HPC (hematopoietic progenitor cells), 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.

Each unit of HPC, Cord Blood contains a minimum of 5.0 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 on the container label and in accompanying records.

HPC, Cord Blood is contraindicated in patients with known hypersensitivity to dimethyl sulfoxide (DMSO), Dextran 40 or plasma proteins. [See Description (11) and Dosage and Administration (2.2)]

Day-100 mortality from all causes was 25%.

The most common infusion-related adverse reactions (≥5%) are hypertension, vomiting, nausea, bradycardia, and fever. (6.1)

HPC, Cord Blood consists of hematopoietic progenitor cells, monocytes, lymphocytes, and granulocytes from human cord blood. 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 HPC, Cord Blood 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 HPC, Cord Blood 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 on the container label and/or accompanying records sent with each individual unit.

HPC, Cord Blood has the following inactive ingredients: dimethyl sulfoxide (DMSO) and Dextran 40. When prepared for infusion according to instructions, the infusate contains the following inactive ingredients: 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 and in retrospective reviews of data from an observational database for HPC, Cord Blood and data in the dockets and public information. Sixty-six percent (n=862) of the 1299 patients in the docket and public data 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 mismatch were inversely associated with the time to neutrophil recovery in the docket data.

HPC, Cord Blood 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 30-124 milliliters (ISBT 128 Product Code S1393, ISBT 128 Facility Identifier Number W3213). The exact pre-cryopreservation volume and nucleated cell content are provided on the container label and accompanying records.

Store HPC, Cord Blood at or below -150°C until ready for thawing and preparation.

Discuss the following with patients receiving HPC, Cord Blood:

• 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.

1 Equipment, reagents, Materials, and forms

Equipment
Water bath
Plasma Extractor
Centrifuge - refrigerated
Balance
Tubing stripers
Sealer
Hemocytometer chamber
Cell counter
Thermometer

Reagents
5% Albumin (human), USP
10% Dextran 40 in Sodium Chloride Solution, USP

Materials
Plasma transfer set
150 mL double transfer pack, 150 mL transfer pack, or 300 mL transfer pack
Centrifuge bag
Plastic tubing clip
Sterile disposable syringes: 1, 5, 10, 20, 30, and 60 mL
18 gauge needle
70% isopropyl alcohol
Sterile water

Forms Provided by ClinImmune Labs
Transplant Center Hematopoietic Progenitor Cells, Cord Blood (HPC, Cord Blood) Thaw Worksheet
Form E5.103 - HPC, Cord Blood Release Report
Form E6.251 - Human Cord Blood Unit Receipt Form
Form E8.102 - Adverse Product Event and Infusion Reaction

2 ADMINISTRATIVE REQUIREMENTS

1. Immediately following receipt of product - Complete Form E6.251 – HPC Unit Receipt Form and fax it to ClinImmune Labs (303-724-1849). Document:
   • Patient's name, medical record number
   • Date and time prior to opening the dry shipper
   • Weight of the dry shipper
   • Match of the HPC, Cord Blood identification number expected with the HPC, Cord Blood number received
   • Condition of the HPC, Cord Blood upon arrival (i.e., still frozen)
   • Internal temperature of the dry shipper
   • Transplant facility information
   • Comments and/or explanation for any deviations
2. Prior to thawing - Review and complete all transport verification to document receipt of the unit against Form E5-103 – HPC, Cord Blood Release Report. If there are any errors or ambiguity, do not proceed. Report any problems to ClinImmune Labs (303-724-1306) and the transplant physician.
3. During thawing - Complete the thaw worksheet.
4. Ensure that Form E8.102 (Adverse Product Event and Infusion Reaction) accompanies the product to the transplant unit.
5. Return the dry shipper as soon as possible. After transplant, return the metal canister at earliest convenience.

Contact Information for ClinImmune Labs at the University of Colorado Cord Blood Bank (UCCBB):

3 VERIFICATION OF PRODUCT IDENTITY

HPC, Cord Blood is shipped frozen in an overwrap in the metal canister. HPC, Cord Blood must be kept at or below -150° C, either inside the container used for shipping (Dry-Shipper) or in vapor phase of a Liquid Nitrogen (LN2) storage device at the Transplant Center (recommended).

1. Check the HPC, Cord Blood identification number (ID) on the label to confirm its identity with the ID of the expected product as soon as it is received (Figure 1).
   

   Figure 1

2. Wearing protective cryogloves, transfer the HPC, Cord Blood from the Dry-Shipper to the vapor phase of a LN2 storage tank.
3. Carefully open the canister while it is in the vapor of the freezer to prevent the bag from cracking and the yellow port covers from popping off (Figure 2).
   

   Figure 2

4. Work carefully to avoid damaging the frozen plastic product bag.
5. Check the bar-coded label on the product against your records to verify that the bar code and visually-readable printed number absolutely conforms to the information previously provided and the documentation included with the HPC, Cord Blood product (Form E6.251 - Human Cord Blood Unit Receipt Form).

