Final Review Memo, CMC - Ruconest

Subject:     Final Review Memo (CMC): BLA 125495/0 (Rhucin)   
 Recombinant human C1 Esterase Inhibitor, rhC1INH (Rhucin) by Pharming Group, N.V. for the treatment of acute attacks of hereditary angioedema (HAE) in adult and adolescent patients with specific emphasis on the molecular validation and characterization of the transgene construct and transgenic founder and production colonies, as described in Section 3.2.S.2.

From:        Dominador J. Manalo, Ph.D.; HFM-343; LBVB, DH, OBRR, CBER; (301) 451-8359, FAX (301) 402-2780.    

Through:   Abdu Alayash, Ph.D.; HFM-343; LBVB, DH, OBRR, CBER; (301) 827-3813; FAX (301) 402-2780.

                  Basil Golding, MD; Director, DH, OBRR; Telephone: 301-496-4396
BLA Chairperson: Elena Karnaukhova
CMC Team:

Todd Mollan (Characterization and Method Validations)
 Wayne Hicks (CMC/Clinical - Viral Clearance Method Validation)                                                                     
To:             Nannette Cagungun, RPM; HFM-370; RPMB, DBA, OBRR,  CBER; (301) 827-6161,. FAX: 301-827-2857.

Recommended Action:  This BLA is recommended for approval

Summary
 Submission received: 23-Sept-2013 (electronic)
 Sponsor: Pharming Group, N.V.
 Submission Type: CBE Supplement, pursuant to 21 CFR, Part 314 601.12
 Product: rC1INH (Rhucin), aka hrC1INH
Manufacturing facilities:

Breeding/Milk Collection:
 -------(b)(4)-----------
 ----(b)(4)--------
 ------(b)(4)--------
 ----(b)(4)-----:
 --------------(b)(4)------------------             --------------(b)(4)------------------             
 --------------(b)(4)------------------             -----------------(b)(4)--------------------            

Drug Product:                                                 Drug Substance:
 -----(b)(4)-----                                                  ----(b)(4)--------
 -------(b)(4)-----------                                      ----(b)(4)--------
 ----(b)(4)--------                                               ------(b)(4)----------

I. BLA Background (CMC)

Pharming Group, N.V. (Pharming) submits BLA 125495/0 for a recombinant human C1 Esterase Inhibitor (hC1INH) under the trademark name, RhucinTM, which is produced in transgenic rabbits to treat acute attacks of hereditary angioedema (HAE) in adult and adolescent patients.  Human hC1INH is a glycosylated plasma serine protease inhibitor in the serpin superfamily. At 478 amino acids long, the secreted form of hC1INH possesses --------------------------(b)(4)--------------------------------------.

This review memo will mostly address CMC issues with specific emphasis on the molecular validation and characterization of the transgene construct in the rabbit transgenic founder and production lines prior to formulation of the Drug Substance (DS) for hC1INH, as described in Section 3.2.S.2 in the BLA package. This review will include, but may not be limited to an assessment of the method validation studies that were employed to characterize the fidelity of transgene in the host rabbit colonies, characterization of ----------------------------------(b)(4)--------------------------------- , as well as assessment for host-related impurities in the milk ----------------------------------(b)(4)------------------------.

II. CMC Review 
A.----------------(b)(4)-----------------

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(b)(4)

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Redact 6 pages (b)(4)

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B.CMC Issues raised during pre BLA meeting with Pharming (CRMTS #7281)

In a pre BLA Meeting with sponsor in Dec 2009, FDA raised the following CMC concerns and issues. The following response is added to this review to detail scope the issue with respect to the production colony. The response satisfied CMC product review concerns and are acceptable.
FDA Pre-BLA Meeting Information Request, Question 14: 

Please clarify (a) how many animals are currently utilized in the rC1INH production, (b) how duration of lactation and number of lactations of production rabbits may affect the level of expression and structural properties of rC1INH, and (c) how the animals are/will be disposed.
Pharming Response to Question 14a

