Sanitation & Environmental Technology Institute dba SDWH MARCS-CMS 687970 — September 10, 2024

WARNING LETTER

• Product: Medical Devices

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• Recipient: Qiming Tian, Ph.D.; CEO; Sanitation & Environmental Technology Institute dba SDWH; 88 Zhenbei Road; Suzhou Shi; Jiangsu Sheng, 215153; China; (b)(4)@sudatest.com

• Issuing Office: Center for Devices and Radiological Health; United States

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WARNING LETTER

September 10, 2024

Dear Dr. Tian:

This Warning Letter is to inform you of objectionable conditions observed during the United States Food and Drug Administration (FDA) inspection conducted at Sanitation & Environmental Technology Institute (dba SDWH), Ltd. from March 6, 2024, to March 15, 2024, by investigators from the FDA’s Office of Bioresearch Monitoring Operations (OBIMO) Foreign Inspection Cadre. This inspection was conducted to determine whether activities and procedures related to your participation in Good Laboratory Practice (GLP) nonclinical studies complied with applicable federal regulations. Specifically, FDA investigators focused on the list of studies below including, but not limited to, guinea pig maximization sensitization, acute systemic toxicity, complement activation, hemolysis, and cytotoxicity tests conducted at your facility. The list of studies below is not an all-inclusive list of studies and submissions impacted by the inspection or by the violations cited in this letter:

Study number	Test
(b)(4)	Guinea pig maximization sensitization test 0.9% NaCl Extract
(b)(4)	Guinea pig maximization sensitization test, Sesame oil extract
(b)(4)	Guinea pig maximization sensitization test 0.9% NaCl Extract
(b)(4)	Guinea pig maximization sensitization test, Sesame oil extract
(b)(4)	Acute System Toxicity
(b)(4)	Complement Activation
(b)(4)	Hemolysis
(b)(4)	MTT cytotoxicity
(b)(4)	MTT cytotoxicity
(b)(4)	MTT cytotoxicity
(b)(4)	MTT cytotoxicity
(b)(4)	MTT cytotoxicity
(b)(4)	Subcutaneous implantation test
(b)(4)	Subcutaneous implantation test
(b)(4)	Subcutaneous implantation test
(b)(4)	Guinea pig maximization sensitization test, Sesame Oil Extract

These tests are used in nonclinical studies for the development of devices as that term is defined in section 201(h)(1) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h)(1), 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.

The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemption, Premarket Approval applications, and Premarket Notification submissions are scientifically valid and accurate. Another objective of the program is to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.

Our review of the inspection report prepared by the OBIMO revealed serious violations of Title 21, Code of Federal Regulations (CFR) Part 58 - Good Laboratory Practice for Nonclinical Laboratory Studies, which concerns requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g). Compliance with Part 58 is intended to assure the quality and integrity of the safety data filed in a premarket submission. At the close of the inspection, the FDA investigators presented the inspectional observations Form FDA-483 for your review and discussed the observations listed on the form with you.

We received a response from your firm dated April 2, 2024, concerning our investigator’s observations noted on the Form FDA-483. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:

1. The study director failed to assure that (1) the protocol, including any change, is approved as provided by § 58.120 and is followed; (2) all experimental data, including observations of unanticipated responses of the test system were accurately recorded and verified; (3) unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study were noted when they occurred, and corrective action was taken and documented; and (4) all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study; (5) all applicable good laboratory practice regulations are followed. [21 CFR 58.33(a), (b), (c), (e) and (f)].

The study director has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and represents the single point of study control.

a. The study director failed to assure that the protocol, including any change, is approved as provided by 58.120 and is followed; that all experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified; and that unforeseen circumstances that might affect the quality and integrity of the nonclinical laboratory study were noted when they occurred and corrective action was taken and documented. Examples of the study director’s failures include, but are not limited to, the following:

i. All data resulting from in vitro cytotoxicity tests have not been reported and/or used in the analysis. Specifically, electronic data for Study (b)(4) noted 6 replicates were tested for each group (100%, 75%, 50%, 25%). However, the form Raw Data of ln Vitro Cytotoxicity Test (SDWH-402-C01b) documents the technician selected 5 of the 6 results obtained on the microplate reader for analysis (i.e., mean, standard deviation) and reporting of results.

