, your firm did not provide evidence that staff were trained on the revisions to procedures QM-01, 7.2.2(c), OP-170, and form F710-02.  In addition, your firm did not provide evidence of comprehensive retrospective review of complaints to ensure that complaints were evaluated for MDR reportability as required, as well as the five complaints, CP15-01 dated 05/22/2015, CP13-05 dated 10/23/2013, CP13-04 dated 03/14/2013, CP12-02 dated 04/02/2012, and CP11-01 dated 05/17/2011.
 
3.    Failure to review and approve changes by an individual in the same function or organization that performed the original review and approval, unless specifically designated otherwise, and failure to communicate approved changes to the appropriate personnel in a timely manner, as required by 21 CFR 820.40(b).
 
For example, your firm has no documented evidence that document changes were communicated to affected personnel as required by section 4.2.3(i) of your firm’s Quality Manual, QM-01, Rev. 3.  Specifically, document changes made to the Medical Device Reporting procedure, OP-811, MDR, Rev. 01, were not communicated to affected personnel.  You confirmed verbally there is no training or education for the employees affected by document changes.
 
We reviewed your firm’s response and conclude that it is not adequate.  As part of your corrective action, your firm did not provide evidence that all staff were trained on the document control revisions outlined in the QM-01, Rev.3.0 Quality Management Manual.  A revision in procedure OP-601, Human Resource-Training & Education Report, includes a clause pertaining to any significant change in the Quality Management System that outlines document control will require staff training.  The SOP OP-601 outlines all staff will be trained on document revisions based on document control requirement outlined in the revised Quality Management Manual QM-01 Rev3.0.  However, your firm did not provide documentation of revisions nor staff training to these revisions in the Medical Device Procedure-OP-801, Rev1.0.  In addition, your firm did not provide a plan or evidence of a retrospective review of all changes to document procedures to ensure that changes to documents were conducted as required by document control requirements based on revisions to SOPs QM-01, Rev3.0, OP-601, and OP-801 to ensure regulatory requirements are being met.
 
4.    Failure to establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics where appropriate, as required by 21 CFR 820.250(b). Specifically:
 
1.    The sample sizes selected for final quality control testing/checks for the C-Chip are not based on a valid statistical rationale.  An insufficient number of sample units (five or ten units) are used for final testing/check regardless of batch size.  You stated C-Chip batch sizes range from 5000-10000 units.
 
2.    The process validation conducted for the C-Chip Packaging System in August 2015 included a sample size not shown to be statistically valid.  Your firm manufactured one run with 500 C-Chip units and selected 10 units for the air balloon test and seal strength test.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm indicated that it will perform and document the sampling size based on KS Q ISO-2859 (2010) to confirm the final packaging inspection/check and process validation for the C- Chip.  Your firm also translated in the product Device Master Record (DMR) a revision to the pass/fail criteria of the final inspection testing outlining sampling criteria in accordance with KS Q ISO-2859(2010). However, your firm did not provide evidence that process validation was conducted based on the change of the sampling size.  In addition, your firm did not provide evidence that staff were trained on the revised procedure.  Also, your firm did not present a plan or provide documentation of a comprehensive retrospective review of all product DMRs and final acceptance activities to ensure all DMRs and results of final acceptance activities reflected the sampling method revision for verification in your final inspection reports in accordance with regulatory requirements.  Your firm did not provide evidence that final quality control testing/checks for the C-Chip were completed based on the revised statistically based sampling plan as required.
 
5.    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 requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22.
 
For example: Your firm’s internal audit SOP, OP-802, Internal Audit, Rev. 1.0, dated 04/04/2011, does not include audit criteria and this was confirmed by you.  The last page of exhibit #15 includes a translation from the first page of SOP OP-802, which the firm provided to the investigator, confirmed the procedure does not mention the audit criteria because it is written in the audit plan prior to conducting the audit.  The procedure does not include a requirement for Incyto to conduct an internal audit covering 21 CFR 820.
 
We reviewed your firm’s response and conclude that it is not adequate.  Your firm provided documentation of the revised audit procedure, OP-802, Internal Audit Rev.1.0 outlining the internal audit criteria including the internal audit check list from form F802-2.  Your firm also notes the internal audit criteria procedure will be regularly updated following the current regulation.  However your firm did not provide evidence that the internal audit criteria will be based on the requirements of the Quality System (QS) regulation and that an internal audit will be conducted as required to assure your firm’s quality system is in compliance with the QS regulation.  Also, your firm did not provide documentation that staff was trained on revisions to the Internal Audit procedure OP-802, Rev1.0.  In addition, your firm did not provide evidence that it considered a systemic corrective action to include a retrospective review of all quality system procedures to ensure they are in compliance with the QS regulation.
 
6.    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 the DMR and requirements of this part (21 CFR 820) are met, as required by 21 CFR 820.184.
 
For example, your firm does not maintain a device history record (DHR) for the Incyto C-Chip device.  Specifically, your firm does not have a DHR procedure which describes requirements including, but not limited to the records that are part of the DHR and the requirement to include the primary identification label and labeling used for each production unit.  The primary identification label used for each production unit was not properly identified in the C-Chip device DHR.  You confirmed that the only record reviewed by Quality Assurance (QA) prior to approval of a C-Chip batch is the Final Inspection Report Sheet which does not include date of manufacture and the primary identification label. The DHR procedure did not exist for five (5) DHR records, including record numbers 5124A233, 5333A233, 5228B233, 4464B233, and 5386B233. The DHR records provided did not include a copy of the primary identification label used for each production unit.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm has made the required revisions to the DHR section in the Identification and Traceability SOP- OP-709 as a correction to this deficiency.  Your firm has also applied the revisions outlined in OP-709 as part of the DHR process in production.  However, your firm noted that an audit of the revisions to the DHR process will be applied based on the revised SOP OP-709, but no evidence of how this will be performed or evidence of this application was provided.  Your firm did not provide evidence that revisions to Record Control OP-402 procedure clearly outlined the documents that will be part of the DHR.  Your firm also provided no evidence that production staff was trained in the revised procedures OP-709 and OP-402.  Also, your firm did not present a plan or provide documentation of a comprehensive retrospective review of all product DHRs to ensure the DHRs were documented as required by your firm’s procedures OP-402 and OP-709 to ensure regulatory requirements are met.
 
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 #497916 when replying. If you have any questions about the contents of this letter, please contact: Janine Bey at (301) 796- 6955.
 
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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