Consult Review Memo, October 4, 2013 - Ruconest

Date:               October 04, 2013

BLA #:            STN 125495/0

Applicant:       Pharming Group N. V. License# 1857

Product:         Ruconest (Conestat Alfa/Recombinant Human C1 Esterase Inhibitor/rhC1INH) for the treatment of acute attacks of hereditary angioedema (HAE) in adult and adolescent patients
 Lyophilized powder; 2100 U; IV administered

Lead Office:  OBRR

From:              Rabia Ballica, PhD, CBER/OCBQ/DMPQ/BI, HFM-675
                         Consult Reviewer

To:                  Nancy Waites, CBER/OCBQ/DMPQ/BI, HFM-675
 Reviewer

Through:         Carolyn Renshaw, Branch Chief/MBR1/DMPQ/OCBQ/HFM-675

Subject:          Consult Review of Biologics License Application (BLA)  
electronically received 04/16/2013 for Sterile Filtration Process

 

Recommendation:

There are no objectionable issues. Approval of the sterile filtration is recommended based on the review of the pertinent information provided in this BLA submission.

SUMMARY

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The firm indicates that sterilizing grade filters are ---(b)(4)---, but does not indicate in the sections - reviewed (3.2.P.3.3 and 3.2.P.3.5) by which method is -----------------------------------------------------------------(b)(4)---------------------------------------------------. However, validation report for the sterilization --------(b)(4)-------- of equipment, which is included in Section 3.2.A. 1 Facilities and Equipment of the submission, summarizes the heat sterilization of the filtration system along with other equipment and materials used in manufacturing (in facilities-and-equipment-validation-sterilizers.pdf). Note that according to the information published on ----(b)(4)---- Website, the filter manufacturer recommends -----------------------------------------------------(b)(4)-----------------------------------------------------. Also, note that this review memo does not cover the evaluation of sterilization validation.

The ---(b)(4)--- sterilizing grade filters were qualified for product compatibility (Appendix 6) and --(b)(4)- (Appendix 5). No major objectionable issues are noted (refer to the pertinent review section of this memo). Assessment of the extractables/leachables information for -------(b)(4)-------- (Appendix 8) is deferred to the product reviewer.  It should be noted that the firm does not indicate any ---(b)(4)--- procedure of the filters prior to use, but ---(b)(4)--- on their Website states that ------(b)(4)------ unit will meet the ----------(b)(4)------------ test requirements after a --------(b)(4)--------.  This ---(b)(4)--- procedure can be followed up either during pre-license inspection or during review process by the product office.

(b)(4) drug product batches were manufactured to validate the drug product manufacturing process (refer to 3.2.P.3.5.). Results for the sterile filtration met the acceptance criteria for the parameters evaluated (e.g, bioburden before the ----(b)(4)---------------------------------(b)(4)-----------------------------------------------------------.  Product release specifications were also met for sterility, endotoxin and ---------(b)(4)--------- as well as product quality attributes.  Even though sterility testing is indicated to be performed on -(b)(4)- samples following ----------------(b)(4)---------------, sterility testing results are not included in the submission.  No deviation is reported for the sterile filtration step.

REVIEW

3.2.P.3.3 Description of Manufacturing Process and Process Controls 

rhC1INH Drug Product is manufactured from the formulated bulk drug substance according to the following scheme. 

(b)(4)

Sterile filtration -----------(b)(4)---------------- is performed as illustrated in the following scheme:

(b)(4)

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3.2.P.3.5. Process Validation and/or Evaluation

(b)(4) consecutive drug product batches were produced for process validation (PV).  In process controls for the sterile filtration step are provided in the table below.

Table. In process controls for the sterile filtration step

(b)(4) 

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Results from the process validation runs met the acceptance criteria for sterile filtration:

Table:  Results from (b)(4) process validation runs for sterile filtration

(b)(4)

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

Product release specifications were met for sterility, endotoxin (---(b)(4)---) and -------------(b)(4)---------- as well as for other product quality attributes. Release testing on the drug product for sterility is reported as sterile for all the lots indicated in the table above (Table 3.2.P.3.5-4 of the submission). Note that the in process controls table above indicates sterility testing on the -------------(b)(4)-------------- be performed, but -----(b)(4)--------- sterility results are not provided**. No deviations are reported for the sterile filtration step.

The sterilizing-grade filters are tested with respect to ------------(b)(4)---------------- by the manufacturer of the filters and ---------(b)(4)-------------- testing is performed by the CMO (----(b)(4)-----). The ------(b)(4)------ test performed is the -------------(b)(4)------------------ test in accordance with the prescription of the manufacturer. The acceptance criteria for the ---(b)(4)--- test are in accordance with the acceptance criteria as defined by the manufacturer of the filter

The following validations (in Appendices 5-8 of the submission) for the sterile filter were performed by ----(b)(4)---- for the firm:
1.Validation report (Appendices 6- process-validation-val-r-03-083.pdf) Report for compatibility study of ------------------------------------(b)(4)------------------------------------------- (VAL-R-03-083):

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2.Validation report (Appendix 7- process-validation-val-r-03-084.pdf) Report for   ----(b)(4)---- determination of ---------------------------------------------------(b)(4)-----------------------------------: 

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3.Validation report (Appendix 5- process-validation-val-r-03-085.pdf) Report for   ----(b)(4)---- validation of ----------------------------------(b)(4)--------------------------------------- in the presence of rhC1INH (VAL-R-03-085):

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(b)(4)

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There was only one deviation in that ---------(b)(4)--------- was not met for -(b)(4)-, but the average ---(b)(4)--- for all test (b)(4) was met.
4.Review of extractables/leachables information provided in Appendix 8 is deferred to the product reviewer (Appendix 8- VAL-R-03-086).

**Comment:  The filter manufacturer, ---(b)(4)---, conducted a validation study for         -------(b)(4)---------  using the product and ------------------------(b)(4)------------------------, but ---(b)(4)--- test results are not reported in the submitted validation report and the scaled down actual ---(b)(4)--- was not used for the validation.  There is also no an established correlation between -----(b)(4)------ results and ---------(b)(4)-------- test values to be utilized in actual --------------(b)(4)----------------- testing. However, the product -(b)(4)- testing range was determined (Appendix 7- process-validation-val-r-03-084.pdf).  Because the sterile filtered drug product is sterility - tested following the ---------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------) and for release, the ------(b)(4)------ validation study is acceptable. There are no other objectionable issues with the sterile filtration process. 

It was also demonstrated that a ---------(b)(4)----------- was routinely obtained prior to ----(b)(4)-- during the validation of the rhC1INH Drug Product manufacturing process: In summary, ------------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------. During process validation, samples were taken at the -------------------(b)(4)---------------------- process, and at the ------------------------(b)(4)---------------- process. These samples were tested for ----(b)(4)----. Based on the results, the firm concluded that there were no significant differences in --------(b)(4)--------- at the ---------------------------------(b)(4)-------------------------------------------------- procedure, which demonstrates that the solution is ------------(b)(4)-----