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

          -----------------------------(b)(4)--------------------------------
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Redact 8 pages (b)(4)

V. CMC Supplemental and Reference Review Material: 

            A. DS Specification for rhC1INH 

Table 2 lists the DS Specification for rhC1INH, which is included below as a reference aid in this component of the CMC review with respect to detection for ----------------------------(b)(4)------------------------------------------------------------. The Drug Substance is recombinant human C1 inhibitor (rhC1INH) highly purified from the milk of transgenic rabbits and is formulated with ----------------------(b)(4)----------------------------------. 

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

(b)(4)

B. FDA and Pharming pre-IND/pre-BLA Meetings: 
 Pharming Group requested a CMC pre-BLA meeting on September 30, 2009 which CBER scheduled for December 3, 2009.  CBER received the briefing material on November 2, 2009.  CBER faxed written responses to the questions posed in the briefing material on November 24, 2009. 

Soon after receipt of the fax, Pharming informed CBER that they would still like to meet with the Agency to obtain clarification on some of the Agencys responses.

Meeting Discussions:  

The following IND and pre BLA communications between FDA and Pharming are added below for this review to address whether earlier CMC issues were adequately addressed in the BLA.

1.   Compliance with cGMP in the Rhucin manufacturing process begins with                ----------(b)(4)------------. Does FDA agree with this approach?

FDA Response:

No, we do not agree.  -------------------------------------------------------------------------------------
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Discussion:
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FDA stated these measures are acceptable and recommended that the sponsor describe traceability in the BLA. 

2.   Does the FDA agree that the proposed release specifications for skimmed milk, drug substance and drug product, that will be provided in the briefing package, are appropriate?

FDA Response:
 Based on the information provided in the briefing package, the proposed release specifications appear to be acceptable. However, the adequacy of the proposed specifications will be further evaluated by FDA during the review of the BLA.  FDA has the following recommendations and questions on your proposed specifications:

a.   With regards to the proposed -------------------------(b)(4)---------------------------- (page 69 of 255):  the acceptance criteria for (a) ----------------------------(b)(4)-------------------------------------- have to be established before the licensure of your product.
 b.   In addition to the measurement of -----------(b)(4)------------, please add ----------------------------(b)(4)--------------------------------.

3.   Please clarify if the Drug Substance will be subject to a --------------------------------------------------(b)(4)----------------------------------------------------.

      CMC Comment: Pharming adequately addressed issue in BLA.

4.   Please justify the release specification for bioburden ---------------------------------------------------------------------------------(b)(4)-----------------------------------------------------------------------------.

      CMC Comment: Pharming adequately addressed issue BLA.

5.   Please explain why you do not perform endotoxin testing on the -----(b)(4)-------.

6.   Please justify the bioburden specification of ---------------------------------------------------------------(b)(4)------------------------------------------------------ when the final specification for the -----------------------------------------------------------(b)(4)----------------------------------------------------------------.

7.   Please clarify the endotoxin specifications for the -------------------(b)(4)------------------ the final Drug Product.  The specification of endotoxin -----------------(b)(4)---------------------------------- for Drug Product in Table 88 is ----(b)(4)---- whereas the specification of endotoxin -----------------(b)(4)----------------- for Drug Product in Table 96 is ---(b)(4)---.

8.   Please indicate if you perform (b)(4) Drug Product sterility testing -----(b)(4)-----.

Meeting Discussion:
 Pharming indicated they will address 2.1 and 2.2 in the BLA.   New specifications and justifications will be included in the BLA (2.4). FDA said it would like to see historical data but in this situation, the specifications would suffice.

With regard to 2.5, Pharming stated that endotoxin in ----(b)(4)---- is not feasible according to experts.  They will provide an explanation in the BLA and do their best to address FDA concerns.

