Information Request, January 20, 2011 - Kedbumin	

Our STN:  BL 125384/0

Kedrion, S.p.A.
Attention:  Mr. Urs E. Aeberli
FFF Enterprises, Inc.
January 20, 2011
Sent by email: uaeberli@fffenterprises.com

Dear Me. Aeberli:

We are reviewing your August 2, 2010 submission to your original BLA for Albumin (Human).  We determined that the following information is necessary to continue our review
1.Please note that the manufacturing process for plasma-derived products must be validated for its capacity to clear enveloped viruses (HIV, and model viruses for HCV and HBV) by at least two major and independent viral clearance steps. The cumulative log reduction for a given virus should be > 10 logs. Considering these principles, your viral validation studies have not provided acceptable level of virus clearance, and therefore, are incomplete for reasons outlined below:
a.You have overestimated the level of HIV clearance by the precipitation steps. Specifically, “fraction of effluent I to effluent II+ III” and “depth filtration of fraction V suspension” steps are not orthogonal, and therefore the clearance provided by these steps are not additive. Thus, claim of 3.4 log10 clearance for each step for total of (b)(4) for both is an overestimation and must be revised to include log clearance by only one of these steps.  Considering these corrections, the total HIV clearance ((b)(4) logs) provided by the precipitation steps (3.4 logs) and that of heat treatment ((b)(4) logs) is less than minimum acceptable level (>10 logs) of clearance for this virus, and therefore, insufficient to provide a reasonable degree assurance regarding the safety of the product with regard to a potential HIV contamination. 
b.Please also note that the level of HIV inactivation by terminal heat treatment (> (b)(4) logs) provided in your validation studies is lower than what has historically been reported for HIV, using this heat treatment. Low initial virus load and limit of the detection of your infectivity assay may have contributed to low clearance demonstrated in your studies.  If that is the case, you need to repeat the validation studies to provide more accurate estimate of the capacity of your inactivation step. 
2.In Figure A.2-1, Module 3.2.A.2, the heat treatment step is indicated after albumin bulk and before finished product. Please clarify that the heat treatment is carried out for final containers rather than albumin bulk.
3.Please clarify what grade of filter aid was used in the manufacturing process. Please specify whether it is pharmaceutical or food industrial grade, and also provide summaries of related validation study reports.
4.Please follow FDA procedures for conformance lot samples and release protocol submissions which are part of the requirements for a BLA approval.
5.For product characterization, please provide additional information to the impurity profiles, including the summary of test results of accompanying plasma proteins such as  ---------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------.
6.Please be advised that the performance of the General Safety Test on final container product lots is mandatory, and that a lot-by-lot release could not be waived until a sufficient history of quality and compliance is accrued overtime by the firm.
7.Please confirm that --------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------.
8.Please verify that in addition to the proposed time points of the long term stability study at 0, 6, 12, 24, 36, (b)(4) months, more time points are needed at 3, 9, and 18 months. Please also note that updated stability data from the conformance lots should be submitted for review prior to the final approval of the product.
9.Protein composition of Albumin (Human) products appeared as (b)(4) in this BLA submission, rather than no less than 96% as committed previously. Please confirm all your commitments made during your meetings with the FDA regarding Kedbumin occurred prior to the BLA submission.
10. In the section on "accuracy" in summary table P.5-19 of module 2.3.P, please clarify the meaning of "found solutions" in the statement "Assessed on found solutions having different (b)(4) activity." 
11.Based on the p-values in the summary table P.5-21, module 2.3.P, you concluded that the (b)(4) and (b)(4) standards were equivalent.  However a calculated p-value greater than 0.05 (or failed to reject null hypothesis) does not imply that the two standards are equivalent. Please provide pre-specified error margins, or equivalence margins used for the equivalence conclusion, if any.
12.In the summary table P.5-19 in module 2.3.P, one could calculate the worst case as (b)(4) mmol/L with Kedbumin containing the upper limit for protein concentration, and the upper limit for excipient concentration, rather than 20 mmol/L of excipients.  Please explain this discrepancy and provide data if there was any additional testing done at this upper limit for excipient concentration.
13.The sponsor has listed significance values (a) used to determine Ftabulated, or ttabulated for some tests, (e.g. summary table P.5-18, module 2.2.P, aluminum determination) and not for others. For all assays where an f-test, or t-test has been done to determine fit, the significance (a) value used to determine Ftabulated, or ttabulated must be reported.  This specifically refers to the following summary tables/modules (P.5-10/ 2.3.P; P.5-14/2.3.P; P.5-22/ 2.3.P; P.5-27/ 2.3.P; P.5-30/ 2.3.P; P.5-35/ 2.3.P.
14.In assay validation reports for total protein determination, sodium caprylate, -----------------(b)(4)------------------- rather than only citing "linearity, accuracy and precision.", please also provide validated ranges for each individual method, as was done for the sodium, and potassium ions determination for the drug product, Kedbumin (module 2.3.P summary table P.5-16).
15.In the table P.5-28 in module 2.3.P that summarizes the assay validation specifications for N-acetyl tryptophan; (b)(4) replicates were reported for accuracy, between run precision and within run precision. Please explain why a minimum of three replicates was not used? Please also provide information for additional replicates.
16.In the table P.5-30, module 2.3.P the acceptance criteria for (b)(4) determination contains a calculated [(b)(4)] value.  Please explain how the [(b)(4)] value was calculated, and what the associated error with this value was, and whether samples with (b)(4), and without excipients compared? 
17.Attachment P53-13-MTA-050-R pg 21/40 indicates that (b)(4) replicates of (b)(4) samples were measured by this method and compared to "Ordinary samples".  Please clarify the term ordinary as it used in this context.
18.In table P.5.16, module 2.3.9 quantitation and detection limits for potassium are given but not for sodium.  Please explain why these values are not listed, and please provide this information.

The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission. If we determine that your response to this information request constitutes a major amendment, we will notify you in writing.

Please submit your response to this information request as an amendment to this file by February 20, 2011.  If you anticipate you will not be able to respond by this date, please contact the Agency immediately so a new response date can be identified.  The action due date for this file is June 3, 2011.

If you have any questions, please contact me at (301) 827-3927.

Sincerely,

 

Crystal Allard
Regulatory Project Manager
FDA/CBER/OBRR/DBA/RPMB
