WARNING LETTER

June 25, 2025

Dear Mr. Su:

This Warning Letter is to inform you of objectionable conditions observed during the United States Food and Drug Administration (FDA) inspection conducted at CCIC Huatongwei International Inspection (Suzhou) Co., Ltd. from January 6, 2025, to January 14, 2025, by investigators from the FDA’s Office of Bioresearch Monitoring Inspectorate (OBMI) 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, rabbit muscle implantation, acute systemic toxicity, MTT cytotoxicity, rabbit pyrogen, intracutaneous reactivity, and hemolysis studies conducted at your facility.

The list of studies below is not an all-inclusive list of studies impacted by the inspection or by the violations cited in this letter:

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 OBMI revealed serious violations of Title 21, Code of Federal Regulations (CFR) Part 58 - Good Laboratory Practice for Nonclinical Laboratory Studies, which concerns, among other things, 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 February 4, 2025, concerning our investigators’ 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 all experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified and that all raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study [21 CFR 58.33(b), and 58.33(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. The study director’s responsibilities include ensuring that all experimental data are accurately recorded and verified. Additionally, the study director is responsible for assuring that all raw data, documentation, protocols, specimens, and final reports are transferred to the archives as required by the regulations. Examples of the study director’s failures to adhere to these requirements include, but are not limited to, the following:

a. Study records for nine GPMT studies ((b)(4)) conducted by four different study directors throughout (b)(4) to (b)(4) contained six pages of source data that were photocopied and reused across different studies. The copied data included documentation of all animal preparation, administration of test and control articles, observations, and results. Additionally, the technicians’ signatures included within the source data were photocopied and reused across different studies. The experimental data was therefore not accurately recorded and verified.

b. In all of the seven significant risk device muscle implantation studies reviewed, for the Weeks 4, 13, and 26 datasets, multiple examples were found where the entries on the animal observation tables and the signature of the person completing them appeared to have been photocopies of the same document with only a change to the week number and the date. These studies all started on (b)(4) and ended on (b)(4). The bolded numbers in the chart below indicate records that are also copied across the data sets within the same study. For example, in (b)(4), the observation data for the weeks bolded in the 13-week study (weeks 2-9) and the observation data for the weeks bolded in the 26-week study (weeks 2-12) are all identical. The experimental data was therefore not accurately recorded and verified. Some examples are as follows:

c. The study director used templates with pre-completed information to generate study final reports that included pre-completed study observations and results. As confirmed by the study director during the inspection, these templates utilized red font and/or brackets to indicate where new information is to be populated within the documents. However, several sections of the template reports which should have been study-specific were pre-completed and not identified in red font and/or brackets as requiring updates (i.e., the template reports did not indicate that the template should be revised to incorporate the study-specific observations and results), including:

1. Muscle Implant Test Report Template: statements regarding animal observations, macroscopic assessments, the microscopic semiquantitative score for the tests, and overall conclusions.
2. Acute Systemic Toxicity Test Report Template: pre- and post-extraction conditions of the test article and control, statements regarding the results of the test article and negative controls and overall conclusions.
3. Guinea Pig Maximization/Skin Sensitization Test Report Template: pre- and post-extraction conditions of the test article and control, skin reaction results and clinical observations for the test article and control, and overall conclusions.

The use of templates such as these indicates a failure of the study director to assure that all experimental data, including observations of unintended responses of the test system are accurately recorded and verified. Each test article is nuanced in its combination of materials, construction, intended use, and duration of use. Use of templates that contain pre-completed observations, results, and overall conclusions indicates lack of proper scientific assessment and calls into question whether the experimental data was accurately recorded and verified in the final reports.

d. During the inspection it was observed that all study folders on the GLP archivist's portable hard drive had been modified on or about January 5, 2025, shortly prior to the inspection. According to the Quality Assurance Unit Manager and GLP archivist, prior to the pre-announcement of this inspection on December 27, 2024, they had not archived any study protocols or sample submission forms, and so they added them to the archive index ahead of the inspection. The required records were therefore not transferred to the archives during or at the close of each study. In addition, the following deficiencies regarding the archival practices were found:

1. Of the 21 study records initially requested for review, only seven were found in the dedicated GLP archive room.¹
2. The tissue slides from Muscle Implantation study (b)(4) were not retained.
3. There were no tissue blocks and cassettes for any studies stored in the GLP archive room.
4. For both Muscle Implantation studies (b)(4) and (b)(4), tissue slide "20" of the 20 tissue slides was missing from the archives.
5. The electronic source data for the rabbit pyrogen tests is not maintained. Only the hand-transcribed data is included in the study records. The rabbit pyrogen test is conducted using a pyrogen meter that provides machine-generated results, which are then transcribed by hand to a paper record.

As the principal point of study control, the study director did not assure that all experimental data were accurately recorded and verified, that applicable good laboratory practice regulations were followed and that all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study. Failure to ensure accurate data such as individual animal weights, animal preparation, the administration of test and control articles, observations, and results, yields questionable study results and conclusions. Furthermore, failure to ensure all data is retained and timely transferred to the archives can result in incomplete documentation of the study in the archives and could limit reconstruction and evaluation of the study. 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. Complete and accurate study data are necessary to allow FDA to fully assess the overall safety and risk of a device with an associated premarket submission. The unreliable data raises concerns about the quality and integrity of associated premarket submissions, which may put public health and safety at risk. 

Your written response is inadequate. You acknowledge in your response that “there are issues with personnel's understanding of 21CFR Part 58 and the implementation of standard operating procedures,” including that “It was found during the inspection that QA was unfamiliar with GLP regulations” and that “[d]uring the investigation, it was shown that SD cannot clearly understand the responsibilities required in 21CFR part 58.” The response provided indicates that certain standard operating procedures (SOPs) relevant to the concerns noted in the Form 483 were revised, new procedures related to data integrity were developed, and some related staff training was conducted. Additionally, the response stated that new electronic systems for document management and training will be implemented and additional training provided. However, your response does not provide: (1) documentation of actions that have been or will be taken to fully address and correct the specific violations observed during the studies, including the conditions which allowed them to occur; (2) detail regarding how your testing facility will ensure that GLP regulations and applicable SOPs will be followed to ensure the quality and integrity of data generated in a study; (3) detail regarding how appropriate documentation/follow-up will be ensured when deviations arise in the future; (4) detail regarding planned preventive actions such as frequency (e.g., quarterly, annual) of audits to check for compliance or future training of new study directors, as applicable; and (5) detail regarding how the effectiveness of proposed preventative actions such as the implementation of electronic systems (which have not yet been implemented) will be assessed. Thus, your response does not provide assurance that similar violations would not occur again. 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. Failure to properly identify specimens used in nonclinical laboratory studies by test system, study, nature, and date of collection [21 CFR 58.130(c)].

Not all specimens were identified by test system, study, nature, and date of collection. This information was not located on the specimen container or did not accompany the specimen in a manner that precluded error in the recording and storage of data. Your failures to adhere to this requirement include, but are not limited to, the following examples:

a. Six muscle implantation studies ((b)(4)) conducted on a high-risk device had the following deficiencies regarding the histopathology slides that contained the study specimens:

1. The slides did not have a study ID and were only identified by the numbers 1-20 written in pencil. There was also no information provided about the test system, nature, or the date of collection. Additionally, the animal identification numbers in the related source records for all six studies do not correspond to the labels on the slides. The animal and implant site identification in the source records only included numbers 1-10, and therefore, the slides are not attributable. In addition, the animal identification numbers in the source records were the same for both the tests and controls (both were labelled 1-10), such that test and control samples cannot be distinguished.
2. Some of the numbers written on the slides were no longer legible and it appeared some numbers had been wiped off and/or written over, including the complete set of slides for study (b)(4) Week 4 and (b)(4) Week 13. These slides therefore have no identification at all.

