7/17/2008 Results of Telecon -Ixiaro

M E M O R A N D U M

To: Dr. Paul Wilson, Intercell
From: Drs. Li Yu, Destry Sillivan, Dick Daemer, Daryll Miller, Lewis Markoff
Subject: Results of telecon, July 17, 2008, and further CBER comments

During the telecon today, items 5 and 6 from the form 483 outlining deficiencies cited in the manufacture of Ixiaro, as a result of the inspection conducted by CBER, were further discussed.

Item #5 cited possible problems related to the sucrose gradient purification process (step 8). FDA was concerned due to deviation report DR/067/08, which led to rejection of product batch ---(b)(4)---. Conduct of the sucrose gradient purification has been the subject of an ongoing discussion. In their latest response, Intercell presented data from a "typical" successful sucrose gradient purification, in the form of a figure showing the disposition of sucrose, ---(b)(4)-- -------------------------------------------- in the gradient. ----------------------(b)(4)-------------------- ------------------------------------------------------------------------------------------------------. Intercell also correctly noted that significant changes to the sucrose gradient purification step would incur a risk of altering the final product and pointed out that the successful lot consistency trial IC51-310 suggests that lots are very comparable using the existing manufacturing process. Dr. Li Yu of FDA then pointed out that not all gradients were as perfect as the one shown in the Intercell response, alluding to data provided in the BLA which showed that on occasion ---(b)(4)--- was ---------------------------------------------------(b)(4)--------------------------------------------------------- -------------------------------------------------------------------------------------. Intercell acknowledged that there have been occasional problems with the procedure and proposed to introduce new assays and aceptance criteria for critical process impurities (e.g., -------------(b)(4)----------------) on pooled sucrose gradient purified material to enable rejection of batches that are not the result of successful gradient separation and fraction collection. Intercell also proposed to collect data to confirm that these new assays actually contribute to the robustness of the sucrose gradient purification step. Further, they attributed the occasional problems with the procedure to operator error in -(b)(4)- and/or collecting gradient fractions and suggested that better training might help improve the consistency of the process. FDA agreed to consider the utility of these proposed new measures and to respond after further internal discussion.

After further consideration, FDA wishes to inform the sponsor that it agrees in essence with the immediate implementation of measures sponsor has proposed in order to improve this process, to include the institution of validated assays on sucrose gradient fractions which are used to accept or reject selected gradient fractions for inclusion in vaccine lots. Further, FDA accepts the concept that sponsor will take immediate steps to improve the training of laboratory personnel in the generation of sucrose gradients and collection of fractions, so as to minimize errors in future. Sponsor should ideally report to FDA on the nature of any training program. FDA urges the sponsor to take all these actions as soon as possible, so as not to jeopardize the approval process. In the post-licensure phase, sponsor might wish to consider implementation of automated gradient makers and fraction collectors, in order to streamline this stage of the manufacturing process. Such changes could be submitted as BLA Amendment(s).

Item #6 relates to the FDA request for a suitable immunological method to be used in the drug substance release protocol, as a kind of identity or quality test. In response, Intercell proposed to develop an -(b)(4)- capable of measuring ----------(b)(4)----------. Thus in future quality of the drug substance will be determined by content of specific ---(b)(4)----, expressed as -----(b)(4)----. Sponsor proposed to implement this assay as of July 31, 2008. FDA responded that an -(b)(4)- -------------------------------------------------------------------------------------------------------------------------- to detect same could be used in the interim, until the -(b)(4)- is fully developed and satisfactorily validated. Further, all new lots or batches should be compared to the reference lot by one of these ----(b)(4)---- techniques. Results should show that the amount of --(b)(4)-- protein in new product is ----------------------------------(b)(4)----------------------------------. On p. 4 of their read-ahead material for this telecon (i.e., slide #4), sponsor states that --(b)(4)-- assays were evaluated and found to be insufficiently "robust". Intercell should further clarify this statement; in what way was the ----(b)(4)--- not robust? In slide #5, Intercell indicates that the JEV -(b)(4)- will be implemented at several steps prior to and at release. FDA agrees that if this proposal is carried forward in all its detail, ---(b)(4)---- would not be necessary either in process or at lot release. However, FDA needs to review and approve the plan for validation of the -(b)(4)- a priori. FDA advises that validation of the -(b)(4)- should include a study comparing the -(b)(4)- to the -(b)(4)- potency assay on lots used in the accelerated stability study, to demonstrate that the -(b)(4)- is detecting immunogenic protein in the vaccine preparation.
