Mid-cycle Meeting Summary, June 11, 2013 - Alprolix

From: Thompson, Edward
Sent: Monday, July 01, 2013 2:11 PM
To: 'Nadine D. Cohen PhD (nadine.cohen@biogenidec.com)'
Cc: Debra Segal; Kirschbaum, Nancy (Nancy.Kirschbaum@fda.hhs.gov)
Subject: Information Request for BL 125444/0

Contacts: Nadine D. Cohen PhD

Dear Dr. Cohen:

We are reviewing your December 28, 2012 biologics license application (BLA) for Coagulation Factor IX (Recombinant), Fc Fusion Protein [rFIXFc]. We are providing the following comments and requests for additional information to continue our review.

Facility
1.Regarding depyrogenation: a.Please provide a description of all of the depyrogenation ovens that will be used for the vials, syringe barrel, and plunger.
b.Please provide the depyrogenation validation studies for the plunger for the diluent.

2.Regarding sterilization:
a.Please provide a description of each autoclave used for the drug product or diluent and each sterilization method. Please also describe what is sterilized in each autoclave.
b.Please clarify if the production sterilization loads are fixed/defined or flexible/undefined. If the loads are flexible, please explain the flexibility and restrictions of the load.
c.Please clarify if submitted sterilization validation studies were specifically for equipment and components used during rFIXFc manufacture. If not, please explain how the loads that were validated compare to the loads that will be used for rFIXFc.
3.Regarding lyophilization:
a.Please provide the study report for validation of the lyophilization process and a description of the lyophilizer(s). Please ensure the validation report includes all deviations and how each deviation was resolved.
b.Please clarify if a validation study was performed for each dosage strength and fill volume. If not, please justify why this is acceptable.
c.Please clarify if validation studies were performed using vials from each qualified vendor. If not, please justify why this is acceptable.

4.Regarding the --(b)(4)-- test for container closure integrity testing (CCIT): a.Please provide the validation report(s) for CCIT for the drug product and diluent.
b.You stated that the positive control was -(b)(4)-. Please provide your rationale for why this size was selected as the positive control and why it is appropriate.
c.You stated the acceptance criterion for this study as, “any visual incursion of -(b)(4)- into the test vials constitutes a failure.” Please clarify if you have qualified the operators to be able to detect small leaks approaching worst case and if the concentration of (b)(4) is sufficient to be detected by visual inspection.
d.Please clarify if you have shown the presence of (b)(4) with the (b)(4) positive control size in your study.
e.Please clarify if CCIT was performed on vials from –(b)(4)-- qualified vendors for the drug product and please specify which vial size(s) were tested.
f.Please clarify if any part of the container closure system that is product contact contains latex.

5.The submission states that -------------(b)(4)--------------- during drug product and diluent manufacture. Please clarify for which part of each process the ------(b)(4)------ is used.
6.Please provide the fill volume and vial sizes for all dosage strengths.
7.Please provide the fill volume and syringe size for the diluent.
8.Please clarify if the drug product and diluent manufacturing processes are performed in closed or open systems.
9.Regarding visual inspection: a.Please clarify if the inspection is manual, semi-automated, or automated.
b.Please describe the visual inspection procedure performed for the drug product and diluent. Information provided should include, but not be limited to, what defects are being evaluated, what are the acceptance criteria, and the criteria for accepting or rejecting a lot.

10.You state, “equivalent equipment may be used” for the manufacturing of the drug product and diluent (module 3.2.A.1). Please clarify what equivalent equipment will be used and if those pieces of equipment are validated specifically for manufacturing rFIXFc.
11.Please clarify the bioburden in-process specification for the ------(b)(4)------- ---------------------- process. Table 23 in module 2.3.S states an acceptance limit of (b)(4).
12.Please clarify if vials are ---(b)(4)----------------------------. If they are, please clarify if any ----(b)(4)----- studies have been performed.