Failure to properly label specimens in a manner that precludes error in the recording and storage of data can attribute to evaluating specimens for the wrong animal, wrong implant site, and wrong study. Therefore, the reliability and quality of data of these studies are in question. This in turn 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 legally marketed device or for purposes of beginning clinical trials.

Your written response is inadequate. You acknowledge that the procedure lacks some instructions for the study ID requirements and that correct identification was not included on the specimens. The new procedure has details regarding how to identify the slides, blocks, etc. However, your response does not address the issue of providing a unique animal identification system that would allow adequate traceability of specimens to prevent attribution of incorrect or invalid histopathology data to the test articles under study. Therefore, your written response does not provide assurance that similar violations would not reoccur.

3. Failure to ensure that warm-blooded animals, excluding suckling rodents, receive appropriate identification [21 CFR Part 58.90(d)]. 

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, shall receive appropriate identification. Your failures to adhere to this requirement include, but are not limited to, the following examples:

a. Some source records do not include unique animal ID numbers. For example:

1. In the AST study, (b)(4), both the test and control animals are only identified as numbers 1 through 5, which is not consistent with SOP (b)(4): Animal Marking Method.
2. In muscle implantation studies, rabbits implanted with control and test articles are both named only “1”, “2”, or “3,” without identifiers to indicate the study numbers for these animals or to distinguish between control and test.

Identifying multiple animals in a particular study with the same number, as noted above, indicates that the animals did not receive appropriate identification. Failure to properly identify each animal within an animal-housing unit raises concerns about the potential for animals to be incorrectly assigned to studies or study groups. The accuracy of study results cannot be verified since the ability to identify specific animals is foundational to being able to draw scientifically valid conclusions from the studies.

Your written response is inadequate. You acknowledge the observation and have identified the root cause as being due to inadequate procedures and have acknowledged that the non-traceability of animal identification numbers can lead to the loss of tracking of testing systems, which can affect the reconstruction of experiments and data integrity. Proposed corrective actions include the revision of procedures, creation of new procedures and creation of guidelines for electronic data management. Your response indicates that your corrective and preventive action plan has been initiated to track animal numbers for testing for high-risk products. However, this does not appear to be adequate. This action should include all animals received and used at the facility to address the overall system and not isolated practices or only for certain products. Also, as not all of the corrective actions have been implemented at this time, the adequacy cannot be evaluated. Therefore, your written response does not provide assurance that misidentification of animals would not reoccur.

4. Failure to conduct nonclinical laboratory studies in accordance with the protocols [21 CFR 58.130(a)]. 

Nonclinical laboratory studies shall be conducted in accordance with the study protocol(s). Your failures to adhere to this requirement include, but are not limited to, the following examples:

a. Regarding the ongoing GPMT studies ((b)(4) and (b)(4), both started on (b)(4)), on (b)(4) none of the guinea pigs' cages contained water bottles. Study protocols (b)(4) and (b)(4) Animal management, states “Water: Drinking water met the Standards for Drinking Water Quality (b)(4) 5749-2022.” However, no water was observed to be provided to the guinea pigs, and when asked, the veterinarian stated they used cabbage as the water source. Additionally, it was observed that feed pellets were intermixed with bedding/excreta. Per the aforementioned protocol, feed should consist of “Full-price pellets, (b)(4).” and there should be “no known contaminants present in the feed, water, or bedding expected to interfere with the test data.” Additionally, in multiple cages, the feed box was empty and feed pellets fell into the beddings through the spacings between metal wires of the feed box. Due to the large gaps between the wires of the feed box, the feed box could not provide “reliable and easy” access for guinea pigs to eat the feed pellets. Per the SOP (b)(4)-SOP-IAC-001 Animal welfare, Section 3.2, “Drinking and feeding devices for animals should be safe, reliable and easy to eat, and should be kept clean and in normal use.”

b. Within the aforementioned studies, on (b)(4), it was observed that the recorded weights for multiple guinea pigs were less than 300 grams (22 of 30 in the (b)(4) study and 24 of 30 in the (b)(4) study). Per study protocols (b)(4) and (b)(4), section 7.2 Test Animal, all animals should weigh 300-500 grams at the initiation of the study. Per the study protocols and internal procedure (b)(4)-SOP-BIO-003, all animals should weigh 300 - 500 grams at the initiation of the study.

