Inspections, Compliance, Enforcement, and Criminal Investigations
Testing Center of Sanitation & Environment Technic Institute 10/13/11
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|10903 New Hampshire Ave.|
Silver Spring, MD 20993-0002
October 13, 2011
VIA UNITED PARCEL SERVICE
Testing Center of Sanitation and Environment Technic Institute
199 Ren’Ai Road
Suzhou, China 215123
Dear Mr. MIAO Shi-lin:
The purpose of this letter is to inform you of the findings of a United States (US) Food and Drug Administration (FDA) inspection of your nonclinical laboratory, Testing Center of Sanitation and Environment Technic Institute, in Suzhou, China, from May 30, 2011, to June 3, 2011, by an investigator from the US FDA China Office. The US FDA inspected the following nonclinical laboratory studies conducted by your facility under US FDA Good Laboratory Practice for Nonclinical Laboratory Studies, Title 21, Code of Federal Regulations (CFR), Part 58:
- (b)(4) Premarket Notification (510(k)) supplement (b)(4), and
- (b)(4), Premarket Notification (510(k)) supplement (b)(4).
The purpose of this inspection was to determine whether activities and procedures related to your participation in these nonclinical studies complied with applicable federal regulations. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 USC 321(h), (b)(4) and the (b)(4) are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body. This letter also discusses your written response, dated June 10, 2011, to the noted violations.
This inspection is a part of the US FDA’s Bioresearch Monitoring Program, which includes inspections designed to verify compliance with 21 CFR Part 58--Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies regulation. The regulation at 21 CFR Part 58 applies to nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the US FDA.21 CFR 58.1(a).
Our review of the inspection report prepared by the US FDA investigator revealed several violations of 21 CFR Part 58. At the close of the inspection, the US FDA investigator presented an inspectional observations Form FDA 483 for your review and discussed the observations listed on the form with you. The deviations noted on the Form FDA 483, your company’s written response, and our subsequent review of the inspection report, are discussed below:
Failure of the study director to assure that each study has an approved written protocol and fulfill his/her responsibilities [21 CFR 58.33(a) and (f) and 58.120]
For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the study director. The study director shall ensure that each protocol, including any change, is written and approved in accordance with GLP regulations. Your study director failed to ensure that the studies, (b)(4) had approved written protocols prior to the initiation of the study. Although copies of the final study reports were maintained, your staff could not produce the approved protocols for these studies.
The study director shall also ensure that all raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study. Your study director failed to ensure that all documentation and protocols were transferred to the archives during or at the close of the study. Specifically, your study director could not provide documentation of when the raw data, documentation, and final reports were transferred to the archives for each nonclinical laboratory study.
The lack of a study protocol makes it difficult to assess and verify the quality and reliability of data contained within the final study report, as well as the overall safety or risk of the product prior to beginning clinical trials involving human subjects. Your company’s written response states that your company plans to write a protocol for every nonclinical laboratory study intended for submission to the US FDA. However, your company’s response is inadequate because your company did not provide a copy of its newly created standard operating procedures (SOPs), as well as documentation of proposed dates of implementation, dates of training, and a list of staff trained. Please provide a copy of these documents.
You also stated that, within 30 days, your staff will arrange a new room for archiving study records and ensure that all raw data, documentation, protocols and final reports are transferred to the archives during or at the close of each study using forms (b)(4) and (b)(4). These forms should assist your company in documenting study records transferred to the archives. With response to this letter, provide a copy of the corresponding SOP that provides instructions to your staff on the use of these forms, as well as dates of training and a list of staff trained.
Failure to prepare an adequate final study report [21 CFR 58.185]
A final study report shall be prepared for each nonclinical laboratory study that shall include, but not necessarily be limited to, the following: a description of all circumstances that may have affected the quality and integrity of the data; statistical methods employed for analyzing the data; names of other scientists or professionals and all supervisory personnel involved in the study; signed and dated reports of each of the individual scientists or other professionals involved in the study; and a statement prepared and signed by the quality assurance unit (QAU). In addition, corrections or additions to a final report shall be in the form of an amendment by the study director. The amendment shall clearly identify the part of the final report that is being added to or corrected, and the reasons for the correction or addition, and must be signed and dated by the person responsible.
The final study report for (b)(4), approved and signed by (b)(4), study director, on March 29, 2010, lacked all of the above documentation, including the statistical methods employed for analyzing the data, the signed and dated pathology reports, and names of the animal managers and pathologist involved in the study. Furthermore, instead of making corrections or additions to the final study report in the form of an amendment, your study director issued a new version of the final study report.
Your company’s response states that, for future studies, your study director will provide only one final report and provide any additions in the form of an amendment, and for the current studies, that your study director will design new final reports that include the signed and dated reports of the individual scientists or other professionals. Your company’s response is inadequate because it lacked a timeline for completion of the new final reports for the current studies related to studies conducted under 21 CFR Part 58, which will be submitted to the US FDA. With your firm’s response to this letter, provide a timeline for completion of the newly designed final reports for (b)(4), and a copy of each study’s final report, as well as any additional corrective and preventive actions being taken to ensure that final study reports contain the required components.
Failure of the quality assurance unit to maintain a master schedule sheet and to prepare and sign the final study report statement [21 CFR 58.35(b)(1) and (7)]
The QAU shall 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, the nature of the study, the date the study was initiated, the current status of each study, the identity of the sponsor, and the name of the study director. Additionally, the QAU shall prepare and sign a statement to be included in the final study report that specifies the dates of inspections made and findings to be reported to management and to the study director.
Your QAU failed to maintain a copy of the master schedule sheet for all nonclinical studies. Instead, this document was created during the inspection. Moreover, as stated previously, the study director’s final study reports failed to contain a QAU statement.
