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Review Memo - Atryn




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Memorandum

To: File, BLA, STN 125284/0, Antithrombin alfa GTC Biotherapies , Inc. (License 
# 1794) 

From: Chiang Syin, Ph.D., Chief, CBER/OCBQ/DMPQ/MRB II, HFM-676 

Subject: Review Memo 

Through: Laurie Norwood, M.S., Deputy Director, CBER/OCBQ/DMPQ 

Recommendation: Based on the information provided, I recommend approval of this 
BLA. 

Summary:

GTC Biotherapeutics, Inc. (GTC thereafter) has submitted a rolling BLA in early 
2008 with manufacturing information for ATryn® (antithrombin alfa) for 
Injection, which is a sterile, terminally heat-treated product that when 
reconstituted and diluted, as directed, is intended for intravenous infusion for 
the treatment of congenital antithrombin deficient patients. Antithrombin is a 
serine protease inhibitor that is the principal inhibitor of the blood 
coagulation serine proteases thrombin and Factor Xa, and to a lesser extent, 
factors IXa, XIa, XIIa, trypsin, plasmin, and kallikrein. It neutralizes the 
activity of thrombin as well as other serine proteases by forming a 1:1 
stoichiometric complex between enzyme and inhibitor. The active moiety in ATryn 
is antithrombin alfa, a recombinant DNA-derived product expressed in and 
purified from the milk of transgenic goats into which the human gene for 
antithrombin has been stably integrated. Antithrombin alfa is not derived from 
human blood, serum or plasma, nor is it formulated with such components.

GTC maintains the closed, USDA certified scrapie-free herd of goats, its 
transgenic operations and the research activities at a farm located across both 
---------b(4)--------------. GTC also performs QC microbiological testing in the 
laboratory at the farm, and other QC and final release testing at its 
headquarters in Framingham, MA. The major manufacturing operations are performed 
in two contract facilities: ----------------b(4)------------------------------ 
for bulk manufacturing and formulation, then the formulated bulks are shipped to 
-------b(4)--------------------------------------------, Netherlands) for 
aseptic fill, lyophilization and heat inactivation of final container product. 
Both facilities also perform in-process testing as specified in the Quality 
agreement with GTC. Bulk purified antithrombin alfa and subsequent lots of ATryn 
are manufactured on a campaign basis.

PRE-LICENSING INSPECTION ISSUE

In April 2008, GTC were inspected for its milk collection operation and QC 
testing lab, and --b(4)-----facility was inspected for the bulk purification 
process and testing. The 483 observations have been satisfactorily resolved by 
both GTC and --b(4)--. The corrective actions should be verified in the next 
inspection.

For ------b(4)---------------------------- facility, please see “Recommendation 
to Waive Pre-Licensing Inspection” memo dated January 15, 2009.

Review Summary

PART 1 ROLLING BLA

Drug Substance

For the production of antithrombin alfa, the goat was chosen as the animal of 
choice primarily, at that time, because goats are known to produce suitable 
volumes of milk and because of the relatively short gestation period but long 
lactation period. The transgene that GTC has developed consists of portions of 
the goat beta casein gene, as a promoter which directs expression of the human 
protein in the mammary gland, and human antithrombin cDNA. The human cDNA used 
in the transgene 
-----------------------------------------b(4)--------------------------------------------------------------.

Source material (milk) is collected daily from transgenic hAT female goats and 
is frozen until further processing. The upstream purification process consists 
of thawing, pooling and clarification of the milk and initial antithrombin alfa 
isolation. Thawed and pooled milk is diluted with an equal weight of EDTA 
buffer, and clarified by tangential flow filtration (TFF) with a nominal 500 
kD-pore size hollow fiber membrane filter. The soluble whey fraction permeate, 
containing the antithrombin alfa, is cycled through a closed loop linking the 
filtration system to a heparin column until more than 90% of the antithrombin 
alfa is captured (about b(4) to b(4) volume cycles). Antithrombin alfa is then 
eluted from the heparin column with a sodium chloride buffer and transferred to 
a downstream processing and formulation area.