CMC Comment: CMC issue was adequately addressed in BLA. In the BLA, Pharming had performed validation studies

Regarding 2.6., Pharming said they will lower the bioburden specifications of the     --------------------------------------(b)(4)-----------------------------------------------.

Pharming is using (b)(4) endotoxin specification for --------------------------(b)(4)--------------------- the final Drug Product. 

CMC Comment: CMC issue was adequately addressed in BLA. In the BLA, Pharming lowered the endotoxin level to (b)(4) CMC issue has been adequately addressed.

For item 2.8, Pharming indicated that they perform (b)(4) Drug Product sterility testing ----(b)(4)----. They follow the ----(b)(4)---- as well as 21 CFR 610 .  The results of the sterility testing will be submitted to the IND

(DMPQ) FDA stated that no sterility testing is necessary if procedures are in place for bioburden control.  FDA asked if the sponsor had a -------(b)(4)-------.  If they did, FDA asked the sponsor to look into the possibility of applying for an alternate method of --(b)(4)--.  FDA pointed out that the bioburden test must be done ----------(b)(4)-----.

FDA asked the sponsor if they keep a ----------------------(b)(4)--------------- and if it is not a continuous process?  FDA said the sponsor should validate the time the------------------------------------------------------------(b)(4)--------------------------------------------------------; however, sterile testing must be done on the final container.

3.   In addition to data from supportive stability studies, the BLA will contain pivotal stability data collected on ------------------(b)(4)----------------- lots of DP up to 36 months (of which one lot has data through 24 months) to support the requested shelf life for each.  A summary of these stability studies and an outline of the updated stability protocols to be used for new stability programs are included in the briefing package.  Does the FDA consider the stability data, and the updated stability protocols, to be acceptable?

FDA Response:
 Based on the information provided, the stability data and protocols appear to be         acceptable.  However, FDA will fully assess your stability program when more data will become available in the BLA package. 

Discussion:
 Pharming stated that they will address the stability studies in the BLA.

CMC Comment: CMC issue was adequately addressed in BLA that included stability studies for the ---------------------(b)(4)-------------------------/DP.

4.   Based on the analytical testing strategy and summary of results in the pre-BLA package, does the FDA agree that the experimental design for assessing the analytical comparability between pilot and full-scale batches of ----------------(b)(4)----- drug product is adequate?

FDA Response:
 Based on the information provided in your briefing package, the experimental design for assessing the analytical comparability between pilot and full-scale batches appears to be acceptable.

We have the following questions/comments:

a.   Will the (b)(4) validation batches at full-scale be used for BLA filing? Do you anticipate any additional change in manufacturing processes?
 b.   Different terms such as sterility, bioburden, ---(b)(4)---, sterility assay, and microbial limit test are used throughout the text to describe the sterility and bioburden. These terms should be used consistently.

Discussion:
 Pharming indicated they will use (b)(4) validation batches for the BLA.  In addition, all terms will be clearly defined in the BLA.

CMC Comment: Pharming has adequately addressed this issue in the BLA, as detailed in this CMC review.

5.   Does the FDA agree that the ----------------------------------------------------(b)(4)------------------------------------------------, has been adequately demonstrated based on the data provided in the pre-BLA package?

Pharming Response:
 Our response to this question refers to the comments provided by the FDA at the pre-IND meeting hold with Pharming representatives on February 5, 2004 (i.e., other comments provided by the FDA), namely:  -------------------------------------------------(b)(4)--------------------------------.  Evaluations of other quality attributes of the product need to be provided to establish the capability of Pharming to consistently produce a product of acceptable quality.  Assays should include but not be limited to those for activity, purity, potency -----------------------------------------------------------(b)(4)------------------------------------------------------------------------------ analysis, are informative in assessing the correct processing of the final product, including -----(b)(4)-----.

