WARNING LETTER
Mid-Link Testing Company, Ltd
MARCS-CMS 687111 —
September 10, 2024
Product:
Medical Devices
Recipient:
Recipient Name
Xiaoming (Diana) Hong
Recipient Title
President
Mid-Link Testing Company, Ltd
Rongda Science Park No 51
1/F Block B 9th Street
Tianjin Shi
,
300457
China
Issuing Office:
Center for Devices and Radiological Health
United States
WARNING LETTER
September 10, 2024
Dear Ms. Xiaoming (Diana) Hong:
This Warning Letter is to inform you of objectionable conditions observed during the United States Food and Drug Administration (FDA) inspection conducted at Mid-Link Testing Company, Ltd from February 26, 2024, to March 6, 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 acute systemic toxicity and rabbit pyrogen 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)
Acute Systemic Toxicity
(b)(4)
Acute Systemic Toxicity
(b)(4)
Acute Systemic Toxicity
(b)(4)
Acute Systemic Toxicity
(b)(4)
Acute Systemic Toxicity
(b)(4)
MTT cytotoxicity
(b)(4)
Rabbit Pyrogen
(b)(4)
Rabbit Pyrogen
(b)(4)
Rabbit Pyrogen
(b)(4)
Rabbit Pyrogen
(b)(4)
GPMT
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. This letter also requests prompt corrective action to address the violations cited and discusses your written response received on March 25, 2024, to the noted violations.
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 investigator 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 March 25, 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 all experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified, and unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented [21 CFR 58.33(b) and 58.33(c)].
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 unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented. Examples of the study director’s failures include, but are not limited to, the following:
a. Study records for several studies (
(b)(4)
) showed incorrect information on weight gain for multiple animals. Specifically, that multiple animals in the same study gained the exact same weight (0.5 gram) between weight timepoints, which is improbable. During the inspection, FDA investigators asked Ms. Xiaoming Hong (Mid-Link President) and Mr. Lee Fu (also the Study Director for two of the studies:
(b)(4)
and
(b)(4)
), if they thought it was possible that these many animals gained precisely 0.5-gram in the same study. They [Ms. Hong and Mr. Fu] agreed that it is not possible, and Mr. Fu explained that “When technicians could not get a stable reading, they recorded a number by adding a certain number based on the animal weights in the previous day’s measurement.” Your CAPA investigation (QA-0036 A/3 No: 202209002) similarly concluded that staff were "[u]nable to get a stable reading, [so] they considered the previous day's weight data, added a certain value, and if within the range of scale fluctuation, directly recorded the reading." Furthermore, in a second CAPA investigation (QR-0036 A/3 No: 202212001), it is acknowledged that “the study supervisor did not pay attention to the data during the process." Therefore, even though the study director is required to be the single point of study control, these fabricated data were not identified by the study director as improbable, and the erroneous data were incorporated into the final study report.
b. Evidence that clinical observations have been performed for each animal in accordance with SOP-180 A/0 - Animal Clinical Observations was either not recorded or recorded incorrectly. For example, this procedure requires the physical examination assessments (coded) for each animal to include categories for animal spirit (excited, drowsiness); respiratory system; activity level; circulatory; and external appearance. However, for study
(b)(4)
, our inspection revealed that only a subjective evaluation of ‘abnormal/normal’ is recorded and that the date of the observations required by the standard operating procedure (SOP) was not recorded. In addition, for multiple studies, study records fail to document the room in which animals for each study are housed during the conduct of a study. Thus, daily observations recorded on form QR-0038 (Experimental Animal Feeding Records) cannot be attributed to any designated study because animals from multiple studies may be co-housed in any given room. These practices are inconsistent with the requirements of SOP-180, and the missing/incorrect data were not addressed in the final study report.
As the principal point of study control, the study director did not ensure that all experimental data were accurately recorded and verified, did not document when unforeseen circumstances occurred that may affect the quality and integrity of the study, or take corrective action. Failure to ensure accurate data such as individual animal weights and assessments yields questionable study results. 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. The response provided shows that relevant SOPs were revised, amendments and re-testing were done, and staff training was recorded, but it 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 and the conditions which allowed them to occur; (2) clarification regarding whether the study directors are required to train on your revised procedures and reference documents related to accurately recording data, completing individual animal health assessments, and performing appropriate follow-up; and (3) any planned preventive actions, such as frequency (i.e., quarterly, annual) of audits or future training for new staff, including study directors, and/or new procedures, as appropriate. 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. Thus, your response does not provide assurance that similar violations would not occur again.