ii. Samples from multiple study protocols are simultaneously tested for in vitro cytotoxicity tests on the 96 well plates. No study related documents (electronic and/or transcribed) for (b)(4) have been recorded that can attribute which test results are associated with each sample. For in vitro cytotoxicity studies (e.g., (b)(4) that use a microplate spectrophotometer to read absorbance data of a 96-well plate, there should be a process to attribute the raw data generated by the microplate spectrophotometer to each sample in the 96 well plate. Without a process designed to track the exact study sample and sample condition tested and the data from each protocol tested, the data obtained cannot be attributed to specific samples, especially when samples from multiple studies are analyzed on the same 96-well plate and measured at the same time by the microplate spectrophotometer. During the FDA’s inspection, the study director at SDWH was unable to attribute the raw data to each sample for certain studies. These studies include: (b)(4) and (b)(4).

iii. Protocols specific for the testing of in vitro cytotoxicity testing state that cell suspensions will be evaluated with a measurement at (b)(4)nm and reference wavelength at (b)(4)nm. However, the study records show that this protocol was not followed. The study records state that only absorbance data at (b)(4)nm were used for calculation of cell viability and reported in the final study reports (e.g., (b)(4).

iv. Electronic records for in vitro cytotoxicity testing document measurements have only been recorded at mean optical density (OD) of (b)(4). Per the study protocols and study reports, the cell viability is supposed to be calculated based on the value of (b)(4). However, the reported results for the calculation for viability was only based on (b)(4). Therefore, the reported results for the calculation for viability was not accurately measured for the studies listed ((b)(4). The study director did not assure that this was noted or that corrective action was taken and documented as is his responsibility to do so.

b. The study director failed to assure that all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study. Examples of the study director’s failures include, but are not limited to, the following:

i. Not all raw data were transferred to the archives. For MTT cytotoxicity tests (e.g.,(b)(4), complement activation tests (e.g.,(b)(4), and hemolysis tests ((b)(4), there was no documented evidence that study directors assured computer-generated raw data for absorbance (i.e., optical density) were archived as part of the raw data records. Only an incomplete version of transcribed absorbance data was verified and sent to the archives by the study director.

c. The study director did not assure that all applicable good laboratory practice regulations were followed. Examples of the study director’s failures include, but are not limited to, the following:

i. For Study (b)(4) the sponsor submitted a change application to amend the name/description of the test material to (b)(4) in the final report. This description of the test article, which is designed to be used in vivo during (b)(4) surgery, is different from the test material described in the approved protocol, sample submission form, and raw data sampling form (SDWH-402-A15a), which all describe the test material as “(b)(4)” While the two materials ((b)(4) are commonly used polymers in medical devices, there are some substantial differences in the physical properties and physical appearances such as texture, color, and opacity. Hence one polymer cannot be mistakenly swapped with the other as the two polymers look very different physically. Per GLP regulations, a change in the approved protocol, such as a change in material, requires the reason to be documented, signed by the study director, dated, and maintained with the protocol. The signed final report does not definitively state there is a difference between the test article; nor does it include any description of a deviation in the identification of the test article.

As the principal point of study control, the study director did not assure that they had the responsibility for the technical conduct of the study, that the protocol was followed, that protocols were properly amended when changes occurred, or that all experimental data were accurately recorded and verified. In addition, the study director did not assure that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur and did not ensure that corrective action is taken and documented when appropriate. When the protocols are not followed, data is erroneously analyzed, or other unforeseen circumstances occur that negatively affect the data, important findings in the study may be overlooked and the data cannot be accurately interpreted. Failure to follow the protocol impacts the quality and reliability of data contained within the final study report. This adversely impacts a manufacturer’s and FDA’s ability to assess the overall safety and risk of the subject device prior to use in humans as a marketed devices or for the purposes of beginning clinical trials. Patient or user exposure to a medical device could result in adverse health effects such as cytotoxicity, allergic reactions, skin irritation or inflammation, fever, toxicity that leads to loss of tissue/organ function or failure, and anaphylaxis. This represents a clear risk to patients and clinical practitioners. Thus, adequate biocompatibility assessment to determine the potential for an adverse biological response resulting from direct and/or indirect contact with a medical device is important.

