Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Silver Spring, MD 20993|
RETURN RECEIPT REQUESTED
Reference No: 10-HFD-45-08-01
Hideshi Tsusaki, D.V.M., Ph.D.
SNBL USA, Ltd.
6605 Merrill Creek Parkway
Everett, WA 98203
Dear Dr. Tsusaki:
Between July 21 and August 1, 2008, and between November 16 and 20, 2009, representatives of the Food and Drug Administration (FDA) inspected SNBL USA, Ltd. (SNBL) in Everett, WA. These inspections are part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to verify compliance with Title 21 of the Code of Federal Regulations (CFR), Part 58 – Good Laboratory Practice (GLP) regulation. The regulations at 21 CFR 58 apply to nonclinical laboratory studies of products regulated by FDA. We are aware that at the conclusion of both inspections, our investigators presented and discussed with Steven L. Meyer and James K. Klaassen, DVM, Ph.D., Form FDA 483, Inspectional Observations, for the respective inspections in 2008 and 2009.
From our review of the establishment inspection reports and the documents submitted with those reports, and your firm’s written responses dated August 20, 2008, October 2, 2008, and December 9, 2009, we conclude that SNBL did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of nonclinical laboratory studies. We wish to emphasize the following:
1. Testing Facility Management failed to ensure that personnel clearly understand the functions they are to perform [21 CFR 58.31(f)].
Specifically, Testing Facility Management did not provide personnel with proper instructions on the preparation of final reports. As a result, Study Directors routinely prepared, and the Quality Assurance Unit audited, final reports based in part on unsigned draft reports of contributing scientists. FDA found numerous examples of this significant deficiency during the inspections conducted in both 2008 (Studies SNBL.118.06, SNBL.210.07, and SNBL.053.06) and 2009 (Studies SNBL.258.10, SNBL.010.27, SNBL.289.03, SNBL.293.01, and SNBL.010.22). We note that the preamble to the 1978 Final Rule emphasized the importance of individually signed and dated contributing scientist reports in establishing the contributing scientists’ individual accountability for accurate reporting.1
Furthermore, the preamble to the 1987 Final Rule stated that “…only the signed and dated final report of the pathologist comprises raw data respecting histopathological evaluation of tissue specimens.”2 Because SNBL Study Directors prepared and submitted final reports to sponsors with draft contributing scientist reports that were not signed and dated, they lacked accountability and confirmation that the contributing scientists’ raw data was accurate. Furthermore, given that SNBL Study Directors invite the study sponsors to comment on and edit both the contributing scientist reports and the final report, bias in data interpretation and reporting cannot be ruled out.
Your December 9, 2009, written response claimed that SNBL misunderstood this issue as it was cited on the Form FDA 483, Inspectional Observations, dated August 1, 2008. Your claim has no basis for the following reasons:
• Inspectional Observation Item 7 clearly documented the deficiency found during the 2008 inspection thus: “The Study Director prepared the final report using unsigned draft reports of Contributing Scientists.”
• The SNBL written responses dated August 20, 2008, and October 2, 2008, stated that “Study Directors will be instructed to ensure that the final versions of contributing scientist reports are utilized during final report preparation.”
Consequently, your claim of misunderstanding the issue is not justified and lacks merit. In this regard, SNBL offers no assurance that SNBL will effectively correct this ongoing deficient practice and will adhere to GLP regulatory requirements for reporting nonclinical safety data.
2. Testing Facility Management failed to ensure that test article mixtures were appropriately tested for stability [21 CFR 58.31(d)].
At the 2009 inspection, for Study SNBL.284.01, the final report stated that the test article mixture was considered stable under the conditions of use (i.e., ambient temperature) even though the testing method did not demonstrate stability. Thus, SNBL failed to ensure that test systems were administered with the protocol-required dose of test article.
In your response dated December 9, 2009, you indicated that SNBL will conduct appropriate stability testing and amend the final reports for all studies that used the same test article as Study SNBL.284.01. However, because your standard operating procedures (SOPs) failed to require the use of methods appropriate for demonstrating stability, the impact of this deficiency extends beyond the test article used in Study SNBL.284.01. Although you stated that SNBL initiated a review of other studies in which inappropriate methods were used to assess stability, FDA is concerned that Testing Facility Management did not recognize this failure previously or assign qualified staff to address this issue, and that as a result, this deficiency adversely affected multiple safety studies for multiple sponsors.
3. Testing Facility Management failed to implement standard operating procedures (SOPs) in writing setting forth nonclinical laboratory study methods that are adequate to ensure the quality and integrity of the data generated in the course of a study [21 CFR 58.81(a)].
