CORDCYTE, HPC (Hematopoietic Progenitor Cell), Cord Blood is an allogeneic cord blood hematopoietic progenitor cell therapy indicated for use in unrelated donor hematopoietic progenitor stem cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.

The risk benefit assessment for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells.

• For intravenous use only.
• Do not irradiate.

Unit selection and administration of CORDCYTE should be done under the direction of a physician experienced in hematopoietic progenitor cell transplantation.

Each unit of CORDCYTE contains a minimum of 5 x 108 total nucleated cells with a minimum of 1.25 x 106 viable CD34+ cells, suspended in 10% dimethyl sulfoxide (DMSO) and 1% Dextran 40, at the time of cryopreservation.

The exact pre-cryopreservation nucleated cell content is provided in the accompanying records.

None.

Day-100 mortality from all causes was 25%.

The most common infusion-related adverse reactions (≥ 5%) are hypertension, vomiting, nausea, bradycardia, and fever.

CORDCYTE consists of hematopoietic progenitor cells, monocytes, lymphocytes, and granulocytes from human cord blood for intravenous infusion. Blood recovered from umbilical cord and placenta is volume reduced and partially depleted of red blood cells and plasma.

The active ingredient is hematopoietic progenitor cells which express the cell surface marker CD34. The potency of cord blood is determined by measuring the numbers of total nucleated cells (TNC) and CD34+ cells, and cell viability. Each unit of CORDCYTE contains a minimum of 5 x 108 total nucleated cells with at least 1.25 x 106 viable CD34+ cells at the time of cryopreservation. The cellular composition of CORDCYTE depends on the composition of cells in the blood recovered from the umbilical cord and placenta of the donor. The actual nucleated cell count, the CD34+ cell count, the ABO group, and the HLA typing are listed in the accompanying records sent with each individual unit.

CORDCYTE has the following inactive ingredients: dimethyl sulfoxide (DMSO), Dextran 40, and hydroxyethylstarch. When prepared for infusion according to instructions, the infusate contains the following inactive ingredients: Dextran 40, human serum albumin, residual DMSO, and residual hydroxyethylstarch.

The effectiveness of CORDCYTE, as defined by hematopoietic reconstitution, was demonstrated in one single-arm prospective study (COBLT Study), and in retrospective reviews of data from an observational database for CORDCYTE and data in the dockets and public information. Of the 1299 patients in the dockets and public data, 66% (n=862) underwent transplantation as treatment for hematologic malignancy. Results for patients who received a total nucleated cell dose ≥ 2.5 x 107/kg are shown in Table 2. Neutrophil recovery is defined as the time from transplantation to an absolute neutrophil count more than 500 per microliter. Platelet recovery is the time to a platelet count more than 20,000 per microliter. Erythrocyte recovery is the time to a reticulocyte count greater than 30,000 per microliter. The total nucleated cell dose and degree of HLA match were inversely associated with the time to neutrophil recovery in the docket data.

CORDCYTE is supplied as a cryopreserved cell suspension in a sealed bag containing a minimum of 5 x 108 total nucleated cells with a minimum of 1.25 x 106 viable CD34+ cells in a volume of 25 milliliters (ISBT 128 Product Code S1393, ISBT 128 Facility Identifier Number W2434). The exact pre-cryopreservation nucleated cell content is provided in the accompanying records.

Store CORDCYTE at or below -150°C until ready for thawing and preparation.

Discuss the following with patients receiving CORDCYTE:

• Report immediately any signs and symptoms of acute infusion reactions, such as fever, chills, fatigue, breathing problems, dizziness, nausea, vomiting, headache, or muscle aches.
• Report immediately any signs or symptoms suggestive of graft-vs.-host disease, including rash, diarrhea, or yellowing of the eyes.

INSTRUCTIONS FOR PREPARATION FOR INFUSION

The CORDCYTE unit is stored continuously inside a steel canister in liquid nitrogen at temperatures ≤ -150° C. For shipment, the canister is placed inside a container specifically designed to keep the temperature at or below -150° C (dry shipper). It is recommended to keep the canister inside the dry shipper for short-term storage (up to 48 hours) or transfer it into a liquid nitrogen (LN2)-cooled storage device at the Transplant Center for storage greater than 48 hours.

