- X12 Co., LTD.
- Issuing Office:
- Center for Devices and Radiological Health
10903 New Hampshire Avenue
Silver Spring, MD 20993
VIA UNITED PARCEL SERVICE
MAR 23, 2017
X12 Co., Ltd.
J&L Center, Floor 4, Room 418
46 Lubliana Str
Dear Mr. Jordanov:
During an inspection of your firm located in Sofia, Bulgaria on September 5, 2016, through September 7, 2016, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures sterile reflective marker spheres. 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 responses from you, dated September 21, 2016, and October 23, 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 to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30. For example, the following deficiencies were observed during a review of the design activities for the sterile reflective marker spheres:
a. Design requirements that address the intended use of the device have not been adequately established.
b. Your firm has no documentation of design outputs in terms that allow evaluation of conformance to design input requirements.
c. Your firm has no documentation of design reviews. Your firm stated no design review meetings were held.
d. Your firm has no design verification records. Your firm stated no design verification records exist.
e. Your firm has no documentation indicating shelf life studies were conducted to support the expiration date labeling of 24-months.
f. Your firm has no documentation indicating that the device design was correctly translated into production specifications.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should submit the design inputs and outputs, design verification records, shelf life studies, and evidence that the device design has been translated into production specifications.
2. Failure to ensure that when the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedure, as required by 21CFR820.75(a). For example, your firm did not validate the (b)(4) sterilization process, the pouch sealing process, the foil adhesion process, or the packaging used in the manufacturing and storage of the reflective marker spheres.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should submit validation summary reports and protocols for the sterilization process, pouch sealing process, foil adhesion process, and the packaging validation for review.
3. Failure to establish and maintain procedures to control environmental conditions that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(c). For example:
a. Opened unscreened windows in the production area. As a result, raw, in-process and finished materials are exposed to outdoor conditions.
b. Walls in the production, packaging and storage areas in poor condition. For example: peeling paint, dirty walls and holes in the walls of the production areas were observed.
c. Dirty floors in the production, packaging and storage areas. Damaged flooring was also observed.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide procedures and records for the cleaning and repair of production and storage areas and evidence that the holes in the walls, peeling paint and the damaged floors have been repaired and addressed.
4. Failure to establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(e). For example:
a. There are no controls in place to ensure storage containers used to hold in-process and finished devices are suitable for its intended use. For example, styrofoam trays, plastic containers and aluminum pans are re-used for storage of in-process and finished devices. However, soiled plastic containers were observed storing device components in the production area. In addition, there are no facilities in production to facilitate the cleaning of these trays, containers and pans before re-use.
b. Work surfaces, (b)(4) machines, and test equipment in use in production were not clean. Surfaces were observed with black or gray grease.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide procedures and records for cleaning work surfaces, (b)(4) machines, and test equipment and also provide procedures that describe the controls necessary to ensure storage containers used to hold in-process and finished devices are suitable for its intended use.
5. Failure to establish and maintain procedures for receiving, reviewing, and evaluation complaints by a formally designated unit, as required by 21CFR820.198. For example:
a. Your firm's compliant handling procedure, WIS 01-01, does not include requirements to ensure that:
i. Complaints are processed in a uniform and timely manner.
ii. Complaints are evaluated for Medical Device Reporting (MDR). Five of five complaint records reviewed did not contain documentation of MDR reportability assessments.
b. Your firm's complaint handling procedure does not include requirements that records of investigation include, but are not limited to: any device identifications and control number used; the name, address, and phone number of the complainant; the dates and results of the investigation; and any reply to the complainant. For example:
i. Complaint# 2, dated January 2013, related to sterile pouches opening too easily. The complaint record did not include the device identification, results of the investigation, or reply made to the complainant.
ii. Complaint# 3, dated April 2013, related to sterile pouches being too hard to open. The complaint record did not include the address and phone number of the complainant, the results of the investigation, the device identification and reply made to the complainant.
c. Your firm's procedure does not include requirements that records of MDR investigations include:
i. Whether the device failed to meet specifications.
ii. Whether the device was being used for treatment or diagnosis.
iii. The relationship if any, of the device to the reported incident or adverse event.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide a revised complaint handling procedure that meets the requirements of 21 CFR 820.198.
