
  


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)--------------------------------------------------------------------------------------t
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.
 

   
 