Failure to follow the protocol impacts the reliability and quality of data contained within the final study report. This in turn 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 legally marketed device or for purposes of beginning clinical trials. Deprivation of food and water is inhumane, and can have adverse effects on animal growth, the immune system, and metabolic state, as well as impact how the body responds to the extract (i.e., device) that is being tested, thus impacting the reliability of the data generated from the nonclinical laboratory studies conducted at your testing facility. Likewise, utilizing animals that do not meet the protocol-specified weight requirements can impact the interpretation and validity of the test results.

Your written response is inadequate. You acknowledge the concern raised by the investigator that not all nonclinical laboratory studies were conducted in accordance with the protocol. Your response indicates that certain SOPs relevant to the concerns noted in the Form 483 were revised, protocol amendments and deviations for certain studies were documented, training for the laboratory supplier was conducted, and a plan was developed for inviting a third-party consultant to audit the animal tracking process. However, your response does not: (1) demonstrate how you will ensure that all personnel will follow study protocols; (2) provide documentation of deviation incidents for all impacted studies; and (3) address any planned preventive actions, such as frequency (e.g., quarterly, annual) of audits to check for compliance following completion of the submitted audit plan or future training for new staff and/or new procedures, as appropriate. Therefore, your written response does not provide assurance that similar violations would not occur again.

5. Failure of the Quality Assurance Unit (QAU) to maintain a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing facility indexed by test article and containing the test system, nature of study, date study was initiated, current status of each study, identity of the sponsor, and name of the study director [21 CFR 58.35(b)(1)]. 

Your failures to adhere to this requirement include, but are not limited to, the following examples:

a. Of the 26 studies requested, 14 of them listed below were not found on the master schedule (MS):

(b)(4)

b. The MS has not been updated since September 30, 2024. However, studies (b)(4) and (b)(4), which were not included in the MS, were observed to be ongoing on (b)(4).

c. The MS does not include the name of the study director, the test system, or the sponsor. 

A reliable QAU is integral to the successful completion of any nonclinical laboratory 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 can have a negative impact on a study because it indicates a lack of monitoring and oversight of each study to ensure compliance with all applicable GLP regulations, and calls into question the quality and integrity of studies conducted. 

Your written response is inadequate. You acknowledged in your response the concern that the quality assurance unit failed to maintain a copy of a MS sheet that contained all required elements for all nonclinical laboratory studies, and you indicated that this was likely due to an inadequate MS procedure, as well as QA personnel having overlooked their responsibilities. Your response indicates that SOP (b)(4)-SOP-GEN-008 Master Schedule will be revised, QA personnel will be trained on responsibilities, and the FDA GLP studies in the past three years will be sorted out and “a complete GLP master plan” will be submitted to FDA. However, your response does not address how missing studies will be systematically identified and included in the MS. 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. Therefore, your response does not provide assurances that QAU failures will be avoided in the future.

6. Failure to prepare final reports that were signed and dated by each of the individual scientists or other professionals involved in the studies [21 CFR 58.185(a)(12)].

Nonclinical laboratory study results are to be documented in a final study report that must include the signed and dated reports of each of the individual scientists or other professionals involved in the study. Your failures to adhere to this requirement include, but are not limited to, the following example:

The final reports of all of the seven muscle implantation studies for significant risk devices that were reviewed ((b)(4) through (b)(4)) did not include the signature of the responsible pathologist that provided the histopathology assessment. The pathologist’s signature and date were also missing on the source records where the tissue reaction scores were reported.

