- Delivery Method:
- VIA UPS
- Medical Devices
Recipient NameHideaki Onishi
- USHIO Europe B.V.
1438BD Oude Meer
- Issuing Office:
- Center for Devices and Radiological Health
December 3, 2019
Re: FDA Reference Number: CMS# 596106
Dear Mr. Onishi:
During an inspection of your firm located in Bavaria, Germany on August 19 – 23, 2019, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures UV lamps. 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 Thorsten Baum, General Manager of R&D and Quality Issues, dated August 26, 2019, 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 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 procedure, as required by 21 CFR 820.75(a).
For example: your firm does not have validation protocols for all of the processes that require validation. Additionally, several of your firm’s machines and the software they use have not been validated. For example, your firm has not validated the automated pumping, filling and pinching processes performed using the Isolde-HPA pumping, filling and pinching machines with machine numbers 2281 and 2282. This is a repeat observation from the previous inspection.
Your firm’s response, dated August 26, 2019, is not adequate. Your firm stated that it would create a detailed procedure which describes the process of process validation. Once completed your firm would perform process validation of some of their related processes. However, your firm has not provided any documented evidence of its corrections. Your firm did not state if it they would conduct a review of previously released product to determine if it was impacted by the lack of validation. Your firm needs to conduct process validation for all processes that cannot be fully verified by subsequent inspection and test.
2. Failure to validate computer software for its intended use according to an established protocol, as required by 21 CFR 820.70(i).
For example: your firm’s software used to operate the Isolde-HPA pumping, filling, and pinching machines with machine numbers 2281 and 2282 has not been validated for its intended use. Your firm stated that the pinching, pumping, filling, and sealing processes can affect the UV output of the finished lamps.
3. 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, as required by 21 CFR 820.250(b).
For example: Procedures have not been established for identifying valid statistical techniques for taking samples for in-process testing of UVA emission, UVC/UVB ratios and erythema values. FDA Quartz, AA 05-11 documents that a sampling size of 5 lamps are tested for UVA emission and FDA Quartz Spectrophotometry, AA 05-12 describes that a sample of 2 lamps are tested for UVC/UVB ratios and erythema values for each lot of bare lamps manufactured regardless of lot sizes with no documented statistical rationale.
Your firm’s response, dated August 26, 2019, is not adequate. Your firm stated that it planned to establish a statistical rationale and to increase sampling size. However, your firm provided no statistical rationale or evidence of action taken to correct this deficiency. Additionally, your firm has not considered any plans to evaluate if the lack of valid sampling plans could have resulted in distribution of nonconforming product.
4. Failure to adequately establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a).
For example: Nonconforming material procedures documented in Control of Nonconforming Outputs, U3-Z, Index 2 documents an overview of the nonconforming material process but lacks sufficient details to ensure the process is completed consistently. Additionally, bare UV lamp lots 176331 and 176841 contained failures in UVA emissions tests and no nonconformances were documented. This is a repeat observation from the previous inspection.
Your firm’s response, dated August 26, 2019, is not adequate. Your firm stated that they would add new work instruction for the disposition and documentation of nonconforming product. Your firm created a form for reporting and documenting nonconformities. Your firm also stated that they would train all relevant individuals on the new procedures and use of the form. However, your firm did not provide enough supporting evidence of their actions. For example, your firm has not provided a copy of their new procedure which ensures that control of nonconforming product is completed consistently. Your firm has not conducted a retrospective review to identify whether there were other instances where nonconforming product was not handled in accordance with their procedure. Your firm has not evaluated if any such instances could have resulted in distribution of nonconforming product or voids in the data analyzed under the CAPA system.
5. Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a).
For example: Preventive & Corrective Measures, Modifications, Improvements, U8-Z, Index 04 does not include a requirement to investigate the cause of nonconformities and does not include a clear requirement to verify or validate that corrective actions taken are effective and do not adversely affect the finished device. Additionally, 4 of 6 CAPAs reviewed did not include an adequate verification or validation that corrective actions taken were effective and did not adversely affect the finished device. In addition, 3 of 6 CAPAs reviewed did not describe the cause of the nonconformances that took place. This is a repeat observation from the previous inspection.
Your firm’s response, dated August 26, 2019, is not adequate. Your firm stated that they will revise their U8-Z CAPA procedure to include root cause analysis for all CAPAs. Your firm also stated that they would revise the 4 CAPAs from the inspection that had insufficient verification and validation with a completion date of September 30, 2019. This revision also includes verification that the CAPA did not have an adverse impact on the finished product. However, your firm did not provide any supporting evidence. Your firm has not reviewed its other CAPAs for sufficient verification and validation and to ensure they did not have an adverse impact on the finished product. Your firm has not conducted a retrospective review of previous CAPAs to determine if the investigation was sufficient.
6. Failure to establish and maintain acceptance procedures, where appropriate, to ensure that specified requirements for in-process product are met, as required by 21 CFR 820.80(c).
For example: UV emission measurement procedures documented in FDA Quartz, AA 05-11 do not include acceptance criteria for the test or procedures for when a bare lamp does not meet specifications.
Your firm’s response, dated August 26, 2019, is not adequate. Your firm stated that it has revised its work instruction to include acceptance criteria and change the definition of lifetime testing. Your firm also stated that it would revise its instruction again once it has a new sampling plan for UV measurement. However, your firm did not provide any supporting evidence. Your firm has not evaluated the existing acceptance records to determine whether the lack of defined acceptance criteria could have resulted in distribution of nonconforming product.
7. Failure to maintain device history records (DHR's), as required by 21 CFR 820.184.
For example: None of the 11 DHRs reviewed for UV lamps with BLV part number 23595001 included or referred to the location of the primary identification labeling used or unique device identifiers. This is a repeat observation from the previous inspection.
Your firm’s response, dated August 26, 2019, is not adequate. Your firm stated that they would establish a work instruction for storing outgoing DHR inspection. Your firm also stated that they planned to have UDI labeling for their products. However, your firm did not provide any supporting evidence.
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 (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:
U.S. Food and Drug Administration
Center for Devices and Radiological Health
Document Control Center -- WO66-G609
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
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.
Should you have any questions or comments pertaining to this letter, please contact Andrew Keys by telephone at (240) 402-3075 or by e-mail at Andrew.Keys@fda.hhs.gov. In any follow-up correspondence, please clearly reference FDA reference number CMS#596106 and include a contact email address.
Binita Ashar, M.D., M.B.A., F.A.C.S.
OHT4: Office of Surgical
and Infection Control Devices
Office of Product Evaluation and Quality
Center for Devices and Radiological Health