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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Midcycle Review - Isoplate Solution

FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
 


MEMORANDUM

From:               Yolanda Branch, Ph.D., Pharmacologist, CBER, OBRR, DH

To:                   Iliana Valencia, OBRR, DBA, RPMB

Through:          Iftekhar Mahmood, Ph.D., Team Lead, CBER, OBRR, DH

Subject:            Mid-Cycle Review - Pharm/Tox Review of Isoplate (NDA BN090067), a platelet additive solution for the storage of leukoreduced hyperconcentrated platelets

Sponsor:           B. Braun Medical Inc.  


Recommendations:
Isoplate appears to be a ‘combination’ product as it is only to be used with CaridianBCT’s Trima Accel® System.  Although, there appears to be no limit on the maximum daily use (dose) of platelets, the sponsor needs to demonstrate that the levels of each extractable/leachable are within acceptable range with multiple use (worst case scenario).  From a pharmacology/toxicology perspective, this is a potential issue as the safety of the product has not been adequately addressed. 

Background:
Isoplate, also known as the FDA approved drug Isolyte S, is a platelet additive solution for the storage of leukoreduced hyperconcentrated apheresis platelets collected on CaridianBCT’s Trima Accel® System.  Isoplate Solution is identical in formulation, packaging, sterilization, and manufacturing to B. Braun’s already approved Isolyte S, pH 7.4 (Multi-Electrolyte Injection), ANDA 019696, with the only difference being the name of the product and the indications. 

The container closure system used in manufacturing the FDA approved product Isolyte is identical to that used in the Isoplate Solution product.  The analysis of the material used to manufacture the Excel® plastic container was performed in ----(b)(4)------:

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

All information related to the container closure system presented in this NDA has already been approved for use by the Agency and is currently used in approximately 29 approved products.  The complete description of the testing and the results are provided in B. Braun’s DMF (b)(4),
Material Qualification for the Excel® Plastic Container, submitted to the FDA on June 30, 1986. 

Indication:
Isoplate Solution is proposed for use in blood banks for the preparation and storage of leukoreduced hyperconcentrated platelets for subsequent transfusion.  Isoplate solution is added to leukoreduced hyperconcentrated platelets after the Trima Accel apheresis procedure is complete. 

Letter Ready Comments:
Please note the following concerns have not been addressed (submitted in the Issue Filing Action Letter 8/13/2010):

It is noted that B. Braun Medical Inc. conducted the chemical, biological and physical functional testing on the Excel® plastic container in accordance with the USP requirements and additional B. Braun tests.  The product’s proposed indication is for platelet storage in the following ratio: 65% Isoplate solution and 35% plasma.   It is stated in the label that Isoplate solution will not be used for direct infusion.  However, please note Isoplate will be directly infused into patients as a combination product (Isoplate and plasma), this is of concern because there can be an accumulation of extractable/leachable beyond the acceptable range with multiple use (doses) of product.  The levels of each extractable/leachable need to be assessed at the maximum daily dose of the combination product to ensure it are within an acceptable range.  Please see the comments below:

  1. Please note the toxicological evaluation of leachables/extractables from the plastic should be based on animal studies that defined a toxic dose of an IV administered compound and on the anticipated clinical application of the product.  Please identify each extractable/leachable and calculate their levels at the maximum clinical dose, to ensure that it is within an acceptable range.
  2. Please electronically submit all preclinical (toxicological) studies that are cross referenced in order to complete the file.
  3. Please keep labeling (overdose, warnings, precautions, and contraindications) consistent with the FDA approved product Isolyte.