Lot Release
13.Please provide 10 final container vials from one conformance lot for each of the following strengths: --(b)(4)---, 1000 IU/vial and 3000 IU/vial. Please also provide one vial of diluent with each vial of final container product. Please ship the materials to:

Catherine Poole
 Regulatory Coordinator
 Division of Biological Standards and Quality Control (DBSQC)
 OCBQ/CBER/FDA
 NLRC Bldg. B, Room 2411
 5516 Nicholson Lane
 Kensington, MD 20895
 Office: 301-594-6272
 Please clarify whether or not you intend to market the --(b)(4)-- dosage strength.

Pharmacovigilance
14.Please add to the list of important potential risks in your Pharmacovigilance Plan, the following items and planned actions: a.Immunogenicity including development of anti-FIX binding antibodies
b.Dosing errors due to the prolonged half-life since the dosing schedule is different from currently licensed FIX replacement products
c.Nephrotic syndrome following attempted immune tolerance induction
d.Potential impact on total IgG or subset levels as they relate to a patient's risk of infection

15.Please add the following items and planned actions to your Pharmacovigilance Plan: a.Use for immune tolerance induction
b.Use during pregnancy, labor and delivery, and lactation

16.Please report the occurrence of non-neutralizing, FIX binding antibodies as expedited (15 day) reports.

Chemistry, Manufacturing and Controls
17.Please add the following tests to the rFIXFc drug substance release specification: -(b)(4)-------------------------------------------------------------------------------------------------.
18.Please add a test for each excipient to the rFIXFc drug product release specification to confirm purported content. Neither --------(b)(4)------- is considered a suitable surrogate.
19.Please list in module 3.2.P.5.1, a provisional drug product release specification for ----- --(b)(4)----.
20.For ---(b)(4)---- analyses, please establish specified ranges for -------(b)(4)--------. For example, there is currently no specification to account for the ------------(b)(4)--------------------------------------------- and the specification for ---------(b)(4)---------- has been eliminated from --------------(b)(4)---------------.
21.Please lower the acceptance limit for activated FIXFc from ----(b)(4)-----. The acceptance limit should reflect clinical experience since this product related impurity is directly linked to thrombogenic adverse drug reactions. For example, the range presented for --------(b)(4)-------- batches was --------(b)(4)---------. and the range presented for 28 drug product lots was -----(b)(4)------ mol%.
22.Please lower the ---------(b)(4)-------- drug product release limits for endotoxin to reflect manufacturing capability. For example, data presented indicated levels --(b)(4)-- for ------(b)(4)----- conformance batches and -------(b)(4)------- for drug product conformance lots for all dosage strengths. Please establish the same acceptance limit for all drug product dosage strengths e.g., -----(b)(4)-------.
23.Please maintain shelf life specifications for ----------------------(b)(4)------------------------------------------------------- at the release limit of (b)(4), which is already significantly higher than results presented from lot release and long term stability monitoring e.g., ----(b)(4)--.
24.Regarding your proposed ----(b)(4)---- lot dependent control of ---------(b)(4)-----------------------------------: please submit quality document(s) that cover the activities and requirements for the determination of ---(b)(4)--- lot specific ------------(b)(4)------------------------------------, which may address, as applicable: (i) -(b)(4)- receipt testing, (ii) production controls, (iii) batch record documentation and (iv) in-process monitoring for --------------(b)(4)---------------.
25.Please commit to submitting to FDA, a prior approval supplement pursuant to 21 CFR 601.12(b) for an exception pursuant to 21 CFR 640.120(a) prior to release of any lot whose manufacture experienced an excursion to any critical control parameter (CCP), critical in-process control (CIPC), critical in-process test (CIPT) or in-process specification (IPS).
26.Please lower IPS for bioburden and endotoxin to reflect manufacturing capability, for example: (a) current bioburden IPS is --------(b)(4)--------; yet, process validation data yielded results, -(b)(4)- for all batches, for all phases of manufacture and (b) current endotoxin IPS is --(b)(4)--; yet, process validation data yielded results, -----(b)(4)------- for all batches, prior to -------------(b)(4)----------.
27.Please establish and provide the justification for maximum processing times for defined phases of manufacture.
28.Please shorten maximum process intermediate hold times that were based on small scale studies to times validated during conformance batch/lot manufacture.
29.Conformance batches were manufactured using ---------------------(b)(4)---------------------------------------------------------------------------------------. Please commit to post-marketing, prospective validation of remaining intended commercial manufacturing areas/equipment through conformance batch/lot manufacture.
30.Please commit to post-market completion of ongoing stability studies with: (a) drug substance batches, -------------------------------(b)(4)-------------------------------, (b) all drug product conformance lots and (c) diluent lots: -----------------(b)(4)-----------------. Please submit stability data in annual reports and notify FDA immediately upon occurrence of any out-of-specification result.
31.All drug product stability data were generated with product filled in -(b)(4)- vials. Please be advised that additional drug product stability monitoring data will be required to support the use of -(b)(4)- vials.
32.Please provide in-use stability monitoring data from (b)(4) IU/vial and 3000 IU/vial lots.
33.Please add the test for --(b)(4)--- to the stability monitoring program.
34.Please provide representative -------(b)(4)------ from the study validating polysorbate 20 determination in -----(b)(4)------.
35.Please provide complete validation of the Factor IX potency assay, to include testing of multiple commercial ------------(b)(4)------------- drug product lots.
36.Regarding the test for ------(b)(4)-----, please provide further detail on method development for generation of the detecting -------(b)(4)------. Specifically, please provide evidence that the -------(b)(4)------- is capable of detecting all ------(b)(4)-----.
37.Please provide validation of the --------------(b)(4)------------- test against the accepted, compendial ----(b)(4)---- test. Please provide further detail regarding the procedure for --(b)(4)-- the drug product lyophilized cake used in the method.
38.Please clarify whether or not the analytical procedure for protein determination in -(b)(4)------------------ drug product are the same.

