ALLOCORD, 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 ALLOCORD should be done under the direction of a physician experienced in hematopoietic progenitor cell transplantation.

Each unit of ALLOCORD 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 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.

ALLOCORD 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 ALLOCORD 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 ALLOCORD 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 accompanying records sent with each individual unit.

ALLOCORD has the following inactive ingredients: PrepaCyte-CB separation solution, citrate-phosphate-dextrose, dimethyl sulfoxide (DMSO) and Dextran 40. When prepared for infusion according to instructions, the infusate contains the following inactive ingredients: PrepaCyte-CB separation solution, citrate-phosphate-dextrose, Dextran 40, human serum albumin, and residual DMSO.

The effectiveness of HPC, Cord Blood, 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 ALLOCORD 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.

ALLOCORD 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 35 milliliters (ISBT 128 Product Code S1393, ISBT 128 Facility Identifier Number W1205). The exact pre-cryopreservation nucleated cell content is provided in accompanying records.

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

Discuss the following with patients receiving ALLOCORD:

• 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

1 EQUIPMENT, REAGENTS, AND SUPPLIES

EQUIPMENT:

Biologic safety cabinet

Waterbath, 37°C

Heat sealer

Scale

Automated cell counter

Flow cytometer

Microscope

REAGENTS:

25% Albumin (Human), USP

Dextran 40 in Sodium Chloride Injection, USP or Dextran 40 in Dextrose Injection, USP

SUPPLIES:

Sterile sealable zip lock bag

Syringes - 1 mL, 3 mL, 5 mL, 30 mL, 60 mL

18 gauge safety needles

Blunt plastic cannulas

Sterile syringe caps (dual end: male/female)

Alcohol wipes

Plasma transfer sets (2 inch tubing, female luer adapter) – included with product shipment

Transfer packs – 150 mL, 300 mL

Blood culture vials

Blood culture device

Hemostat

2 mL cryovial

2 RECEIPT INSTRUCTIONS

ALLOCORD is shipped frozen in a steel canister that is contained in an insulating foam sleeve. ALLOCORD must be stored at or below -150 °C, either inside the container used for shipping (dry-shipper) or in a liquid nitrogen (LN2)-cooled storage device at the Transplant Center (recommended).

Upon receiving the shipment, perform the following steps:

1. Confirm receipt of the shipment and the identity of the expected unit.
2. Inspect the shipper for tampering or damage prior to opening.
3. Weigh the shipper and document the weight on the Unit Receipt Form.
4. Note the temperature displayed on the data logger and document the temperature on the Unit Receipt Form.
5. Using cryoprotective gloves, remove the product from the canister and place in a reservoir with LN2 or in the vapor phase of aLN2freezer.
6. Carefully open the cassette. Inspect the integrity of the unit(s) received and document its conditions on the Unit Receipt Form.
7. Confirm the identity of the cord blood unit. Include this check on the Unit Receipt Form.
8. Store the product in an LN2 storage vessel that maintains a temperature below -150°C.
9. Reserve the samples that accompany the unit as a DNA source for confirmatory testing or post engraftment studies:
   1. a segment remains on the unit; reserve it prior to thawing the unit
   2. an aliquot containing the material remaining from the red blood cell/plasma reduction
   3. an aliquot containing unmanipulated cord blood collected in Citrate Phosphate Dextrose (CPD)
   4. a spot card containing unmanipulated cord blood collected in CPD (in envelope)

   NOTE: Aside from the segment, ancillary samples are not intended to represent the cell count or potency of the cryopreserved product.

10. Replace data logger temperature probe wire inside the inner dry shipper container if necessary, and reassemble the shipper for return.
11. Fax the completed Unit Receipt Form to St. Louis Cord Blood Bank of the SSM Cardinal Glennon Children's Medical Center at 314-268-4186.

    NOTE: If there is any error or ambiguity with regard to the product documentation, close the canister and keep the product at LN2 temperature. Immediately advise the staff of the St. Louis Cord Blood Bank and the transplant physician. Do not proceed until the problem is resolved. If your LN2 storage tanks have no space to store the product in its canister and insulated sleeve, add LN2 to the St. Louis Cord Blood Bank dry-shipper to keep the product frozen until a completely satisfactory determination is made.