Downstream processing includes filtration using a ----b(4)------------------ 
nanofilter as a viral removal step and subsequent purification by anion exchange 
chromatography and hydrophobic interaction chromatography (HIC). Specifically, 
the collected heparin eluate is passed through a viral removal filter, 
concentrated and diafiltered by membrane filtration and applied to the anion 
exchange column. The anion exchange eluate is applied to the HIC column and the 
purified antithrombin alfa eluted from the media. The HIC column eluate is 
concentrated and diafiltered into a citrate, glycine, sodium chloride buffer, 
the protein solution is adjusted to a final concentration of approximately 25 
mg/mL and passed through a 0.2 μm filter into a pre-sterilized 20 L stainless 
steel shipping container. Upon release, formulated drug substance is shipped to 
----b(4)---- for fill-finish.

The purification process nominally produces 300 grams of purified antithrombin 
alfa per batch from no more than 375 liters of source material containing 
approximately -b(4)-grams of antithrombin alfa.

[ b(4) ]

Manufacturer and Contractors

GTC Biotherapeutics, Inc. utilizes multiple facilities for the manufacture, 
storage, and testing of antithrombin alfa. The name, address, and responsibility 
of each manufacturer or contractor are provided below:

GTC Biotherapeutics, Inc. (Framingham, MA) is responsible for QC testing of 
animals, of source material, of composites and pools and of purification process 
in-process samples, of drug substance and identity testing of drug product upon 
receipt of commercial supplies from --b(4)------------.). GTC’s farm operation 
(-----b(4)--------------) handles Animal housing and care, source material 
collection, testing and storage, drug substance quality control testing 
(microbiology tests only).

----------b(4)------------------------------- is responsible for GMP 
purification and QC testing of drug Substance. 
-----------b(4)------------------------------- is used for storage of source 
material (milk). Other major contract testing labs include 
------------b(4)----------------------------- for mycoplasma testing, 
---------b(4)---------------------- for peptide mapping, and 
--------b(4)---------------------------- for viral testing.

CBER conducted in April 2008 the pre-licensing inspections of the milk 
collection, QC testing and bulk purification process for antithrombin alfa 
manufacture at both GTC (headquarters and farm) and ---b(4)----- facility.

Drug Substance manufacturing Process

-------------------------------------------------b(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

----------------------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

---------------------------------------------------b(4) 
-----------------------------------:

1. Thawing and Pooling of Source Material 

1 Page determined to be not releasable:

b(4)

-------------------------------------------b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

------------------b(4)-------------------------- 
--------------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

-----------b(4)------------------- 
----------------------------------------------b(4) .

Process Validation for Drug Substance

The purification process has been validated in a series of scaled-down and full 
scale process validation studies . These studies were designed to assess the 
capability of the process to eliminate process-related components/impurities, as 
well as to develop data to assure product safety in terms of removal of 
potential adventitious agents.

Process validation has been carried out at the proposed commercial manufacturing 
site using the manufacturing process. -b(4)-consecutive lots of antithrombin 
alfa were manufactured. As part of the process validation study, the-b(4)- lots 
of drug substance were manufactured into-b(4)- lots of drug product at the 
proposed commercial manufacturing site. T wo of the -b(4)- lots met product 
acceptance criteria but one failed due to an operator error during 
lyophilization which resulted in incomplete purge of oxygen with -b(4)- 
resulting in an elevated -----b(4)---------- (5.3%) and, consequently, increased 
oxidation of antithrombin alfa. Please refer to Table 1 for a schematic of the 
purification process as well as a description of the function of each 
purification process unit operation.

---------------b(4)----------------------- 
--------------------------------------------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------:

[ b(4) ]

6 Pages determined to be not releasable:

b(4)
  ----------b(4)---------------
  ---------------------b(4)--------------
  --------------------------------------------b(4)------------------------------------------------------------------------.

