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Vaccines, Blood & Biologics

DMPQ questions for STN 125248 - RECOTHROM

From: Waites, Nancy

To: Shields, Mark

CC: Renshaw, Carolyn; Byrd, Sean (CBER)

Subject: DMPQ questions for STN 125248

Date: Monday, June 18, 2007 11:59:32 AM

Attachments: DMPQ Questions STN 125428 rev 1.doc

Hey Mark,

Here are DMPQ's questions for ZymoGenetic's BLA. If you have any questions let me know. Thanks!


Nancy Waites
Phone: 301.827.3031

I have the following questions for ZymoGenetics based on my review:

  1. Please confirm IQs and OQs were performed on the lyophilizer, dry heat oven, ----------------, and autoclave used in the production of rhThrombin. Please provide dates of completion. Please provide a short description of each.
  2. Summary Report for the Lyophilizer Sterilization Validation Package. Please provide the rationale for the placement of the TCs and BIs in the validation runs.
  3. Summary Report for the Steam Autoclave Validation Package.
    1. Please provide the rationale for the placement of the TCs and BIs in both validation runs.
    2. Please explain why --- TCs used in the heat distribution studies for FR-VP-PQ-150-05 while ---- TCs were used in FR-VP-PQ-150-06.
    3. Please explain how the D values for the BIs are confirmed or verified.
  4. Summary Report for the --------------- Sterilization Validation Package
    1. Please provide the rationale for the placement of the TCs and BIs in the validation runs.
    2. Please provide the rationale for the use of -------------------------------------------------------------------------------------------, to determine when to start the -------- time for sterilization ----------------------------------------------------------------------------------?
  5. Summary Report for the Dry Heat Oven Validation Package. Please explain how the locations of the thermocouples and BIs were determined for the validation.

  6. Summary Report for the Lyophilization of Drug Product
    In your summary report, the following statement is made, "Moisture testing is performed on ----- vials and reported as the average. This is considered acceptable; it is not unexpected that an occasional vial will have residual moisture content above ------- which does not impact the quality of the drug product or the robustness of the lyophilization process and the uniformity of lyophilization throughout the entire chamber. This is further supported by -------------------------------------- demonstrating acceptable stability of rhThrombin lyophilized drug product with moisture levels of --------.

    1. Please provide the rationale as to why it is acceptable to average the moisture results from the -------- vials as opposed to recording each result separately especially if one or more vials do not meet set release specifications.
    2. Please provide the rationale as to why it is acceptable for a vial to have a moisture result above the moisture content specification of -----------.
    3. Please provide the data to show that a moisture content ----- does not adversely effect the product.
    4. Was the expiration date based on any of the vials that had a moisture content ---------? If not, please explain why not.
    5. Was temperature mapping performed to correlate product temperature to shelf temperature? If so, what were the results?
    6. How was it determined which vials to sample during the validation?
    7. Please provide a copy of Deviation 129/06.
  7. Summary Report for the Media Fill Validation Package (Please reference Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products, Nov. 1994)
    1. Please provide specific details of the aseptic process media fills Batch numbers ---------- and --------- that were performed. The report summary only gave a general description of what criteria were considered during the description of a "worst case" fill such as number of people, duration of fill, etc. The report never indicated what actually happened during the fill.
    2. At what step does the media fill begin and end? Are all routine samples taken at each point? Is a batch record followed? Are weight checks and volume adjustments performed? What was the line speed? What was the fill volume? What was the duration of fill?
    3. What was the number of units actually filled?
    4. What was the number of units rejected and what was the cause? Please provide a list of what is considered a major or minor defect and what the alert and action levels are for each.
    5. Please provide a copy of the SOP for Visual Inspection.
    6. Any interventions or line stoppage incorporated into the media fill? If so, give some examples of what the interventions were and duration of line stoppage.
    7. What were the --- results?
    8. Were personnel monitored during the media fill? What were the results?
    9. Please describe the conditions under which the lyophilization cycle was simulated. What type of gas was used to break the vacuum?
  8. Validation.
    1. Please indicate where the information for the validation of the stopper washer is located within the submission or provide a summary of the validation. If the stoppers are washed by the stopper manufacturer, please include information about how the depyrogenation of stoppers is verified.
    2. Please indicate where the information for the validation of the --------- ----------------------- is located within the submission or provide a summary of the validation.
    3. Please provide detailed information on the container/closure integrity testing including information on the sensitivity of the test or indicate where in the submission this validation is located. The only information I can locate is a statement that a ---------------- test was performed. No other information can be located. Was a spark test performed?
    4. Please provide a summary of the validation of the ---------- carts used for transporting the filled vials to the lyophilizer.
  9. Batch Production Records (BPR)
    1. The batch records are not complete. A number of steps state to attach specific data to the BPR. This has not been done. Please provide completed BPRs.
    2. Please clarify when the -----------------------------------------------. Is it after the ----------------------------------------------------------------------------------------------please provide the rationale of how this is representative of the bulk material? What is the bulk material specification for ----------------------------------------------? Where is this information recorded in the BPR?
    3. When is ---- started during the fill? I could not see where this was recorded in the BPR. Please indicate where this information is recorded or how batch monitoring is traced to the batch record.
    4. Are personnel monitored during the fill? Please indicate where in the BPR this is recorded or how this information can be traced to the batch record.
    5. Where is it recorded the cause of filled vial rejection either by production or QA/QC personnel?
  10. Shipping. Please provide more detailed information on the shipping studies performed at all stages of manufacture and storage. What studies were performed and under what conditions? A statement in the BLA said that the shipping studies from ----------------------- would be completed in March 2007. Has this information been submitted to the BLA? Please provide completed shipping studies for all stages to the BLA.

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

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