1. MATERIALS
   Equipment:
   • Refrigerated centrifuge
   • Plasma extractor/expressor
   • Biological safety cabinet
   • Scale
   • Tube sealer compatible with polyvinyl chloride plastic
   • Water bath
   • Canister-opening tool (supplied by LifeSouth Community Blood Centers)
   • LN2 storage freezer at -150° C or colder
   • Sterile docker
   • Automated cell counter and/or microscope and cell count chamber for cell count and viability determination (optional)

   Personal Protective Equipment:

   • Gloves (sterile preferred)
   • Protective cryogloves
   • Safety goggles or face shield
   • Lab coat

   Reagents:

   • 10% Dextran 40 in Sodium Chloride Injection, USP
   • 5% Albumin (Human), USP

   Supplies:

   • Sterile disposable syringes - (2) 30-mL, (8) 60-mL
   • 18-gauge injection needles
   • Hemostat
   • Small plastic zip-lock bags (sterile preferred)
   • Alcohol prep pads
   • (3) sampling site couplers
   • (4) 300-mL transfer bags
   • Sterile pipettes
   • Sterile sampling cups
   • Bacterial culture bottles (aerobic and anaerobic) or other supplies for conducting sterility testing
   • Tubes for cell counts, progenitor assays (optional)

   Forms:

   • Receipt of Cord Blood Unit form
   • Umbilical Cord Blood Cryopreserved Transfer Report form

2. PRODUCT IDENTITY VERIFICATION

   1. Apply personal protective equipment.
   2. Open the dry shipper lid upon receipt using scissors to remove the tie-tag from the outside of the shipper.
   3. Verify that the National Marrow Donor Program (NMDP) number on the tie-tag matches the NMDP number on the Umbilical Cord Blood Cryopreserved Unit Transfer Report. If the NMDP numbers do not match, contact LifeSouth Community Blood Centers (LifeSouth) at 1-888-795-2707.
   4. Remove the canister from the dry shipper and the canister-opening tool from the shipment documentation packet (see Figure 1).

      Figure 1:
                         

   5. Compare product bar code information on bar-coded label on the side of the canister (see Figure 1) with the product identification (ID) information included in the packaging. Verify this information as soon as the shipment arrives and before administering the CORDCYTE unit. If the bar-coded label is not found on the outside of the canister, the product bar code information can be found on the frozen cord blood unit enclosed in the canister.
   6. Using protective cryogloves and the canister-opening tool, open the canister at top and bottom using the following steps:
      1. Avoid damaging the frozen cord blood bag.
      2. Align the canister opening tool with the slot in the bottom of the canister (see Figure 2).
      3. Turn the canister opening tool clockwise to open the bottom of the canister (see Figure 3).

         Figure 2:
                            

         Figure 3:
                            

         Figure 4:
                            

      4. Locate the opening at the top of the canister and use the tool in a counterclockwise motion to open the top of the canister (see Figure 4).
      5. Open the canister hinges so the CORDCYTE unit can be removed (see Figure 5).

      Figure 5:
                         

   7. Once the canister is open, compare the product bar code information with your records.
   8. Close canister after verification is complete. Using protective cryogloves, return the canister to the dry shipper for short term storage (up to 48 hours) or to LN2-cooled storage device for storage greater than 48 hours.
   9. Once records are all verified, indicate acceptance by initial and date on the indicated space on the Receipt of Cord Blood Unit and Umbilical Cord Blood Cryopreserved Transfer Report forms.

      For Incorrect Information:

      1. If any information is incorrect or cannot be verified, close the canister and return the frozen unit to the dry shipper for short term storage (up to 48 hours) or into a LN2-cooled storage device for storage greater than 48 hours.
      2. Report the discrepancy immediately to LifeSouth at 1-888-795-2707 and to the transplant physician.
      3. Perform a thorough investigation, keeping the CORDCYTE unit frozen at or below -150° C until all discrepancies are resolved.
      4. Once records are all verified, indicate acceptance by initial and date on the indicated space on the Receipt of Cord Blood Unit and Umbilical Cord Blood Cryopreserved Transfer Report forms.
3. PREPARATION

   1. Prepare Thawing Solution

      1. Label a 300-mL transfer bag "Thaw/Wash Solution" (see Figure 6 below).
      2. Clamp the “Thaw/Wash Solution” bag with a hemostat to prevent leaking.
      3. Refrigerate the 10% Dextran 40 in Sodium Chloride Injection, USP and the 5% Albumin (Human), USP at 2-6ºC.
      4. Complete the following steps inside a biological safety cabinet:
         1. Add 72.5 mL of refrigerated 10% Dextran 40 in Sodium Chloride Injection, USP to the 300-mL transfer bag labeled Thaw/Wash Solution using two 60-mL sterile syringes.
         2. Add 72.5 mL of refrigerated 5% Albumin (Human), USP to the same 300-mL transfer bag labeled Thaw/Wash Solution using two 60-mL syringes.
         3. Mix by inverting the bag at least 10 times.