To ensure control of the purification process, in-process tests and acceptance 
criteria have been established to monitor each of the process solutions, process 
intermediates and ----b(4)------- conditions.

--------------b(4)----------------------

--------------------------------------------------b(4) 

-------------b(4)---------------------------------

------------------------------------------------b(4)----------------------------------------------------------------------------------------------------..

------b(4)-------------

-------------------------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

-----------------------------------b(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

------------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------:
  ----------b(4)---------------
  ---------b(4)----------------
  -----------b(4)--------------
  ----------------b(4)------------
  ----------b(4)--------------

-------------------------------------------------------------b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

1 Page determined to be not releasable:

b(4)

--------------------------b(4)---------------------------------------------------------------------------------------------------------.

-------------------------------------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

--------b(4)---------------

----------------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

GTC’s headquarters and farm has been inspected on April 10 to April 18, 2008 and 
a Form FDA 483 was issued with six observations. Please refer to the EIR for 
details. The 483 observations have been resolved and the inspection is 
classified as VAI with the corrective actions to be verified in the future.

----------------b(4)---------------------------

---------------------------b(4) .

----------------------------------------b(4) .

3 Pages determined to be not releasable:

b(4)

[ b(4) ]

---------------------------------b(4) .

------b(4)-----------------

--------------------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

Batch Analysis

A total of --b(4)--- lots of ATryn have been manufactured at the proposed 
commercial manufacturing site (----b(4)--------------------) using --b(4)------ 
lots of bulk purified and formulated antithrombin alfa having been stored at 
--b(4)-- for periods to --b(4)-- days prior initiation of fill. Based upon 
analytical tests, one of the lots was rejected due to an out-of-specification 
(OOS) result for ------b(4)----------- with a corresponding elevated and OOS 
result for ----b(4)-------- antithrombin. --b(4)--- of the lots were 
manufactured for use in clinical trials and b(4) lots have been manufactured as 
commercial product for sale in the European Union. In addition, --b(4)-- lots of 
ATryn were manufactured by ---b(4)------Corporation in support of certain 
nonclinical and clinical studies which are presented in this BLA. All --b(4)--- 
lots met both ---------b(4)--------------- and Sterility acceptance criteria.

8/20/2008 AMENDMENT

GTC initially submitted information on drug product manufacturing in Section 
3.2.P.3.5 of Part 1 of the rolling BLA with the majority of processing 
validation and facility/equipment information referring to the 
------------------b(4)-----------------------------------. We advised GTC that 
the information pertaining to ATryn manufacture should be submitted to the BLA 
directly, and the process validation should include more detailed information to 
support ATryn production, instead of relying on the generic information listed 
in --------b(4)------------. In addition, it was noted that - 
-----------b(4)----------------------- facility was shut down in 2007 for about 
a year for major renovation and ---b(4)----- planned to update their DMF in 
April 2008. After consulting with CBER, GTC and --b(4)------- agreed to provide 
their facility information, operational conditions and utilities and equipment 
descriptions, as well as facility and equipment specific validation data in 
Section 3.2.A.1 of the amendment to be submitted in August 2008 (see below). 
With regard to the manufacture of ATryn, GTC emphasizes that the 
-----------b(4)--------------- and - -----b(4)-------------------- were not 
changed pre- and post-facility renovation. The amendment for drug product 
manufacturing was received on 8/20/2008 to include expanded process validation 
section and renovated ---b(4)------ facility and equipment information.

This amendment to BLA STN 125284/0 contains the following sections:
  Section 1.4.1: An updated letter of authorization to cross-reference 
  -------b(4)---------------------------, dated April 2, 2008.
  Section 3.2.P.3.5: Expanded process validations for manufacturing of ATryn.
  Section 3.2.A.1: Updated information on -----b(4)------- renovated facilities.
  Section 3.2.R.1: An executed batch record for ATryn lot --b(4)--- that was 
  manufactured in ---b(4)----- renovated facility in May 2008.
  Section 3.2.P.3.1: Performance of two QC tests (i.e., 
  ---------b(4)-----------------) at an alternative testing site: The 
  ----------------------------------b(4)------------------------------------------------------------------------------------------------------..