Furthermore, the study director did not ensure that raw data, specimens, and reports were transferred to the archives for the nonclinical study during or at the close of the study. Failure to ensure all data is retained and transferred can result in incomplete documentation of the study in the archives and could limit reconstruction and evaluation of the study. Having the raw data accessible to the FDA reviewer enables the study to be recreated as needed to facilitate review and ensures patient safety. Based on these failures, FDA has concerns about the quality and integrity of the data generated from the nonclinical laboratory studies conducted at your testing facility.

Your written response is inadequate. The response you provided states that the relevant standard operating procedures (SOPs) addressing the concerns noted in the Form 483 were revised, proposed retraining revisions to certain SOP amendments were made, and that re-testing was performed.

Furthermore, you provided training evaluation records but did not provide the actual training documents to determine the adequacy of the corrective trainings for the in vitro cytotoxicity testing protocols. Given the deviations and issues cited in the violations, it is necessary to review the training materials to determine their adequacy for the trained individuals to both conduct the test and produce accurate, traceable results.

Your response does not provide assurance that these violations will not occur again. Specifically, your response did not: (1) detail how your testing facility will insure that applicable SOPs will be followed to ensure the quality and integrity of data generated in a study; (2) address any planned preventive actions such as frequency (i.e., quarterly, annual) of audits to check for compliance or future training of new study directors, as applicable; and (3) detail how appropriate documentation/follow-up will be ensured when deviations arise in the future. Your explanation, when taken into consideration with the violations described above, which occurred in multiple studies with various study directors over many months, suggests systemic failures in study director oversight of nonclinical laboratory studies and brings into question the quality and integrity of safety data collected at your testing facility.

2. Testing facility management failed to assure that there was a quality assurance unit as described in 21 CFR 58.35 and failed to assure that any deviations from these regulations reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented. [21 CFR Part 58.31(c), and 58.31(g)].

Testing facility management (TFM) is responsible for the organization and operation of a testing facility that conducts studies according to GLP regulations. A testing facility shall have a quality assurance unit (QAU) as described in 21 CFR Part 58.35, which shall be responsible for monitoring each GLP study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in Part 58. Any deviations from these regulations reported by the quality assurance unit shall be communicated to the study director, and corrective actions shall be taken and documented. Examples of the TFM’s failures include, but are not limited to, the following:

a. Testing facility management failed to assure that any deviations from FDA GLP regulations reported by the QAU were communicated to the study-director and corrective actions were promptly taken and documented.

i. Specifically, on (b)(4) the test facility discovered data duplication in the study reports for MTT cytotoxicity studies ((b)(4)). The test facility's inspection corrective action was inadequate:

1) The inspection failed to include an evaluation of deficiencies and did not include an inspection of the study director and QAU’s responsibilities, who signed each study report with the duplicate data, to determine how the issue arose.

2) The investigation for MTT cytotoxicity studies ((b)(4) only includes raw data from 5 out of 6 replicates of test and control articles used in the test system. According to the SOP (SDWH-302-C011 Rev 1/1) that was in effect at the time of the studies, raw data for 6 replicates of test and control articles were generated. The investigation failed to identify the root cause of why the technician only selected 5 of the 6 results for analysis.

3) Re-training was only provided to study report editors. However, no training was provided to either study directors or members of the QAU, who also have responsibilities for the quality and integrity of the data.

4) The test facility failed to document the impact of duplicated data in these reports. As of March 13, 2024, no amendment has been made to the study reports. Furthermore, it is unclear whether the companies who requested their respective devices to be tested have been informed of the duplicated data.

b. Testing facility management failed to assure that there was a QAU functioning in accordance with FDA GLP regulations. The QAU shall periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken. However, the QAU did not submit periodic written status reports on each study. Rather, records documenting QAU findings were presented on the same day in which the final report was signed. Examples include:

Study#	Phase Audit	QAU Inspection Date	Date Final Report Signed by Study Director & QAU Findings Reported to Management
(b)(4)	Protocol Study Procedure	07/06/2022 07/21/2022	07/28/2022 07/28/2022
(b)(4)	Protocol Study Procedure	10/15/2020 10/19/2020	11/18/2020 11/18/2020
(b)(4)	Protocol Study Procedure Raw Data	01/28/2021 02/04/2021 03/12/2021	03/12/2021 03/12/2021 03/12/2021

Failure of testing facility management to assure a properly functioning QAU that reports deviations from protocols and standard operating procedures (SOPs) and initiates immediate corrective actions creates the potential for a high level of variability and inaccuracy that does not ensure the validity, quality, and integrity of the data.

