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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Vaccines

Information Request Letter - Adenovirus

Our STN: BL 125296/0

Duramed Research, Inc.
Attention: Joseph A. Carrado
One Belmont Avenue, 11th Floor
Bala Cynwyd, PA 19004

Dear Mr. Carrado:

We are reviewing your biologics license application (BLA) dated September 30, 2008 for Adenovirus Type 4 and Type 7 Vaccines Live Oral and have determined that the following information is necessary to take complete action. Please promptly submit your written response to the following items so that we may continue evaluating your BLA:

  1. You intend to -(b)(4)-- the lyophilization capacity from -------(b)(4)------ of lyophilized intermediate for commercial production of the product after approval. To achieve this, you plan to -(b)(4)- the formulated virus manufacturing process to formulate a -------------------------(b)(4)------------------------------------------------------------------------------------. However, validation data for --(b)(4)--- lyophilization and mixing studies have not been submitted. We would like to advise you that without the validations for ----(b)(4)------ lyophilization and mixing, CBER can only consider approval of the currently submitted (b)(4) validated procedure.
  2. You state that the final report for cleaning validation for Adenovirus 4 and Adenovirus 7 and residual solvents in Barr Laboratories has not been completed. Only an interim report for cleaning validation has been submitted in this BLA. Please submit a summary of the final report for cleaning validation for each piece of product-contact equipment, lyophilizer, and the facility.
  3. Cleaning/disinfecting validation for rooms of lyophilizing, blending, core compression, core coating compression and coating were not performed. It was stated that ----(b)(4)------------------------- cleaning and disinfection of rooms were performed per SOP. Please explain why cleaning validations were not performed for these rooms.
  4. The cleaning validations of residual solvents in the Barr facility do not appear to be complete. Cleaning validations for some equipment were not included in your submission. Please provide a list of product-contact and solvent-contact equipment and indicate which ones have been validated and which ones have not been validated for cleaning/disinfecting and provide data for those that are missing.
  5. Please clarify if aseptic process validation has been done at the ----(b)(4)---- facility. If so, please submit a summary of the final report.
  6. You stated that “Microbial testing will continue to be performed on the finished products but will not be done as part of routine in-process testing for commercial products.” Please explain your rationale for not performing microbial testing as part of routine in-process testing and justify ----------------------(b)(4)---------------------------------------------------------------------------
  7. You have used two different sized -----------(b)(4)-------------------- to conduct stability studies of the drug product. Please clarify which size bottles will be used for commercial product and justify that the bottles and caps used during stability studies are comparable to those used in the final product.
  8. Please provide a summary of validation studies for the filters used for ---------------------------------------------(b)(4)---------------------------------- followed by a ------------(b)(4)-------------------------------------
  9. In section 3.2.S.6 Container Closure System, you stated that for the commercial process, ----------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------. In section 3.2.A.2 Manufacture, you stated that for commercial manufacturing, (b)(4) of Bulk Virus will be filled into --------------------------(b)(4)--------------------------. You also mentioned that you have used ---------------------(b)(4)---------- containers for storing Bulk Virus at --(b)(4)-- Please clarify what size bottles you will use for commercial product. Please provide a summary report of validation studies for all the containers and closure integrity and bulk shipment.
  10. Please clarify if the formulated virus will be shipped ---------------------------(b)(4)--------------- If the product is shipped -------(b)(4)------, the shipping validation should cover ------(b)(4)-----. Please submit a summary of your shipping validation.
  11. You referenced a cross-reference letter for DMF BB-MF --(b)(4)- from (b)(4) for their --------------(b)(4)------------ used in lyophilization of intermediate product. We would like to remind you that you should be responsible for providing a summary report of the validation study for the container closure system.
  12. The lyophilized intermediate product in --------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------. Please provide a summary of validation studies for the container/package integrity.
  13. --------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------. Does this pressure represent the pressure encountered during the --------------(b)(4)-------- i.e., does this condition represent the worst case condition? For commercial product, --(b)(4)--- will be used for shipment. Does the leak testing condition performed on --(b)(4)--- also represent the worse case condition for shipment of the product in --(b)(4)---
  14. Please provide a summary of IQ/OQ/PQ for the lyophilizer in the Barr facility and PQ of the steam sterilization validation of -----(b)(4)-------.
  15. Please provide a summary of qualifications for the Grade (b)(4) Cleanrooms and the EM data at the ---(b)(4)---- facility.
  16. Please justify the specification for personnel monitoring for fingers, chest and arms.
  17. Please specify the usage of (b)(4) and (b)(4) in the -----(b)(4)----- facility. You stated that you use (b)(4) water to generate steam for autoclaves. Please specify what equipment is autoclaved and justify why you use (b)(4) water for autoclaves.
  18. Please describe the HVAC systems and provide color floor diagrams illustrating flows of material, product, personnel, equipment and waste. Please also provide color diagrams illustrating differential pressures, room classification and AHU. Please clarify if the air in your production area is single-passed or re-circulated? The above request applies to both ---(b)(4)---- and Barr Laboratories facilities.
  19. The specification for moisture -------(b)(4)------ for your drug product was set for -----------(b)(4)-- The actual moistures for your six consistency lots of Adenovirus 4 and Adenovirus 7 range from 2.3 – 3.6%. Please justify the specification and the discrepancy.
  20. In the Barr facility, the EM samples were taken under both dynamic and static conditions and sampled ---------(b)(4)-------------. Please justify the sampling frequency and why you think ----(b)(4)------ is sufficient.
  21. PQ for (b)(4) is incomplete and did not meet protocol criteria for humidity as described in your VMP Final Report in 2006. Has the (b)(4) been re-qualified since then? If so, please provide a summary of the final report.
  22. Please provide a summary report of validations on the computer system. Please clarify your statement about computer validation as described in VMP Final Report. What do you mean “this risk analysis and assessment is not documented explicitly in a separate document or within the protocol but was performed as a function of protocol development as required by the original master plan.”?
  23. In your Amendment to VMP Final Report (Document # 406060EM-1), you stated that EM testing (PQ) for ----------------------(b)(4)----------------------- static requirements. What are the EM testing results under dynamic conditions?
  24. Please provide a summary of results of the container closure testing for ---------------------------------------------------(b)(4)-----------------------------------------------------------------------------------------------------------
  25. The ---(b)(4)--- facility has (b)(4) production labs, -------(b)(4)-------------------------- for manufacture of Adenovirus 4 and Adenovirus 7. Please clarify what the other (b)(4) production labs, ----------(b)(4)------------- are used for? If they are used for other products, please provide the name of the products and describe the segregation, containment and procedural controls that you have in place to prevent contaminations and cross-contaminations.
  26. You stated that the air classification at the lyophilization loading door at the Barr facility is unclassified. Please justify why it is not.
  27. Please clarify your statement that bioburden testing of lyophilization powder is “limited from R&D” as described on page 3 of 5 in 2.3 Introduction.
  28. Please submit a draft of your lot release protocol.

Please submit your response no later than Friday, January 30, 2009, so we may continue the review of your application. If we determine that your response to this information request constitutes a major amendment, we will notify you in writing. If we receive your major amendment during the last three months of the review period, we will extend the review period an additional three months.

If you have any questions, please contact the Regulatory Project Manager, Darlene Hithe, at (301) 827-3070.
 

Sincerely yours,

 

Loris D. McVittie, Ph.D.
Chief
Viral Vaccine Branch
Division of Vaccines and
Related Products Applications
Office of Vaccines
Research and Review
Center for Biologics Evaluation and Research