6. Failure to establish and maintain procedures for acceptance of incoming product, as required by 21 CFR 820.80(b). For example, your firm has not established incoming acceptance requirements for incoming raw materials and components used in the production of class 2 devices. There is no established inspection, examination, or test for any components to verify they are suitable for use in production nor has your firm confirmed whether suppliers are conducting complete testing of these components and raw materials.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should categorize and document which components and raw materials require incoming inspection criteria; document specifications for acceptance criteria; and revise the applicable procedures to specify the required inspection, and testing needed or the other methods of verification appropriate to demonstrate suitability of raw materials and components prior to use in production. Your firm should also provide evidence of completion of these corrective actions.
7. Failure to establish and maintain procedures for implementing corrective and preventive action (CAPA), as required by 21 CFR 820.100(a). For example:
a. Your firm's CAPA procedure, QP8 04, "Corrective and Preventive Actions," does not include the following provisions:
i. Verifying or validating corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device.
ii. Ensuring information related to quality problems or nonconforming product is disseminated to the individuals responsible for assuring the quality of the product or prevention of the problem.
b. CAPA activities are inadequate in that they do not include investigation details and verification and/or validation activities to ensure that such actions are effective and do not adversely affect the finished device.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide a revised procedure that describes requirements for verifying or validating corrective and preventive action and disseminating information regarding quality problems to employees. Your firm should also provide evidence of implementation of the corrective actions described in the response.
8. Failure to ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21CFR820.70(g). For example:
a. Production equipment leaking an unidentified substance on the floor has not been repaired. Instead, a plastic shopping bag was used to catch the leakage.
b. Your firm confirmed that preventive maintenance activities (e.g. changing of the (b)(4)) for the (b)(4) and the (b)(4) have not been documented.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide evidence that the production equipment leaking the unidentified substance on the floor has been repaired.
9. 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 did not establish a production procedure for the preparation, use, and testing of the adhesives used to (b)(4) foil to the (b)(4).
The adequacy of your firm's responses cannot be determined at this time. Your responses indicated that protocols will be created for the (b)(4) and usage of the adhesive. Your firm should provide evidence of implementation of these corrective actions.
10. Failure to establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria, as required by 21 CFR 820.80(d). For example, your firm did not adequately establish suitable final product testing to verify Tyvek/plastic pouch seals. Pouches are released based on only visual inspection of the sealing.
The adequacy of your firm's responses cannot be determined at this time. Your responses indicated that a protocol regarding packaging and how it is performed will be created and will include some strength tests for each batch of sealed pouches. Your firm should provide evidence of implementation of these corrective actions.
11. Failure to evaluate and select potential suppliers, contractors, and consultants on the basis of their ability to meet specified requirements, including quality requirements, and document the evaluation, as required by 21 CFR 820.50(a)(l). For example, your firm has no documentation to support evaluations of the foil material and the (b)(4) suppliers were conducted, since the initial supplier evaluations were conducted in 2011. In addition, there is no documentation showing that the (b)(4) suppliers had been qualified by your firm.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide its "Purchasing Goods and Supplies" procedure, QP7 03, for review; approved supplier listing and documentation supporting that supplier evaluations have been conducted for all listed suppliers.
12. Failure to establish and maintain adequate procedures to ensure that device history records (DHRs) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record (DMR) and the requirements of this part, as required by 21CFR820.184. For example, a review of three DHRs revealed they do not include:
a. Acceptance records, including acceptance activities performed and the results. Your firm only records the number of acceptable devices and rejects.
b. The primary identification label and labeling.
c. The date and signature of the individual performing the labeling inspection.
d. The equipment used in production.
e. The instruments used for in-process and finished device testing.
f. Identification of the raw materials and components used in the production of devices.
We reviewed your firm's responses and conclude that they are not adequate. Your response did not address documenting the date and signature of the individual performing the labeling inspection and the instruments used for in-process and finished device testing in the DHR' s. Your firm should provide evidence of completion of the corrective actions described in the responses.