Your written response is inadequate. Your written response provided shows that you established a CAPA system procedure, revised associated SOPs, and included retraining revisions incorporated to train technicians, the study director, QAU and TFM on SOP SDWH-ADM-020 CAPA system procedure and investigation report template SDWH-ADM-020-02. Your response also includes an inspection mechanism for QAU to occur once every six months. However, the issue regarding why data was duplicated from the test reports performed years ago was not addressed.

3. Failure of the Quality Assurance Unit (QAU) to fulfill responsibilities [21 CFR 58.35(b)(5), 58.35(b)(6), and 58.35(b)(3)].

The QAU shall (1) determine that no deviations from approved protocols or standard operating procedures were made without proper authorization and documentation; (2) review the final study report to assure that such report accurately describes the methods and standard operating procedures, and that the reported results accurately reflect the raw data of the nonclinical laboratory study; and (3) inspect each nonclinical laboratory study at intervals adequate to assure the integrity of the study and maintain written and properly signed records of each periodic inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, action recommended and taken to resolve existing problems, and any scheduled date for reinspection. Any problems found during the course of an inspection which are likely to affect study integrity shall be brought to the attention of the study director and management immediately. Examples of the QAU’s failures include, but are not limited to, the following:

a. The QAU failed to determine whether any deviations from approved protocols or standard operating procedures had been made without proper authorization and documentation.

i. QAU failed to identify a protocol deviation in which the raw data and final reports do not include the age of the rabbits for implantation studies (b)(4) as per the protocol.

The (b)(4) final protocol stated that healthy young adult New Zealand White rabbits should be used. However, the Jiangsu Province Animal Health Certificate for the rabbits did not include any information on age. The Final Report and SDWH-402-B12a Raw Data form, had no indication that the age of the rabbits was checked, documented, and reported.

b. The QAU failed to review the final study report to assure that such report accurately described the methods and standard operating procedures, and that the reported results accurately reflected the raw data of the study. Specifically,

i. The QAU failed to assure that the reports were accurately reported from the original source data generated in electronic form in association with the in vitro cytotoxicity and hemolysis (per ASTM F756-17) testing. Because the data in the study archive are transcribed data, the results included within the final report (e.g., in vitro cytotoxicity using 5 out of 6 measurements, and using OD570 data instead of OD570-OD650 per study protocol and report) do not accurately reflect the raw data that were collected during the study. This is required by your procedure SDWH QAU-003, Study Inspections. As a result, the QAU failed to assure that “the reported results accurately reflect the raw data of the nonclinical laboratory study.”

1) In Vitro cytotoxicity: Phase audits conducted by the QAU described as "raw data" are limited to transcribed data which is recorded on form SDWH-402-C0lb.

2) Hemolysis: Phase audits conducted by the QAU described as "raw data" are limited to transcribed data which is recorded on form SDWH-402-D0lb.

ii. The QAU failed to identify the differences between the description of the test material listed within the final report and raw data, protocol, and sample submission form for Study (b)(4). The study protocol identifies the test material as “(b)(4)” In contrast, the final report identifies the test material as “(b)(4)” However, the final report did not note deviations from the protocol.

iii. The final study report for the following in-vitro cytotoxicity tests state 5 replicates of each test tested. However, electronic records document that 6 replicates were tested (e.g., (b)(4)

c. The QAU failed to inspect each nonclinical laboratory study at intervals adequate to assure the integrity of the study and maintain written and properly signed records of each periodic inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, actions recommended and taken to resolve existing problems, and any scheduled date for reinspection. Any problems found during the course of an inspection which are likely to affect study integrity shall be brought to the attention of the study director and management immediately.

i. Specifically, for (b)(4) the QAU inspected the study report on June 15, 2023. The final study report was completed on June 14, 2023. In the inspection, the QAU failed to report all problems that are likely to affect study integrity to the study director and management immediately. Specifically, the QAU failed to report the differences in the test article material information between the study protocol and the final study report. Similarly, for M202302405-11 the QAU failed to report the differences in the test article material information between the study protocol and the final study report when it inspected the study report on July 24, 2023. The final study report was completed on July 5, 2023.

