Valley Biosystems

This Warning Letter informs you of objectionable conditions observed during a Food and Drug Administration (FDA) inspection conducted at Valley Biosystems, West Sacramento, California between August 26 and October 8, 2021. FDA investigators met with your staff during the inspection to review your firm’s conduct of the following nonclinical Good Laboratory Practice (GLP) studies:

(b)(4)

(b)(4)

FDA conducted this inspection under the Bioresearch Monitoring Program, which includes inspections designed to review the conduct of research involving investigational products and to help ensure that the data are scientifically valid and accurate, in accordance with Title 21 of the Code of Federal Regulations (CFR), Part 58 – Good Laboratory (GLP) regulations (available at eCFR :: 21 CFR Part 58 -- Good Laboratory Practice for Nonclinical Laboratory Studies), which are requirements promulgated under section 351 of the Public Health Service Act (PHS Act), 42 U.S.C. § 262, and section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. § 355, among other provisions. You were not present in person during the inspection but were available via Zoom on September 2, 2021, and October 8, 2021. At the end of the inspection, the FDA investigator presented a Form FDA 483, List of Inspectional Observations (Form FDA 483) and discussed the listed observations with you and your staff.

Based on our review of the Establishment Inspection Report (EIR), the documents submitted with that report, and your firm’s response dated November 1, 2021, to the Form FDA 483 (“Response Letter”), signed by Mr. Cello, we determined that you violated GLP regulations in 21 CFR Part 58. The violations include, but are not limited to the following:

1. Failure to ensure that each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study has education, training, and experience, or a combination thereof, to enable that individual to perform the assigned functions; that each testing facility maintains a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study; and that 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. [21 CFR §§ 58.29(a), 58.29(b), and 58.33].

Your firm failed to maintain records of trainings that your staff had received to adequately assess their competency and qualifications to perform their assigned tasks for Studies (b)(4). Examples, include, but are not limited to, the following:

a. There is no documentation of protocol-specific trainings for the following individuals who participated in these studies:

Dr. GGCH, the Chairman of the Board, and Test Facility Management who was involved in editing and reviewing the final reports for Study (b)(4) and Study (b)(4)

Three (3) Veterinarians

Gross Pathologist

Operations Manager

Director of Animal Program & Facilities & Chief Operating Officer

QA Manager

Nine (9) Research Technicians

b. Your firm failed to adequately fulfill your regulatory responsibilities by assuring that your study director is qualified and appointed to be the single point of control for Studies (b)(4) and Study (b)(4). Your QA Manager (hereafter referred to as the Quality Assurance Unit (QAU)) stated that your firm’s study director is not a position and is a title on an “as needed” basis.

In your Response Letter, you expanded your pre-project planning meetings and required Read Only Trainings for all protocols and protocol amendments. We also reviewed your SOP QA25.4, submitted with your Response Letter, and it appears adequate, if properly implemented.

Your firm has also assigned the supplemental GLP training CAPA PA-21-072-01, which was expected to be completed on or before January 31, 2021. We request that you provide all documentation of the GLP training that you have stated to be completed on or before January 31, 2022, including the materials used for the trainings.

In your Response Letter, you restated your position that the study director is a title at Valley Biosystems, but not a position, and that you therefore do not plan to create a Study Director position description. This approach is not compliant with the applicable requirements. In response to this letter, please review 21 CFR § 58.33, which sets forth the regulatory requirements for the role of the study director, and inform FDA how you intend to comply with this and the other GLP requirements.

2. The study director failed to assure that the protocol, including any change, is approved as provided by 21 CFR § 58.120 and is followed; that all experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified; and that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented. Additionally, all data entries shall be dated on the date of entry and signed or initialed by the person entering the data. Any change in entries shall be made so as not to obscure the original entry, shall indicate the reason for such change, and shall be dated and signed or identified at the time of the change. [21 CFR § 58.33 (a)(b)(c) and 21 CFR 58.130(e)]

a. The study director failed to assure that the study was conducted according to the protocol and was accurately recorded. Specifically, the section of the study #(b)(4) protocol entitled, “Monitoring of Animal Welfare” required that “signs of animal illness, injury, or pain and distress will be communicated to the Study Director and Sponsor Monitor” and “Recommendations for the treatment of the animals must be approved by the Study Director and Sponsor Monitor.” However, it was not documented that these requirements were met for the following animals:1

Animal (b)(4) – hemorrhagic diarrhea on 3/2/19 – 3/4/19 and treatment with (b)(4) on 3/2/19.