3 PREPARATION

1. Coordination with the clinical team
   1. Confirm the infusion time in advance, adjusting the start time for thaw so the unit is available for infusion when the recipient is ready.
   2. Consult with the clinicians about final product volume based on the recipient's weight and possible fluid restrictions.
2. General Information
   1. Use aseptic technique in a biological safety cabinet for all processing steps, including all open-container processing and all spiking of container ports.
   2. Use only sterile materials when processing the cellular product.
   3. Record the manufacturer information, lot number and expiration date (if applicable) of all reagents and disposables.
   4. Prepare the water bath and verify that the temperature is 37°C.
3. Prepare the reconstitution solution
   1. Combine 250 mL Dextran 40 and 50 mL 25% albumin in a 300 mL transfer pack. Clamp the tubing with a hemostat.
   2. Using appropriate sized syringes, withdraw the following and cap the syringes with blunt plastic cannula:
      1. 50 mL of reconstitution solution. If the total frozen volume (product + DMSO volume) exceeds the standard 50mL reconstitution solution, use a volume of reconstitution solution equal to the total frozen volume so the dilution ratio is at least 1:1
      2. 30 mL of reconstitution solution to be used as a container rinse for microbial culturing
4. Obtain product
   1. Prepare a portable canister with LN2 using appropriate personal protective equipment (gloves, gowns, face shield).
   2. Product verification requires two members of the laboratory staff. With product and recipient files at hand, locate and remove the product from its location in the freezer, but maintaining in vapor phase. Expeditiously verify product identity, labeling, accuracy of information, and container integrity.
   3. Remove any segment attached to the unit, place into a 2 mL cryovial and store in either vapor or liquid phase of nitrogen (<-150°C).
   4. Immediately transfer the product from LN2 storage tank into the portable canister containing LN2.

4 PROCEDURE

Reconstitution or simple dilution of ALLOCORD with dextran/human serum albumin (HSA) solution, using the Thawing and Diluting procedures described below, is recommended. The Alternate Procedure – Washing may be considered if the infusion volume and/or DMSO dose are contraindicated (>1 mL/kg).

NOTE: Minimize the time from initiation of thaw to completion of infusion.

THAWING:

1. Verify the identity of the product being thawed.
   
2. Remove the ALLOCORD unit from the cassette. Examine the cryobag for breaks or cracks.
   
3. Carefully place the unit inside a sterile sealable zip-lock bag, and submerge in the 37°C water bath, keeping port(s) dry and above water.
   
4. Document the thaw start time.
5. To accelerate thawing, gently knead contents of bag.

   NOTE: Inspect for leaks! If container integrity is observed to be compromised, position the cryobag and/or clamp with hemostats to prevent further escape of blood.

6. When the contents of the cryobag become slushy, remove the bag from the 37ºC water bath.
   
7. Note the thaw stop time. Product expiration time is four hours from this step.
8. Gently wipe the outside surface of the cryobag with alcohol, and place the cryobag into the biologic safety cabinet.

   DILUTING:

9. Insert a plasma transfer set into the cryobag.
10. Attach the syringe containing the 50mL reconstitution solution to the transfer set on the cryobag.
11. Slowly introduce approximately half the volume of the reconstitution solution to the thawed product while mixing the fluids in the bag.
    
12. Insert the spike of a correctly labeled appropriate volume capacity transfer pack into the second access port of the cryobag.
13. Weigh the empty transfer pack to determine the tare weight of the bag.
    
14. Drain the contents from the cryobag into transfer pack.
    
15. Clamp the tubing between the bags with a hemostat.
16. Add the remaining reconstitution solution to the cryobag.
17. Mix well to rinse the cells from the bag and drain into transfer pack.
18. Clamp the tubing between the bags.
19. Weigh the transfer pack subtracting the tare weight to get product volume.
20. Insert a transfer set into the product transfer pack.
21. Aseptically attach a 3 mL syringe and aspirate a 1 mL aliquot for quality control testing.
22. Deliver the 1mL testing aliquot into a labeled aliquot tube.
23. Subtract the 1mL (testing aliquot) from product volume to determine infusion volume. Record the infusion volume which will be used for calculating cell numbers.
24. Heat seal the tubing between the cryobag and the transfer pack.
25. Cut tubing at the seals and separate the bags.

    NOTE: At this point, it is approximately 30 minutes from infusion. Notify the clinical transplant team to pre-medicate the patient as ordered.

26. Aseptically introduce the 30 mL of reconstitution solution from the syringe prepared in step 3.c.ii.2) into the (now empty) original product cryobag.
27. Immediately transport the product to the clinical transplant site per the facility's SOP.