A reliable QAU is integral to the successful understanding and completion of any GLP study. Without appropriate QAU oversight, neither the sponsor nor FDA reviewers have assurance that the data in the final study report is accurate and valid. Failure to perform QAU functions, such as monitoring studies to ensure protocols were followed and data is accurately recorded, over the course of multiple studies also calls into question the quality and integrity of studies conducted at your testing facility.

Your written response is inadequate. Your written response includes revisions to various related SOPs, among them (not all listed) SDWH-QAU-005 Study Report Inspection, SDWH-ADM-009 Laboratory Data Collection and Verification, SDWH-QAU-001 QA Statement Section 4.1, as well as training of personnel regarding these revisions. However, it does not provide a level of assurance, through associated documentation (e.g., signed and dated checklists, certifications, etc.) that the SOPs will be followed as instructed. In addition, your response does not discuss whether there will be preventative actions implemented such as audits to check for compliance to the SOPs, nor does it discuss future training for new staff and/or new implemented procedures as applicable.

4. Failure to ensure that each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study have the education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions [21 CFR Part 58.29(a)(b)]

Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study. Examples of the nonclinical laboratory supervisor’s failures include, but are not limited to, the following:

a. Your firm conducts testing per ISO 10993-10, an FDA-recognized consensus standard, in various studies including, but not limited to, protocols SOP SDWH-302-B01f and SOP SDWH-30-B02b. Accordingly, the personnel involved in testing should be trained to ISO 10993-10 to adequately conduct testing per ISO 10993-10. This includes training to adequately observe, correctly identify, differentiate, and describe different skin reactions and grade the severity of skin reactions.

i. For the guinea pig skin sensitization and intracutaneous reactivity tests, there is no documentation that shows that the personnel involved in the studies are trained to monitor the adverse reactions (e.g., eschar, excoriation, infection) at the injection sites. In addition, training records fail to demonstrate that the personnel involved in these studies are trained to score skin reactions for erythema and edema from score 0 through 4 (for intracutaneous reactivity test) and Magnusson Kligman scale 0 through 3 (for guinea pig skin sensitization).

Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have the education, training, and experience, or combination thereof, to enable that individual to perform the assigned duties and tasks. The personnel involved in the various studies were not correctly trained for the tasks they performed. This failure raises questions regarding the validity of the tests.

Your written response includes revisions to various procedures for weighing of test animals, on-site supervision, and quality control training for test technicians. Your response is not adequate because it lacks updated documentation of job descriptions, training, and experience for each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study.

It is necessary to document the training and experience for each person who is either engaged in the conduct of the study or supervising the conduct of the study for assurance that each person has the appropriate training and experience to adequately perform the tasks that are related to his or her roles and responsibilities pertaining to the nonclinical study. Please provide updated documentation of training and experience and job description for each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study.

5. Failure of the testing facility to have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study. The study director failed to authorize all deviations in the study from standard operating procedures and ensure the deviations were documented in the raw data. The testing facility failed to establish standard operating procedures for animal room preparation, animal care, and test system observations, and failed to maintain a historical file of revisions to the standard operating procedures [21 CFR Parts 58.81(a)(b)(1-6) and (d)]; Failure to prepare a final study report that included (1) corrections or additions in the form of an amendment by the study director and (2) the name of study director, the names of other scientists or professionals, and the names of all supervisory personnel involved in the study. [21 CFR Part 58.185(a)(9),(c)].

Standard operating procedures (SOPs) should be adequate to insure the quality and integrity of data generated in the course of a study. Standard operating procedures shall be established for, but not limited to animal room preparation, animal care, and receipt, identification, storage, handling, mixing, and method of sampling of the test and control articles, etc. Significant changes in established standard operating procedures shall be properly authorized in writing by management. The study director must authorize all deviations from SOPs in a study and document all study deviations in the raw data as amendments in the final report. Your testing facility did not adhere to these requirements. Specifically:

a. The testing facility does not have written standard operating procedures (SOPs) setting forth nonclinical laboratory study methods that are adequate to insure the quality and integrity of the data generated in the course of a study. There are no SOPs regarding amendments to the final report made by the study director that describes the changes authorized and deviations made to the report. Lastly, there are no SOPs that document the circumstances that may have affected the quality or integrity of the data.

