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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Pharmacology Toxicology Review - SOLX® System

Memorandum                                                                                                                          Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research


 

Pharmacology/Toxicology Review
Division of Hematology
Office of Blood Research & Review  
 
Product: Hemerus leukocyte reduction system with Solx
Purpose: Review of new label ink stability, integrity and toxicology data 
Sponsor: Hemerus, NDA BN110059/8 (x-ref IND 14199)
Date received: March 7, 2012
Reviewer: M. Keith Wyatt, Ph. D., Pharmacologist, CBER\OBRR\DH
Through: Jaroslav Vostal, M. D., Ph. D., Supervisory Medical Officer,   
                CBER\OBRR\DH\LCH
 
 
Hemerus (Sponsor) has submitted results from toxicology and ink stability/resistance studies conducted on printed labels in support of NDA BN110059. FDA requested the studies in an information request sent to the Sponsor on January 25, 2012.
 
Herein is a review of results from the (1) Resistance [studies] of Hemerus bag label prints to various liquid agents and the (2) Agar diffusion test also conducted with Hermerus printed labels.
  
Recommendation
 
The resistance study selected by the Sponsor did not include caustic or potent solvents representative of a worst case leaching scenario but was still adequate to assess the safety and stability of inks printed on Hemerus label stocks. A more rigorous study was preferred but will not be required. Results from the Agar diffusion test were sufficient to ensure the print label inks are safe provided the Sponsor can confirm that cultured mammalian cells came into contact with both the ribbon and acrylate inks during the study.    
 
Letter-ready Comments
 
1. Regarding Resistance study, FR409400, March 6, 2012
 
a)     Please justify why the stability of label inks was not evaluated against detergents, denatured alcohols, acids and other solvents specified in ISO 2836 as exposure to these liquids may represent a worst case leaching scenario.
 
b)     The Sponsor should confirm labels evaluated in the resistance study were printed with the ribbon ink –(b)(4)--- manufactured by ---(b)(4)-------- and with red and black acrylate inks manufactured by -----(b)(4)--------------. The Sponsor should also confirm that label stocks used in this study were manufactured by -(b)(4)-.
 
c)     The ink used to print the letter “T” on the label presented in Appendix A (located in the image on the right side at the bottom of page 13 of 17) was significantly reduced following treatment. The Sponsor should quantify this reduction in ink intensity according to -------------(b)(4)-------------------------- referenced in ----(b)(4)---.
 
2. Regarding the Agar diffusion study-ISO, 12-603-G1
 
a)     The Sponsor should confirm both the ribbon and acrylate inks were present on the label strips and came into direct contact with cells during the study.
 
Resistance of Hemerus bag label prints to various liquid agents, FR409400, conducted in house by Hemerus, March 6, 2012
Purpose: To evaluate the resistance and stability of inks used on bag labels to various chemical agents.
Methods: ----------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------.  
Results: Photographic images of the labels after exposure suggest that none of the treatments, with one exception, had any effect on print legibility, ink film integrity, print integrity, color fastness or substrate color. No print discoloration or change in solvent color was observed after the study.
 
Reviewer concerns:
 
The solvents used in the study were not potent enough to assess stability and safety of inks printed on Hemerus labels during worst case leaching scenarios.  
 
Agar diffusion study-ISO, 12-603-G1, ---(b)(4)---- Feb, 21, 2012
Purpose: To determine the biological reactivity of a mammalian monolayer cell culture (ATCC: L929) in response to Hemerus labels printed with ribbon and acrylate inks.  
Methods: The study was performed according to methods described in ISO 10993-5 and ISO 1093-12.
Results: No biological reactivity was observed in cells exposed to Hemerus printed labels. Therefore, the printed labels are considered non-cytotoxic.