ALTERNATIVE PROCEDURE - WASHING:

Perform steps a. through r. of the Thawing Procedure and Diluting Procedure as outlined above, then complete the following:

1. Place the transfer pack into a sterile overwrap bag ready for centrifugation.
2. Support bag in centrifuge bucket insert to prevent the formation of creases during centrifugation.
   
3. Balance carriers and centrifuge at 650 x g (1500 rpm) for 20 minutes at 10°C (no brake).
4. Carefully remove the transfer pack from the centrifuge into the biologic safety cabinet, placing the transfer pack into a plasma expresser.
5. Using the original cryobag to collect the waste volume, express 75% of the volume of reconstitution solution originally added to the thawed product pre-centrifugation. Avoid accidental passage of cells with the supernatant.
   
6. Allow the cells to rest for five minutes. Resuspend the sedimented cell pellet by gentle agitation.
7. Obtain quality control samples as described in steps s. through aa. above.

5 QUALITY CONTROL:

Perform quality control assays per transplant center policies and procedures using the aliquot of thawed product obtained in step u above. Recommended assays include:

1. Nucleated Cell count
2. Viability test
3. Viable CD34+ cell count
4. Colony Forming Unit
5. Microbial cultures (aerobic, anaerobic and fungal)

CALCULATIONS:

Infusion TNC [x109] = (WBC/mL + NRBC/mL [x106]) x infusion volume (mL)

TNC dose [x107/kg] = Infusion TNC [x109]
                                       Recipient wt (kg)

Post-thaw TNC recovery [%] =      TNC of thawed product [x109]           x 100
                                                     TNC of original frozen product [x109]

Total CD34+ cells [x106] = CD34+ cells/mL x dilution factor x 1000 mL x product volume (mL)

CD34+ cell dose [x105/kg] = Absolute CD34+ cell cells (x106) ÷ Recipient weight (kg)

Product RBC volume [mL] = product hematocrit x product volume (mL)

RBC dose [mL/kg] = Product RBC volume [mL] ÷ Recipient weight (kg)

Product CFU count [x105] = Colonies scored per 105 NC x product TNC [x109]
                                                                     105

CFU dose [x104/kg] = Product CFU count [x105] ÷ Recipient weight (kg)

6 CONTACT INFORMATION

SSM Cardinal Glennon Children's Medical Center
St. Louis Cord Blood Bank (SLCBB)
3662 Park Avenue
St. Louis, MO 63110

SLCBB Hours:                   Monday-Friday, 7:00am – 5:00pm, Central Time
SLCBB Phone Number:      314-268-2787 or 888-453-CORD (888-453-2673)
SLCBB Fax Number:          314-268-4186

After Hours Numbers:
Director:          314-486-2488
Distribution:      314-277-1638

DISTRIBUTED BY:
SSM Cardinal Glennon Children's Medical Center
dba St. Louis Cord Blood Bank
1465 South Grand Blvd
St. Louis, MO 63104
US License 1873

Principal Display Panel - Canister Label

6200

A
Rh POSITIVE

For Use By Intended Recipient Only

Properly Identified Intended
Recipient and Product

Expiration Date/Time

26 Feb 2017 10:15 CST
(26 Feb 2014 16:15 UTC)

See package insert for full prescribing
information and instructions for
preparation

Processed By:

SSM Cardinal Glennon Children's Medical Center
St. Louis Cord Blood Bank

3662 Park Avenue
St. Louis, MO 63110

US Lic# 1873

"W1205 14 000014"

Collection Date/Time

25 Feb 2014 15:45 CST
(25 Feb 2014 21:45 UTC)

Do Not Irradiate

Do Not Use Leukoreduction Filter

S1393V00

Cryopreserved

HPC, Cord Blood

Approx. 29 mL including

10% DMSO, 1% Dextran 40;
approx 42% Prepacyte®-CB and 10% CPD

Store at ≤ -150C

Rx Only

For Intravenous administration

Principal Display Panel - Bag Label

"W1205 14 000014"

Product: S1393 V 00
Cryopreserved
HPC, CORD BLOOD

Store at ≤ -150°C

Product Prepared by:

SSM Cardinal Glennon Children's Medical Center
St. Louis Cord Blood Bank

3662 Park Avenue, St. Louis, MO 63110

EXPIRATION DATE:

See Attached Product Tag

FOR USE BY INTENDED
RECIPIENT ONLY

PROPERLY IDENTIFY
INTENDED RECIPIENT AND
PRODUCT

DO NOT USE
LEUKOREDUCTION FILTERS

DO NOT IRRADIATE