Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Center for Biologics Evaluation and Research|
1401 Rockville Pike
Rockville MD 20852-1448
By Certified Mail - Return Receipt Requested
And By Facsimile Transmission
FEB 17 2009
Sean P. O'Neill, Ph.D., President
Washington Biotechnology, Inc.
9075 Guilford Road
Columbia, Maryland 21046
Dear Dr. O'Neill:
This letter describes the results of a Food and Drug Administration (FDA) inspection that concluded on October 3, 2008. An FDA investigator from the Baltimore District Office and a toxicologist from the FDA Center for Biologics Evaluation and Research met with you and members of your staff to review your firm's conduct of studies TOX-[(b)(4)] TOX-[(b)(4)] and [(b)(4)] performed under the Good Laboratory Practices (GLP) regulations [Title 21, Code of Federal Regulations, (CFR) Part 58]. The inspection was conducted as part of FDA's Bioresearch Monitoring Program, which includes inspections designed to review research involving investigational products.
At the conclusion of the inspection, a Form FDA 483, Inspectional Observations, was issued to and discussed with you.
Based upon the information obtained during the inspection, we conclude that Washington Biotechnology Inc. (WBI) has violated GLP regulations governing the proper conduct of nonclinical studies as published under 21 CFR Part 58. The applicable provisions of the CFR are cited for each violation.
1. Failure to ensure that each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study has the education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions. [21 CFR §§ 58.29(a), 58.33].
a. The study director for the three studies reviewed during the inspection lacks the education, training, and experience, or combination thereof, to perform his functions as GLP study director.
b. The project manager for study TOX-[(b)(4)] performed a necropsy despite lacking the education, training, and experience; or combination thereof, to perform necropsies.
2. Failure to ensure that the 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. [21 CFR § 58.29(b)].
You failed to maintain such documentation for the following individuals:
a. The study director for studies TOX-[(b)(4)] TOX-[(b)(4)] and [(b)(4)]
b. The replacement study director for study TOX [(b)(4)]
c. The senior scientist responsible for overseeing the statistical analysis of data for study TOX-[(b)(4)]
d. The statistician responsible for performing statistical analysis for study TOX-[(b)(4)]
e. The project manager for study TOX-[(b)(4)]
f. The laboratory technician responsible for performing necropsies for study TOX[(b)(4)]
3. Failure of testing facility management to fulfill its responsibilities. [21 CFR § 58.31(a) and (g)].
a. The testing facility management failed to designate a qualified study director as described in 21 CFR 58.33.
b. The testing facility management failed to assure that deviations from the regulations were reported by the quality assurance unit and communicated to the study director, and that corrective actions were taken and documented.
4. Failure to ensure that the study director fulfills his or her responsibilities. [21 CFR § 58.33(a), (b), (c), and (f)].
a. The study director failed to assure that the protocols for each study were followed or that changes to the protocol were documented and approved.
b. The study director failed to assure that experimental data was accurately recorded and verified as required by each study protocol.
c. The study director failed to assure that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study were noted when they occurred, and that corrective action was taken and/or documented. Specifically, the TOX[(b)(4)] protocol contained specific requirements about conducting necropsies but these requirements were not followed. The study director failed to note this deviation from protocol and to take corrective actions.
d. The study director for studies TOX [(b)(4)] and [(b)(4)] failed to assure that all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the studies.
5. Failure of the Quality Assurance Unit (QAU) to fulfill its responsibilities. [21 CFR §§ 58.35(a); 58.35(b)(1), (3), and (7); 58.35(c)].
a. The QAU was not entirely separate from and independent of the personnel engaged in the direction and conduct of that study. The QAU manager for study TOX [(b)(4)] reported directly to the study director.
b. The QAU failed to maintain a complete copy of the master schedule sheet of all nonclinical laboratory studies conducted at the testing facility. Specifically, the master schedule failed to identify the test article, test system, the dates studies were initiated, the sponsor, and the name of the study director.
c. The QAU failed to inspect studies at intervals adequate to assure the integrity of the studies. Specifically, the QAU failed to maintain written and properly signed records of each periodic inspection of studies TOX [(b)(4)] and [(b)(4)]
d. The QAU failed to prepare and sign a statement to be included with the final report for study TOX [(b)(4)] which specified the dates of inspection and findings reported to management and the study director.
e. There is no written documentation of the responsibilities and procedures applicable to the QAU, the records maintained by the QAU, and the method for indexing records.