We acknowledge that, in general, Pharming has fulfilled those recommendations.    ---------------------------------------------------------------------------------------------------------------------------
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Discussion:
 Pharming stated they will include the following ------------------------------(b)(4)-------------------------------:  
           -----------(b)(4)-----------
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           ---------------(b)(4)-------------------
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6.   Does the FDA agree that the characterization of host-related impurities in drug product as measured by the ---(b)(4)--- provides reassurance that the HRI-level is consistently controlled during manufacturing?

FDA Response:
 Based on the information provided in your briefing package, the host-related impurities (HRI) -level appears to be adequately controlled during manufacturing. However, the FDA will further evaluate the clearance of all potential HRI by the purification steps and suitability of the ---(b)(4)--- method when BLA becomes available.

Discussion:
 Pharming will address host-related impurities in the BLA.

CMC Comment: CMC issue was adequately addressed in BLA as detailed in its (b)(4) Assay.

7.   As all animal husbandry related activities as well as all manufacturing activities take place in -------(b)(4)--------, does FDA agree that Pharming does not need to submit either an INAD or a NADA in support of the BLA for Rhucin?

FDA Response:
 It is CVMs belief that Pharming needs to submit an INAD/NADA in support of FDA approval for Rhucin.  However, CVM is seeking further guidance from the FDA Office of Chief Counsel.

Discussion:
 FDA said the two regulatory applications are independent of each other and advised the sponsor to start a dialogue with CVM.  CVM indicated that the Chief Counsels response will be conveyed to the sponsor. 

8.   The CMC establishment description information for manufacture of Recombinant human C1 esterase inhibitor (Rhucin) to include identification of place of manufacture, floor diagrams, and cross-contamination precautions will be filed in the BLA consistent with CBER/CDER, August 1996 Guidance for Industry for the Submission of Chemistry, Manufacture and Control Information for a Therapeutic Recombinant DNA-Derived Product for In-Vivo Use.

Consistent with FDA CMC guidance for Recombinant DNA Derived products, water system validation summaries/routine monitoring program description, lyophilization equipment summary reports and relevant computer system validation summary reports will not be included in the BLA but will be available on site for review during the prior approval inspection (PAI).

Does the Agency concur with content and format of facilities information Pharming proposes to submit in the application?

FDA Response:
 We agree that you may submit information as consistent with the aforementioned guidance.  Please note that lyophilization validation description and results should be included in the process validation section of the BLA.  We also recommend that you consider the guidance, Guidance for Industry M4Q: CTD  Quality, August 2001, for the type of information to submit in a CTD.  In particular, please consider the information to be submitted for Appendix A, 3.2.A.1, Facilities and Equipment.  Please see an excerpt of this guidance below:

A diagram should be provided illustrating the manufacturing flow, including movement of raw materials, personnel, waste, and intermediates in and out of the manufacturing areas.  Information should be presented with respect to adjacent areas or rooms that may be of concern for maintaining integrity of the product. Information on all developmental or approved products manufactured or manipulated in the same areas as the applicant's product should be included.

A summary description of product-contact equipment and its use (dedicated or multi-use) should be provided. Information on preparation, cleaning, sterilization, and storage of specified equipment and materials should be included, as appropriate.

Information should be included on procedures (e.g., cleaning and production scheduling) and design features of the facility (e.g., area classifications) to prevent contamination or cross-contamination of areas and equipment where operations for the preparation of cell banks and product manufacturing are performed.

Discussion:
 Pharming stated that all relevant facilities information will be addressed in the BLA.

9.   Recombinant human C1 esterase inhibitor is a human protein and is similar to its natural counterpart which is present in human blood.  Based on this similarity, any potential risks for the environment are not anticipated and therefore an environmental risk assessment is not warranted.  As such a statement of exemption under categorical exclusion per 21 CFR Part 25.31(c) will be provided for recombinant human C1 esterase inhibitor as a substance that naturally occurs in the environment. Does the Agency concur?

FDA Response:
 If an INAD/NADA is required, then Pharming will need to submit an Environmental Assessment (EA) to that application and a categorical exclusion may be able to be submitted to the BLA.  The final decision for the acceptability of categorical exclusion will be based in part on CVMs review of the EA.