Clinical/Statistical
39.Regarding the study report for 99HB102 submitted in module 5.3.5.2, Table 12, “Disposition All Enrolled,” pg. 107, states that in the study, 59 subjects completed Arm 1, 27 subjects completed Arm 2 and 26 subjects completed Arm 3. However, there are 26 observations listed for Arm 2 and 27 observations listed for Arm 3 in data file adef.xpt. Please clarify the discrepancy and provide an accurate flow diagram of subject disposition.
40.Please provide case report forms for all subjects who developed rFIXFc binding antibodies. For each subject, please provide the following information in tabular format: a.PK data
b.Number of bleeding episodes before vs. after antibody detection
c.Percent eosinophil content and change from baseline after antibody detection
d.Pre- vs. post-detection IgE levels
e.Anti-allergy medication (e.g., antihistamines, epinephrine, steroids) use pre- vs. post-antibody detection
f.Clinical findings/ other adverse drug reactions reported on the day of antibody detection, if applicable
g.Patient disposition e.g., withdrew from study or still receiving rFIXFc
h.Results from most recent antibody testing

41.Please provide the case report form for the subject who experienced obstructive uropathy.
42.Please provide case report forms for the two subjects who experienced rFIXFc overdose (700-001, 881-004).

The review of this submission is ongoing and issues may be added, expanded upon, or modified as we continue our review.

Please submit your response to this information request as an amendment to this file by August 12, 2013 referencing the date of this request. If you anticipate you will not be able to respond by this date, please contact the Agency immediately so a new response date can be identified.

If we determine that your response to this information request constitutes a major amendment, we will notify you in writing.

The action due date for this file is December 28, 2013.

If you have any questions, please contact me at (301) 827-9167.

Sincerely,

Edward Thompson
 Regulatory Project Manager
 FDA/CBER/OBRR/DBA/RPMB

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