Information Request, December 13, 2013 - Ruconest

DEPARTMENT OF HEALTH & HUMAN SERVICES                                                               
 Public Health Service

Food and Drug Administration
 1401 Rockville Pike
 Rockville, MD 20852-1448


 

Our Reference:  BL 125495/0

Pharming Group N.V.
 Attention:  Mr. Matthew Moran
 December 13, 2013
 Sent by email:

Dear Mr. Moran:

We are reviewing your April 15, 2013 biologics license application for C1 Esterase Inhibitor (Recombinant).  We determined that the following information is necessary to continue our review: 

CMC

Skimmed Milk
1.In your justification for not testing for ---(b)(4)--- for release of skimmed milk you state that  ---(b)(4)--- content is not a relevant parameter for release of skimmed milk batches since the milk batches tested contained ---(b)(4)--- levels at or below the assay detection limit of ---(b)(4)---.  This rationale is not completely acceptable since ---(b)(4)--- contamination could occur from the environment and product contact materials.  Please comment.

Drug Substance

Manufacture
2.You state you do not perform ----(b)(4)---- steps during the manufacture of the drug substance; however, you state that a --------(b)(4)------------  step may be performed.  The FDA considers ---(b)(4)--- to be a ---(b)(4)--- step.
3.-------------------------------------------------------------------------------------------------------------------------------------------
-------------------------------------------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------
-----------------------------------(b)(4)---------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------.

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

Facility
5.Based on the description of the drug substance manufacturing facility, ---(b)(4)---, it is a multi-product facility.  Please provide the following information: 
a.A summary of the procedure followed when new products are introduced into workshops ---(b)(4)--. 
b.Indicate if any products have been made in those workshops before or after rhC1INH was manufactured.

Drug Product

Sterile Filtration and In-process Controls

6.At the time of the Type B Pre-BLA meeting, regulations required that the sterile bulk be tested for sterility per 21 CFR 610.12.  At this date, the regulations have changed and it is no longer a requirement.  It is not necessary to change your manufacturing process, we are only informing you of the change.


Facility
8.Based on the description of the filling facility, ---(b)(4)----, it is a multi-product facility.  Please provide the following information:
a.Additional information about the other types of products that can be filled in the filling rooms on the (b)(4) floor where rhN1INH in filled. 
b.Please indicate how cross-contamination is mitigated such as through cleaning validation, single use materials, area/line clearance, etc.

Process Description / Process Validation
8.In your description of the lyophilization process, you state that the vials are closed in the presence of ---(b)(4)-----.  Please provide the reason for the use of ---------(b)(4)---------- instead of ---(b)(4)----.
9.Please include a more detailed description of the filling process such as is it automated, how many vials are filled, what speed, etc.
10.There was no information in the application for the visual inspection process.  It appears the visual inspection may be an ---(b)(4)--- process.  Please provide a summary of that process and include any applicable acceptance criteria such as types of defects and classification of defects that are inspected, acceptance criteria for the primary visual inspection and the AQL inspection.
11.Please provide a summary of the process validation for the ---(b)(4)--- filling equipment and the -------(b)(4)--------  machine. 

Equipment
12.The translated batch production record (BPR) for the manufacture of the drug product includes a -------------(b)(4)-------------  equipment in the equipment list.  This ---------------------(b)(4)------  machine is never mentioned in the application.  Please comment.
13.There is no information in the application on the pieces of equipment listed below.  Please provide a description of each piece of equipment along with summaries of qualifications performed.  This equipment is important and they are considered part of the aseptic fill and lyophilization processes. a.-----------------(b)(4)-------------------
b.-----------------------------------------------------------------------------------------(b)(4)-----------------------------
c.-----------------(b)(4)-------------------
d.----------(b)(4)--------
e.------(b)(4)------
f.-----------------(b)(4)-------------------


-----(b)(4)------ Process Validation
14.The description of the process validation for the -------(b)(4)-------  is insufficient.  Please provide the following: a.----------------------------------------------(b)(4)---------------------------------------
b.----------------------------------------------------------------(b)(4)--------------------------------------------------------
c.----------------------------------------------------------------(b)(4)--------------------------------------------------------


Lyophilization Process Validation
15.In Appendix 1: VAL-R-03-096 (NL0064250) Drug Product produced using (b)(4) Drug Substance batch and Appendix 2: VAL-R-03-097 (NL0065161) you changed the ------------------------------------------------------------------(b)(4)-----------------------------------------------------------------------.  You stated this was acceptable because the ----------------------------------(b)(4)----------------------------.  Please provide additional information to support this statement, including additional data from lots manufactured after the validation lots.

