- TYRX Inc.
- Issuing Office:
- New Jersey District Office
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
New Jersey District Office
Waterview Corporate Center
10 Waterview Blvd. 3th Floor
Parsippany, New Jersey 07054
Telephone: (973) 331-4900
FAX: (973) 331-4969
June 2, 2016
VIA UNITED PARCEL SERVICE
Ms. Rebecca Seidel
Vice President and General Manager
1 Deerpark Drive Suite G
Monmouth Junction, New Jersey 08852
Dear Ms. Seidel:
During an inspection of your firm at 1 Deerpark Drive Suite G, Monmouth Junction, New Jersey from November 30, 2015 through February 12, 2016, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures TYRX Antibacterial Envelope, TYRX Antibacterial Absorbable Envelope, and the TYRX Neuro Antibacterial Absorbable Envelope. 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 is intended 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 (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. We received written responses on March 7, April 7, and May 6, 2016 from you regarding our investigator’s observations noted on the Form FDA 483, List of Inspectional Observations, that was issued to you on February 12, 2016. We address the response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
1. A process whose results cannot be fully verified by subsequent inspection and test has not been adequately validated according to established procedures, as required by 21 CFR 820.75(a).
Specifically, your firm failed to adequately validate the (b)(4) for large TYRX Antibacterial (AIGIS Large Devices) Envelope, (b)(4) for drying the (b)(4), polyarylate polymer production process, and the (b)(4) which is used to apply the (b)(4) to the firm’s Antibacterial Envelopes. For example:
A) The performance qualification for the large TYRX (AIGIS Large Devices) Envelope did not document (b)(4) of the (b)(4) which are required for performing the (b)(4) during manufacturing.
B) No Performance Qualification (PQ) was performed for the (b)(4) in order to test and validate the below and above (b)(4) necessary to (b)(4) prior to the (b)(4) for the TYRX Antibacterial Envelopes.
C) The batch records for the following validation lots used to support the polymer production process for TYRX Antibacterial Envelopes documented a failure and deviations from the instructions in the batch records. Specifically,
- Lot FP12J10011 failed for water content since the tests showed that it exceeded the specification of (b)(4), material from Lot FP12B27010 which was mixed (b)(4) where the instructions in the batch record states that the material was to be mixed for (b)(4), and
- Lot FP12J17012 records a deviation in (b)(4) from (b)(4) documented in the Polymer Manufacturing Batch record ((b)(4)) to (b)(4), and the batch record for lot FP12J17012 documents that there was a (b)(4) leak and the (b)(4) was extended to make up for the leak detection and repair time.
D) The Process Qualification Protocol for the (b)(4) was performed to provide evidence that (b)(4) is capable of (b)(4) to the Antibacterial Envelopes. TYRX Absorbable production Lot # 14D10437 manufactured under this approved protocol failed the content uniformity test for Minocycline where (b)(4) devices were outside the (b)(4) label claim for L1 and (b)(4) devices were outside the (b)(4) label claim for L2. The Process Qualification report, dated May 15, 2014 states under lot disposition (section 9.1) that all (b)(4) lots were released to commercial inventory and the (b)(4) was qualified to (b)(4) for the TYRX family of products. However, Lot 14D10437 was documented on August 14, 2014 as being rejected and not for commercial use.
We reviewed your firm’s responses and conclude that they are not adequate. Specifically, incomplete process validations were provided in your written responses for the (b)(4) for large TYRX Antibacterial (AIGIS Large Devices) Envelope, (b)(4) for (b)(4) after (b)(4) production process, and the (b)(4) Machine. For example: change order CO10173144 (dated April 4, 2016) was performed for only the (b)(4) portion of the process for manufacturing TYRX envelopes; (b)(4) has not been performed to identify the (b)(4) in order to maintain the (b)(4) when set at the target (b)(4) of (b)(4) (the IQ, OQ, and PQ for the (b)(4) has still not been completed based on your May 6, 2016 response); the validation of your polymer production process and (b)(4) Machine have not been completed based on your May 6, 2016 response.
2. Failure to adequately establish procedures for corrective and preventive action as required by 21 CFR 820.100(a). Specifically, your firm failed to establish procedures for the control and action to be taken on devices distributed, and those not yet distributed, that are suspected of having potential nonconformities. For example:
A) CAPA # 262121, dated October 19, 2015, documents seven lots (14M19556, 15C19582, 15D10588, 15E09591, 15E17594, 15F25611, and 15F26612) of TYRX Antibacterial Envelopes that were out of specification (OOS) for drug content where the CAPA was closed with no action taken because “3 OOS have a suspected common root cause.” “Per SOP 10213183DOC TYRX CAPA Data Source Monitoring, (b)(4)”. Your CAPA Board agreed to close this CAPA since “this is not considered a quality issue since it does not meet the requirements stated in the CAPA trend SOP 10213183DOC”.
B) Non-Conformance Procedure (NCR), SOP-13-001, Rev. 1A, Section 2.9 states that any outstanding tasks shall be followed by opening a CAPA in the CAPA system or documenting it on a NCR form; however, your NCR form does not include any requirements for verification or validation of effectiveness of CAPAs that are being documented as part of a NCR form. For example, NCR 15-026 was opened on May 19, 2015 due to a calculation error that resulted in (b)(4). In addition, the (b)(4) was increased by (b)(4) due to the (b)(4) running out and needing to be changed out by the manufacturing operator to a new (b)(4). No verification was performed for the effectiveness of the corrective measure of retraining the manufacturing operator and the NCR was closed on May 28, 2015.
