- Delivery Method:
- United Parcel Service
- Medical Devices
Recipient NameW. James Noble
- Biomedix WAI
3895 W. Vernal Place
Bloomington, IN 47404
- Issuing Office:
- Office of Medical Device and Radiological Health Operations
CMS # 598171
February 12, 2020
Dear Mr. Noble:
The United States Food and Drug Administration (FDA) conducted an inspection of your firm’s medical device operations at 3895 W Vernal Pike, Bloomington, IN, from October 21, 2019 to October 31, 2019. During the inspection, an FDA investigator determined that your firm is a manufacturer of the SELEC-3 gravity I.V. administration sets and extension sets medical devices. 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 any 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 dated November 19, 2019, December 31, 2019, and January 31, 2020 from you, concerning our investigator’s observations noted on the Form FDA 483, List of Inspectional Observations (FDA 483) that was issued on October 31, 2019. We address the November 19, 2019 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 product that does not conform to specified requirements, including a determination of the need for an investigation and documentation of that investigation, as required by 21 CFR § 820.90. This is a repeat observation from the Warning Letter of 2013. For example:
a) Review of your firm’s (b)(4) Test Results, F-8025-1 rev. 4, from 06/06/2018 to 10/23/2019 revealed 233 out of (b)(4) documented tests had anomalous or apparently failed test results that were not identified or investigated. Of these 233 test results, 151 of them could be attributed to directly meeting the fail criteria defined in SOP 8025 with 14 of the 151 being attributed to Biomedix applied seals.
b) Non-Conforming Materials procedure, 8038 Rev. 6 effective 12/22/15, is inadequate in that nonconforming product is not evaluated and investigated in accordance with established procedures. Section 3.3 of the procedure states “(b)(4).” Review of thirteen randomly selected device history records revealed that eleven of them documented one or more instances of (b)(4) of a single defect type in production. None of these eleven DHRs had a documented event number or evaluation to determine if an investigation was necessary. For example:
i. B76-102 Lot 904976 documented 23 rejects with a defect type of “Bond," 138 rejects with a defect type of "Damaged by Biomedix," and 7 rejects with a defect type “Glue runs, puddles.”
ii. B72-102 Lot 923172 documented 55 rejects with a defect type of “Glue runs, puddles,” 33 rejects with defect type “Embedded material,” 5 rejects with a defect type of “Dirty,” 13 rejects with defect type “Bond (out of rounds),” and 20 rejects with defect type “Other (describe).” Notably, there was no description documented for the other defects.
iii. B72-102 Lot 914472 documented 24 rejects with defect type “!!Paint splotches,” 35 rejects with a defect type of “Bond (out of rounds)”, 123 rejects with defect type “Damaged by Biomedix,” 8 rejects with defect type “Pop-ups,” and 7 rejects with defect type “Glue runs.”
We have reviewed your firm’s response and have determined that it is not adequate. Regarding part a) of this item, in your response you stated that you will conduct new (b)(4) tests using (b)(4) newly-sealed pouches and compare results with established settings, settings suggested in the equipment manual, and results obtained from (b)(4). Please provide documentation of this study including evidence that it addresses the causes of the deficiencies described in part a) above. Regarding part b), your response states that SOP 8038, Non-Conforming Materials, will be revised to include alert and action limits for nonconforming materials, including tracking for trending purposes according to defect type and causal factors. Your response does not address performing a retrospective review of your device history records to determine whether investigations of the documented nonconformities are required. Please provide this revised procedure, as well as documentation demonstrating that you have performed investigations of the nonconformities described in i, ii and iii above and retrospective review of your device history records.
2. Failure to validate a process whose results cannot be fully verified by subsequent inspection and test,as required by 21 CFR §820.75(a). This is a repeat observation from the Warning Letter of 2013 and the regulatory meeting of 2018. For example, during the inspection we observed that:
a) Operational Qualification (OQ) Protocol and Report for the (b)(4) Heat Sealer(b)(4), rev. 001, dated May 13, 2019, and Performance Qualification (PQ) Protocol and Report for Biomedix-WAI Packaging, rev. 1, dated May 15, 2019, do not include testing for seal integrity, only (b)(4) and visual defects. Additionally, (b)(4) test equipment was calibrated for a range of use that did not include the entire range used for the validation study.
b) Performance Qualification (PQ) Protocol and Report for Biomedix-WAI Packaging, rev. 1, dated May 15, 2019, showed that the number of samples required by the protocol was not used for the study, with no deviations documented. Additionally, the number of samples used for the study did not reflect the high level of risk assigned to packaging breach and incomplete seal.
c) Performance Qualification (PQ) Protocol and Report for Assembly Operations at Biomedix-WAI, rev. 001, dated May 15, 2019, required a (b)(4) test which used a sampling plan whose AQL was not commensurate with the high risk assigned to certain failures as listed in B10 Design FMEA, rev. 1.