2. 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. Raw data for
(b)(4)
rabbit pyrogen tests (
(b)(4)
) fail to include documentation of calibration of the temperature probes before each use, as required by each associated study protocol to follow US Pharmacopeia (151) Pyrogen Test. The temperature probes were not adequately calibrated to ensure that rabbit temperature changes can be measured with ±0.1 ℃ accuracy per USP <151>, which is designed to limit to an acceptable level the risks of febrile reaction.
Lack of adequate calibration is a protocol deviation, as USP <151> is the basis for rabbit pyrogen test and is identified as the guideline to follow in the
(b)(4)
rabbit pyrogen tests. It requires that temperature probes be calibrated to assure an accuracy of ±0.1°. Because it is unknown whether the previously used temperature probes can accurately measure temperature changes of the rabbits during testing, the validity of those previously conducted rabbit pyrogen studies (e.g.,
(b)(4)
) is questionable. In addition, rabbit temperature changes are within a small window (<0.5 ℃ is one of the acceptance criteria). Records from the
(b)(4)
rabbit pyrogen tests document almost no change in rabbit temperature during testing, and these questionable results were not identified for retesting. Without a calibration check of temperature probes, the accuracy of temperature measurement by the temperature probes is questionable.
b. Study Protocol
(b)(4)
requires occlusive dressing be utilized to secure the test article on the study animals. Elastic net bandages were used to wrap the patches around the trunk of animals. Study records document the elastic net bandages (including test and control articles) were supposed to be removed on
(b)(4)
. However, on
(b)(4)
during the inspection, some bandages were observed on the bedding, as they had not been secure and fell off from some animals within cage #
(b)(4)
and #
(b)(4)
(RM
(b)(4)
).
In addition, the following was observed:
• Cage
(b)(4)
for study
(b)(4)
, all wraps from
(b)(4)
animals fell off into the bedding
• Cage
(b)(4)
for study
(b)(4)
, elastic bandages fell off from
(b)(4)
animals
• Cage
(b)(4)
for study
(b)(4)
, elastic net bandages fell off from
(b)(4)
out of
(b)(4)
animals
• For animals in cages
(b)(4)
that still had bandages on them, all elastic bandages rolled up or down along the trunk of the animals.
Moreover, in some cases where the elastic net bandages were not splayed along the animal trunks, the bandages became tight, and some animals did not appear to breathe normally. As not all the test and control articles were in contact with animals for a period of time, the data collected is unreliable, and the validity of guinea pig maximization tests (GPMTs) is questionable. Study records provided did not include any written records documenting this incident or approving any change in the protocol, as required by Section 1.4 of the study protocol, nor any actions that were taken to correct it.
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.
Your written response is inadequate. The response provided shows that the relevant SOP was revised, personnel were trained and evaluated, and an internal audit was performed, but does not: (1) demonstrate how you will ensure that all staff will follow study protocols; (2) provide documentation of deviation incidents; (3) provide documentation of performing appropriate follow-up procedures; and (4) address any planned preventive actions, such as frequency (i.e., quarterly, annual) of audits to check for compliance or future training for new staff and/or new procedures, as appropriate. In addition, the revised SOP regarding the use of occlusive dressing to secure the test article on the study animals does not adequately address ensuring that the dressings do not become too tight for the animals. Your written response therefore does not provide assurance that similar violations would not occur again.
3. Failure of a testing facility to have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to ensure 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 [21 CFR 58.81(a)].
Standard operating procedures (SOPs) should be adequate to ensure the quality and integrity of data generated in a study. However, all SOPs do not appear to be adequate. The study director also must authorize all deviations from SOPs in a study and document all study deviations in the raw data. However, the study director at your testing facility did not adhere to these requirements. Deviations from standard operating procedures in a study were not authorized by the study director and documented in the raw data. Examples include the following:
a. According to Section 7.2.1 of SOP-004 A/2, ear cut was used as the identification for animals. However, according to raw data form QR-0044 A/1, all acute systemic tests associated with Study
(b)(4)
required animals to be identified with cage number and sex. The cage number was not documented for animals involved in this study. Five animals were housed in each cage, and without documenting the cage number, there is no way to know the animal identification and which treatment (test article vs control articles) the animals were exposed to because all animals in different cages were numbered as animals 1, 2, 3, 4, and 5.