         4. Label a 60-mL sterile syringe "Resuspension Solution"; fill with 50 mL of the solution from transfer bag labeled Thaw/Wash Solution (1:1 ratio of 10% Dextran 40 in Sodium Chloride Injection, USP / 5% Albumin (Human), USP) for final end-product re-suspension. Refrigerate until ready for use.

         5. Label two 60-mL sterile syringes and two 30-mL sterile syringes as "Thaw/Wash Solution."

         6. For the two 60-mL syringes draw 20 mL of thaw/wash solution into each syringe; refrigerate until ready for use.

            1. For the two 30-mL syringes draw 5 mL of thaw/wash solution into each syringe; refrigerate until ready for use.

            2. Using a sterile docker, connect two 300-mL transfer bags into a transfer set (see Figure 6 below).
         7. Label one transfer bag with the CORDCYTE unit Donation Identification Number (DIN) and "Thaw/Wash Solution."
            1. Label the second transfer bag with the CORDCYTE unit DIN and "Expressed Solution."
            2. Insert a sampling site coupler into the port closest to the tubing on the DIN and Thaw/Wash Solution labeled transfer bag (see Figure 6).
         8. Attach a hemostat to the tubing approximately one inch above the sampling site coupler on the DIN and Thaw/Wash Solution transfer bag (see Figure 6).

      Figure 6: Transfer Set Diagram

      

   2. Thaw CORDCYTE Unit

      Schedule the infusion time of the transplant with the transplant team in advance of the procedure. Re-confirm on the day of infusion with the transplant team so that the start time for the thawing procedure can be adjusted to have the unit ready for infusion at a time the patient can receive the infusion.

      If canister is stored in LN2, wear protective cryogloves, lift canister containing the CORDCYTE unit from the liquid phase of the LN2 container, and rest canister in the vapor phase within the container for five to ten minutes before proceeding.

      Note: Carefully check the identity of the unit to be thawed.

      1. Open canister with the canister opening tool (refer to section II PRODUCT IDENTITY VERIFICATION). Avoid damage to the plastic bag containing the frozen CORDCYTE unit. Carefully examine the plastic bag for breaks or cracks.
      2. Remove the CORDCYTE unit bag from the canister.
      3. Place the CORDCYTE unit bag into a clean plastic zip-lock bag. Let the air out, and close it tightly. Use a sterile plastic zip-lock bag if available.
      4. Place the plastic zip-lock bag containing the frozen cord blood unit into a warm water bath at a temperature of 37° C +/- 1° C. Gently and carefully agitate the bag in the water bath to accelerate thawing and resuspension of the cells. Use your fingers to massage the bag to ensure equitable distribution of heat (see Figure 7).

         Figure 7:
                            

      5. Watch closely for any cracks or breaks, as shown by red cells leaking from the cord blood bag into the plastic zip-lock bag.
      6. If any leakage is seen, keep the leakage site upright to prevent further leaking while continuing to gently agitate the bag until the product is slushy. (See section V EMERGENCY RECOVERY PROCEDURE IN THE EVENT OF A CONTAINER FAILURE for procedures for emergency recovery of the thawed cord blood cells).
      7. If no leakage is seen, remove the plastic zip-lock bag from water bath. Dry the outside of the bag, disinfect it with alcohol, and place it inside a biological safety cabinet.
   3. Transfer the Thawed CORDCYTE Unit to Transfer Set
      Complete the following steps inside a biological safety cabinet:
      1. Obtain pre-labeled transfer set (see section IIIA, step 4vi).
      2. Obtain CORDCYTE unit; clean both sealed ports with alcohol.
      3. Obtain scissors; disinfect port covers and cut off top of port to create an opening for insertion of sampling site coupler.
      4. Disinfect cut port-cover surfaces with alcohol and attach one sample site coupler to each port.
      5. Obtain one of the prepared 30-mL syringes containing 5 mL of thaw/wash solution (see section IIIA, step 4v).
      6. Connect the 30-mL syringe into the 5-mL cord blood compartment port; slowly dispense thaw/wash solution into this compartment.
      7. Slowly pull back and push in the syringe plunger to mix the cord blood and thaw/wash solution; repeat three to four times. After the last one, draw all the fluid from the compartment into the syringe.
      8. Disperse all the fluid in the syringe obtained in step 7 into the labeled DIN and Thaw/Wash Solution bag.
      9. Repeat steps 5 through 8 with the second prepared 30-mL syringe containing 5 mL of thaw/wash solution to wash any remaining CORDCYTE from the 5-mL compartment. The DIN and Thaw/Wash Solution Bag should contain 15 mL of CORDCYTE and solution.
      10. Obtain one of the prepared 60-mL syringes containing 20 mL of thaw/wash solution (see section IIIA, step 4v).
      11. Connect the 60-mL syringe into the larger 20-mL cord blood compartment port; slowly dispense the thaw/wash solution into this compartment.
      12. Slowly pull back and push in the syringe plunger to mix the cord blood and thaw/wash solution; repeat three to four times. After the last one, draw all the fluid from the compartment into the syringe.
      13. Disperse all the fluid in the syringe obtained in step 12 into the labeled DIN and Thaw/Wash Solution bag.
      14. Repeat steps 10 through 14 using the second prepared 60-mL syringe containing 20 mL of thaw/wash solution to wash the remaining contents from the 20-mL compartment. The DIN and Thaw/Wash Solution bag should contain 75 mL of CORDCYTE and solution.
      15. Allow five minutes for the mixture to equilibrate.
      16. Draw any remaining thaw/wash solution from the Thaw/Wash Solution transfer bag into a 60-mL syringe and add solution into the DIN and Thaw/Wash Solution transfer bag. The DIN and Thaw/Wash Solution bag should contain approximately 120 mL of CORDCYTE and solution.
      17. Mix the DIN and Thaw/Wash Solution transfer bag well by inverting the transfer bag 180° 10 to 15 times.
      18. Discard the empty Thaw/Wash Solution bag.