Your company’s response states that your firm will design a new report and include the statement prepared and signed by the QAU. Your response additionally stated that the QAU will perform inspections during every study intended to be submitted to or reviewed by the US FDA. You included a sample form to be included in future final study reports. Your response also stated that your staff will design a software program within 30 days to facilitate the retrieval of the master schedule sheet. The response is inadequate because it did not provide a copy of any newly created SOPs or revised SOPs, documentation of the proposed dates of implementation, dates of training, or a list of staff to be trained in order to prevent the recurrence of the QAU’s failure to maintain a master schedule sheet, and prepare and sign the final study report statement for any future studies conducted under 21 CFR Part 58.
The QAU statement is important and indicates that the nonclinical study has been inspected at intervals to assure the integrity of the study, and that the protocol and SOPs have been followed. In addition, the statement indicates that the data summarized in the final report accurately reflect the results of the study. The QAU should maintain a copy of the master schedule sheet, which lists all nonclinical laboratory studies that are conducted and are intended to support product safety.
Failure to ensure that all deviations from standard operating procedures are authorized by the study director and documented in the raw data [21 CFR 58.81(a)]
A testing facility shall have SOPs in writing, which set 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. All deviations in a study from SOPs shall be authorized by the study director and shall be documented in the raw data. Deviations from the SOPs shall be properly authorized in writing by management. Studies (b)(4) appear to have deviated from your company’s SOPs in ways that were neither authorized by the study director nor documented in the raw data for the applicable study. Specifically, SOP SDWH302, Section 18.104.22.168, requires the changing of animal cages (b)(4) however, your staff could not provide documentation that the animal cages were changed.
Your company’s response states that staff changed the animal cages (b)(4), even though staff did not document these changes. Your firm’s response included a form for documenting animal cage and stated that staff would begin using the form immediately. Your response is inadequate in that there was no documentation of staff training, a list of staff trained, or dates of training included. In addition, you have not provided measures that will assure deviations from the SOPs are authorized by the study director.
Failure to limit access to the archives to authorized personnel only [21 CFR 58.51]
Space shall be provided for archives, limited to access by authorized personnel only, for the storage and retrieval of all raw data and specimens from completed studies. (b)(4)
Your company’s response stated that the archives would be moved to a room that meets the requirements of 21 CFR Part 58 within the next 30 days. Your response is inadequate in that no description or supporting documentation of the new archive room and how it meets the requirements of 21 CFR 58.51 and 58.190 was provided.
Failure to provide storage areas for feed and bedding that are protected against infestation or contamination [21 CFR 58.45]
There shall be storage areas, as needed, for feed, bedding, supplies, and equipment. Storage areas for feed and bedding shall be protected against infestation or contamination. Perishable supplies shall be preserved by appropriate means.
Specifically, your company failed to provide storage space that protected against infestation or contamination by storing animal feed next to and touching an overfilled, open refrigerator that held carcasses of laboratory animals. In addition, the door to the feed and bedding storage room did not close flush to the floor, leaving a gap large enough for rodents and insects to enter. Moreover, there is no system in place to control entry of rodents or insects into the facility.
Your company’s response states that arrangements have been made to provide a new room to store feed and bedding. Furthermore, it includes that your company will improve methods to protect against infestation and contamination within the next 30 days. Your response is inadequate because there is no description of the new storage room for feed and bedding, including documentation of how this new room meets the requirements of 21 CFR 58.45. In addition, a description of the methods put in place to protect against infestation and contamination was not included.
Failure to adequately inspect, maintain, test, calibrate, and standardize equipment. [21 CFR 58.63(a)]
Equipment shall be adequately inspected, cleaned, and maintained. Equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated, and/or standardized. Your staff could not provide documentation that the (b)(4) used in study (b)(4) was ever calibrated. This study required that the room temperature and humidity for the test systems be controlled within (b)(4), respectively.
Your company’s response states that the (b)(4) was replaced with a calibrated thermo-hygrometer and included a picture of the new equipment. However, this response is inadequate in that it does not address maintenance of this equipment. In your response to this letter, please provide a plan for maintaining calibration of this equipment.
This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility as a testing facility to ensure compliance with the Act and all applicable regulations.
Your facility must address these violations and establish procedures to ensure that any ongoing or future studies be conducted in compliance with the Act and applicable implementing regulations.
Within 15 working days of receipt of this letter, you must provide notification to the Division of Bioresearch Monitoring of the specific corrective actions that your company has taken or will take to address all of the violations noted above and to prevent recurrence of similar violations in current or future nonclinical laboratory studies conducted by your facility. Any submitted corrective action plan must include projected completion dates for each action to be accomplished. We will review your response and determine whether it is adequate. Failure to respond satisfactorily to this letter and take appropriate corrective action could result in US FDA taking regulatory action without further notice to you, including disqualification in accordance with 21 CFR Part 58 Subpart K.
Your response should reference “CTS # (b)(4)” and be sent to:
Attention: Linda D. Godfrey
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3462
Silver Spring, Maryland 20993-0002.
A copy of this letter has been sent to FDA’s China Office, American Consulate General-Shanghai,1469 Huai Hai Zhong Lu, Shanghai, P.R.C. 200031. Please send a copy of your response to that office.
For further information about the Bioresearch Monitoring program, please visit our Internet homepage. Valuable links to related information are included at this site. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/BioresearchMonitoring/default.htm.
If you have any questions, please contact Linda Godfrey, (301) 796-5654, Linda.Godfrey@fda.hhs.gov.
Steven D. Silverman
Office of Compliance
Center for Devices and