- Delivery Method:
- Via Email
- Medical Devices
Recipient NameMehmet Kayabaş
Recipient TitleCo-Founder & Chairman of the Board
- Turkuaz Sağlik Hizmetleri Medikal Temizlik Kimyasa
Akcaburgaz Mahallesi, Muhsin Yazicioglu Caddesi No:45/5
- Issuing Office:
- Center for Devices and Radiological Health
December 29, 2022
Dear Mr. Kayabaş:
During an inspection of your firm located in Esenyurt-Istanbul, Turkey, on September 19, 2022, through September 23, 2022, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures ultrasound gel products. 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 two responses from Hanifi Karahan Bozkurt, R&D & Quality Director, and Seçgül İnce, Quality Assurance and Regulatory Affairs Manager, dated October 14, 2022, and November 30, 2022, respectively, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm. We note that the second response covered only Observations 2 and 9. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
1. Failure to adequately establish and maintain procedures for validating the device design including documenting the results of the design validation in the design history file (DHF), as required by 21 CFR 820.30(g). For example, your firm conducted both microbiological aging stability and challenge validations for your firm’s sterile and non-sterile ultrasound gel products. However, your firm has no data to support the following validation testing:
a) Sterile Ultrasound Gel Stability Accelerated Report, dated November 15, 2015
b) Sterile Ultrasound Gel Challenge Realtime Test Report, dated February 4, 2015
c) Non-Sterile Ultrasound Gel Stability Accelerated Report, dated February 22, 2015
d) Non-Sterile Ultrasound Gel Challenge Realtime Test Report, dated June 8, 2014
We reviewed your firm’s response and concluded that it is not adequate. Your firm’s response indicates that the Design and Development Procedure ((b)(4), dated (b)(4)) was updated to cover minimums of DHF file requirements, and a new DHF content page was provided. You stated that “DHF approach will be revised to include all data and information beginning from the concept stage of the product to where it is fully realized.” Moreover, your firm provided new formula history documentation for both Non-Sterile and Sterile Ultrasound Gel; however, these documents are in Turkish. Your firm’s response is inadequate because it does not include the following:
• Documentation of raw data supporting the aforementioned validation tests.
• Documentation of corrective and preventive action (CAPA) effectiveness.
• Documentation of a retrospective review of other testing to ensure results of all (other) design validations are documented in DHF.
• Documentation demonstrating personnel were trained on the updated DHF procedure.
2. Failure to adequately 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 customer complaint procedure has no requirement to ensure that complaints received from distributors, marketing and distributing the device, are provided to your firm. Additionally, there is no documented agreement with your firm’s distributors requiring them to provide your firm with complaints to ensure all complaints are reviewed and evaluated in a uniform and timely manner to determine whether an investigation is necessary and are evaluated to determine whether the complaint represents an event required to be reported under 21 CFR 803 - Medical Device Reporting (MDR).
Additionally, a complaint was received from your firm’s distributor on April 8, 2021, related to the Sterile Ultrasound Gel (lot number SJ30071120), containing “black/dark blue fragments inside the gel packs.” Your firm opened complaint number (b)(4) on April 8, 2021, and closed the complaint on May 25, 2021. However, your firm did not review the complaint to determine whether an investigation was necessary or if the complaint represents a reportable event under 21 CFR 803. Your firm only documented the complaint-related email correspondence between your firm and the distributor.
We reviewed your firm’s response and concluded that it is not adequate. Your firm’s response documents that a MDR procedure will be established and an e-MDR process will be initiated. Your firm’s response documents that your firm’s complaint handling procedures were revised to include MDR reporting requirements. The revised complaint handling procedure does not adequately address the requirements of 21 CFR 803. Additionally, you did not provide documentation demonstrating personnel were trained on the updated procedure; you did not provide documentation of a retrospective review of complaints to determine if events are reportable; and nor did you provide documentation of CAPA effectiveness.
3. Failure to adequately establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a). For example, your firm’s “Supplier Selection and Evaluation Procedure” ((b)(4), dated March 29, 2021, section 5.0) requires that approved suppliers are evaluated. However, your firm has not documented an evaluation for your firm’s (b)(4) irradiation contract sterilizer, (b)(4), listed on your firm’s approved supplier list and responsible for sterilizing your firm’s Konix sterile ultrasound gel. Additionally, your firm has not established an agreement with (b)(4), to ensure – among other items – that your firm is notified of changes to the (b)(4) irradiation processes, parameters, and related services so that your firm can determine if the changes affect the quality and safety of the product.
We reviewed your firm’s response and concluded that it is not adequate. Your firm’s response includes your firm’s updated Supplier Selection and Evaluation Procedure, ((b)(4), dated October 7, 2022). Your firm’s response also includes the revised Supplier Evaluation Form ((b)(4), dated October 7, 2022), which is not readable, the Supplier Selection Form ((b)(4), dated October 7, 2022), and the Approved Suppliers and Critical List ((b)(4), October 7, 2022). Moreover, your firm’s response documents that Supplier Selection and Evaluation Procedure training were provided to personnel dated October 7, 2022. You stated that “since we could not reach the old records, a re-evaluation will be made for our (b)(4) supplier.” Additionally, your firm’s response includes your firm’s revised Distributor Quality Agreement including the contract between your firm and the (b)(4) importer/distributor, signed on October 11 and 14, 2022; and the new Service and Quality agreement (Contracted Service agreement) between your firm and the (b)(4), signed on October 11, 2022. You also stated that contracts with other suppliers will be completed until December 31, 2022. Your firm’s response is inadequate because it does not include:
• Documentation of CAPA effectiveness.