Media Simulation
16.There is insufficient information provided in the application to determine the acceptability of the media simulations.  Please provide the following:
a.A summary of the filling process reproduced in the media simulation.  Include a description of the entire process starting when the drug substance is sterile filtered all the way through vial inspection and -----(b)(4)------.
b.While it is never explicitly stated in the submission, we are assuming the filling process is an -----(b)(4)---- process.  Please include processing parameters such as -----------(b)(4)-------------.
c.Acceptance criteria for vial ---(b)(4)--- and number of vials allowed to be contaminated, if any.
d.Please confirm environmental monitoring and personnel monitoring occur during the media simulation, especially during setup of the equipment and after each intervention.
e.A description of the number and types of interventions performed during the simulation.
f.Please confirm a batch record is used during the media simulation.
g.Please indicate the number of vials filled and confirm this is representative of an rhC1INH fill.
h.Please indicate if growth promotion testing was performed on the media in the vials after they were filled ----(b)(4)----.
i.Please provide the -----------------------(b)(4)----------------------------------- required for the vials during a media simulation.
j.Please provide a description of the freeze drying performed during the media simulation.
k.------------------------------------------------------------(b)(4)-----------------------------------------------------------.  Please confirm this step is also performed during the media simulation.
l.Please summarize the qualification of the -----------------(b)(4)------------------------.
m.-----------------------------------------------------------------(b)(4)-------------------------------------------.  Please confirm that all sampling is reproduced during the media simulation.

Drug Product Batches
17.None of the information submitted for the drug product manufacture or process validation used the drug substance manufactured at -----(b)(4)------, which used the revised manufacturing process and a new manufacturing scale.  Please provide the rationale for not performing any validation studies or at least confirmation studies using drug substance manufactured at -----(b)(4)----.  In addition, please provide the translated batch production record for the drug product manufactured from -----(b)(4)------ drug substance batch               ----(b)(4)----.

Labeling and Packaging Facility
18.Please provide a list of the equipment used in labeling and packaging of the vials and a summary of their qualifications.

Comments (No response expected)
 We have the following comments about the drug product batch production records (BPRs).  These comments are not all inclusive.  The BPRs are not sufficiently detailed to allow for consistent manufacturing.  For example:
a.It is unclear if the filling process is automated or manual since there is not a description of the setup of the equipment.
b.Step NM03 states to “Inspect all vials according to the valid inspection criteria.”  No valid inspection criteria are listed and there is no place in the BPR to record the number of vials rejected and the reason they were rejected. 
c.It is unclear if the visual inspection is an automated or manual process since the BPR does not capture the setup of any equipment.
d.In step NM04, the operator is instructed to “Determine the required number of AQL samples and collect these from the batch in a -----(b)(4)-------.”  There is no instruction on how to make that determination.
e.Step NM05 stated to “Perform an AQL check” and record the “-------------(b)(4)-------------.”  There is no indication of the types of defects being inspected for during the inspection.  There is also no place to record what the defects were and how many vials of the different types of defects were observed.
f.Numerous times within the BPR the operator is instructed to “Print the batch data from the previous step using ---(b)(4)-- and check the data.  Insert as an appendix.”  There is no indication what the operator is checking the data for and what is considered acceptable data.  No appendices were included in the executed BPR so I am unable to determine if there were any issues encountered during the run.
g.Step VWF09 states to “---------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------.”  There are no instructions on how to perform this step.  If the operator is required to use an SOP for the filling set-up, no SOP is referenced.  This does not ensure consistent set-up of the filling apparatus.

19. Regarding the proposed method for Water Content by --------(b)(4)--------.  In the response made on October 15, 2013 to CBER’s information request of September 17, 2013, you had indicated that a Validation Report for this procedure would be submitted by November 22, 2013.  Please submit this document for review.

Clinical

20. In the October 25, 2013, submission you state in your response:

4. RESPONSE TO FDA ISSUE #4
 Please submit data obtained using the serum or plasma samples from subjects who were positive for antibodies against rhC1INH that can determine whether the observed antibodies are neutralizing for rhC1INH.

Pharming is currently in the process of establishing and validating an assay to provide direct evidence for the absence or presence of neutralizing activity against rhC1INH among antibodies against rhC1INH. An update on the assay validation and a tentative timeline for providing the requested data will be provided as part of the response to the Mid-Cycle Communication, dated 10 October 2013, that will be submitted by the end of November, 2013.

We have not received the update you mention above.

The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission. 

Please submit your response to this information request as an amendment to this file by January 10, 2014 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.

The action due date for this file is April 16, 2014.

If you have any questions, please contact me at (301) 827-6174.

Sincerely,

Nannette Cagungun, MS, PD, RAC
 Regulatory Project Manager
 FDA/CBER/OBRR/DBA/RPMB 