b. Section 7.1.2 of SOP-019 A/0 for MTT cytotoxicity test states that the negative control is High density polyethylene (HDPE) that meets the requirement of U.S. Pharmacopeia. However, the study report for study
(b)(4)
MTT cytotoxicity test states that the negative control used in the study is high density polyethylene (HDPE) (Manufacturer:
(b)(4)
). Therefore, the study records for
(b)(4)
MTT cytotoxicity show that the HDPE used in the study is not U.S. Pharmacopeia high density polyethylene (HDPE).
c. The Laboratory Animal Ethics Review Form for IACUC proposal #202202016 (QR-0067 A/1), which outlines the procedures to be followed for rabbit pyrogen testing, states Japanese White Rabbits will be restrained for 3 hours. Study records from the following rabbit pyrogen studies document that the animals were restrained up to 5 hours, as noted in the chart below:
Study number
Restraint Start time
Restraint
End Time
Total time Restrained
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
d. Section 11.0 of SOP-305 (Standard Operation Procedure for FDA GLP Study A/0) requires protocols to include identification of the test system (i.e., animal model) with all appropriate elements (including animal biological features such as body weight, sex, age, and its stock/strain characteristic through the supplier). However, several protocols (listed below) are lacking all appropriate elements. This deviation of SOP-305 (Standard Operation Procedure for FDA GLP Study A/0) was not authorized by the study director. A prerequisite for beginning an animal study is to know that the right animal model is included in the protocol. This should inform approval and acceptability of the protocol, animal ordering, criteria for animal selection, husbandry and animal care, conduct of animal study, and analysis of the data.
Because the SOP was not followed, relevant protocols are lacking this information, as exemplified in the following protocols:
i. Protocols for studies
(b)(4)
do not contain body weight range, sex, age, or source of supply.
ii. Protocol for study
(b)(4)
does not contain body weight range, age, and source of supply.
iii. Protocol for study
(b)(4)
does not contain specific study objectives and test system's source of supply and age.
Failure of a testing facility to have adequate standard operating procedures, or follow established SOPs if adequate, raises questions about the reliability and accuracy of the data and does not ensure the quality and integrity of data generated in a study. Failing to follow SOPs and having inadequate SOPs yield inadequate protocols that introduce ambiguity and uncertainty as to how study requirements are to be followed. Any deviations from the SOPs must be authorized by the study director and documented in the raw data. Failure to properly document any authorized deviations could result in study data with a high level of variability that challenges ability to effectively interpret the study results associated with a device. 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. Your response acknowledged the observations cited, included revised SOPs, confirmed that personnel were trained and evaluated, and provided amended reports, protocols, and data records, but it does not: (1) detail how your testing facility will ensure that 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 for new staff and/or new procedures, as applicable; and (3) detail how appropriate documentation/follow-up will be ensured when deviations arise in the future. In addition, your response regarding use of a different source of HDPE included revision of SOP-019 A/0 for MTT cytotoxicity test from “(HDPE) that meets the requirement of US Pharmacopoeia” to “Negative control is HDPE”. Per ISO 10993-5: 2009, “Equivalent products may be used if they can be shown to lead to the same results.” The revised SOP does not identify how HDPE will be confirmed to be equivalent and lead to the same results (i.e. testing or documentation such as Certificate of Analysis (COA)). Your explanation, when taken into consideration with the violations described above, such as failing to follow your SOPs for multiple studies over multiple months, suggests systemic failures in ensuring the quality and integrity of data generated in these studies, bringing into question the quality and integrity of safety data collected at your testing facility. Thus, your written response does not provide assurance that similar violations would not occur again.
4. Testing Facility Management failed to ensure that personnel clearly understand the functions they are to perform [21 CFR 58.31(f)].
Testing facility management failed to assure that all personnel clearly understood the functions they were to perform. For example, training documentation for intracutaneous reactivity testing are incomplete as they do not include information on how to distinguish erythema and edema scoring (erythema scores 1, 2, 3, 4 and edema scores 1, 2, 3, 4), which are separately recorded in the raw data for study
(b)(4)
. Additionally, the training records for individuals performing this test only include scores of "0" for both erythema and edema and do not demonstrate the testing facility management can accurately assess and report erythema and edema responses per the grading scale identified in the training slides.
Failure of testing facility management to assure that all personnel are adequately qualified and trained creates a high level of variability that does not ensure the validity and quality of the data. The training records did not show that personnel can clearly distinguish erythema and edema scores per the grading scale. This does not provide assurance that testing facility management can accurately assess that personnel are qualified to accurately report erythema and edema scores. Personnel that do not clearly understand the functions they are to perform cannot consistently perform tasks according to the SOPs. This can have a negative impact on a study and calls into question the integrity of studies conducted.