Discussion:
 Pharming said they understood that the environmental assessment depends upon the INAD/NADA.

(Roman Drews)  CBER said it did not see a problem with regard to the drug product.  FDA advised the sponsor to request a categorical exclusion in the BLA and deal with it separately from the environmental exclusion.  CBER will work with CVM.

10. Does the FDA agree that the overall viral safety program, which includes                 -----------------------------------(b)(4)----------------------------------- viral clearance study data, is acceptable?

FDA Response:
 Your viral safety program appears acceptable. However, please note that our final evaluation of your program will be based on a complete viral validation data that are expected in the BLA. With regard to other pathogen safety, please describe how Pharming intends to demonstrate that the production colony is free of ----------------------------------------------------(b)(4)----------------------------------.

Discussion:
 Pharming stated that they will perform ----------------------------------------------------------------------------------------------------------
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FDA said it is important to -------------------------------(b)(4)----------------------------------.  FDA advised the sponsor to do -----------(b)(4)--------------. 

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B. Additional FDA Questions and comments:

1.   In your BLA, please submit the following data:
The outline and full description of transgene cloning strategy;
The complete nucleic acid sequence of the rhC1INH transgene construct that includes ATG start codon, stop codon(s), poly-adenylation sequence, intron/exon boundaries and restriction enzyme sites.

c.   --------------------------------------------(b)(4)--------------------------------------------------------.
 d.   --------------------------------------------(b)(4)-----------------------------------------------------.
 e.   Sponsor should include an assessment that determines integrity of the RNA transcript for rhC1INH transgene, as an additional criterion for the inclusion of transgenic does to the production colony.

CMC Comment: CMC issues were adequately addressed in the BLA.

2.   Please provide qualification studies for your -------------------------------------------------(b)(4)---------------------------------------;

3.   Please clarify (a) how many animals are currently utilized in the rhC1INH production colony, (b) what is the protocol for disposal of an animal in the production colony that does not meet rhC1INH production standards or qualifications and (c) what is a protocol for the disposal of an animal that gets sick?

4.   Will the milk from each rabbit be collected in --------------------------(b)(4)------------- or will the milk from multiple rabbits -------------(b)(4)---------------?

5.   Will ---(b)(4)--- level be tested on the milk collected?

CMC Comment: ---(b)(4)--- parameters were adequately addressed in the BLA

6.   Please consider the possible effect of --(b)(4)-- on the container integrity of the  ----(b)(4)-----.

CMC Comment: Stability hold times and parameters of ---------------------(b)(4)------------------ were reviewed in this review and adequately addressed in the BLA.

7.   You state on page 94 that the initial ----------------(b)(4)----------------- was developed to produce sterile, pyrogen-free rhC1INH. However, the specification of bioburden for Drug Product is at ----(b)(4)---- which is not considered sterile.

CMC Comment: Endotoxin level parameters for ---------(b)(4)--------- final DP were considered acceptable by Pharming to be -----(b)(4)------. Specification was determined to be acceptable by FDA for this product and issue has been adequately addressed, as based on the sponsors consistencies in the processing and manufacture of DP for this BLA.

8.   Please be aware that there is a possibility of multiple inspections associated with this BLA and if Pharming is using testing laboratories for drug product release testing that do not have an inspectional history with the Agency, there may be an impact on the review timeline for the action date of the submission.

CMC Comment: All CMC issues were adequately addressed in BLA.

Meeting Discussion:
 Pharming indicated that the information for 1a, b, c , 2, 3, 4, 5 and 6 will be provided in the BLA. 

With regard to 1d, Pharming stated that that ---------------------------(b)(4)---------------------------.

FDA asked why Pharming detected ----------------------------------(b)(4)---------------------------------------------------.  Pharming said they could not explain why there are  -----------(b)(4)-----------.

