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WARNING LETTER

American Preclinical Services MARCS-CMS 562382 —

Product:
Biologics
Medical Devices

Recipient:
Recipient Name
Michael L. Conforti, D.V.M., M.S., M.B.A
Recipient Title
President
American Preclinical Services

8945 Evergreen Boulevard NW

Minneapolis, MN 55433
United States

Issuing Office:
Center for Devices and Radiological Health

10903 New Hampshire Avenue
Building 66, Room 3508
Silver Spring, MD 20993
United States


February 12, 2019                         

                    WARNING LETTER

                

VIA UNITED PARCEL SERVICE

 

NOTE: This Warning Letter corrects the Warning Letter issued on October 4, 2018.

 

Michael L. Conforti, D.V.M., M.S., M.B.A

President

American Preclinical Services, LLC

8945 Evergreen Boulevard NW

Minneapolis, MN 55433

Dear Dr. Conforti:

This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your site from March 19, 2018 to April 13, 2018, by investigators from the FDA’s Office of Bioresearch Monitoring Operations (OBIMO). This inspection was conducted to determine whether your activities and procedures related to your participation in nonclinical laboratory studies complied with applicable federal regulations. The investigators reviewed the following nonclinical studies conducted at your facility:

(b)(4)

The (b)(4) are devices as that term is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), 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 responses dated April 24, 2018, May 9, 2018, May 23, 2018, June 6, 2018 and July 2, 2018 to the noted violations.

The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions, Premarket Approval applications, Premarket Notification submissions and Pre-Submissions are scientifically valid and accurate. 

Our review of the inspection report prepared by the OBIMO revealed several violations of Title 21, Code of Federal Regulations (CFR) Part 58- Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies, which concerns requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g). 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 FDA [21 CFR 58.1(a)]. At the close of the inspection, the FDA investigators 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 written response, and our subsequent review of the inspection report, are discussed below:

1.    Failure of the study director to fulfill responsibilities [21 CFR 58.33(a), 58.33(c) 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. Examples of your study director’s failures include, but are not limited to, the following:

a.    The study directors did not take corrective action for animal deaths and unexpected study findings for studies (b)(4). In (b)(4), the study director did not address the fact that the ventilator was not used properly. The animals experienced persistent respiratory alkalosis while ventilated during surgery and 5 out of 10 study animals died. In (b)(4), there was no documentation that the study director addressed the fact that 9 of 10 study animals had marked tissue infarcts from thromboembolic events at necropsy. 

b.    The study director failed to ensure that the protocol was followed.

i.      The protocol for study (b)(4) required evaluation of the activated clotting time (ACT) during the implant procedure every (b)(4) minutes. The ACT for several animals were not evaluated at least every (b)(4) minutes as required by the protocol.

ii.   The study protocol required (b)(4) device from each lot used to be retained and archived consistent with regulation 21 CFR 58.105(d). Your firm did not retain and archive (b)(4) device from each lot used for studies, including but not limited to studies (b)(4) and (b)(4).

c.    The study director failed to ensure that all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study. 

The study director is tasked with the final interpretation of all study data in order to write the final study report. When study directors do not have the appropriate expertise, important findings in the study may be overlooked. This represents a clear risk to patients if safety signals from animal studies are not addressed in the animal study report. Failure to follow the protocol impacts the quality and reliability of data contained within the final study report, as well as the overall safety and risk of the device prior to beginning clinical trials involving human subjects. Failure to retain and transfer raw data results in incomplete documentation of the study in the archives and could limit the reconstruction and evaluation of the study. 

Your response noted the following corrective and preventive actions:

  • holding training sessions for the study directors and staff;
  • updating your Standard Operating Procedures (SOPs);
  • creating reference documents to provide clarity for surgical technicians and requiring formal blood gas training for surgical technicians twice per year;
  • conducting process audits;
  • increasing the number of study directors and study coordinators;
  • documenting errors for the ACT values;
  • updating the APS protocol template with prompts for archiving requirements;
  • creating a retention inventory form, amending reports and creating deviations to address the lack of retention of test or control articles;  
  • creating a new process related to archiving requirements; and
  • implementing a protocol comprehension form.