   4. Wash the Thawed CORDCYTE Unit

      1. Place the DIN and Thaw/Wash Solution transfer bag containing the hemostat, sampling site coupler, and DIN and Expressed Solution transfer bag into refrigerated centrifuge in upright position. Do not allow bags to crease. Inserts may be used to achieve upright position and to prevent damage as a result of centrifugation with a sampling site coupler.
      2. Balance the centrifuge before beginning centrifugation cycle.
      3. Centrifuge at 400 g for 20 minutes at 10°C.
      4. After centrifugation, look for clear separation of red blood cell (RBC) pellet.
      5. Place transfer bag labeled DIN and Thaw/Wash Solution into a plasma extractor (see Figure 8) and allow the supernatant to flow into the transfer bag labeled DIN and Expressed Solution by removing the hemostat from the tubing. Do not disturb the cells. If cells transfer, restore everything back into the primary transfer bag, re-centrifuge, and repeat extraction procedure.

         Figure 8:
                            

      6. Allow all supernatant to leave bag but do not allow the RBC pellet to escape (see Figure 9). Hemostat the tubing after expressing to close tubing on the DIN and Thaw/Wash Solution transfer bag. Seal tubing with heat sealer on DIN and Thaw/Wash Solution transfer bag where the tubing begins. Make two seals; cut in between the two seals. Discard the line and DIN and Express Solution transfer bag.

         Figure 9:
                            

      7. Obtain the prepared 60-mL “Resuspension Solution” syringe containing 50 mL thaw/wash solution (see section IIIA, step 4iv). Slowly add 50 mL of thaw/wash solution to the DIN and Thaw/Wash Solution transfer bag.
      8. Obtain an unlabeled 300 mL transfer bag. Seal the tubing of the transfer bag approximately one inch above the introduction of the tubing into the bag. Remove the excess tubing. Weigh the bag to obtain a tare weight of the transfer bag.
      9. Weigh the DIN and Thaw/Wash Solution bag. Calculate volume based on weight of bag minus tare weight obtained in step 8.
      10. Complete sampling for CFU, TNC, CD34+, viability, and ABO/Rh and HLA, if necessary.
      11. Label DIN and Thaw/Wash Solution transfer bag with the expiration time and the time of completion of washing. The recommended expiration time is 2 hours after the completion of wash until infusion, if stored at room temperature (19-25ºC) or 4 ºC.
      12. Notify the Transplant Center that the CORDCYTE unit is thawed, washed, and available for infusion.
4. ADMINISTRATIVE REQUIREMENTS
   1. Prepare a written summary of the procedure, including:
      1. CORDCYTE ID number
      2. Date of receipt of CORDCYTE unit
      3. Liquid nitrogen storage temperature
      4. Date of thaw, including whether and at what stage leaks or cracks occurred
      5. Date and time CORDCYTE unit removed from liquid nitrogen storage
      6. Volume of final product
      7. TNC (Total nucleated cell) count, CD34+ count
      8. Viability of recovered cells (TNC or CD34+) plus name of method used
      9. Results of bacterial and fungal cultures
   2. Make a copy of the report for your records.
   3. Fax a copy of the report to LifeSouth at 352-224-1650.
   4. Return the dry shipper to LifeSouth. The return address is:

