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Vaccines, Blood & Biologics

Review of IR Letter Responses


To:                  File STN: 125285/0/22
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 October 6, 2009 by Protein Sciences Corporation (hereafter referred to as PSC).
Action Due Date: January 28, 2009
I can not recommend approval at this time; PSC has indicated that they will submit the following information prior to approval:
  • Two full scale validation runs for filling from their contract manufacturer Hospira.
  • Revalidation of container closure integrity under dynamic conditions using a test with adequate sensitivity to detect a critical leak.
  • Resolution of all outstanding inspectional issues.
IR letter comment 1(C)dii:
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.
According to a memo from R. Boulanger dated August 13, 2009, production operators installed --------(b)(4)------- and followed the preparation and cleaning procedures as outlined in the Batch Production Record. In addition, the --------------------------(b)(4)-----------------------------------------------------------------------------------------------------------------------------------------------. We note that the Batch Production Record (------(b)(4)---------, Attachment 5) includes a notation for the   ---------------------------(b)(4)------- but does not include any reference to the -----(b)(4)------- step mentioned above. Please clarify this discrepancy.
According to Batch Production Record ----------(b)(4)-------, submitted August 24, 2009 the         ----------------------(b)(4)-------------------------------------------------. However, your Interim H3 Process Validation Report submitted June 15, 2009 indicates on page 18 of 27 that the -----(b)(4)------------------------------------------------------. Please clarify the discrepancy between your statement from the Interim Validation Report submitted June 15, 2009 and the Batch Product Record submitted August 24, 2009.
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.
Review of response 1(C)dii:
PSC states that they recognize that the documentation associated with the -----(b)(4)----- of batch --------------(b)(4)---------- was incomplete. Specifically: Quality Unit approval to ----(b)(4)---, the documentation for the ----------------------------(b)(4)--------------------------- described in the Interim Process Validation report, and SOP QG0041 (------------(b)(4)--------------- Procedure) was not followed.
SOP QG0041 includes specific requirements for written instructions for production operators for --------------(b)(4)----------. These instructions must be issued and approved prior ------------(b)(4)----------. SOP QG0041 was not correctly followed in this event because we initially failed to        --------------(b)(4)----------.
The following CAPAs have been implemented:
1.     Training on --------------(b)(4)--------  for Production and QA personnel was conducted on Oct 2, 2009.
2.     QA has assigned the appropriate lot number (---(b)(4)--) to this batch consistent with our SOPs on 01Oct2009. Our records for this batch are being amended to document the change in lot number.
Upon further review and to more completely address agency concerns, deviation D-09-71 was opened (on Sept 25, 2009) to investigate our response to this event. This lot will remain in quarantine until final batch disposition.
A comprehensive audit of Quality systems will be performed by qualified external experts before commercial distribution of FluBlok. Additional training of Manufacturing Operators in documentation practices will be completed by Oct 16, 2009.
The firm’s response appears acceptable. Follow-up should be performed during the October 19 -23, 2009 re-inspection.
IR letter comment 1a:
Please provide data to validate the bulk filtration step.
Review of response 1a:
PSC has added ----(b)(4)---  process parameters/in-process tests (i.e. ------------------------(b)(4)---flow) in Section 14 of the DSP Process Validation Report. The data indicates that flow rates and ---(b)(4)----- were maintained.
The firm’s response appears acceptable.
IR letter comment 2g(A):
Please adjust your linear flow rate parameters for the ------(b)(4)------ columns to include a lower limit based on process capabilities.
Review of response 2g(A):
PSC adjusted linear flow rate parameters for the ------(b)(4)----- columns to include a lower limit based on process capabilities
The firm’s response appears acceptable.
IR letter comment 2g(C):
Please clarify testing performed to confirm complete removal of column storage solution prior to use.
Review of response 2g(C):
PSC states that uniform -------(b)(4)--- were maintained throughout the -------(b)(4)---------- chromatography steps, verifying --------------(b)(4)-------------------------- column storage solution. Note: ---(b)(4)--- is also used throughout the process to -------(b)(4)----------.
The firm’s response appears acceptable.
IR letter comment 11f(A):
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.
Review of response 11f(A):
PSC is in discussion with Hospira regarding the sensitivity of the method used in their container closure validation. We will forward this information as soon as it becomes available.
The firm’s response appears acceptable.
IR letter comment 11f(B):
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).
Review of response 11f(B):
PSC acknowledges the agency’s request and will be evaluated in a drug product shipping validation study anticipated to be completed by year end 2009 which will include a challenge of dynamic conditions (------- (b)(4)-----) from Hospira to PSC. This will mimic worst case distance from future packaging/distribution center and include pressure differentials and vibration/movement experienced while in transit.
The firm’s response appears acceptable.
IR letter comment 11g:
Please submit your test plan for confirming reliability of the supplier's results for ---(b)(4)----  for the -----(b)(4)----- stoppers.
Review of response 11g:
To confirm reliability of the suppliers, three lots of stoppers will be tested by Hospira for       
The firm’s response appears acceptable.

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