i. Your testing facility failed to have an SOP regarding human blood collection prior to October 1, 2023. This was after study (b)(4) was initiated on June 23, 2022. Failure to have an SOP specifying where from the body the blood should be collected, along with any restrictions on the health status of the blood donor, results in uncontrolled testing. The study included collection of human blood from volunteers at the test facility for complement activation test, however, the study protocol did not include any details about blood collection.

b. Not all corrections or additions to a final report were in the form of an amendment by the study director.

i. Your testing facility submitted three reports identified as "supplementary" and prepared by the pathologist that were not included as an amendment to the (b)(4) final report and signed by the study director. These reports were submitted after the final report had been signed and archived by the study director on December 30, 2021.

c. Your testing facility failed to have an adequate SOP regarding Biocompatibility Sample Preparation that sets forth the correct and complete procedures used for this process.

i. The SOP SDWH-302-A09 Rev 2 does not include procedures about what containers should be used during the extraction (e.g., using bags vs. test tubes), how to seal the containers, what actions should be taken if there is leakage during the extraction, what equipment should be used during the extraction, what agitation speed should be used for agitation, and how to transfer extracts that are prepared in Building (b)(4) to Building (b)(4) (animal facility). This is necessary to ensure that the sample preparation process, equipment, and materials do not chemically or physically alter the sample extraction and/or interfere with the sample testing, and so the accurate sample preparation volume is present to properly conduct the sample testing.

d. Standard operating procedures have not been established for animal care and test system observations.

i. There is no established SOP that anesthetized animals are monitored during a procedure for common parameters such as: evidence of adequate anesthesia; level of adequate oxygenation; adequate ventilation (i.e., CO2), blood circulation (heart rate, cardiac output, pulse, etc.), and body temperature.

e. Not all significant changes in established standard operating procedures were properly authorized in writing by management. Specifically,

i. During the inspection, FDA observed a lack of aseptic technique and failure to maintain sterility of the test or control article as per SOP 302-B28a on sample extraction and dose administration.

Your firm’s failure to have adequate SOPs and follow established SOPs if adequate, in multiple studies with multiple study directors over many months suggests systemic failures in the operation of your nonclinical laboratory studies and study director oversight of nonclinical laboratory studies. These failures also raise questions about the quality and integrity of data collected at your facility. Inadequate SOPs for test article preparation may result in test articles that do not accurately represent the medical device and can result in false negatives in the biocompatibility testing. Additionally, the accuracy of study results cannot be verified without adequate SOPs for animal care, treatment, and observations, as the initial health of the animals, their treatment, and reporting of adverse responses are critical to making scientifically valid conclusions from the studies. Adequate biocompatibility assessment is important because patient or user exposure to a medical device could result in adverse health effects such as cytotoxicity, allergic reactions, skin irritation or inflammation, fever, toxicity that leads to loss of tissue/organ function or failure, and anaphylaxis.

Your response is inadequate. Your written response included the establishment of SOPs relating to animal care, surgery, and handling of animals during a study and retraining of individuals involved in this process. Included in your response are the revisions to nonclinical laboratory study methods to ensure the quality and integrity of the data generated during a study.

However, the observations noted regarding animal care were broad and did not only relate to inadequate SOPs regarding anesthesia and surgery. Your response did not address this. Specifically, your response does not detail how appropriate documentation and follow-up will be ensured when deviations arise in the future.

6. Failure of the testing facility to ensure that all newly received animals from outside sources were isolated and their health status evaluated in accordance with acceptable veterinary medical practice. In addition, failure of the testing facility to ensure warm-blooded animals, excluding suckling rodents, used in laboratory procedures that require manipulations and observations over an extended period of time or in studies that require the animals to be removed from and returned to their home cages for any reason (e.g., cage cleaning treatment, etc.) received appropriate identification [21 CFR 58.90(b), 58.90(d)].

