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Vaccines, Blood & Biologics

Review of IR Letter Responses submitted August 24, 2009 - Flublok


To:                  File STN: 125285/0/19
From:             Deborah Trout, Committee Member, MRB1, DMPQ, OCBQ, HFM-675
Through:        Carolyn Renshaw, Branch Chief, MRB1, DMPQ, OCBQ, HFM-675
Subject:          Review of IR letter responses submitted August 24, 2009 by Protein Sciences Corporation (hereafter referred to as PSC).
Action Due Date: October 28, 2009
Recommendation: Outstanding issues identified below can be addressed in an Information Request.
IR letter comment 1a:
We note from the 2008 manufacturing campaign that approximately 50% of lots were terminated. Please comment on how you are addressing manufacturing consistency for the 2009 campaign.  
Review of response 1a:
PSC indicates that corrective actions were implemented prior to the 2009 FluBlok campaign to improve their overall success rate. They state that as a result of these corrective actions, manufacturing consistency has significantly increased and that their year to date FluBlok lot completion success rate is 94% (successfully completed –(b)(4)-- lots initiated). The 2009 overall year to date success rate for all lots (including non-FluBlok lots) manufactured in the facility is 91% with a total of (b)(4) lots manufactured.
The primary corrective actions from 2008 include improvements in 1) Planning, 2) Process
Transfer, 3) Process Control and 4) Equipment.
  • Planning - PSC implemented a pre-production check to ensure all required materials are available prior to the initiation of a lot as a corrective action; this action was taken after one production lot was terminated in 2008, due a planning error resulting in insufficient filter inventory to support the batch in process. Since that time no lots have been terminated due to insufficient inventory.
  • Process Transfer - Several 2008 batches were terminated due to a failure to successfully transfer the purification process developed in the Process Development Department to full-scale manufacturing. In order improve the transfer of the purification process from Process Development to Manufacturing and respond to CR Letter Comment #7 received on August 29, 2008, PSC implemented SOP RG0006 DSP Process Development of New
rRA strains. Following the procedure outlined in this SOP resulted in a successful 2009 B/Brisbane process transfer from Process Development to Manufacturing, with (b)(4) B/Brisbane lots completed successfully to date.
  • Process Control - Three 2008 lots were terminated due to ------(b)(4)-----------------------------------. PSC implemented Change Control 09-006 to -------------(b)(4)---------------------------------------------------------------------------------------------------------------------. Since the implementation of this modification, there have been no lots terminated due to -----(b)(4)----------.
  • Equipment - One lot in 2008 was terminated due to an ----(b)(4)------------- equipment failure. PSC implemented Change Control 09-003 to upgrade the -----(b)(4)--------------- to improve robustness and data acquisition of the –(b)(4)----. The implementation of the upgrade to the ----(b)(4)----------- has contributed to an improved 2009 consistency in manufacturing, i.e., consistently lower –(b)(4)-- and lower –(b)(4)----.
Regarding loss of entire lots during the 2009 FluBlok manufacturing campaign, a single lot of FluBlok (lot # (b)(4)) of (b)(4) lots initiated was terminated due to insufficient cell growth during Up Stream Production. An investigation determined that this cell growth failure was caused by a        ------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------. A corrective action was implemented to retarget the actual historical value and to modify the range specified in the batch records prior to the 2010 campaign. The deviation has not recurred.
The investigation into the potential root causes evaluated --------------------(b)(4)---------------------------------------------------------------------. PSC will continue to monitor and respond appropriately to any recurrence.
The firm’s response appears appropriate. All corrective actions will be followed-up during the re-inspection currently scheduled for October 19th, 2009.
IR letter comment 1b:
Concerning the 2008 Process Validation Report (R-09-005) for H3: we note that an H1 batch       ---(b)(4)---- was manufactured in between your process validation runs for H3.  The H1 batch       ---(b)(4)--- was terminated for ----(b)(4)------- and irregular column performance. Please provide a justification for not assessing the impact of this deviation on the H3 process validation study.
Review of response 1b:
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------.
I find their response satisfactory.
IR letter comment 1ciii:
Please provide a justification for the -----(b)(4)------------- limit set for (b)(4)--.
---------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ---------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
The firm’s response appears acceptable.
IR letter comment 1dii:
During ---(b)(4)------ of Lot ---(b)(4)------ there was a failure of the (b)(4) and it appears that approximately ---------------------------------(b)(4)----------------------------------------------------------------------------------------. Please provide documentation that the Quality Unit reviewed and approved this ---(b)(4)-- step prior to its execution. In addition, please provide the deviation (#09-026) and associated investigation.
Review of response 1dii:
The firm’s response is unacceptable. The following comments should be conveyed to the firm in an information request:
You have provided no documentation to support your claim that the Quality Unit knew of and approved the ---(b)(4)----- step associated with Process Validation Lot ---(b)(4)-- prior to its execution on May 4, 2009. Please clarify your response concerning this issue. In addition, if documentation is not available please describe corrective and preventative actions you will implement to correct this reoccurring deviation.
Please note that review of your ---(b)(4)------ protocol for ---(b)(4)-------- at this time may cause a delay in approval.   We advise resubmitting the protocol and data as a Prior Approval Supplement after approval of your BLA.
IR letter comment 2g(A):
In your lifetime studies for the ----(b)(4)------- columns, please provide data for protein load capacity and linear flow rate.