Inclusion of the dates and signatures ensures that the findings of the study results can be attributed to the individual scientist completing the study and helps to provide confirmation that the findings are accurately reflected. Without this documentation, it is unknown if the pathologist was involved in the generation of these reports, and whether the data truly reflect the pathologist’s findings. These failures raise questions about the quality and integrity of data collected at your facility.

Your response is inadequate. Your response indicates that SOP (b)(4)-SOP-ORG-003 Study Director Duties and Responsibilities was revised, personnel training was conducted, and a plan was developed for inviting a third-party consultant to audit the pathological report management process. Additionally, you indicated that the final reports of high-risk products from 2020-2024 would be reopened to supplement pathological report and evaluate the impact. However, you have not detailed how you intend to assess and supplement these reports. Additionally, while you have revised the aforementioned SOP, the revisions made do not address the fact that a final report should include the signed and dated reports of each of the individual scientists or other professionals involved in the study. Your response also does not discuss whether there will be preventative actions implemented such as frequency (e.g., quarterly, annual) of audits to check for compliance following completion of the submitted audit plan or future training for new staff and/or new procedures, as appropriate. Therefore, your response does not provide assurances that these failures will not reoccur.

7. Failure to provide for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens and interim and final reports [21 CFR 58.190(b)].

GLP regulations require that archives are maintained in a way that allows for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final reports. Your failures to adhere to this requirement include, but are not limited to, the following examples:

a. Your study archives are not organized to permit expedient retrieval. It was observed that records from multiple different studies were stored together in at least 30 boxes without any labels, and GLP study records could not be readily located. On (b)(4), it took up to eight employees over two hours to locate records from eight studies that should have been in the GLP archive room. Two sets of study data were found in the GLP archive room and the remaining six were in the non-GLP storage room.

b. The original final study report for GPMT study (b)(4) was amended on 10/12/22; however, a copy of the original report was not retained in the GLP archive portable hard drive. It was stored in the non-GLP public folder.

Inadequate archiving practices could result in the loss or destruction of study material, prevent, or reduce the ability to confirm or amend study results, and puts the archive data at risk of being attributed to the incorrect study. Further, having the raw data readily accessible to the FDA reviewer enables the study to be verified as needed to facilitate review and helps to ensure 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 response is inadequate. Your response indicates that SOP (b)(4)-SOP-ORG-005 Archival, Maintenance and Retrieval, Disposal and Transfer of Records and Materials has been revised, and that you intend to take additional actions, including expansion of the archiving area, adding personnel, and verifying and recovering the completed studies. However, your response does not provide complete documentation of actions that have been or will be taken to fully address and correct the specific violations observed during the inspection, including the conditions that allowed them to occur or detail regarding planned preventive actions such as frequency (e.g., quarterly, annual) of audits to check for compliance or future training of new personnel, as applicable. Therefore, your response does not provide assurance that these failures have been corrected and will not reoccur.

In addition to the violations described above, we have concerns about the records generated during GLP studies that were not maintained in a manner to prevent unauthorized access, changes, or deletions, which further calls into question the reliability and integrity of the data. The histopathology results were transferred between the current pathologist and study director on a portable USB device with a shared password and stored in an unlocked cabinet in the pathologist’s reading room. In addition, for 14 of the 24 studies inspected, the study director has her username and password (b)(4), which would allow anyone to log in.

The study director’s workstation is an open cubicle within a large office that did not have controlled access. The combination of shared password access and unsecured physical storage increases the vulnerability of critical data to be altered or deleted by unauthorized individuals. The absence of physical security measures increases the likelihood of unauthorized individuals accessing not only the study director’s laptop but also any sensitive data saved in the laptop.

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 preventative 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# EC250057/E001” and be sent via email to: Irfan.khan@fda.hhs.gov.

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

If you have any questions, please contact Adaliz Santaliz-Cruz by phone at (787) 729-9024 or email at Adaliz.Santaliz-Cruz@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

______________________

1 Facilities must have space provided for archives that is “limited to access by authorized personnel only, for the storage and retrieval of all raw data and specimens from completed studies.” 21 CFR 58.51; see also 21 CFR 58.190(d).