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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Complete Response Letter - SOLX® System

DEPARTMENT OF HEALTH & HUMAN SERVICES                                                     Public Health Service
 


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

Our Reference:  NDA BN110059

Hemerus Medical, LLC
Attention:  Ms. Lynn Jensen
5000 Township Parkway
Saint Paul, MN  55110

Dear Ms. Jensen:

Please refer to your New Drug Application (NDA), dated October 28, 2011, received November 1, 2012, submitted under Section 505(b) of the Federal Food, Drug, and Cosmetic Act, for SOLX® System, HEMERUS LEUKOSEP® HWB-600-XL Leukocyte Reduction Filtration System for Whole Blood with CPD Anticoagulant and SOLX® Additive.

We acknowledge receipt of your amendments dated November 9, 2011; November 15, 2011; November 18, 2011; December 7, 2011; December 9, 2011; December 12, 2011; January 4, 2012; January 11, 2012; March 7, 2012; May 2, 2012; May 17, 2012; June 6, 2012; July 12, 2012; July 17, 2012; July 20, 2012; and July 26, 2012.

Please note that our recommendations are based on the revised IFU statement in your most recent amendment, dated July 26, 2012, --------------------(b)(4)-------------------------------.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form.  We have described our reasons for this action below and, where possible, our recommendations to address these issues.

CHEMISTRY, MANUFACTURING AND CONTROLS (CMC):

1. Please provide a summary of chemical stability studies in support of a --(b)(4)--- shelf life claim.  Real time stability testing of only –(b)(4)-- has been completed.  Please submit stability updates for lot ----(b)(4)----- and lot ----(b)(4)------- to the Agency in periodic reports and at the end of ---(b)(4)---- storage study.  If any data fall out of the stability specification, you should change the shelf life claim accordingly.  You can request a shorter shelf life if it is supported by available data to prevent a delay in approval.  When the ---(b)(4)-- storage study data become available you can then request an extension of the shelf life. 

PHARMACOLOGY/TOXICOLOGY:

2. Regarding extraction studies on SOLX® circuits:

      The responses you provided in Amendment 14 to BN110059 for FDA questions #16, 21b and 24a are not adequate to address the risk associated with the decreased platelet counts observed in mice administered leachate from the circuits and storage bags that comprise the SOLX® system.  Specifically, your response speculates that the lower platelet count in test animals results from in vitro, spontaneous platelet aggregation.  This explanation is not sufficient and this issue remains a safety concern that must be addressed prior to approval.

      To ensure the safety of the blood components produced using the SOLX® system that potentially contain these leachates, provide a risk assessment based on results from the previous extraction study # 06-5803-N2, that was conducted according to procedures described in ISO 3826 on an earlier version of your leukocyte reduction system. Identify any significant differences between the earlier, HRC-600-C Leukocyte Reduction Filtration System for Red Cell (BK070024 8/24/2007) system, and the new SOLX® system, to ensure the relevancy of the results from the previous extraction study to the safety of products produced with the SOLX® system.

      Please be aware you may be required to perform an additional leachables and extractables toxicity study and a separate risk assessment for the SOLX® system, if any significant differences are identified between the earlier HRC-600-C Leukocyte Reduction Filtration System for Red Cell (BK070024 8/24/2007) system, and we are unable to bridge those data to the new SOLX® system.

3. Regarding the Agar diffusion study performed by ------(b)(4)--------------:

      Please identify the names and manufacturers of the three different inks printed on the label strips that were evaluated during the Agar diffusion study.

4. Regarding label inks from -----(b)(4)------:

      Please confirm the ribbon in-house print ink ---(b)(4)----- and --(b)(4)-- manufactured by  -----------------(b)(4)--------------, respectively, will only be used on labels applied to packaging and carton material used to transport the SOLX® system.

      Additional comments on information presented in Master File (b)(4) regarding the inks and label stocks used on SOLXâ blood bags will be submitted directly to the manufacturer and holder of the Master File, JMS-Singapore.

PRODUCT QUALITY:

5. You have performed one acceptable run in the re-validation of Sterilizer (b)(4), which does not demonstrate reproducibility.  Please note that the initial validation (Validation Report LAB/VP/039/06) was performed with a biological indictor (BI) with a D-value which was not determined through a standard referenced method and was not referenced on the certificate of analysis (COA) for the specific sterilization method used in your validation.

For your validation, please provide additional sterilization runs to demonstrate reproducibility of your final load configuration using a sufficiently resistant BI in comparison to your facility bioburden.  The D-value of the BI should be determined by a standard referenced method.  Please note that the D-value cited on the BI vendor’s COA for your chosen sterilization method will suffice.