Your response is not adequate. Please provide the following in your response to this letter:

  • documentation of actions that have been or will be taken to address and correct the specific violations observed during the studies and the conditions which allowed them to occur;
  • documentation of actions taken to ensure that all raw data will be retained and archived at the close of the study;
  • documentation to support your impact statement regarding the use of improper settings during anesthesia;
  • clarification regarding whether the study directors are required to train on your revised procedures and reference documents related to proper settings during anesthesia;
  • copies of the amended reports and deviations created to address reserve sample deficiencies;
  • documentation for the return of the reserve sample for study (b)(4); and
  • documentation of staff training on new and revised procedures, processes, forms and checklists. 

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

A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations. The QAU shall inspect each nonclinical laboratory study at intervals adequate to ensure the integrity of the study and determine that no deviations from approved protocol or standard operating procedures were made without proper authorization and documentation. Examples of your QAU’s failures include, but are not limited to, the following:

a.    For study (b)(4), the QAU did not identify that surgical technicians performed anesthesia of animals but failed to maintain the required tidal volume range. The animals were ventilated on average 38% higher than the maximum amount defined in the “(b)(4)” training provided by your firm’s veterinarian.

b.    The QAU conducted audits of surgery, necropsy, tissue trimming, histology, data, the animal health report, the histology report and the final report for study (b)(4). The QAU did not identify that clinical pathology data used to evaluate overall animal health was not reviewed by the study veterinarian during the in-life phase of the study, including when abnormalities were identified as requiring review by your SOP “(b)(4)”.

c.    The QAU conducted audits of necropsy and tissue trimming for studies (b)(4). The QAU did not identify that the images of the specimens from necropsy and tissue trim were not labeled with the test system, study, nature and date of collection. 

A reliable QAU is integral to the successful completion of any GLP study. Without appropriate QAU oversight, the sponsor and FDA reviewers have no assurance that what is reported in the final study report is accurate. Failure to perform QAU functions calls into question the validity of the entire study. The clinical pathology data are essential to identifying potential health issues and correlating these findings to the test article. When retrospective review of clinical pathology data is performed only after study completion, animals cannot be treated for any abnormal findings during the study and study issues cannot be resolved. 

Your response noted the following corrective and preventive actions:

  • providing training to staff;
  • updating your SOPs;
  • creating reference documents to provide clarity for surgical technicians and requiring formal blood gas training for surgical technicians twice per year;
  • conducting process audits;
  • updating the reference document for clinical pathology;
  • discussing audits at QAU weekly meetings;
  • holding trainings for QAU staff; and
  • increasing your staff in the Process Improvement Department and the Quality Assurance Department.

Your response is not adequate. Please provide the following in your response to this letter:

  • documentation of actions that have been or will be taken to address and correct the specific violations observed during the studies and the conditions which allowed them to occur;
  • documentation to support your impact statement regarding the use of improper settings during anesthesia of animals;
  • clarification regarding whether the QAU is required to train on the revised procedures and reference documents related to proper settings during anesthesia; and
  • documentation of staff training for the new and revised procedures, processes, forms and checklists.  

3.    Failure to ensure that all information needed to specifically identify each animal within an animal-housing unit appears on the outside of that unit and failure to ensure that water used for the animals was analyzed [21 CFR Part 58.90(d) and 58.90(g)].

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. Additionally, water used for the animals must be analyzed periodically to ensure that contaminants known to be capable of interfering with the study and reasonably expected to be present in such water are not present at levels above those specified in the protocol. Documentation of such analyses shall be maintained as raw data. Examples of failure to comply with the animal care regulations include, but are not limited to, the following:

a.    Your firm failed to adequately identify the animals in animal-housing units at the large animal facilities located at (b)(4). Specifically, there was insufficient animal identification information on the outside of the animal-housing units in housing rooms (b)(4).

b.    The SOP titled “(b)(4)” required sampling from (b)(4) rooms and (b)(4) utility sink at the (b)(4) facility, the (b)(4) facility and the (b)(4) facility for (b)(4). Your firm failed to follow your SOP by not analyzing the water samples from the (b)(4) facility in 2016. Additionally, your firm only analyzed water samples from the main taps of the (b)(4) facilities after using alternative water sources in 2016 during water main construction.

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. Failure to follow your water testing SOP was a deficiency noted during a previous FDA inspection which ended on (b)(4). The lack of required water testing for 2016 raises concerns about whether contaminates capable of interfering with the study were within the required specifications. Water contaminants can affect the results of animal studies which may confound the study results and be falsely attributed to the test article and toxicity concerns which, in addition to confounding GLP safety studies, may also affect GLP toxicity testing. 

Your response noted the following corrective and preventive actions:

  • updating your SOPs;
  • revising the Water Collection Log and creating the Water Analysis Resolution form;
  • welding permanent cage cards to each animal kennel;
  • training the necessary departments on the new cage card system; and
  • conducting process audits.