13. Failure to establish and maintain procedures for identifying product during all stages of receipt, production, distribution, and installation to prevent mixups, as required by 21 CFR 820.60. For example:
a. (b)(4) used to (b)(4) during device production are incorrectly labeled. Your firm confirmed the (b)(4) in the (b)(4) is not what is indicated by the labeling (b)(4)
b. Your firm's procedure QP7 05, "Identification and tracking of devices being produced," does not adequately describe the systems used for identifying materials. Your firm's CEO described the information contained in the procedure as being out of date. In addition, the inspection identified raw materials, components, in-process product and finished devices (prior to sterilization) in production with no identification labels.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide a revised procedure that describes the current controls and systems used for identifying materials and their status that includes components, manufacturing materials, subassemblies, finished devices, packaging, and labeling, as well as evidence of the procedure implementation. Your firm should also provide evidence of implementation of the corrective actions described in the response.
14. Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, and include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained, and to ensure equipment is suitable for its intended purposes and is capable of producing valid results, as required by 21CFR820.72(a). For example:
a. Your firm has not established calibration procedures to ensure that equipment is routinely calibrated, inspected, checked and maintained and to include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained.
b. Your firm did not calibrate the following test and measurement instruments since 2011:
In addition, there has been no calibration performed on in-process or final inspection measurement/test equipment, e.g. (b)(4) other instruments because according to your firm's CEO, "no calibrations are needed, as the instruments are accurate enough for the firm's purposes."
c. There is no requirement for inspection or measuring tools made in-house, (b)(4), to undergo a type of measurement system analysis to confirm suitability of its intended use and ability to provide consistent valid results.
We reviewed your firm's responses and conclude that they are not adequate. It is not clear how instruments that were previously calibrated are now accurate enough for your firm's processes, given a lack of design information. Your firm should provide its calibration procedure for review; a calibration schedule for all of its inspection, test and measuring equipment, including the air gun and molding machine pressure gauges; and evidence that calibration has been performed for all of its inspection, test and measuring equipment.
15. Failure to establish and maintain calibration procedures which include specific directions and limits for accuracy and precision, and when accuracy and precision limits are not met, there are provisions for remedial action to reestablish the limits and to evaluate whether there was any adverse effect on the device's quality, as required by 21CFR820.72(b). For example, your firm has not established calibration procedures which:
a. Include specific directions and limits for accuracy and precision. When accuracy and precision limits are not met, there are provisions included for remedial action to reestablish the limits and to evaluate whether there was any adverse effect on the device's quality.
b. Ensure that calibration standards used for inspection, measuring, and test equipment is traceable to national or international standards and if this is not practical or available, ensure the use of an independent reproducible standard.
We reviewed your firm's responses and conclude that they are not adequate. Your firm should provide its calibration procedure for review, and provide evidence that calibration standards used are traceable to national or international standards.
16. Failure to establish and maintain adequate procedures to control product that does not conform to specified requirements, as required by 21CFR820.90(a). For example, your nonconformance procedure, QP8 01, "Management of Nonconforming Products," requires rejected product to be identified with a red label and moved to an appropriate place. However, nonconforming product was observed unlabeled in a cardboard box, on the production floor.
We reviewed your firm's responses and conclude that it is not adequate. Your firm should provide documentation to support that it is identifying each nonconforming product with a red label.
17. Failure to establish and maintain 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 "Measurement, Analysis and Improvements" procedure, QP8 03, lacks requirements which ensure auditors do not have direct responsibility for the areas they audit. In addition, during the 2015 and 2016 Internal Audits, individuals who conducted the quality audits had direct responsibility for the matters being audited.
We reviewed your firm's responses and conclude that they are not adequate. Your response did not address whether the procedure would be revised and if a retrospective review of audit files will be conducted to ensure compliance with the firm's revised procedure.
18. 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, your firm's "Management Responsibility Management Engagement" procedure, QPS 01, includes requirements to conduct management reviews once per year, or more often if needed. However, management reviews were not performed for 2012, 2013, 2014, or 2016.
We reviewed your firm's responses and conclude that they are not adequate. Your response did not address how your firm intends to retrospectively address concerns appropriate for the management reviews of 2012, 2013, 2014 and 2016.
