Inspections, Compliance, Enforcement, and Criminal Investigations
Feel Tech 3/15/13
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|10903 New Hampshire Avenue|
Silver Spring, MD 20993-0002
March 15, 2013
VIA UNITED PARCEL SERVICE
No. 92-4 Haengjeung-ri, Gwangdeok-myeon
Cheonan-si, South Korea 330-922
Dear Mr. Kim:
During an inspection of your firm located in Cheonan-si, South Korea, on November 19, 2012, through November 22, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures insulin syringes and needles. 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 Lee Seung-Geun, QA engineer, dated December 4, 2012, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional 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 for implementing corrective and preventive action to include requirements for identifying the actions needed to correct and prevent recurrence of nonconforming product and other quality problems, as required by 21 CFR 820.100(a)(3). For example:
a) Your firm was informed of needles dislodging from syringe barrels of Accusure Insulin Syringes in October, 2008. Corrective actions were implemented including a product recall conducted by a distributor in June, 2009, and limited to one lot of product. There was no rationale for the extent of the recall. A second recall was implemented by a second distributor in March, 2010, when the identical product was found to not meet (b)(4) requirements for (b)(4).
b) CAPA 11-01 was opened in response to an external audit and identified that sterilization revalidation was not being performed according to procedure schedule. According to your firm, this was due to personnel changes. Your firm did not address the root cause related to personnel changes to prevent recurrence.
We reviewed your firm’s response and conclude that it is not adequate. Your firm indicated that the corrective and preventive action procedure (FTQP-807) will be revised and that training will be provided. However, your firm did not indicate that it implemented corrections for the deficiencies described in this observation, including ensuring that corrective actions for the needles dislodging from the syringe barrels of Accusure Insulin Syringes were implemented as required. Sterilization revalidation issues were not addressed. Your firm also did not indicate that a retrospective review of all previous CAPAs has been conducted.
2. Failure to establish and maintain procedures for implementing corrective and preventive action to include requirements for investigating the cause of nonconformities relating to product, processes, and the quality system, as required by 21 CFR 820.100(a)(2). For example, your firm was informed of dislodging needles. The root cause was determined to be “failure of working procedure at the (b)(4)” and “failure of checking and supplementing appropriate (b)(4).” The (b)(4) process had not been validated and the (b)(4). There was no documentation to support the investigation conclusion. Your firm was informed of further needle dislodging in November, 2009. Mr. Ha Tae Joo, your firm’s Quality Manager, indicated that there was no documentation of additional investigation or corrective and preventive action.
We reviewed your firm’s response and conclude that it is not adequate. Your firm indicated that the corrective and preventive action procedure (FTQP-807) will be revised and that training will be provided. However, your firm did not indicate that it would conduct investigations for needle dislodging. Your firm also did not indicate that a retrospective review of all previous CAPAs has been conducted to ensure that investigations were completed as required.
3. Failure to ensure that where 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, the validation of the (b)(4) process for insulin syringes in April, 2010, and revalidation in January, 2011, did not demonstrate that the process consistently produced product meeting predetermined specifications over the range of process conditions ((b)(4)). The results of the “operational qualification” testing (which included (b)(4)) did not meet the (b)(4) acceptance criteria of > (b)(4) yet the validation was still accepted. The (b)(4) and the (b)(4) in the (b)(4) were not determined during the validation. The (b)(4) process range was not validated. Your firm has a requirement that the (b)(4) is changed after (b)(4) since (b)(4) over that time period. The validation did not specify the (b)(4) used for the validation and did not challenge the (b)(4) at the end of use. The validation did not adequately define the process conditions for the (b)(4) in the (b)(4) and the (b)(4).
We reviewed your firm’s response and conclude that it is not adequate. Your firm identified its failure to perform a full engineering study to identify key process parameters as the cause of these deficiencies. Your firm indicated that it will conduct a validation of the insulin syringe (b)(4) to reflect key process parameters. However, your firm did not indicate that it would retrospectively review all processes that require validation to ensure they were validated as required. Your firm also did not provide evidence that it implemented a correction for this deficiency to include performing a full engineering study to identify key process parameters to ensure this deficiency does not recur.
4. Failure to establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a). For example, Nonconformance 2011-12-27 identified that a portion of devices from Lot (b)(4) were damaged after sterilization. There was no documentation of the inspection process, the quantities found to be acceptable, and the disposition of those devices that were nonconforming and scrapped.
We reviewed your firm’s response and conclude that it is not adequate. Your firm indicated that the nonconforming product control procedure (FTQP-804) will be revised and that training will be provided. However, your firm did not indicate that it would document the inspection process, the quantities found to be acceptable, and the disposition of those devices that were nonconforming and scrapped. Your firm also did not indicate that any retrospective activities for all nonconforming products have been conducted to ensure proper disposition.
5. 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, the ethylene oxide (EtO) sterilization process was not adequately documented to ensure that process conditions were effective. There was no real time data collection of process conditions. The cycle summary did not include actual timing of critical steps. The chamber humidification step only indicated the observed humidity. There was no recording of hold time for the humidification step. Time records for EtO gas dwell stated (b)(4); however, neither the time of gas addition nor the end of dwell time was recorded. The documentation of the vacuum for the sterilization of insulin syringe lot (b)(4), required to be between (b)(4) and (b)(4) kpa, was documented as (b)(4) kpa. The documentation of the vacuums for the degassing steps did not record the actual vacuums or hold times for the (b)(4) required evacuations. The documentation of sterilization of insulin syringe lot (b)(4) also refers to the EtO gas cylinder of lot (b)(4). There was no certificate of analysis that matched this lot number in your firm’s receiving files.
We reviewed your firm’s response and conclude that it is not adequate. Your firm indicated that the sterilization procedure (FTWS-101-05), the sterilization working record sheet, and the incoming inspection procedure will be revised and that training will be provided. However, your firm did not indicate that any retrospective activities for other production processes were conducted to ensure process controls were completed as required.
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 requirements and to determine the effectiveness of the quality system to include requirements for conducting quality audits by individuals who do not have direct responsibility for the matters being audited, as required by 21 CFR 820.22. For example, audit plans indicated that the QC manager, Mr. Kweon-Young, who is responsible for QC operations, was auditing some QC areas.
Your firm’s response did not address this deficiency because it was not listed as an observation on the FDA 483.
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 actions (including any systemic corrective actions) 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, Room 2609, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #391280 when replying. If you have any questions about the contents of this letter, please contact Carl Fischer at 301-796-5770 or 301-847-8137 (fax).
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.
Steven D. Silverman
Office of Compliance
Center for Devices and