Your response is not adequate because you did not identify actions to ensure that water analysis is performed (b)(4) for the representative areas required by your SOP. Additionally, your response does not address the impact of the out of specification results obtained from the (b)(4) main tap during water main construction in 2016 and your response does not include training records to demonstrate that your staff has been trained on your revised procedures.

Please provide the following in your response to this letter:

  • documentation of your plan to prevent recurrence of overlooked water analysis in the future;
  • an assessment of the impact associated with the out of specification results obtained during the water main construction in 2016; and
  • documentation of staff training on your new and revised procedures, processes, forms and checklists for water testing and the new animal identification process.

4.     Failure to ensure required labeling of reagents, storage containers for test and control articles, specimens [21 CFR Part 58.83, 58.105(c), and 58.130(c)].  

Reagents and solutions in laboratory areas shall be labeled to indicate identity, titer, concentration, storage requirements, and expiration date. Each storage container for a test article or control article shall be labeled by name, chemical abstract or code number, batch number, expiration date, if any, and, where appropriate, storage conditions necessary to maintain the identity, strength, purity and composition of the test or control article. Specimens shall be identified by test system, study, nature, and date of collection. This information shall be located on the specimen container or shall accompany the specimen in a manner that precludes error in the recording and storage of data. Examples of your failure to comply with the regulations include, but are not limited to, the following:

a.    The FDA investigators observed that the storage containers for test articles and control articles of 67 GLP studies were not labeled with the required name, chemical abstract number or code number, batch number, expiration dates and storage conditions.

b.    APS stock reagents lacked storage conditions on the labeling.

c.    The ferric chloride for histology staining stored in the refrigerator lacked the concentration and was labeled for room temperature storage.

d.    Three specimen containers stored in the refrigerator contained labeling for room temperature storage. 

Inadequate labeling may contribute to errors related to mix up, inappropriate storage, the use of expired material and may limit the ability to trace back reagents, test articles, control articles, or specimens. Further, this issue raises questions regarding your firm’s ability to maintain the integrity and reliability of study data.

Your response noted the following corrective and preventive actions:

  • holding GLP training for management;
  • creating an Excel spreadsheet to document traceability;
  • documenting the error of inadequate labeling in the raw data for each study identified in the observation for test articles and control articles;
  • creating new label templates for study article storage containers;
  • revising your SOPs;
  • conducting process audits; and
  • conducting staff training on labeling at the Annual GLP Refresher training session. 

Your response is not adequate. Please provide the following in your response to this letter:

  • documentation of staff training for SOP (b)(4)
  • documentation of your actions to address the inadequate labeling errors and storage conditions;
  • documentation to show traceability of the specimen containers found in the refrigerator; and
  • documentation of the processes and procedures in place at your testing facility to prevent specimen mix-ups.

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

We also note that the water supply valves and the hot water heater were broken for an undetermined amount of time at the (b)(4) facility. The water supply valves were not inspected for two years and the hot water heater was not on a maintenance or inspection schedule. On March 19, 2018, hot water was observed to be unavailable in the facility’s animal rooms, restrooms or surgical sink outside of (b)(4). This calls into question whether sanitization was adequate.  We are interested in having a conference call with you to discuss the lack of hot water, the inspection violations and your corrective action plan. Please contact Antionette N. Johnson by telephone at (301) 796-6845 or by email at Antionette.Johnson@fda.hhs.gov with possible dates and times for the conference call.

Within 15 working days of receiving this letter, please provide documentation of the corrective 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 must include projected completion dates for each action accomplished. 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 and test article, 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.

Your response should reference “CTS #EC170690/E001” and be sent to:  

Attention: Veronica J. Calvin, M.A.

Food and Drug Administration

Center for Devices and Radiological Health

Office of Compliance

Division of Bioresearch Monitoring

10903 New Hampshire Avenue

Building 66, Room 3508

Silver Spring, Maryland 20993-0002.

A copy of this letter has been sent to FDA’s OBIMO – West via email at ORABIMOW.Correspondence@fda.hhs.gov.  Please send a copy of your response to that office.

If you have any questions about the content of this letter, please contact Antionette N. Johnson, at (301) 796-6845 or Antionette.Johnson@fda.hhs.gov.

 

Sincerely yours,

/S/ 

William H. Maisel, M.D., M.P.H.

Acting Director

Office of Compliance

Center for Devices and Radiological Health