6. Failure to adequately inspect, clean, and maintain equipment. [21 CFR § 58.63].
There is no written documentation of the inspection, cleaning, maintenance, testing, calibration, or standardization of the [(b)(4)] in which the test article for study TOX [(b)(4)] was stored, the centrifuges used for studies TOX-[(b)(4)] and TOX [(b)(4)] and the [(b)(4)] used in study TOX-[(b)(4)]
7. Failure to establish and follow standard operating procedures (SOPs) setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study. [21 CFR § 58.81 (a) and (b)(6), (b)(7), and (b)(11)].
a. Significant deviations from the SOPs were neither authorized by the study director nor documented in the raw data of the applicable studies. For example:
i. Procedure 1661 .3 requires that anesthesia be used for blood draws, and that the anesthetic used be documented. The final report for study TOX-[(b)(4)] contains no documentation of the anesthesia used for orbital bleeds conducted on October 18, 2007 and November 12, 2007.
ii. Procedure 1686.3 requires that rats be anesthetized prior to exsanguination, and the anesthetic used be documented. There is no documentation that anesthesia was used prior to the exsanguinations of animals 2 through 10 and animals 12 through [(b)(4)] in study TOX [(b)(4)]
iii. Procedure 8060.4 requires facility audits to be conducted on a [(b)(4)] basis. There is no documentation of any facility audits between January 2006 and September 2008.
iv. Procedure 420.11 requires that rooms housing rats be maintained at [(b)(4)] relative humidity. The "Room Temperature/Humidity Daily Record," documents deviations from the required humidity range for rats included in study TOX-[(b)(4)]
v. Procedure 400.8 requires that "Room Temperature/Humidity Daily Record," Animal Inspection Record," " Room/Equipment Status Report," and "Census Activity Record," be audited. There is no documentation that these records were audited for study TOX-[(b)(4)] from August 2007 through November 2007.
b. Written SOPs have not been established for the following:
i. The handling of animals found moribund or dead during a study.
ii. Necropsy or post-mortem examination of animals.
iii. The maintenance and calibration of equipment. Specifically, SOPs have not been established for the maintenance and calibration of the -80°C freezer, the centrifuges, and the spectrophotometer used for studies TOX [(b)(4)] and TOX [(b)(4)].
8. Failure to determine and document the identity, strength, purity, and composition of each batch of the test or control article. [21 CFR § 58.105(a)].
The study director failed to procure a certificate of analysis from the sponsor that documented the identity, strength, purity, and composition for the test article used for study TOX-[(b)(4)]
9. Failure to assure that each study has an approved written protocol that clearly indicates the objectives and all methods for the conduct of the study. [21 CFR § 58.120(a)].
a. The protocol for the TOX [(b)(4)] study failed to identify the statistical methods to be used for data analysis and the laboratory assays to be performed on day [(b)(4)] of the study.
b. The protocols for studies TOX [(b)(4)] TOX [(b)(4)] and [(b)(4)] failed to document sponsor approval of the protocols.
10. Failure to conduct nonclinical laboratory studies in accordance with the protocol. (21 CFR § 58.130(a), (c), and (d)].
a. The following protocol violations occurred in study TOX [(b)(4)]
i. The protocol required that any animal found dead during the study be necropsied, and any organ displaying abnormalities be removed, preserved, and sent for histological examination. The necropsy of animal 11 indicated an enlarged spleen, however, there is no documentation that this organ was preserved and sent for histological examination.
ii. Laboratory analyses were conducted that were not authorized by the protocol. For example,
1. The kidneys from animal 33 and the lungs from animal 35 were sent for histopathological examination, even though these examinations were not required by the protocol.
2. Fluid extracted from the kidney of animal 28 during necropsy was sent to an analytical laboratory for testing, even though this testing was not required by the protocol. The results of the analysis of this sample are not documented in the final report.
iii. Additional animals were added to the study after the final dosing of the [(b)(4)] original animals, which was not authorized by the protocol.
iv. "Exsanguination Serum Samples" were shipped to the study sponsor on November 13, 2007, which was not authorized by the protocol.
v. The protocol required exsanguination to be performed on day [(b)(4)] of the study. However, 35 of the [(b)(4)] animals included in the study were not exsanguinated until day [(b)(4)] the study.
vi. The protocol required necropsies to be performed immediately following exsanguination. However, necropsies were not performed until 30 minutes after the exsanguinations.
b. Specimens for study TOX [(b)(4)] ere not identified by test system, study, nature, and date of collection.
c. Records of gross findings for all specimens from postmortem observations conducted in study TOX [(b)(4)] ere not provided to the pathologist performing the histopathological evaluations.