Your testing facility did not adhere to these requirements.

a. Not all information needed to identify each animal within an animal housing unit appeared on the outside of that unit.

i. Specifically, during the tour of the facility on March 8, 2024, we observed that cage cards for guinea pigs and rats did not include unique animal identification numbers for each animal. It is necessary that the animals’ results in each individual study can be accurately traced. Without proper unique animal identification throughout the animal's care, the animal’s results as the experimental or control cannot be attributed or confirmed.

b. Not all newly received animals from outside sources were isolated and their health status evaluated in accordance with acceptable veterinary medical practice. Specifically,

i. Between November and December 2022, the test facility received a total of (b)(4) guinea pigs. When requested by the FDA investigative team, you could not provide any documentation regarding what physical examination was performed for evaluating the health status of these animals.

ii. For (b)(4) study, animals received on June 12, 2023 were transferred to conventional housing (Bldg. (b)(4) Rm. (b)(4) with other guinea pigs on the same day. The animals did not receive veterinary care and no physical examination records were provided.

Failure to properly identify each animal within an animal housing unit on the outside of that unit raises concerns about the potential for animals to be correctly identified. In addition, failure to ensure that cage cards are identified with unique identification numbers raises the concern regarding lack of traceability of the specific animal in the cage to the test and/or to the results of the testing presented in the reports. The inability to distinguish the test animals and control animals raises serious concerns about the validity of the test results.

Failure to isolate newly received animals or evaluate the animal’s health status can also raise serious concerns about the validity of study data. Animals may be sick upon arrival. If transferred to housing with other test animals already enrolled in another study, the newly received test animal could make the other test animals sick and impact study results. Further, test animals must be free of any disease or condition that might interfere at the beginning of a study or may significantly impact study data and/or results.

Your firm’s failure to have adequate intake and isolation procedures for test animals arriving at your facility suggests systemic failures in your firm’s nonclinical laboratory practices. Further, failures that relate to test animals used in numerous studies raises questions about the quality and integrity of data collected at your facility.

Your response is inadequate. Your written response includes revising the SOP (SDWH-302-B32a Experiment Numbering System Protocol) to clarify that cage card information will require a unique identification number. It also includes the training the study director and associated technicians on the revised SOP of SDWH-302-B32a, and to have the QAU implement information check for animal cage cards, which should be included in process inspection. The inability to distinguish the test animals and control animals raises serious concerns about the validity of the test results, and familiarity with the ISO 10993 standards. However, your response does not discuss whether there will be preventative actions implemented such as audits to check for compliance to the SOPs, nor does it discuss future training for new staff and/or new implemented procedures as applicable. Given the deviations and issues cited in the violations above, it is necessary to review the training materials to determine their adequacy for the trained individuals to both conduct the tests per the standards being used, and to produce accurate, traceable results.

The violations described above are not intended to be an all-inclusive list of problems that may exist with your facility. It is your responsibility as a non-clinical laboratory to ensure compliance with the Act and applicable regulations.

Within 15 working days of receiving this letter, please provide documentation of the additional corrective and preventive actions that you have taken or will take to correct these violations and to prevent the recurrence of similar violations in current or future studies for which you are the testing facility. Any submitted corrective action plan should include projected completion dates for each action to be accomplished as well as a plan for monitoring the effectiveness of your corrective actions. In addition, please provide a complete list of all nonclinical laboratory studies of FDA-regulated devices for the last five years, including the name of the study, the test article, the name of the study director and sponsor, and the current status of the study. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you. In addition, FDA could initiate disqualification proceedings against you in accordance with 21 CFR 58.202. If you believe that you have complied with the FD&C Act and FDA regulations, please include your reasoning and any supporting information for our consideration.

Your response should reference “CTS# GEN2300489/E001” and be sent via email to: Irfan.Khan@fda.hhs.gov.

A copy of this letter has been sent to FDA’s OBIMO Foreign Inspection Cadre via email FDAInternationalBIMO@fda.hhs.gov. Please send a copy of your response to that office.

The Division of Clinical Policy and Quality has developed introductory training modules in FDA-regulated device clinical research practices, which are available on the FDA website. The modules are for persons involved in FDA-regulated device clinical research activities. These modules are located at the following website address: http://www.fda.gov/Training/CDRHLearn/.

If you have any questions, please contact Albert E. Moyal, Engr., by phone at (301) 796-6333 or email at Albert.Moyal@fda.hhs.gov.

Sincerely yours,
/S/

Soma Kalb, PhD
Director
DCEA1: Division of Clinical Policy and Quality
Office of Clinical Evidence & Analysis
Office of Product Evaluation and Quality
Center for Devices and Radiological Health