19. Failure to establish procedures for ensuring that all personnel are trained to adequately perform their assigned responsibilities and for identifying training needs were not established, maintained, and documented, as required by 21CFR820.25(b). For example, your firm's "Work Instruction for Packaging" procedure, WIS 02-01, includes requirements that employees receive training at the start of employment and once per year thereafter. However, there is no documentation of the required yearly employee training.
We reviewed your firm's responses and conclude that they are not adequate. Your firm did not include evidence of the implementation of the corrective actions described in the response.
20. Failure to establish and maintain procedures for the control of storage areas and stock rooms for product to prevent mix-ups, damage, deterioration, contamination or other adverse effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed, as required by 21CFR820.150(a). For example, finished sterile devices were stored within open shipping cartons on the floor of the sterile storage room. The flooring in the room is in poor condition and appears to have water damage next to the window.
Your firm's response to this observation appears to be adequate.
Our inspection also revealed that your firm's devices 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:
21. Failure to develop, maintains, and implements written Medical Device Reporting (MDR) procedures, as required by 21 CFR S03.17. For example, your firm acknowledged that it had not established written MDR procedures.
We reviewed your firm's responses and conclude that they are not adequate. A review of your firm's submitted MDR procedure, titled "Measuring, analyzing and improving: Post-sale engagements, complaint registering and processing and incident notifications," WIS 01- 01, Revision: 02, dated 20.09.2016, is deficient. Specifically: WIS 01-01, Revision: 02, 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:
a. 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 S03.20(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 S03.50(a).
b. WIS 01-01, Revision: 02, 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:
i. There are no instructions for conducting a complete investigation of each event and evaluating the cause of the event. ,
ii. There are no instructions for how your firm will evaluate information about an event to make MDR reportability determinations in a timely manner.
c. WIS 01-01, Revision: 02, does not establish internal systems that provide for timely transmission of complete medical device reports. Specifically, the following are not addressed:
i. The circumstances under which your firm must submit initial 30 days, supplemental or follow-up, 5 day report and the requirements for such reports.
ii. The procedure does not include a reference for the submission of MDR reportable events using the mandatory 3500A or electronic equivalent.
iii. How your firm will submit all information reasonably known to it for each event. Specifically, which sections of the 3500A will need to be completed to include all information found in your firm's possession and any information that becomes available as a result of a reasonable follow up within the firm.
d. WIS 01-01, Revision: 02, does not describe how your firm will address documentation and record-keeping requirements, including:
i. Documentation of adverse event related information maintained as MDR event files.
ii. Information that was evaluated to determine if an event was reportable.
iii. 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.
iv. Systems that ensure access to information that facilitates timely follow-up and inspection by FDA.
Your firm should adjust its MDR procedure to include a process for submitting MDRs electronically in accordance with the Final Rule for electronic Medical Device Reporting (eMDR) published in the Federal Register on February 14, 2014. In addition, your firm should establish an eMDR account in order to submit MDRs electronically. Information about the Final Rule for eMDR and the eMDR set-up process can be found on the FDA website at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/eMDR%E2%80%93ElectronicMedicalDeviceReporting/default.htm
If your firm wishes to discuss the MDR related issues noted above, please contact the Reportability Review Team by email at ReportabilityReviewTeam@fda.hhs.gov
Given the serious nature of the violations of the Act of the violations of the Act, sterile reflective marker spheres manufactured by your firm are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. § 381(a), in that they appear to be adulterated. As a result, FDA is taking steps to refuse entry of these devices into the United States, known as "detention without physical examination," until these violations are corrected. In order to remove the devices from detention, your firm should provide a written response to this Warning Letter as described below and correct the violations described in this letter. 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.
Also, 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 actions (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 Inspections Support Branch, White Oak Building 66, Rm 3540, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case# 518581 when replying. If you have any questions about the contents of this letter, please contact: Daniel Walter, Chief, Foreign Enforcement Branch at firstname.lastname@example.org (email) or + 1 (240)402-4020 (telephone)
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.
CAPT Sean M. Boyd, MPH, USPHS
Deputy Director for Regulatory Affairs
Office of Compliance
Center for Devices and Radiological Health
1901 Carnegie Ave, Ste Q
Santa Ana, CA 92705