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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)----------------------------------------------------------------------.n

 

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:
  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.
  Preparing AS-7 Red Blood Cells – Page 5:  In statement 5 please remove 
  ----------------------(b)(4)------------------------------------.
  Please clarify if non-leukoreduced Red Blood Cell units manufactured are 
  acceptable or should be destroyed.
  Caution:  Please revise the caution statement to replace “practitioner” with 
  physician and include “Rx Only.”
  Blood Collection: Please revise this section to include the actual blood 
  volumes that will be collected during the procedure.
  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:
  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.
  Describe in detail any significant changes or findings in the safety profile.
  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.
  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.
  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.
  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.
  Provide updated exposure information for the clinical studies/trials (e.g., 
  number of subjects, person time).
  Provide a summary of worldwide experience on the safety of this drug.  Include 
  an updated estimate of use for drug marketed in other countries.
  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
 
