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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Discuss Responses to 483 Observations Telecon, January 26, 2012 - Gintuit

 

 
From:                                      Qiao Bobo, Ph.D., Reviewer, CBER/OCBQ/DMPQ/MRBII
 
Date/Time of Call:             January 26, 2012, 3:00 PM
 
CBER Representative:         Qiao Bobo, Ph.D., Reviewer, CBER/OCBQ/DMPQ/MRBII
Gang Wang, Ph.D., Consult Reviewer, CBER/OCBQ/DMPQ/MRBII
Mark Lee, Ph.D., Reviewer, CBER/OCTGT/DCGT/CTB
Eric Dollins, Ph.D., Reviewer, CBER/OCTGT/DCGT/CTB
Organization Representative:          
Kristine Riley, Manager, Regulatory Affairs
Zorina Pitkin, Ph.D., Vice President, Quality Systems
Dan Lesnoy, Director Quality Control
Chris O’Reilly, Director Process Engineering
Patrick Bilbo, VP of Regulatory
Shawn Cain, Director of Facilities Engineering & Maintenance
Paul Strouth, Manager, of Validation
Maria Trolliet, Sr. Regulatory Affairs Specialist
Cheryl McManamin, Director of Production
 
Applicant:                         Organogenesis
 
Manufacturing location:      Canton, Massachusetts (FEI#: 1000148471)
                                                           
Telephone:                             1-866-951-1151; Conference Code: ---b(4)----
 
Subject:                                   Discuss Responses to 483 Observations
                                               
STN:                                  125400/0
                       
 
Summary of Additional Information Requested for BLA Review:
 
From DMPQ:
 
1.      Your heat sealer validation runs consisted of -------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. 
 
a.       For CO2 composition, please clarify how the CO2 composition was verified to meet specification of ---b(4)---- How was the test sensitivity established?
 
b.      For seal integrity, you stated that -----b(4)-------------------------------------------------------------------------------------------. How was the test sensitivity established? The test should be sensitive enough to detect minute leaks.
 
c.       For sterility test, please provide information supporting microorganism growths under the same condition as the ------b(4)--------------------------------------- 
 
2.      Regarding the cleaning validation for you -----b(4)-------------------------------------------------------------------------------------- please clarify what soils and cleaning reagents were used? Please demonstrate that the soils used represented the worst case situation and the  -b(4)- locations represented the worst case locations? Please justify why the conductivity and visual inspection were not included in the acceptance criteria. Please justify using      -b(4)---- as one of your acceptance criteria.
 
3.      Your description of microbial challenge study for –b(4)------ packaging did not specify the ---b(4)------------------- of the positive control. Please provide more information on the positive control. Please note that test sensitivity should be established for container closure integrity studies to ensure minute leaks can be detected. Please submit the study report for the container closure integrity study.
 
4.      Please provide monitoring data for WFI and PW for May, June and July, 2011including bioburden results.
 
5.      During the inspection, we suggested that the revised shared equipment list and additional information related to segregation of Apligraf (Oral) with –b(4)-- be submitted to the BLA. If you have not submitted the information, please do so as soon as possible.
 
6.      Please provide the registeration information for you facility located at 85 Independence Drive in Taunton, Massachusetts 02780.
 
Form OCTGT:
 
7.      Regarding the human recombinant insulin used for product manufacture, please provide clarifications on the following issues:
 
a.       -----b(4)--------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
 
b.      Please provide a cross-reference authorization for the master file
 
8.      Please provide a cross-reference authorization for master file for the ----b(4)------ ----------------------------------------------------------
 
9.      Regarding the bovine pituitary extract manufactured by –b(4)-, please provide a brief summary of procedures that OI has in place to maintain assurance that the contract manufacturer is following the appropriate SOPs for this critical reagent.
 
10. Please provide a brief description regarding how reagent sterility is ensured for the           --b(4)-----------------------------------------------. Please verify that the source of ---b(4)---------------- is a licensed blood product supplier.
 
11. We note that since approval of the PMA in 1998, you have ---b(4)-------------- used for       --b(4)-------------------------------------------. Please provide clarification on the following issues:
 
a.       Please clarify the date at which this manufacturing change occurred and the status of any cell banks in storage that may have been manufactured prior to this change.
 
b.      Please provide the study report that compares the characteristics of the product before and after this manufacturing change.
 
12. During the inspection, we confirmed that the bovine collagen component is –b(4)--------------------------------------- to Apligraf manufacture. Please include your rationale for why the collagen is ---b(4)--------------------------. In addition, please provide a clarification regarding the procedures that are in place to reduce microbial contamination and the sterility assurance level (SAL) that is achieved. 
 
13. We note that collagen ----b(4)---------------- is not a part of the list of tests performed for bovine collagen. As it is a commonly utilized and sensitive test to assess collagen quality, please provide the rationale for why it is not tested as a part of qualification.
 
14. Please verify that the manufacturing process for Apligraf has not been changed since the most recent retrospective process validation report provided in the BLA (December 2007).
 
OCTGT – Additional questions provided to the applicant post-teleconference
 
15. We note that the lot size for Apligraf may vary –b(4)---. Please describe how the number of product samples tested for sterility and endotoxin change as a function of lot size.
 
16.  We note that there were several issues from the approval of the original PMA that may not have been updated and may be of relevance to the current BLA submission.
 
a.       During PMA review, it was determined that the keratinocyte portion of Apligraf    ---b(4)----------------------------------------------------------------------------. It is unclear whether any data collected regarding the type and extent of ----b(4)--------------------- for each keratinocyte donor. Please provide the data or a justification as to why data was not collected.
 
b.      The FDA approval order of 5/22/1998 had identified the need to further evaluate the karyology data for keratinocyte and fibroblast cells used in product manufacturing.  Specifically, it was pointed out that these evaluations should not only quantitate the extent of chromosomal changes but also look for specific markers known to predict neoplastic transformation of keratinocyte cells. Please provide a brief update of any efforts made to identify specific markers known to predict neoplastic transformation of keratinocyte cells.
______________________________________________________________________________
Teleconference ended at 3:45 PM.