Review of response 2g(A):
Protein load capacity and linear flow-rate for their ongoing, full-scale lifetime studies was provided in the amendment. 
Load capacity and linear flow-rate data was presented in Table 2-6 for –(b)(4)-- and Table 2-7 for the (b)(4) column. The flow rate for the ---------------------------(b)(4)-----------------------------------------------------------. PSC should set a range for linear flow rate based on process capabilities. Specifically, a lower limit should be set to optimize their purification process.
The firm’s response is not complete. Please adjust your linear flow rate parameters for the  ---(b)(4)----- columns to include a lower limit based on process capabilities.
IR letter comment 2g(B):
It is unclear if cleaning, sanitization and storage procedures used in your scaled-down study for the ---(b)(4)----- columns are the same as those used in your commercial scale purification process. Please clarify.
Review of response 2g(B):
PSC indicates that in their scaled down studies, the procedures for cleaning, sanitization, and storage of the ---(b)(4)----- chromatography columns were executed as described in the corresponding manufacturing batch record. In their small scale studies, the same buffers and cleaning solutions were used and the same procedures were followed (i.e., the number of column volumes/contact time and flow-rate).
The firm’s response appears acceptable.
IR letter comment 2g(C):
Please provide data for ---------(b)(4)------------------------ in your lifetime studies to support cleaning and sanitization of the ---(b)(4)------- columns.
Review of response 2g(C):
PSC states that --------(b)(4)------------ data were not collected during validation batches.               ---(b)(4)----- data is available for the process validation batches. They claim ---(b)(4)---- and        ---(b)(4)--- data were collected to support cleaning and sanitization of the ---(b)(4)---- columns and support the proposed column re-use ---------------------------------------(b)(4)-------------------------------------------------------------------------------. Data was presented in Tables 2-9 - 2-11 of the amendment.
The firm’s response is not complete. Please clarify testing performed to confirm complete removal of column storage solution prior to use.
IR letter comment 11a:
It is unclear if an identity test is performed as per 21 CFR 211.84(d)(1) on the monovalent bulk concentrates when they are received at Hospira. Please clarify.
Review of response 11a:
Per Hospira raw material monographs ----(b)(4)----- (HI Strain), ---(b)(4)---- (H3 Strain), and
---(b)(4)---- (B Strain), identification via (b)(4) is performed upon receipt of each monovalent strain lot.
The firm’s response appears acceptable.
IR letter comment 11d(A):
Please provide validation data in support of fill volume accuracy for the ---(b)(4)--- filler.
Review of response 11d(A):
The ---(b)(4)-------- were validated for the following volume range/solution type: all mobile products having a target volume between ---(b)(4)----------- The validation concludes that the filling pumps installed on the ---(b)(4)-- filler are capable of filling the required volume. The fill volume accuracy is verified and maintained via the fill volume checks performed during the manufacture of the drug product. Fill volume is established during the line set-up and can be adjusted during the manufacturing process as needed to achieve the required volumes.
The firm’s response appears adequate.
IR letter comment 11d(B):
Please provide the data and associated summary report for Drug Product Validation Runs.
Review of response 11d(B):
PSC will complete drug product process validation after they reach agreement with the agency on drug product specifications (such as release minimum and maximum potency). They anticipate performing the next drug product validation run in the end of September/early October timeframe.
The firm’s timeframe appears acceptable; please submit the data when available.
IR letter comment 11e:
Please provide bioburden testing results for the -----(b)(4)----- time points.
Review of response 11e:
Bioburden testing results for lot ---(b)(4)--- are:
  • -----(b)(4)--- time point - 0 CFU/l00 mL
  • -----(b)(4)----- time point - 0 CFU/mL
The firm’s response appears acceptable.
IR letter comment 11f(A):
Please provide a corresponding leak rate or leak diameter for your positive control vial used in the container closure integrity test study.
Review of response 11f(A):
PSC indicates that the leak diameter for the vented positive control for the container integrity testing was generated by a ---(b)(4)--- needle (nominal outer diameter: ----(b)(4)------------.
The firm’s response is unacceptable. Microbial failure occurs in the leak rate region of 10-4.5 to 10-3 std cc/sec, which roughly corresponds to leak diameters ranging from 0.4 to 2 microns. It is not clear if their method can detect a critical leak in the range mention above. PSC should submit their plan for demonstrating that the sensitivity of their container closure integrity test can achieve adequate levels of detection.
IR letter comment 11f(B):
Please explain how minimum seal pressure would simulate pressure differentials experienced during (b)(4) transportation of your container closure system.
Review of response 11f(B):
PSC states this will be evaluated in a drug product shipping validation study anticipated to be completed by year end 2009. It should be noted that Hospira has never had to recall a vialed product due to a bad seal.
The firm’s response is not complete. Container closure integrity validation must be repeated with vials used in the shipping validation study and this data must be submitted to CBER for review or repeat container closure integrity testing to include dynamic conditions (i.e., exposure to differential pressures to simulate anticipated product processing or distribution conditions).
IR letter comment 11g:
Your response is unacceptable as per 21 CFR 211.84(d) (3). Please provide test data from Hospira confirming reliability of the supplier's results for –(b)(4)-- for the ---(b)(4)-------- stoppers.
Review of response 11g:
Hospira is working with -----(b)(4)-------------- to transfer the appropriate test method and will perform confirmatory testing on ---(b)(4)------ stoppers for –(b)(4)-- prior to commercialization.
The firm’s response is not complete. Please submit your test plan for review.

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