In the 2008 inspection, FDA found that Testing Facility Management failed to maintain an SOP for sterile preparation of dosing solutions, even though SNBL’s workload included studies requiring aseptic preparation (e.g., test article mixtures for intracerebro-ventricular administration). In the 2009 inspection, FDA found continued failure in aseptic preparation. Specifically, an outdated SOP for verification and maintenance of biological safety cabinets in the test article department was not removed and replaced with the current SOP; staff failed to complete required training in biological safety cabinet use; and validation and verification performance of biological safety cabinets was inadequate.
Because Testing Facility Management failed to attend to its core responsibilities to remain GLP-compliant, FDA is concerned about the validity of nonclinical safety data generated by SNBL. Your responses following the 2008 inspection stated that SNBL would initiate corrective actions for the identified deficiencies. The 2009 inspection found that, in direct contrast with SNBL’s statement, some of the identified deficiencies had not been corrected, and indeed many had been repeated. Because Testing Facility Management failed for over a year to implement appropriate corrective actions, SNBL’s ability to effectively manage a GLP-compliant testing facility has not been demonstrated.
4. The Study Director failed to ensure that all applicable GLP regulations were followed and all experimental data, including observations of unanticipated responses of the test system, were accurately recorded and verified [21 CFR 58.33(e) and 58.33(b)].
The following examples are provided:
a. As described above under Item 1, FDA found in both inspections that Study Directors repeatedly prepared draft final reports without the necessary raw data from contributing scientists.
b. At the 2008 inspection, FDA found that the Study Director failed to verify the final toxicokinetics report for Study SNBL.118.06 in that it erroneously contained drug concentrations in dosing solutions, instead of drug concentrations in cerebrospinal fluid.
c. FDA found that Study Directors failed to ensure that bioanalytical methods used in nonclinical laboratory studies were accurate.
i. At the 2008 inspection, FDA found that SNBL failed to use quality control samples in toxicokinetic assays to ensure quantitative accuracy of the bioanalytical method, and to decide acceptance/rejection of individual runs (e.g., Study SNBL.210.07).
ii. At the 2008 inspection, FDA found that SNBL failed to reject bioanalytical runs that exceeded the a priori acceptance limit (e.g., Study SNBL.195.01.BA.1).
iii. At the 2009 inspection, FDA found that significant deficiencies in the bioanalytical method for measuring noradrenaline concentrations samples from Study SNBL.200.13 were not addressed (e.g., large degree of assay imprecision, stability following long-term storage was not demonstrated). In your response dated December 9, 2009, you agreed that the method was not valid for use, yet your facility used the invalid method.
iv. At the 2009 inspection, FDA found that an aberrant precision result was selectively excluded from method validation SNBL.289.05 in support of Study SNBL.289.03.
Although the SNBL responses, dated August 20, 2008 and October 2, 2008, stated that procedures would be revised and additional staff training would be provided to correct
deficiencies in bioanalytical study conduct, the 2009 inspection found continuing deficiencies. In this regard, there is no assurance that SNBL is capable of instituting appropriate controls and correcting procedures to ensure that the Study Director records and verifies the accuracy of bioanalytical methods used in nonclinical safety studies.
5. The Quality Assurance Unit failed to maintain an accurate 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)].
Specifically, at the 2008 inspection, the identity of the Study Director was not listed for several studies. At the 2009 inspection, FDA found that the initial master schedule provided at the start of the inspection contained incorrect entries regarding the current status of several studies which had been archived.
6. The Quality Assurance Unit failed to determine that no deviations from SOPs were made without proper authorization and documentation [21 CFR 58.35(b)(5)].
Specifically, unapproved and undocumented deviations occurred against procedures established by SNBL in the following examples:
a. Facility inspections in the 2008-2009 audit plan were not conducted within the required time frame in 14 of the 21 departments involved in GLP work.
b. Outdated copies of SOPs related to the facility archive and biological safety cabinets were not removed from workspaces and replaced with the new versions.
c. Staff failed to complete required training on SOPs related to the facility archive and biological safety cabinets.
d. Staff failed to follow up on and to document the status of materials checked out of the archive in accordance with the required time frame.
e. Pipettes’ calibrations were not made in accordance with required time frames, as described in Item 7b below.
In your responses dated August 20, 2008, October 2, 2008, and December 9, 2009, SNBL acknowledged these deficiencies and proposed corrective actions. However, you did not provide sufficient information to assess the adequacy of such actions. For example, in your response dated December 9, 2009, you stated that SNBL QAU would closely manage facility inspections in the future without describing how you would achieve timeliness. Furthermore, in light of the overall lack of responsibility of Testing Facility Management to implement basic elements of GLP compliance, FDA is concerned that QAU oversight at SNBL is neither effective nor adequate to ensure data integrity.
7. You failed to adequately inspect, clean, and maintain equipment. Equipment used for the generation, measurement, or assessment of data was not adequately tested, calibrated, and standardized [21 CFR 58.63(a)].