       

      LifeSouth Community Blood Centers, Inc.
      LifeCord Cord Blood Bank
      4039 Newberry Road
      Gainesville, FL 32607

       

      
      Phone: 888-795-2707 x 41738
      Fax: 352-224-1650

5. EMERGENCY RECOVERY PROCEDURE IN THE EVENT OF A CONTAINER FAILURE

   1. Handle the frozen cord blood bag with extreme care at every step including opening the metal containers, inspecting, thawing and/or washing.
   2. Use standard procedures and competent personnel to perform post-thaw sampling and/or bag rescue.
   3. Perform all steps on lab benches, under biological safety cabinet, or another surface to prevent inadvertent drop of the frozen unit.
   4. To facilitate thawing, gradually remove the CORDCYTE unit from the liquid phase of the LN2 storage area, suspending in the vapor phase for at least five minutes prior to bringing the container to room temperature.
   5. Put the frozen bag inside a zip-lock bag prior to initiating the thaw to facilitate salvage of the product and to reduce the possibility of contamination.
   6. If the CORDCYTE unit is seen to be cracked when removed from the LN2 storage container, or if cracks or leaks occur during thawing, immediately notify LifeSouth at 1-888-795-2707. Notify the transplant physician/team and the laboratory director as soon as possible.
   7. The transplant physician or team will determine whether to use or discard the CORDCYTE product and whether any additional units should be requested.
   8. If the transplant physician or team decides that the product in the leaking unit could be used, the CORDCYTE unit may be recovered as follows:
      1. Obtain sterile sampling cups and sterile pipettes.
      2. Open a sterile sampling cup and set cup in working space to receive contents of zip-lock bag.
      3. If any contents remain in the broken CORDCYTE unit bag, remove the contents from the bag using the syringes prepared in section IIIA.
      4. Wash all contents out of the CORDCYTE bag and place contents in the DIN and Thaw/Wash Solution labeled transfer bag.
      5. Using a sterile syringe, transfer 20 mL from the Thaw/Wash Solution bag into a sterile sample cup.
      6. Using a sterile pipette, obtain 3 mL of thaw/wash solution from the sample cup and inject into the zip-lock bag containing the remaining CORDCYTE unit contents that leaked when thawing.
      7. Using a different sterile pipette, remove CORDCYTE and thaw/wash solution from the zip-lock bag and place in a sterile sample cup.
      8. Repeat steps f through g until all remaining CORDCYTE is transferred to the sterile sample cup.
      9. Using a sterile 20-mL syringe, draw the contents from the sterile sampling cup into the syringe. Inject the solution into the transfer bag labeled DIN and Thaw/Wash Solution.
      10. Repeat until all of the contents from the sample cup is transferred into the DIN and Thaw/Wash Solution transfer bag.
      11. After all contents have been transferred from the sample cup and are contained in the DIN and Thaw/Wash Solution transfer bag, mix well by inverting 180° 10 to 15 times.
      12. Continue with Section D Wash the Thawed CORDCYTE Unit.

Distributed by:

LifeSouth Community Blood Centers, Inc.
LifeCord Cord Blood Bank
4039 Newberry Road
Gainesville, FL 32607
License No. 1647

Principal Display Panel - Bag Label

Product:

S1393V00

LifeSouth
Community
Blood Center
Gainsville
FL
32607

CRYOPRESERVED

HPC, CORD BLOOD

Store at - 150 C or colder

Principal Display Panel - Canister Label

Principal Display Panel - Bag Label

LifeSouth Community Blood Centers

4039 Newberry Road

Gainesville, FL 32607

Collection Date/Time:

05 Jul 2015 23:05 EST

(09 Jul, 2015 03:05 UTC)

O

Rh Positive

For Use by Intended Recipient(s) Only

For Intravenous Administration

Do Not Irradiate

Do Not Use Leukoreduction Filter

Rx Only

Cryopreserved

HPC, CORD BLOOD

Approx 25 mL

10% DMSO, 1% Dextran 40

0.8% Hydroxyethylstarch

Store at -150 C or colder

See package insert for
full prescribing information
and instructions for preparation

Expiration

Date/Time

10 Jul 2018 23:59 EST

(11 Jul, 2018 03:59 UTC)

Intended Recipient

NMDP Patient ID: XXX-XXX-X

LifeSouth Community Blood Centers

Gainesville, FL 32607

US License Number 1647