Animal (b)(4) –treatment with (b)(4) for trichuris infection on 5/9/19.

Animal (b)(4) – treatment with (b)(4) for trichuris infection on 1/2/19.

Animal (b)(4) – treatment with (b)(4) for trichuris infection on 1/2/19.

b. A review of 12 of 12 of the Test Article (TA)/Control Article (CA) Preparation Forms revealed that the name, lot number, and expiration date of reagents and solutions used in preparation of test and control articles were preprinted as opposed to being documented contemporaneously. The documents revealed that the preprinted expiration dates were crossed out and changed, without explanation, by the study director to reflect different expiration dates over a month after the actual date of preparation. This occurred for the following animal source records:

Animal ID Date of TA/CA Preparation Completed Date of change/footnote

(b)(4) 9/3/19 11/7/19

(b)(4) 9/5/19 11/7/19

(b)(4) 9/4/19 11/7/19

(b)(4) 9/10/19 11/7/19

(b)(4) 9/6/19 11/7/19

(b)(4) 9/9/19 11/7/19

(b)(4) 9/12/19 11/7/19

(b)(4) 9/16/19 11/7/19

(b)(4) 9/11/19 11/7/19

(b)(4) 10/2/19 11/7/19

(b)(4) 9/17/19 11/7/19

(b)(4) 9/18/19 11/7/19

(b)(4) 9/19/19 11/7/19

Because you failed to ensure that all experimental data were accurately recorded and verified, and that all entries and changes in entries were properly documented, FDA has concerns about the integrity of the data generated from the nonclinical toxicity studies conducted at your testing facility.

In your Response Letter, you listed SOPs that were revised or are being developed since the inspection, including the revised SOP PA01.7. In your response to this letter, please provide documentation of the corrective and preventive actions you have implemented to prevent these types of deviations from recurring in future GLP studies, including a copy of all new or revised SOPs not already provided, and documentation of any related trainings.

3. Failure of the QAU to inspect each nonclinical laboratory study at intervals adequate to assure the integrity of the study and maintain written and properly signed records of each periodic inspection. [21 CFR § 58.35(b)(3)].

The QAU is responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the GLP regulations. 21 CFR § 58.35(a).

a. Your QAU failed to maintain a complete copy of the audit schedule sheet to inspect studies at intervals adequate to assure the integrity of the studies.

b. Your QAU failed to maintain contemporaneously signed and dated documentation or reports of the Critical Phase inspections. Your QAU stated that the Critical Phase inspection results were written directly on the Protocols or on scratch pieces of paper that were thrown away after summarizing the results on the monthly Quality Assurance Status Reports.

Your QAU was not able to provide any source documents of the schedule nor reports for the Critical Phase inspections that were performed for the two GLP studies. We are unable to verify that your QAU audits were adequately conducted according to your SOPs and are in compliance with applicable GLP regulations.

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 integrity of both studies.

Your Response Letter explains that you revised SOP QA 10.4 and the accompanying forms; however, you have not developed effective, contemporaneous audit documents that will serve as source documentation of the audits performed by your QAU, for each Critical Phase defined by your SOP. In your response to this letter, please provide audit document templates to accompany your SOP that will serve to demonstrate full compliance with the regulations.

4. Failure to retain all raw data, documentation, protocols, final reports, and specimens (except those specimens obtained from (b)(4) tests and (b)(4)) generated as a result of a nonclinical laboratory study. [ 21 CFR § 58.190(a)].

For example:

a. Twelve (12) of 48 animals surgically treated with the test or control article were missing original source Laboratory Animal Anesthesia Records, which contain details of the surgical procedure for test or control article administration. According to your QAU, the original paper records were discarded once they were scanned and saved electronically.

b. Your firm failed to preserve any source records demonstrating your study director’s adherence to the GLP requirements in regard to his conduct of writing the final reports for Studies (b)(4). Your firm was not able to provide the redline copies of the draft reports, and your QAU stated that the documents had all been deleted.

