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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Review Memo - Atryn

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

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1. Thawing and Pooling of Source Material 

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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.

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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.

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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.

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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:

  1. Section 1.4.1: An updated letter of authorization to cross-reference -------b(4)---------------------------, dated April 2, 2008.
  2. Section 3.2.P.3.5: Expanded process validations for manufacturing of ATryn.
  3. Section 3.2.A.1: Updated information on -----b(4)------- renovated facilities.
  4. 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.
  5. 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

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Qualification of ATryn-specific Manufacturing Components

 

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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:

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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

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12/16/2008 AMENDMENT

On December 2, 2008, I requested GTC to provide additional information for the following comments.

  1. 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.

  1. 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)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------), 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.

  1. 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.