In the 2009 inspection, FDA found that numerous pieces of equipment were not calibrated according to the schedule defined by SNBL procedures. For example:
a. The temperature verification for a chromatography column heater had expired in August 2008, yet the apparatus was used through September 2009 in two bioanalytical method validations and sample analyses for Study SNBL.990.40.
b. The adequate performance of multiple pipettes in the analytical biology area was not assessed for up to one year, even though SNBL procedures required monthly verification of such active pipettes. Furthermore, multiple pipettes had expired quarterly calibrations, in violation of required SNBL procedures.
In your response dated December 9, 2009, SNBL agreed that the equipment records were inadequate and not up to date. Your response indicated that the pertinent SOP was updated to optimize and control documentation practices for pipette maintenance. However, the utility of this change for future studies is not evident, because at the time of the 2009 inspection, when FDA noted the violations above, the SOP in effect clearly defined the necessary documentation and retention of pipette calibration records.
8. Study Directors failed to sign and date final reports [21 CFR 58.185(b)].
For example, in the 2008 inspection, FDA found that draft reports for Studies SNBL.223.07, SNBL.109.01, and SNBL.053.04 were unsigned for three to five years. The SNBL responses dated August 20, 2008 and October 2, 2008 stated that these reports would be finalized. In contrast to those statements, FDA found during the 2009 inspection that Study SNBL.053.04 still lacked appropriate finalization, in that the Study Director signed and dated the final report without adequate information. Specifically, the Study Director relied on a peer review pathology statement (dated June 1, 2005) that preceded the study pathologist’s actual report (dated April 25, 2009) by about four years.
9. You failed to make corrections or additions to a final report in the form of an amendment by the Study Director [21 CFR 58.185(c)].
In the 2008 inspection, FDA found that toxicokinetic assays in Study SNBL.210.07 lacked quality control samples to determine assay performance, and that the ECG report failed to include relevant data tables. Your responses dated August 20, 2008 and October 2, 2008 stated that SNBL would establish appropriate procedures to address these deficiencies. However, FDA found during the 2009 inspection that the Study Director had not made the necessary corrections or additions to the final report in the form of an amendment.
This letter is not intended to be an all-inclusive list of deficiencies at your facility. As evidenced by FDA’s inspectional findings, SNBL Testing Facility Management failed to fulfill its primary responsibility to establish appropriate policies and procedures intended to ensure the quality and integrity of nonclinical safety data for FDA submission. Furthermore, the serious deficiencies found in oversight by the Study Director and the Quality Assurance Unit can be attributed to the lack of responsibility of Testing Facility Management to establish core elements necessary for GLP compliance. SNBL responses, dated August 20, 2008 and October 2, 2008, promised corrective action following the 2008 inspection. However, during the 2009 follow-up inspection, FDA found that Testing Facility Management failed to correct the deficiencies that SNBL had agreed upon after the 2008 inspection, thus leading to the problems found during the recent inspection and resulting in a continued lack of GLP compliance. For this reason, SNBL’s written response, dated December 9, 2009, does not inspire confidence or provide sufficient convincing evidence that compliance will be achieved. It is your responsibility to ensure that SNBL’s practices and procedures comply fully with all applicable statutes and regulations.
Within fifteen (15) business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Your written response should include any documentation necessary to show that full and adequate correction will be achieved. Please include the projected completion dates for each action to be accomplished. Failure to respond satisfactorily to this letter and take appropriate corrective action could result in FDA taking regulatory action including disqualification in accordance with 21 CFR 58.204.
We acknowledge receipt of your written responses dated January 25, 2010, April 15, 2010, and July 20, 2010, to Form FDA 483, but note that these responses were received more than fifteen (15) business days from close of the inspection. Thus, while we have reviewed these responses, we have not included a discussion of them in this letter as per the Commissioner’s Enforcement Initiative announced August 11, 2009. If you believe these written responses to the Form FDA 483 fully explain the actions you have taken to prevent similar violations in the future, please communicate that to us in writing within fifteen (15) business days. You may reference the written responses dated January 25, 2010, April 15, 2010, and July 20, 2010, in your response to this letter.
We appreciate the cooperation shown to the FDA Investigators during the inspections. If you have any questions, please contact Sam H. Haidar, Ph.D., R.Ph., at 301-796-4777; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to:
Sam H. Haidar, Ph.D., R.Ph.
Acting Branch Chief
GLP and Bioequivalence Investigations Branch
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Bldg 51, Room 5210
10903 New Hampshire Avenue
Silver Spring, MD 20993
Leslie K. Ball, M.D.
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
1 43 Fed. Reg. 60009 (December 22, 1978)
2 52 Fed. Reg. 33770 (September 4, 1987)
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LESLIE K BALL