In your Response Letter, you stated that your SOPs are being revised following the inspection, but you did not provide supporting documentation of your corrective and preventive actions. Please note that good record keeping and an organized archive that allows for the expedient retrieval of raw data are ways in which your firm can ensure the quality and integrity of the data generated from your GLP nonclinical studies.

Incorrect archiving of study materials affects the integrity and reliability of study data as it prevents accurate retrieval of such data for review, analysis, and verification. Also, failure to have an index prevents data from being readily available, located expeditiously, analyzed, and reconciled when necessary.

In your response to this letter, please provide documentation of the corrective and preventive actions you have implemented to prevent these types of deviations from recurring in future GLP studies, including a copy of all new or revised SOPs for archiving source documents, and documentation of any trainings related to this violation.

You failed to include all data observed for Study (b)(4) in the final Study Report. Data that were not included in the final report include, but are not limited to:

Animal Number Source Document Assessment/Comment Assessment Date

(b)(4) Daily Clinical Observations Nervous tapping 9/20/19

(b)(4) Functional Observation Battery Evaluation Day 122 post-dose “Out-of Cage” assessment documented abnormal dysmetria, specifically a new comment of “mild crouching of torso when walking tripedally.” 1/16/20

(b)(4) Animal Health Record Acute emesis 02/19/20

We acknowledge in your Response Letter that you plan to revise SOP QA08.4, Preparation, Review and Approval of Nonclinical Laboratory Study Reports. However, your response cannot be evaluated due to lack of supporting documentation. Please provide a copy of the revised SOP, which you stated will be completed before December 03, 2021, along with documentation of any corrective actions you have implemented thus far.

The records and final study report of an investigation are crucial to the reconstruction of events leading to the collection and reporting of the data and must reflect the procedure and condition of the study. The information in these essential documents form the basis for establishing scientific interpretations and conclusions and must therefore reflect all circumstances affecting the quality and integrity of the data.

We further note during the inspection that the FDA investigators found five (5) reports, “Project Observation Note” (PON), from (b)(4) was the laboratory that you contracted to perform histopathology and immunohistochemical analysis for Study (b)(4). These records revealed numerous comments of poor-quality and insufficient tissue collections received from your firm. Examples of these deviations noted in the PON report from (b)(4), include, but are not limited to, the following:

For Week-5 Animals, various deficiencies were noted for all spinal cords, all eye tissues, all kidney tissues, all heart tissues, and all larynx tissues.

For unscheduled death Animal (b)(4), various observations were noted for ureters, salivary gland, adrenal, heart, femur/sternum bone and marrow, and kidneys.

For the animals sacrificed at 13 weeks, all brain (b)(4) were received with a (b)(4), except for a few animals. It appears the (b)(4) after processing. In addition, for a certain group of four animals, only one liver was received with a (b)(4) (i.e., (b)(4)).

In your response to this letter, we request that you provide all documentation and reports, including any corrective action taken that will demonstrate your firm’s investigation and corrective actions taken regarding the numerous tissue sample collection deviations reported to you by (b)(4).

This letter notifies you of your violations and provides you an opportunity to address the above deficiencies. You should investigate and determine the causes of any violations and take prompt actions to implement corrections to prevent the recurrence of similar violations in current and future studies conducted at your GLP nonclinical laboratory.

This letter is not intended to be an all-inclusive list of deficiencies with your nonclinical studies of investigational new drugs. It is your responsibility to ensure full compliance with the law, including all applicable requirements of the FD&C Act, the PHS Act, and FDA regulations.

Failure to adequately address this matter may lead to regulatory action. Failure to respond to this letter and to take appropriate corrective action could result in FDA taking regulatory action without further notice to you. 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 be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., WO71-G112, Silver Spring, MD 20993-0002. If you have any questions regarding this letter, please contact the Division of Inspections and Surveillance, CBER at 240-402-8038.

We also request that you send a copy of your response to the FDA Office listed below.