Response to FDA Enquiries on Chemistry for IND submission # 73,935 ([11C]PBR 28)
1. We have noted some inconsistencies in “acceptance testing and forms” (Section 8), and inaccuracies between LC/MS criteria (M+1) and observed results for desmethyl PBR 28 precursor and PBR 28 reference standard. It appears that the blank acceptance testing form on page 5 is incorrectly labeled for receipt of compound as Desmethyl PBR 28, rather than PBR28. In the filled-in acceptance testing form ( page 2) for Lot # DEB-1, the opposite side of page 2 is denoted as “page 6” appears out-of-place and is clearly in conflict between the LC/MS m/z (M+1) criterion and observed result as well as HPLC retention times, with data entered on the following page 3. For Lot #EB-1 (PBR 28), filled-in acceptance testing form page 5, the m/z criterion (M+1) in the LC-MS is indicated to be 335.1, but the observed result (M+1) is 349.2. We are concerned about these inconsistencies and inaccuracies, since it is these data forms that would give permission to use a given lot of material as reference standard (desmethyl PBR 28, PBR 28) and ultimately allows for a given lot of precursor (desmethyl PBR 28) to be used in the production of [11C]PBR28. Explain.
Response: We are grateful for the reviewer’s vigilance. The inconsistencies have arisen because the wrong acceptance form (the desmethyl PBR28 form) has inadvertently been used to record the data for PBR28 [(M+1) =349.1]. While this should not have occurred under any circumstance, the great similarity between the pages for recording data for the two compounds may have contributed to this error. Accordingly, to reduce the risk of accidentally repeating this error, each page of the receipt forms will be headed with the compound to which it refers, either PBR 28 or desmethyl PBR 28. It should be noted that the data collected on each compound were correct and within specification. Errors in numbering pages occurred during conversion of a single-sided original to a double-sided document and were missed through oversight. This will be corrected so that pages appear in correct sequence.
2. We have also noted an inconsistency for sterility testing between SOP #QA305 and the controls for release of the finished dosage form (pages 11-12, Section 1). The testing schedule for sterility in the controls is indicated to be initiated “as soon as feasible, typically less than 24 hours after release of the drug product”. Yet, in SOP #QA305, the procedure (#2) states that “sterility testing should commence within 192 hours of the end of synthesis.” Explain.
Response: During the course of producing the IND submission the method of sterility testing was changed to the now preferred BacTec method. Through oversight SOP #QA305 failed to get updated to match the requirements in controls. SOP #QA305 will be updated to match the statement in controls i.e. sterility testing will be performed “as soon as feasible, typically less than 24 hours after release of the drug product”.
3. Release testing for radiochemical identity by HPLC (page 11, Section 1) lists the acceptance criteria of retention time ± 1.0 min, in comparison to standard injection of PBR 28, presumably using SOP # QA 303. Yet, in your validation of SOP # QA303 (pages 10-7 to 10-18, Section 10) the radiochemical identity criterion is indicated to be retention time ± 0.5 min of that of an injected reference standard. If the acceptance criterion in the SOP is the latter, why should the SOP criterion of retention time ± 0.5 min not also be listed in the controls for release of product?
Response: Again we are grateful for the reviewer’s vigilance. The discrepancy arose through failure to revise Page 11, Section 1 during preparation of the document. The controls for release of product will be revised to list the criterion as ± 0.5 min, in accord with SOP # QA 303.
4. The desmethyl PBR 28 precursor is indicated to be acceptable if the chemical purity is ≥90%. Explain why this acceptance criterion is set low, and do you know what the other 10% represents? We are concerned that in an instance where a lot of precursor were to be allowed to be accepted at e.g. as low as 90%, would this have an adverse effect on the chemical or radiochemical purity of the final [11C]PBR 28 product. Is there a justifiable reason for this low acceptance criterion? Explain.
Response: We note the reviewer’s concerns. In view of these concerns, we propose that the acceptance criterion for chemical purity of desmethyl PBR 28 be made more stringent and set at a ≥98% level. This material is a stable powder; all batches to date have easily exceeded 98% chemical purity by HPLC analysis. Desmethyl PBR 28 is made by a route which does not include PBR 28 as an intermediate (see Response to query 5 below). Hence, there is no risk that the residual impurity will be carrier PBR 28, which if present would cause dilution of the specific radioactivity of product. The identities of the low level impurities are unknown, but they should in any case be separated from [11C]PBR during HPLC purification. If unexpectedly appearing in final product these impurities should be detected by the analytical QC procedure.
5. Reference standards for desmethyl PBR28 precursor and PBR 28 for chromatographic identification of [11C]PBR are synthesized in house i.e. at the Molecular Imaging Branch (Radiopharmaceutical Sciences), NIMH, but there is no description provided in the INDof their syntheses. Since part of the assurance of integrity is derived from use of synthetic pathways with defined and well established chemistry, provide a description of the procedures used in the production of desmethyl PBR 28 precursor and PBR reference standard.
Response: We agree that a description of procedures used in the production of desmethyl PBR 28 and PBR reference are needed. Desmethyl PBR 28 is produced in six steps from commercially available salicylaldehyde, 4-chloro-5-nitro-pyridine and phenol, according to the scheme outlined in Appendix A. PBR28 is synthesized according to Nakazoto A. et al. Japanese Patent, 2000/001476, as outlined in Appendix B. A description of these syntheses is included in our revised precursor and reference compound acceptance testing form (Document 8 of CMC section; see attached). Additionally, the synthetic schemes employed for the preparation of desmethyl PBR 28 and PBR 28 are presented below.
Appendix A. Synthesis of desmethyl PBR28 from commercial materials (1,2 and 5).
Appendix B. Synthesis of PBR28 from 4 and commercial material (10).