• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

  • Print
  • Share
  • E-mail

Information Request Email, February 22, 2013 - RIXUBIS

 

From:                       Thompson, Edward
Sent:                         Friday, February 22, 2013 8:26 AM
To:                            'Kevin Smyth (kevin_smyth@baxter.com)'
Cc:                           Ovanesov, Mikhail V.
Subject:                   Information Request for BL 125446/0
 
Contacts:                 Kevin Smyth
 
Dear Mr. Smyth:
 
We are reviewing your August 28, 2012 biologics license application (BLA). We are providing the following comments and request for additional information to continue our review:
 
1. Regarding the multiple out-of-specification (OOS) potency measurements observed in the stability studies, please provide a report with the evaluation of all existing stability data in which OOS potency events are determined against the most current specifications. The report should include assessment of the potential impact of these OOS results on the proposed shelf-life and in-use stability of the --b(4)--------------------------and Final Drug Product (FDP).
 
2. With regard to the poor robustness of the potency assay as a possible root cause for the OOS results during stability evaluations, please
 
a.     Explain the discrepancies in the Factor (F) IX potency values determined by the clotting and chromogenic activity assays;
 
b.    Provide a table that compares the assay conditions and known assay deficiencies for all versions of the potency assay as well as the dates when the specific assay versions were introduced, starting from the beginning of process development;
 
c.     Evaluate the impact of the poor assay robustness on the process validation studies, potency assignment of standards, batch analyses and interpretation of clinical studies, including but not be limited to recoveries and other parameters in the PK studies;
 
d. Retest all product batches used in pre-clinical, clinical, and process validation evaluations, and provide a table that compares the original and retested FIX potencies, as well as the FIX activity by the chromogenic assay.
 
3. Regarding the BDS and FDP release specifications, please
 
a.     Establish the FDP potency specifications which are applicable to each of the nominal vial strengths, e.g., “within minus n% and plus m% of the nominal vial strength”, where “n” and “m” values are derived from the existing manufacturing experience with the respective nominal vial strengths. In addition, please add the following –b(4)----- requirement to ---b(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
 
b.    Provide justification for the FDP –b(4)-- specifications on FIX potency and pre-activation (FIXa impurity) using the data from the lots manufactured for pre-clinical, clinical, and process validation evaluations;
 
c.     Add the following parameters to BDS specifications, levels of –b(4)------------------------------------------------------------------
 
d. Develop appropriate in-process control limits and/or BDS specifications to demonstrate consistent removal of the –b(4)--- impurity in the product.
 
4. The batch analysis tables indicate that FIXa activity assay experienced variations due to changes of reagents. Please submit completed investigation reports on this deviation.
 
5. Regarding the Sterility/Bioburden Test:
 
a.     Sterility method validation (3.2.P.5.3) for the suitability of the method for rFIX FDP was performed by the –b(4)--------------------- method. Baxter stated in the document in Section 3.2.P.5.2 Sterility that the sterility method is described in more detail in ‘OR-12-00005-CTP00.04’. However, the test procedure ‘OR-12-00005-CTP00.04’ describes the        ---b(4)------------- method. Please clarify at what processing stage is Sterility/Bioburden tested using the –b(4)---------------------- method.
 
b. For the Sterility Validation Report ‘Doc ID OR-12-00006-CVRH9.02’ a consolidated report was submitted that has either missing or unreadable lot data on pages 2, 5, 6, 7 of 8, please send the completed validation report to include the method procedures and all data. 
 
6. Regarding the Endotoxin test, please
 
a. Provide a comparative description of all Endotoxin test methods used for the control of the –b(4)- and FDP manufacture.
 
b.    Provide relevant validation reports for each of the endotoxin test methods showing method suitability for the –b(4)- and FDP.
 
c. Correct the inconsistent description of the endotoxin test method in the BLA. According to the validation study ‘Doc ID OR1300043-CTP00.03’endotoxin is performed by the ---b(4)--------------------------------------------------------- method. However, the validation report ‘OR-13-00043-CVRH9.01 includes only the qualification of the –b(4)--------- method.
 
The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission. 
 
Please submit your response to this information request as an amendment to this file by March 10, 2013 referencing the date of this request. 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.
 
If we determine that your response to this information request constitutes a major amendment, we will notify you in writing. 
 
The action due date for this file is tentatively June 30, 2013.
 
If you have any questions, please contact me at (301) 827-9167.
 
Sincerely,
 
 
Edward Thompson
Regulatory Project Manager
FDA/CBER/OBRR/DBA/RPMB
 
THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.

If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure, dissemination, copying or other action based on the content of this communication is not authorized. If you have received this document in error, please notify us immediately by telephone and return it to us at the above address by mail. Thank you.