We have reviewed your firm’s response and have determined that it is not adequate. Although your response states that you will revise your process validation procedure and revalidate this process, it does not address the review of other validations. Please provide your new and revised procedures for process validation, including sampling plans and rationale behind which AQLs you have chosen for each; and your completed revalidation report. Additionally, you should also provide evidence that you have reviewed other validations for the presence of all required testing, calibration of all equipment used for each study for the range of use, number of samples used as required and adequacy of sampling plans.
3. Failure to establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met. as required by 21 CFR §820.75(b). This is a repeat observation from the regulatory meeting of 2018. For example, during the inspection we observed that:
a) Process Validation Procedure 8045, rev. 0, dated November 4, 2013, provides that “(b)(4).” From 06/08/2018 to 10/23/2019, your firm has no documented “trending of process parameters or testing results for validated processes.”
b) No seal integrity testing is being performed as part of monitoring of routine manufacturing operations. A testing program exists only for (b)(4) testing and visual inspection.
We have reviewed your firm’s response and have determined that it is not adequate. Please provide, regarding part a), evidence that your new process monitoring procedure has been implemented, including documentation that your process monitoring results are being reviewed periodically for trends and that you have established upper and lower control limits using appropriate statistical methods, and are reviewing test data according to these limits. Regarding part b), please provide your documented process monitoring program for ensuring the packaging process is under control and within the established parameters during routine operation and consistently producing the specified process output for seal integrity.
4. Failure to establish and maintain acceptance procedures to ensure that specified requirements for in-process product are met, as required by 21 CFR § 820.80(c). During the inspection we observed that equipment settings are not verified prior to use of inspection equipment as required by SOP 8025, Operation of the (b)(4) Tester, rev. 003, effective 08/19/2019. During review of your manufacturing operations on 10/24/2019, the settings of the (b)(4) tester were found to be: (b)(4), and (b)(4). Per your firm’s (b)(4) Test Results form F8025-1 and Process Qualification (PQ) Protocol and Report for Biomedix-WAI Packaging, Packaging-PQ Rev. 1 approved 15 May 2019, production settings should be: (b)(4) and (b)(4). Your firm has not evaluated the impact of this setting change on the validated process. Your firm was unable to determine when the setting change may have occurred because (b)(4) tester settings have not been verified and documented prior to use.
We have reviewed your firm’s response and have determined that it is not adequate. Your response describes a (b)(4) testing analysis study to be performed to provide “(b)(4).” In response to this Warning Letter, you should provide full documentation of this study (also referred to in Item 1 of this Warning Letter), including an explanation as to how it shows that the required and actual machine settings provided equivalent test results. Please also provide the qualification documentation for the new (b)(4) machine described in your response.
5. Failure to 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, during the inspection we observed that:
a) Your Design Control procedure 8033, rev. 003, effective 09/07/2018, contains a provision for design changes that references your Document Management and Change Control procedure 8003, rev. 003, effective 09/07/2018, which does not address design changes, but references in its header your Change Control procedure 8040, rev. 006, effective 05/3/2018, which does not address verifying and/or validating design changes.
b) Changes impacting device design have not been verified and/or validated prior to implementation. Design changes are documented as document changes. For example, Document Change Order D100-00, DCR# QA-2018-051, dated 8/6/2018, Extruded Tubing-PVC Drawing, shows revisions to (b)(4) for part nos. 100-04 and 100-06 for the SELEC-3 product, a Class II device. This document change drawing is the only documentation for this change.
We have reviewed your firm’s response and have determined that it is not adequate. Although you have updated your design control procedures, your response does not address how you will evaluate the design changes identified above in part b) of this item, nor does it include performing a retrospective review of all design changes to determine if validation, or where appropriate, verification has been completed. Please provide evidence that this review has been completed and all design changes, including the change identified in b) above, have been evaluated for effect on design, validated and/or verified, reviewed and that these activities have been documented.
Your firm should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties. Also, 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, 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 corrected. Also, should FDA determine that your devices do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted. More information on processes for persons denied a CFG can be found at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-request-review-fdas-decision-not-issue-certain-export-certificates-devices. If you believe that your products are not in violation of the Act, please respond to FDA with your reasoning and any supporting information for our consideration.
We are requesting that you submit to this office on the schedule below, certification by an outside expert consultant that he/she has conducted an audit of your establishment's manufacturing and quality assurance systems relative to the requirements of the device QS regulation (21 CFR, Part 820). You should also submit a copy of the consultant's report, and certification by your establishment's Chief Executive Officer (if other than yourself) that he or she has reviewed the consultant's report and that your establishment has initiated or completed all corrections called for in the report. The initial certifications of audit and corrections and subsequent certifications of updated audits and corrections (if required) should be submitted to this office by the following dates:
• Initial certifications by consultant and establishment – August 15, 2020.
• Subsequent certification – August 15, 2021.
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, as well as 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. Your firm’s response should be comprehensive and address all violations included in this Warning Letter.
If you have questions regarding any issues in this letter, please contact Compliance Officer Amy Cramer at 732-390-3822 or at firstname.lastname@example.org. Please send your reply electronically to Gina Brackett, Director of Compliance Branch, at email@example.com.
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.
Joseph Matrisciano, Jr.
Program Division Director
Office of Medical Device and Radiological Health
Division 1 East