Drug Product Process Validation/Evaluation

-----------------------------------------------b(4) .

------------------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

Qualification of ATryn-specific Manufacturing Components

7 Pages determined to be not releasable:

b(4)

--------------------------------------------b(4)--------------------------------------------------------------------
 .

------------------------------------------b(4) .

---------------------------------------b(4)- 
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

Process Validation 2008 

A post facility renovation process validation exercise has been undertaken in 
accordance with Protocol VN-700040-PQP which will revalidate the filtration and 
filling operations, lyophilization, capping, dry heat treatment and coding of 
the vials. One lot of product will be processed as a conformance lot. Critical 
parameters to be monitored include:
  -----------b(4)-------------------------
  ---------b(4)---------------------
  ------b(4)------------------
  -----------b(4)---------------------
  --------b(4)----------------------------
  ----------------b(4)----------------
  -------------------b(4)------------------

Provided in Section 3.2.R.1 is copy of an executed batch record for this process 
validation/qualification lot --b(4)--- which was manufactured on May 16, 2008. 
GTC states that at this time, QA reviewed data for this particular lot are not 
available but will be made available during the pre-approval inspection.

I reviewed the Section 3.2.R.1 which contains only one table summarizing the 
components of executed batch record for ATryn Lot --b(4)----. The actual data or 
results were submitted to CBER on 12/16/2008 for review (see Comment #2).

Media Fills and Schedule

The results of- b(4)- post facility renovation media fill studies are presented 
in Section 3.2.A.1.1.13 which will be discussed in more details in the later 
sections of this review memo, one of which (Media Fill No. -b(4)-) simulates the 
ATryn production process using the proposed commercial container closure system. 
Based upon the media fill results, GTC concludes that --b(4)----- operations are 
suitable for the production of aseptically manufactured parenteral drug and 
biological products.

Media fills are conducted ---b(4)----- as per --b(4)-------- procedures. 
Re-qualification of the environmental conditions and processes is achieved by 
generation of acceptable media fill results using a --------b(4)---------------, 
which covers the ATryn ----b(4)----- configuration and filling process. For any 
modification to the ATryn fill process, an assessment on the impact to the 
product quality is performed. Additionally, after major or critical process or 
equipment changes, a media fill validation is conducted to assure the absence of 
an impact on the quality of the product.

Facilities and Equipment

-------------------------------------------b(4)----------------- 
 .

-----------------b(4)-----------------------------------------

-----------------------------------------b(4)------------- 
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

--------------------------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

10 Pages determined to be not releasable:

b(4)

12/16/2008 AMENDMENT

On December 2, 2008, I requested GTC to provide additional information for the 
following comments.
  Please provide a summary of the batch production record for antithrombin alfa 
  drug substance lot -b(4) and a tabulation of the -b(4)--- data, which was 
  committed during our pre-licensing inspection by GTC to collect and submit to 
  CBER. 


As a part of previous discussion to establish in-process microbiological 
controls, such as -b(4)- and -b(4)---- limits, for the ATryn purification 
process, GTC provided results of in-process -b(4)- and -b(4)---------- tests 
performed on samples collected at specific points during the purification of lot 
---b(4)-----.

With the exception of low -b(4)-- collected from 
------------------------b(4)----------------------------------------------------------------------------------,-
the majority of the samples had no detectable --b(4)--. The level of 
-b(4)-------- in the bulk drug substance was within specification 
-b(4)----------------. The level of 
------------b(4)------------------------------ source material was reduced 
following clarification (TFF) and heparin affinity chromatography and further 
reduced by subsequent filtration/purification steps. The 
-------b(4)------------- level in bulk purified drug substance was --b(4)-----, 
well below the specification of --b(4)-----

GTC has agreed to continue to evaluate the --b(4)--- levels in future 
manufacturing campaigns together with implementation of real-time monitoring and 
trending of the data. Once sufficient data are collected, GTC will establish 
alert and action limits for --b(4)-- and --b(4)-------- levels at each of the 
steps.
  Please provide a summary and tabulation of data generated during the ATryn 
  process validation study performed at ----------b(4)-------------------------- 
  following the facility renovation. 