Your written response is inadequate. Your response provided a revised SOP, staff training materials, and training and evaluation records of the personnel involved in scoring, but it does not address any planned preventive actions such as frequency (i.e., quarterly, annual) of audits to check for compliance or future training for new staff and/or new procedures, as applicable, to help ensure that this violation will be avoided in the future.
5. Failure of the Quality Assurance Unit (QAU) to fulfill responsibilities [21 CFR 58.35(a),58.35(b)(1), 58.35(b)(5), and 58.35(b)(6)].
The QAU is responsible for monitoring each study to assure that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with GLP regulations. These responsibilities include, among other things: maintaining a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing facility, determining that no deviations from approved protocols or standard operating procedures were made without proper authorization and documentation, and reviewing 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. Examples of failures include, but are not limited to, the following:
a. The QAU failed to maintain a complete Master Schedule sheet of all nonclinical laboratory studies conducted at the testing facility. Specifically, the following studies were not listed on the Master Schedule reflective of the last five years:
(b)(4)
.
b. The QAU failed to determine whether any deviations from approved protocols or standard operating procedures had been made without proper authorization and documentation. For example, in Study
(b)(4)
, animal weights for the 48-hour time point were documented as completed at
(b)(4)
using EQ0046. However, the use log reports for this scale (QR-0186 A/1 NO202205004) indicate that it was utilized between
(b)(4)
on this day. There were also weight discrepancies that were not identified in the QAU audit.
c. The following discrepancies were noted in the final study report despite QAU audit:
1. Study
(b)(4)
: The final report only described one survival surgery, but the raw data documents a second survival procedure from anesthesia. Additionally, the final report stated that, for termination of animals,
(b)(4)
2. Study
(b)(4)
: The final report does not state the method of euthanasia. However, the protocol indicates that euthanasia was performed by
(
b)(4)
A reliable QAU is integral to the successful completion of any nonclinical laboratory study. Without appropriate QAU oversight, neither the sponsor or 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 and calls into question the integrity of studies conducted.
Your written response includes SOP revisions to QP-026 GLP Study Control Procedure, SOP- 305 A/0 Standard Operating Procedure for FDA GLP, and SOP-305 A/1 Standard Operating Procedure for FDA GLP, as well as personnel training records and description of a three-week monitoring period of the current master schedule. However, your response is inadequate because it 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 and the conditions which allowed them to occur; (2) clarification regarding whether the QAU is required to train on the revised procedures and reference documents related to maintaining a complete master schedule, noting deviations from approved protocols, and proper procedures/settings during anesthesia; and (3) any planned preventive actions such as frequency (i.e., quarterly, annual) of audits to check for compliance or future training for new staff and/or new procedures, as applicable. These systemic data integrity issues, such as failing to monitor each study for conformance with GLP requirements, involved numerous quality assurance staff in multiple studies and were occurring at your facility for multiple months, which brings into question the quality and integrity of the safety data collected at your testing facility. Therefore, your response does not provide assurances that QAU failures will be avoided in the future.
6. Failure to ensure that warm-blooded animals shall receive appropriate identification where all information needed to specifically identify each animal within an animal-housing unit appears on the outside of that unit [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. All information needed to specifically identify each animal within an animal-housing unit shall appear on the outside of that unit. You failed to adhere to this requirement. For example, for study
(b)(4)
, although animal IDs were recorded within a spreadsheet, the cage cards for animals (e.g., mice, guinea pigs) did not include the animal ID (number) for all animals housed in a single cage during the time the study was conducted.
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 does not adequately address the issue of misidentification. Your responses provided a revised SOP and personnel training records; however, the SOP appears to be a different identification process for mice that does not include the individual animal ID on the cage card. This poses a potential for misidentification. In addition, your response does not: (1) document your plan to prevent recurrence of animal misidentification in the future; (2) provide an assessment of the impact associated with the misidentification issue; (3) clearly document the types and content of staff training provided related to your new and revised procedures, processes, forms, and checklists for the new animal identification process; and (4) address any planned preventive actions such as frequency (i.e., quarterly, annual) of audits to check for compliance or future training for new staff and/or new procedures, as applicable. Your written response therefore does not provide assurance that misidentification of animals would not occur again in the future.
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# EC240187/E001” and be sent via email to: Albert.Rodriguez@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 Marisa White by phone at (301) 796-5653 or email at Marisa.White@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
Content current as of:
09/11/2024
Regulated Product(s)
Medical Devices