• Documentation demonstrating personnel were trained on the agreement establishment with suppliers.
4. Failure to adequately 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 820.30(i). For example, on December 29, 2014, your firm made design changes to its Konix sterile ultrasound gel, switching the neutralizing agent from triethanolamine to sodium hydroxide, and switching the preservative from methylchloroisothiazolinone, methylisothiazolinione to phenoxyethanol, ethylhexyglycerin. Additionally, on May 7, 2014, your firm made a design change to its Konix non-sterile ultrasound gel, adding benzyl alcohol as a preservative to its formulation. However, in addition to not having raw data to support validation/verification for the design change, your firm’s risk analysis, Konix Sterile failure modes and effects (FMEA) ((b)(4), dated July 27, 2022), and Konix Non-Sterile FMEA ((b)(4), dated March 04, 2021), did not contain evaluations of potential risks of your firm’s design changes on the patient.
We reviewed your firm’s response and concluded that it is not adequate. Your firm’s response includes your firm’s updated risk management procedure and changes to the FMEA table. Your firm’s response is inadequate because it does not include:
• An updated FMEA table incorporating the risk associated with changing Neutralization Agent for the Konix Sterile Ultrasound Gel.
• Documentation of CAPA effectiveness.
• Documentation of a retrospective review of other risk controls to ensure they meet the regulation according to your firm’s design changes.
• Documentation of personnel training associated with your updated firm’s FMEA.
5. Failure to adequately establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(d). For example, your firm’s cleanroom entry and application instructions ((b)(4), dated August 05, 2022), section 5.2 (Change of Clothes for Cleanroom Staff) states “put on your cap bonnet by gathering your hair so that it does not stick out.” However, on September 22, 2022, during the inspection of the non-sterile ultrasonic gel production process, a filling line operator with her hair exposed outside of the disposable hair bonnet while actively working in the Class D cleanroom (100,000) was observed.
Additionally, your firm’s hygiene control procedure ((b)(4), dated July 20, 2022), section 5.1, states “it is strictly forbidden for the personnel to store any food/beverage raw or cooked in their cupboard, on, in their bag, on their desk and at the beginning of the machine they work, to bring them to the working area, to leave then on or next to the products, to keep the wastes of consumed food.” However, on September 22, 2022, an empty water bottle in the trash bin located next to the Class D cleanroom was observed.
The adequacy of your firm’s response cannot be determined at this time. Your firm’s response documents that clean room entry and hygiene training were provided to personnel, and documentation of training was provided. However, your firm’s response does not include documentation of CAPA effectiveness.
6. Failure to have personnel with the necessary education, background, training, and experience to assure that all activities required by this part are correctly performed, as required by 21 CFR 820.25(a). For example, throughout the inspection, your firm was not familiar with the USFDA regulations and requirements for medical device manufacturers exporting medical devices intended for the US market, to include:
a) 21 CFR Part 820 - Quality System Regulation
b) 21 CFR Part 803 - Medical Device Reporting
c) 21 CFR Part 806 - Medical Devices; Reports of Corrections and Removals
d) 21 CFR Part 807 - Establishment Registration and Device Listing for Manufactures and Initial Importers of Devices
The adequacy of your firm’s responses cannot be determined at this time. Your firm’s response indicates that relevant trainings were provided by your firm’s Technical Advisor (Quality Assurance and Quality Control Team) on September 27-30, 2022. Additionally, your firm’s response includes FDA CFR Title 21 Part 820/803/806/807 Training Participation Certificates of your firm’s personnel. The training was held on November 24 and 25, 2022. However, your response does not include documentation of a retrospective review of other related trainings to determine if any new training is needed.
7. Failure to adequately maintain device history records (DHRs), as required by 21 CFR 820.184. For example, your device history records for the Konix sterile ultrasound gel and non-sterile ultrasound gel do not contain the primary identification label and labeling used for production units.
We reviewed your firm’s response and concluded that it is not adequate. Your firm’s response indicates the DHR procedure was updated; however, updates are not apparent, and the procedure does not address the requirements of 21 CFR 820.184. You also provided example DHRs for the sterile gel for Advance Medical Design, Inc., and non-sterile gel for Medline Industries. However, your response does not include documentation demonstrating personnel were trained on the updated procedure, documentation of a retrospective review of DHRs to ensure primary labels and labeling were added, nor documentation of CAPA effectiveness.
Other federal agencies may take your compliance with the FD&C Act and its implementation regulations into account when considering the award of federal contracts. Additionally, should FDA determine that you have Quality System regulation violations that are reasonably related to premarket approval applications for Class III devices, such devices will not be approved until the violations have been addressed.
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 address 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. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.
Your firm’s response should be sent via email to CDRHWarningLetterResponses@fda.hhs.gov or by mail to Food and Drug Administration, Center for Devices and Radiological Health, Office of Regulatory Programs, Division of Regulatory Programs 2, FDA Regulatory Inspections and Audits Team, White Oak Building 66, 10903 New Hampshire Ave., Silver Spring, MD 20993.
Refer to CMS case #482018 when replying. If you have any questions about the contents of this letter, please contact: Yanna Kang, Ph.D. at +1(301)796-6704.
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 any violations and take prompt actions to address any violations and bring the products into compliance.
Robert Ochs, Ph.D.
OHT8: Office of Radiological Health
Office of Product Evaluation and Quality
Center for Devices and Radiological Health
ST&T Research International, Inc.
88 McFaul Way
Zephyr Cove, Nevada 89448