 GTC provided VN-700040-PQR-R entitled “Final report for the process 
revalidation for the ATryn (GTC) fill and finish process after 2007/2008 -b(4)- 
plant modifications”. This process revalidation report includes a summary and 
tabulation of data of the revalidation run, lot -b(4)-------, generated during 
the process validation study conducted at ------b(4)-------------------- 
following the facility renovation. GTC performed two process validation in 2003 
(-b(4)-- bulk lot) and 2006 (-b(4)- bulk lots for one drug product lot) for 
ATryn. However, we pointed out during our the pre-licensing inspection in April 
2008, GTC need to perform a revalidation study to demonstrate no process or 
product impact due to the major renovation in --b(4)---- Manufacturing Facility. 
We agreed to a single revalidation lot after GTC presented the argument that 
most of the major equipment has remained unchanged.

The test results of lot -b(4)-- performed by --b(4)------met the acceptance 
criteria for the In-process Bulk -b(4)-Filteration (identity and 
-----b(4)-------------------), In-process Transferred Bulk -b(4)-Filtration 
(-----b(4)-------------------------------------------), In-process Bulk -b(4)- 
Filtration (-b(4)- weight consistency), Lyophilized Product -b(4)-Heat Treatment 
(------b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------),i
and Finished Product Post Heat Treatment (final release specifications).

However, during the process validation study, certain samples were also tested 
at GTC for QA purpose. Results of tests performed at GTC for aggregates -b(4)- 
by --b(4)-- analysis were variable and yielded two results that were 
out-of-specification. GTC attributed the root cause for the exceptions to the 
aging of the --b(4)--. At the request of GTC, ----b(4)----------------- 
performed additional tests for aggregates by --b(4)------ (official QC test site 
for release of product) and found all results were within specification -b(4)-.

In addition, GTC provided the validation report, VN-800036-PQP-R1, for the 
homogeneity comparison study during the --b(4)------- of ATryn drug product 
after the 2007 renovation. Results of the study demonstrate that ATryn is 
homogeneous and the changes in facilities and equipment used to produce ATryn 
had no adverse impact on product homogeneity.

GTC also referred to the additional data presented in Section 3.2.A.1.1.15 of 
the 8/20/2008 amendment and more specifically to the data in Table 93 which 
present analytical data on b(4) lots of ATryn manufactured at 
--b(4)--------------------- before the facility renovation and b(4) lots of 
product manufactured after the facility renovation. GTC indicated that the data 
shown in Table 93 demonstrated the comparability of ATryn manufactured before 
and after the facility renovations.
  We noted in the submission that the final product lot --b(4)------ 
  manufactured by ----b(4)----------------- has not been released by GTC. As 
  this is the lot manufactured after facility renovation, we are concerned 
  whether there is any product comparability issue. In our discussion on 
  November 13, 2008, you have suggested that this is only limited to the testing 
  for the ---------b(4)--------------- step. Please provide a detailed 
  investigation report and any corrective actions implemented to address the 
  testing problem. 


As stated in their response to #2, GTC confirms that all lots of ATryn 
manufactured at ---b(4)------------------ after the facility renovation have met 
QC release specifications when tested at the QC testing laboratories stated in 
the BLA. The delay in release of product was directly linked to completion of 
the process validation study and all associated testing required per that study.