C) Out of Specification Investigation, SOP-13-004, Revision 1A, section 4.15 states “Quality Assurance initiates corrective and preventive activities to correct and mitigate future incidents as per the CRDM CAPA process”. However, OOS number 15-017, dated November 25, 2015, for Lot #15L12665 was opened due to impurity/related substance (b)(4) result (24%) which was above your specification of (b)(4) and the possible root cause could not be determined, “no definitive lab error”, and all of the retest analysis performed on November 25 and 30, 2015 were reintegrated and recalculated by your firm based on new chromatographic integration (signal to noise ratios were decreased). As a result of the reintegration, all of the retest results were within specification and your investigation conclusion states that “due to the change in the integration of the chromatograms, the raw data is the source of the error”. Your Quality Assurance Disposition was that no further investigation was needed and your OOS investigation was closed without knowing the root cause of the original failure. Additionally no verification of effectiveness of your corrective measure (mitigate future incidents) was performed to see if by updating your test method, ATM-0442, that you mitigated future incidents of impurity/related substance failures.
D) Failure to follow procedure SOP 10050491DOC, Revision 1H (CAPA Action, Effectiveness & Closure) section 3 which states “the effectiveness phase of a CAPA collects evidence to establish whether the actions taken were effective at addressing the identified causes.” “(b)(4).” The (b)(4) includes checks to detect recurrence/occurrence of the identified causes, and if there is evidence or data collected after the actions were completed to prove the actions effectively addressed the causes.
For example, CAPA 186642 was opened February 19, 2014 due to low molecular weight of the Tyrosine polymer which will have a potential impact to the product(s) directly since this causes higher drug elution (b)(4). Your root cause assessment was that prolonged exposure to (b)(4), and the combination of both has a detrimental effect on molecular weight. Your corrective actions were at the supplier ((b)(4) received from the supplier is at the (b)(4) of the molecular weight specification) by controlling material handling at different steps during their process ((b)(4)) will better control (b)(4). Your effective summary states that the “measurement of molecular weight after the supplier change proves that the corrective action addressed the cause” and was “effective”.
This CAPA was then closed; however, two other CAPA’s 206563 (dated August 6, 2014) and 214737 (dated October 10, 2014), were open due to low molecular weight of Tyrosine polymer. CAPA 206563 states that the root cause was (b)(4) impurity, (b)(4), and inconsistencies in the (b)(4) polymer process. CAPA 214737 states that the low molecular weight was being investigated under CAPA 206563. CAPA 214737 was closed with no action taken and CAPA 206563 was still open at the time of this inspection.
E) CAPA 241704 (dated May 14, 2015) documents a nonconformance for the TYRX Absorbable Antibacterial Envelope Project Design Matrix (DCP-2009-09, Rev 9) where the verification/validation evidence cited in your design matrix does not confirm that the design output meets the design input and user requirements. The CAPA further states that the cited studies only meet some of the design inputs and specifications, while others were missed. The design verification and validation fields should have included additional references to support all inputs and specifications. Your firm failed to verify the effectiveness of your corrective and preventive actions by reviewing and revising your project design to include appropriate verification and validation references in the design matrix document. This CAPA was still open at the close of our inspection.
We reviewed your firm’s responses and conclude that they are not adequate. Specifically, your firm has not provided documentation that shows you have adequately identified the actions needed to correct and prevent recurrence of out of specification (OOS) results for drug content and low molecular weight of the Tyrosine polymer for your TYRX Antibacterial Envelopes. Your firm needs to control and take action on devices distributed, and those not yet distributed, that are suspected of having potential nonconformities.
3. Failure to establish and maintain procedures for changes to a specification, method, process, or procedure where such changes shall be verified or where appropriate validated according to 21 CFR 820.75 before implementation, and these activities shall be documented as required by 21 CFR 820.70(b). Specifically, no validation was performed to support DMR deviation TC10002270 (dated June 17, 2015) for TRX Absorbable Antibacterial Envelopes that allowed polymer molecular weight specifications to be changed from (b)(4) since the molecular weight analyses were processed using a (b)(4) instead of a (b)(4), which was specified in your ATM-0401 test method. As a result, (b)(4) had molecular weights below (b)(4) and (b)(4) had molecular weights below your lower limit of (b)(4). The molecular weight requirements are associated with drug elution rate after implant, and with the ability of the (b)(4) to be (b)(4) envelopes during manufacture.
We reviewed your firm’s responses and conclude that they are not adequate. Specifically, your responses fail to comply with 21 CFR 820.70(b) where production and process changes (changes to a specification) shall be verified or where appropriate, validated according to 21 CFR 820.75 before implementation and these activities shall be 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 FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or 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, premarket approval applications for Class III devices to which the Quality System regulation violations 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 (15) business days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan 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 15 business days, state the reason for the delay and the time within which these activities will be completed.
Your firm’s response should be sent to: U.S. Food and Drug Administration, New Jersey District, 10 Waterview Boulevard, 3rd Floor, Parsippany, New Jersey, 07054. Refer to the Unique Identification Number (CMS case #497549) when replying. If you have any questions about the content of this letter, please contact Mr. Robert J. Maffei, District Compliance Officer, at 973-331-4906.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (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 to bring your products into compliance.
Craig W. Swanson
Acting District Director
New Jersey District Office