Pharming indicated that ----------------------------------------------------------------------------
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Pharming stated that they had not determined the ---------------------------------------------------------------
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--------------(b)(4)--------------------------------------------------.  Pharming further noted that they are continuing to investigate the basis for its formation. 

To help address a potential ---------------------------------------------------------------------------------------------------------------
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CMC Comment: In a later meeting, Pharming noted that a criteria and method to      ----------------------------------------------(b)(4)--------------------------------------.  From a CMC standpoint, this justification is acceptable given the --------------------------------------------------------------------------------------------------------------------------
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For 7, specification of bioburden for Drug Product will be corrected in the BLA.

CMC Comment: CMC issue on bioburden was adequately addressed in the BLA.

FDA clarified that the sponsor may use a contract laboratory; however, the contract lab might not get inspected which could impact approval of the BLA.

Pharming indicated the facilities are -------------------(b)(4)---------------------. 

FDA advised Pharming to provide a short summary regarding their interaction with European and Dutch authorities in relation to the environmental impact associated with rabbits.

Pharming stated that the Netherlands issue licenses to keep genetically-modified organisms; and inspects facilities on a regular basis to look at animals and wastes.  Pharming will provide the information in the BLA.  The sponsor also informed FAD that the EMEA and the veterinary department inspected their facility about 3 years ago.

FDA asked if ----------------------------------------------------------------------------------------------
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Pharming then described the sanitation procedures at the animal facility.  They provide --------------------------------------------------------------------------------------------------------------------------
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Pharming asked FDA to clarify what is meant by a ----(b)(4)----. 

FDA asked the sponsor to address consistency between the --------------------(b)(4)---------------------------. 

Pharming said they use ------------------------------------------------------------------------------------------------------------------
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FDA-Pharming IR Responses (CMC-relevant Clinical; 17-Dec-2008): 

FDA IR (Clinical): 
 For the meeting, FDA asked sponsor to provide greater details of rabbit HRI (b)(4) Assay. The following response is an excerpt in their written response to FDA.

Pharming IR Response: (b)(4)-HRI (b)(4) Assay Description: 

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------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------- The method has been validated.

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(b)(4)

CMC Comment:  Details from the sponsors response on the (b)(4) assay are acceptable and adequately addressed in the BLA.

- (b)(4)-HRI assay validation:
 The following validation parameters have been evaluated: specificity and precision. ----------------------------------------------------------------------------------------------------------------------
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CMC Comment:  The sponsors response concerning validation of the HRI-(b)(4) assay are acceptable and were adequately addressed in the BLA.

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CMC Comment:  The sponsors ------------(b)(4)------------ assay to ------------------------------------------------(b)(4)-------------------------- assay are acceptable and were adequately addressed in the BLA.

VI. Final CMC Review Summary

In this BLA submission, Pharming Group (N.V.) seeks approval for its recombinant human C1 Esterase Inhibitor, rhC1INH (RhucinTM), which is purified from the milk of transgenic rabbits and indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults and adolescent patient.  My final review memo is part of the CMC Review Team for the BLA --(b)(4)-- submission, who includes Todd Mollan and Wayne Hicks at OBRR/DH.  This CMC review has primarily focused on the molecular validation and characterization of the transgene construct and the transgenic founder lines and production colonies, as described in Section 3.2.S.2.

No information requests were requested following review of this BLA, as all were adequately addressed in the previous sponsor meetings and in the BLA. The information and data provided by Pharming from its studies have demonstrated that all CMC issues for this specific review assessment were adequately addressed both in the BLA from FDAs earlier communications and meetings with the sponsor.

In the BLA, the sponsor has adequately characterized the transgenic founder and colony production line to produce rhC1INH, including its validation of the manufacturing processes, process parameters, acceptance criteria and product specification of drug substance and drug product from the milk of transgenic rabbits. 

From this CMC standpoint, BLA ---(b)(4)--- is recommended for approval.