The reason for delay in completion of the process validation report was because 
GTC (not the official QC test site listed in the BLA for testing finished 
product) performed -b(4)-------- analyses on b(4)- vials of ATryn from lot 
--b(4)----. Due to issues with the --b(4)------ analyses performed at GTC, 
testing of two vials showed out-of-specification result for aggregates -b(4)- An 
investigation was initiated and a work plan was implemented. In the Attachment 5 
of the process validation report (VN-700040-PQP-R), a summary of data generated 
at GTC, investigation activities undertaken and a description of the Phase II 
investigation plan which was implemented. The Phase II investigation plan 
included --b(4)-- testing of -b(4)- vials at ---b(4)------------------------, 
the BLA listed finished product release testing site. Based on acceptable 
results, the Phase II investigation plan was expanded according to the process 
validation protocol to include -b(4)---- testing of an additional 20 vials at 
---------b(4)----------------------------. Results of the tests performed at 
------b(4)------------------ on the initial b(4) vials, as well as the 
additional 20 vials, were included in the process validation report. All -b(4)- 
vials met the acceptance criteria of -b(4)-.

The validation reports were reviewed and I found GTC’s explanation acceptable.

RESPONSE TO 1/14/2009 INFORMATION REQUEST

I requested additional information from -----b(4)------------------ for ATryn 
lyophilization load size on 1/14/2009.

Please provide the maximum and minimum load configurations for ATryn product in 
--b(4)-- Lyophilizer. If no validation report specifically addresses the max/min 
load, include the data from 2003 and on to show all the ATryn lots that have 
undergone lyophilization in the --b(4)----- lyophilizer, including total number 
of vials loaded into the lyo, how many trays, how many shelves, which shelves. 
Please indicate how many product vials could fit in a tray. It was stated that a 
maximum of b(4) trays could be loaded onto each shelf. Provide the SOP and form 
documenting specifically for ATryn, for the number of vials/trays/shelves used.

Based upon the process validation batches and the product release testing data 
(Table 1), the minimal number of acceptable filled ATryn vials successfully 
processed in the --b(4)-- Lyophilizer is -b(4)- (VSR-3185N “Final Report for the 
rhAT Fill and Finish Process Validation at --b(4)------------,” lot number 
--b(4)------). The maximum number of filled Atryn vials successfully processed 
in the -b(4)- lyophilizer is -b(4)---- (VN-700024-PQP “Final Report for the 
Process Validation for the ATryn Fill and Finish Process,” lot number 
--b(4)-----). Table 1 provides a summary of the total number of vials 
lyophilized, shelves used, shelf number used, and total number of trays used for 
each lot from each campaign. GTC/---b(4)--------- acknowledged that the 
--b(4)---- Lyophilizer is validated for loading up to -b(4)-shelves of ATryn (in 
-b(4)- vials) with a range of approximately --b(4)----- vials and if the 
lyophilization load exceeds this range, a new validation study will be performed 
to support new lyophilization load.

According to Work Instruction NI-WI-MAN-067 “Shelf inter-distance adjustment 
-b(4)----- ---b(4)----,” shelf numbering is defined with shelf number b(4) being 
the top shelf. Filling would start on the top shelf (number b(4)) with 
subsequent filling on tray -b(4)- as described in Work Instruction NI-WI-MAN-066 
“Loading and Unloading of the ----b(4)------------------.” A maximum of b(4) 
trays can be loaded on each shelf. The maximum number of b(4) vials that can fit 
in a tray is b(4). Lyophilizer loading (during manufacturing and during process 
validation) is performed starting with the top shelf (number -b(4)-) and covers 
up to b(4) shelves. 
-----b(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

GTC has updated the ATryn lyophilization batch records with the verification of 
lyophilizer shelf adjustment to b(4) shelves including a reference to work 
instruction SOP NI-WI-MAN-067. Critical process parameters are chamber pressure 
and shelf temperature at each respective control set point. GTC stated that the 
pressure control was validated through (VSR-2006N “Validation of 
----b(4)------------------” and is assured by regular pressure sensor 
calibration. The control of shelf temperature (within a shelf and between 
shelves) is validated through VSR-2166N "Temperature mapping of the shelf 
temperature of --b(4)---- lyophilizer."

I consider this response acceptable.

Conclusion:

I found the information submitted in the BLA and the appropriate amendments 
adequate to support its approval. In conjunction with the resolution of all 
pending inspectional issues, I recommend approval of this BLA.
 

 


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