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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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1/31/2007 Filing Meeting Email 2 - RECOTHROM

From: Renshaw, Carolyn
Sent: Wednesday, January 31, 2007 2:30 PM
To: Shields, Mark; Aebersold, Paul; Drews, Roman T; Gallagher, Maryann; Hshieh, Paul; Buehler, Paul (CBER); Kirschbaum, Nancy; Lee, Timothy; Lindsey, Kimberly; White, Janet; Buehler, Paul (CBER)
Cc: Trout, Deborah; Eltermann, John
Subject: RE: 125248/0 Filing Meeting

I recommend filing STN 125248/0 based on the facility and microbiology information in the BLA. However, I have the following issues/comments:

  • ------------------------
    • Action limit of final ------ during consistency lot campaign was ------------. Proposed action limit for future manufacturing is ----------------.
      • During PAI, review historical ------------ results to determine if the action limit is appropriate.
    • -------------------------------------------------------------------------------------------------------. This seems high for a recombinant product. Typically see lower for other products.
  • Endotoxin
    • ---------------------------------------- endotoxin limit is -------------------. -----------------------------------------------------------. This seems rather high although the route of administration may warrant less stringent requirements (topical rather than IV) and also it is a blood component 610/14(b).
  • Environmental Assessment
    • 21 CFR 25.31(e) is quoted as the reason for categorical exclusion. This is only relevant for an IND. They should use 25.31(c) , naturally occurring substance.
  • There is a problem with popped-up stoppers after lyophilization. These vials are discarded but this raises concerns regarding sterility assurance. They have modified the vials and revalidated CC integrity for future lots.
  • Integrity testing of the container/closure for the final bulk was not described.
  • Why is the ----------------------------------------------------------------------------------------------------------------------------?
  • Sterilization and depyrogenation of the CC, equipment, and components is described in the BLA. The descriptions provide some details but the information is still highly summarized.
    • Either ask for executive summary reports or review during the PAI.
  • Actual media fill validation results were not provided. They only described the requirements for performing and passing media fills and stated the media fills had passed.
    • Ask for the summary report or review during the PAI.
  • The moisture specification for final drug product is --------------. Do they have stability data to support the upper limit?
  • Lyophilization validation was described but the actual results were not submitted.
    • Ask for validation summary reports or review during the PAI.

I have requested the following master files:

  • --------------------------------------
  • Two amendments from ---------- regarding the stoppers:
    • --------------------------------------------------------------------------------

The ------------------are out but I will receive them when they are available.

Pre-approval inspection status:

  • Most likely will need three PAIs.
  • Decision will occur this week.
  • Firm is sending production schedules for --------------------------.
  • Most likely will perform a combined inspection with Team Bio for the -------------------. -----------. The participation of Team Bio is unannounced - please do not inform the firm.


Carolyn Renshaw
NLRC, Room 233A



From: Shields, Mark
Sent: Wednesday, January 31, 2007 9:56 AM
To: Shields, Mark; Aebersold, Paul; Drews, Roman T; Gallagher, Maryann; Hshieh, Paul; Buehler, Paul (CBER); Kirschbaum, Nancy; Lee, Timothy; Lindsey, Kimberly; Renshaw, Carolyn; White, Janet; Buehler, Paul (CBER))
Subject: Updated: 125248/0 Filing Meeting
When: Wednesday, January 31, 2007 1:00 PM-2:00 PM (GMT-05:00) Eastern Time (US & Canada).
Where: By email.

The filing meeting will be held by email. Please provide an email that states that this can be filed and share any known problems. Thanks!

Short Summary: New BLA - Thrombin (Recombinant)


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