6. For the heat shock studies used to evaluate the resistance of organisms at your facility, it is not clear how your study correlates to actual production sterilization conditions. Specifically, the heat shock conditions --------------------(b)(4)-------------------------- than the actual sterilization production cycle for all of the spore formers and mold found in the facility.  It is not clear if the heat shock condition or the sterilization production cycle is actually the worst case.

Please perform additional studies to compare the resistance of spore formers and mold in your facility using test conditions that can be correlated with your sterilization production cycle.  To facilitate comparison to your chosen validation biological indicator, we recommend that your thermal studies also include the biological indicator as a control. 

7. The transportation simulation study (Report Number 0706135) evaluated in Report TP/077/PED/2008 did not meet the acceptance criteria (packaging damaged, moisture found in the package, label peel test failed).  We noted that the packaging configuration was changed and shipped from Singapore to Hemerus under unknown shipping conditions.

Please complete additional transportation studies with the new shipping configuration using defined shipping conditions that represent the worst case conditions (e.g. temperature extremes, humidity extremes, time, and etc.).

LABELING:

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

9.  We reserve comment on the proposed labeling until the application is otherwise adequate. If you revise labeling, your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at  http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

10. Please submit draft labeling revised as follows:

Package Insert:

  1. Please submit the open package stability studies when they are completed.  Are the individual collection sets overwrapped?  In the meantime foil pouches should be used on the day they are opened.  The IFU should be revised.
  2. Preparing AS-7 Red Blood Cells – Page 5:  In statement 5 please remove ----------------------(b)(4)------------------------------------.
  3. Please clarify if non-leukoreduced Red Blood Cell units manufactured are acceptable or should be destroyed.
  4. Caution:  Please revise the caution statement to replace “practitioner” with physician and include “Rx Only.”
  5. Blood Collection: Please revise this section to include the actual blood volumes that will be collected during the procedure.
  6. Additional Items:
    • Please revise the package insert to include instructions in the procedure for Quality Control of the Red Blood Cell, Leukocytes Reduced products.
    • Please revise the package insert to include the procedure to be followed when the entire Red Blood Cell unit is not leukoreduced. (e.g. check volume, residual WBC count etc.)

Container Labels:

  1. The container labels do not follow ISBT consensus standard 2.0.  Please review the ISBT standards and revise the labels. Additionally, ICCBA has assigned AS-7 to your SOLX Solution.  Please refer to the ICCBBA website for standards:  http://iccbba.org/

The labels submitted for review in your response are not IBST acceptable.  There may be other revisions requested based on additional information that may be submitted in support of this application. 

Your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at  http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy should include annotations that support any proposed changes.

GENERAL COMMENT:

The draft Summary Basis of Approval (SBA) submitted will need to be revised to reflect comments made to your directions for use, etc.

FACILITY INSPECTIONS:

During a recent inspection of the JMS Singapore manufacturing facility for this application, our field investigator conveyed deficiencies to the representative of the facility.  Satisfactory resolution of these deficiencies is required before this application may be approved.

SAFETY UPDATE:

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b).  The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

  1. Describe in detail any significant changes or findings in the safety profile.
  1. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:
  • Present new safety data from the studies/clinical trials for the proposed indication using the same format as the original NDA submission. 
  • Present tabulations of the new safety data combined with the original NDA data.
  • Include tables that compare frequencies of adverse events in the original NDA with the retabulated frequencies described in the bullet above.
  • For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.
  1. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials.  Describe any new trends or patterns identified.
  1. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event.  In addition, provide narrative summaries for serious adverse events.
  1. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original NDA data.
  1. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
  1. Provide a summary of worldwide experience on the safety of this drug.  Include an updated estimate of use for drug marketed in other countries.
  1. Provide English translations of current approved foreign labeling not previously submitted.

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110.  If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under 21 CFR 314.65.  You may also request an extension of time in which to resubmit the application.  A resubmission must fully address all the deficiencies listed.  A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.  

Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss what steps you need to take before the application may be approved.  If you wish to have such a meeting, submit your meeting request as described in the FDA’s “Guidance for Industry - Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM153222.pdf.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, please call Sonday L. Kelly, Regulatory Project Manager, at
(240) 507-8446.

Sincerely,
 

 

Basil Golding, M.D.
Director
Division of Hematology
Office of Blood Research and Review
Center for Biologics
Evaluation and Research