Increased Regulatory Vigilance With Respect to GLP Test Article Characterization

1. Increased Regulatory Vigilance With Respect to GLP Test Article Characterization George L. DeGeorge, Ph.D., DABT MB Research Laboratories

2. Although no Form FDA 483, Inspection Observations, was issued….the applicable statutory requirements and FDA regulations governing the conduct of nonclinical laboratory studies…. Our review of the inspection report found that the protocols for study MB 01-XXXXX state that test article characterization information is filed with the sponsor. While sponsor can maintain such information, you conducted study MB 01-XXXXX without obtaining from the sponsor the necessary characteristics of the test article administered. FDA Findings Testing facility management must assure that the test article and mixtures of the test article in a carrier were appropriately tested for identity, strength, purity, stability, and uniformity, as applicable [21 CFR 58.31(d)].

3. The final reports prepared at your facility by study director for study MB 01-XXXXX did not include characteristics of the test article. The characteristics of the test article (e.g. purity, strength, and stability) are critical to the study director’s assessment of study outcomes, and the absence of this information does not assure the quality or integrity of the data. FDA Findings (cont.) Test Facility must include characteristics of the test article in final study report [21 CFR 58.185(a)(4)] and 21 CFR 58.185(a)(9)…

4. 21 CFR 58 • [Code of Federal Regulations][Title 21, Volume, 1][Revised as of 1 April 2002]From the U.S. Government Printing Office via GPO Access[CITE: 21CFR58.31] • Title 21 – Food and Drugs • Chapter 1 – FDA, Department of HHS • Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies • Sec. 58.31 Testing facility management • For each nonclinical laboratory study, testing facility management shall: • Designate a study director as described in Sec. 58.33, before the study is initiated. • Replace the study director promptly if it becomes necessary to do so during the conduct of a study. • Assure that there is a quality assurance unit as described in Sec 58.35. • Assure that test and control articles….. (d) Assure that test and control articles or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable.

5. 21 CFR 58 • [Code of Federal Regulations][Title 21, Volume, 1][Revised as of 1 April 2002]From the U.S. Government Printing Office via GPO Access[CITE: 21CFR58.185] • Title 21 – Food and Drugs • Chapter 1 – FDA, Department of HHS • Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies • Sec. 58.185 Reporting of nonclinical laboratory study results. • A final report shall be prepared for each nonclinical laboratory study and shall include, but not necessarily be limited to, the following: • Name and address…. • Objectives….. • Statistics…. • The test and… • Stability… • A description… (4) The test and control articles identified by name, chemical abstracts number or code number, strength, purity, and composition or other appropriate characteristics. (9) A description of all circumstances that may have affected the quality or integrity of the data.

6. Dear Sponsor: As a result of a regulatory GLP inspection conducted earlier this year, MB has been advised by FDA that test article characterization, i.e., identity, strength, purity, composition or other characteristics which define the test article, must be documented for each batch and must be supplied to the study director and included in the final report. Previously, if the characterization was not provided but was filed with the sponsor, the study director did not include an exception to the GLP Compliance Statement. Apparently, this procedure is no longer acceptable to the regulatory authorities. Accordingly, effective immediately, test article characterization must be provided to the study director. In instances where it is not provided, the Compliance Statement will reflect an exception to the GLP requirements, citing the following GLP sections: FDA 21 CFR 58.31(d) and 58.185(a)(4) and (9) (Text attached for your information) EPA 40 CFR FIFRA 160.31(d) and TSCA 792.31(d) (Text is almost identical to FDA) This procedure will be followed for all GLP studies conducted at MB Research. Therefore, the Sponsor Request Form (Sec. 13 of protocol) of all MB protocols has been modified to reflect this new procedure. For your next study, please call me to obtain the revised Sponsor Request Form (Sec. 13 of protocol). As always, MB is committed to providing you with quality, reproducible and scientifically sound studies that comply with GLPs. Should you have any questions or comments, please do not hesitate to contact us. Sincerely,  MB RESEARCH LABORATORIES Corrective Action Previously, if the characterization was not provided but was filed with the sponsor, the study director did not include an exception to the GLP Compliance Statement. Apparently, this procedure is no longer acceptable to the regulatory authorities. Accordingly, effective immediately, test article characterization must be provided to the study director. In instances where it is not provided, the Compliance Statement will reflect an exception to the GLP requirements, citing the following GLP sections: ….all MB protocols has been modified to reflect this new procedure.

7. Test Article Characterization is required in support of data submissions and must be reviewed by the Study Director and included in the final report. (EPA 40 CFR 160.105 and 792.105; FDA 21 CFR 58.105, OECD 6.2). This information is: Corrective Action BEFORE  Included  File with Sponsor  Not available AFTER  Included (or)  Not available