11. Failure to prepare complete reports of nonclinical laboratory study results. [21 CFR § 58.185(a)(2)-(4), (6), (9)-(10), (13); (b); and (c)].
a. The final study report for TOX [(b)(4)] does not document all changes to the original study protocol, or the study director's approval of the changes.
b. The final study report for study TOX [(b)(4)] fails to identify the statistical methods employed for data analysis.
c. The final study report for study TOX [(b)(4)] fails to identify the test and control articles by name, chemical abstracts number or code number, strength, purity, and composition or other appropriate characteristics.
d. The final study report for study TOX [(b)(4)] does not include an accurate description of the methods used. For example,
i. The final report states that the animals were randomly assigned to study groups; however, there is no documentation that animals were randomized, and the firm does not have a written procedure for randomization of animals
ii. The final report conflicts with the laboratory notebook regarding the method employed to euthanize the study animals.
e. Final study reports fail to describe all circumstances that may have affected the quality or integrity of the data. For example:i. The final report for study TOX-[(b)(4)] refers to the [(b)(4)] treatment groups as [(b)(4)] but the protocol and raw data document the [(b)(4)] treatment groups as [(b)(4)]
ii. The final report for study TOX-[(b)(4)] does not describe the circumstances under which a separate research laboratory was used to store samples or analyze [(b)(4)] scans. There is no documentation of the storage of the samples between preparation on July 22, 2008, and analysis on August 7, 2008.
f. Final study reports do not include the name of the study director, the names of other scientists or professionals, and the names of all supervisory personnel involved in the studies. Specifically,
i. The final report for study [(b)(4)] does not include the name of the study director, and was not signed and dated by the study director.
ii. The protocol for study TOX [(b)(4)] lists Dr. Sean P. O'Neill as the study director; however, the final report for study TOX-[(b)(4)] lists [(b)(6)] as the study director. There is no documentation of the change in study directors.
iii. The final report for study TOX-[(b)(4)] does not include the names of all of the scientists or professionals involved in the study.
g. The final report for study TOX [(b)(4)] does not document the location where all specimens were stored.
h. Corrections or additions to the final reports were not submitted by the study director in the form of an amendment. Specifically, there are two versions of the final report for study TOX [(b)(4)], one of which was signed by the study director on January 18, 2008 and the other on June 18, 2008. The June 2008 final report is not identified as an amended final report.
12. Failure to store and retain all raw data, documentation, protocols, final reports and specimens generated as a result of nonclinical laboratory studies. (21 CFR §§ 58.190(a) and 58.195(b)].
The study director for studies TOX [(b)(4)] and [(b)(4)] failed to assure that all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study. For example:
a. The animal organs directed for collection in study TOX[(b)(4)] were not transferred to the archives at the close of the study.
b. The protocol for study [(b)(4)] was not transferred to the archives at the close of the study.
The deviations listed above are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment is in compliance with all requirements of the law and applicable federal regulations. You are responsible for investigating, determining causes of, and correcting violations identified by the FDA, and for reviewing your firm's operations as a whole to ensure that you are in compliance with the regulatory requirements applicable to nonclinical laboratory studies. You should take prompt action to correct these deviations and prevent their recurrence. Failure to do so may result in FDA initiating regulatory action without further notice.
We request that you notify this office in writing, within fifteen (15) working days of receipt of this letter, of the specific steps you have taken to correct the noted violations and to prevent their recurrence. If you cannot complete all of the corrections before you respond, please state the reason for your delay and the time frame within which the corrections will be completed.
Please notify the sponsors of the three studies that were the subjects of the inspection, TOX-[(b)(4)], TOX-[(b)(4)] and [(b)(4)] advising them that your firm failed to conduct the corresponding GLP studies in compliance with Federal regulations under Part 58 of the CFR. As part of your response to this letter, please include a copy of your written notification to these sponsors.
Please send your response and the requested documentation to:
Robert L. Wesley, CSO
Division of Inspections and Surveillance (HFM-664)
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
1401 Rockville Pike, Suite 200N
Rockville, Maryland 20852-1448
Telephone (301) 827-6338
We also request that you send a copy of your response to the FDA District Office listed below.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research