4 METHOD

4.1 Preparation of Water Bath

1. A water bath with minimum 2 L capacity is recommended.
2. Clean water bath with 70% isopropyl alcohol and fill with appropriate volume of sterile water.
3. Maintain the temperature of the water bath between 36-38°C prior to thawing the HPC, Cord Blood.

4.2 Preparation of Wash Media

1. Prepare wash media no sooner than one hour prior to the thaw for infusion. Media expires 4 hours after preparation.
2. Determine the total volume of media needed. For reconstitution only, use an equal volume of media to the total HPC, Cord Blood cryo volume. For wash and reconstitution, use twice the total HPC, Cord Blood cryo volume.
   Example:        50 mL of HPC, Cord Blood cryo volume
                            For reconstitution only: 50 mL of media are needed.
                            For reconstitution and wash: 100 mL of media are needed.
3. Prepare the media by mixing equal amounts of 5% albumin and 10% Dextran 40.
   Example: To prepare 50 mL of media, mix 25 mL of 5% albumin and 25 mL of 10% Dextran 40.

4.3 Thawing HPC, Cord Blood

1. Carefully cut and remove the overwrap (Figures 3, 4, and 5).
   

   Figure 3

   

   Figure 4

   

   Figure 5

2. Put the HPC, Cord Blood into a sterile centrifuge bag and place HPC, Cord Blood in the water bath. If there are two cryo bags for the same HPC, Cord Blood, thaw both bags in separate sterile centrifuge bags at the same time.
3. Thaw the HPC, Cord Blood until all frozen portions dissolve into solution.
4. Take the bag(s) out of the water bath, remove the HPC, Cord Blood from the sterile bag(s), and place it into a laminar flow hood.
5. To access a bag with a configuration as shown in Figures 6 and 7, remove the yellow port protector and insert a plasma transfer set into the port. For a bag with configuration as shown in Figure 8, open the port by twisting the upper part of the port.
6. Measure the volume by syringe or weight as per transplant center procedures.
7. Remove a small volume for quality control (QC) testing as per transplant center procedures. If the HPC, Cord Blood has two cryo bags, pool both portions together in the same transfer bag before removing the sample.
   

   Figure 6

   

   Figure 7

   

   Figure 8

8. The thawed HPC, Cord Blood is ready for reconstitution or washing (see below).

4.4 Reconstituting and Washing HPC, Cord Blood

For reconstituting HPC, Cord Blood (dilution)

1. If using a 150 mL double transfer pack, clamp off one of the bags with a plastic clip and drain the HPC, Cord Blood into the open transfer bag (Figure 9).
   

   Figure 9

   For two cryo bags, drain both bags into the double transfer bag or use a 300 mL transfer bag.

2. Use a hemostat to clamp the line to the transfer bag containing the HPC, Cord Blood.
3. Wash the cryo bag by injecting the wash media (equal to the total volume of the frozen HPC, Cord Blood) into the empty bag and rinsing thoroughly (Figure 10).
   

   Figure 10

4. Open the hemostat and slowly drain the wash media into the bag with the HPC, Cord Blood while gently mixing the cells in the bag with a rocking motion. Seal off the empty freezing bag.
5. Remove a small volume of the reconstituted product for QC testing (such as complete blood count (CBC), CFU, CD34+ counts, viability, and sterility) as per transplant center procedures.
6. Allow five minutes for the cells to equilibrate.
7. HPC, Cord Blood is ready for infusion or for washing out the cryoprotectant.
8. The recommended expiration time is four hours at 1-8°C from the time of thaw.

For removing cryoprotectant (washing)

1. Centrifuge the diluted HPC, Cord Blood (with ports up) at 1300 rpm (473 x g) for ten minutes at 1-6°C.
2. Remove the supernatant (equal volume of added wash media) using a plasma extractor (Figure 11).
   

   Figure 11

3. Slowly add the remaining washing media (that was not used in reconstitution).
4. Mix the bag gently.
5. Remove a small volume of the reconstituted product for QC testing (such as CBC, CFU, CD34+ counts, viability, and sterility) as per transplant center procedures.
6. HPC, Cord Blood is ready for infusion.
7. The recommended expiration time is four hours at 1-8°C from the time of thaw.

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

1. Emergency product recovery at transport: If the alarm is blinking red upon receipt of the dry shipper, document on Form E6.251 and immediately use an alternative means to monitor and document the dry shipper temperature. If the temperature is higher than -150°C and there are ice crystals observed in the HPC, Cord Blood, immediately store the HPC, Cord Blood in liquid nitrogen vapor phase and notify the transplant physician. Document the temperature on Form E6.251 and notify ClinImmune Labs, University of Colorado Cord Blood Bank immediately at 303-724-1306.
2. Emergency product recovery at thaw: If any cracks or port integrity leaks are observed in the cryo bag at thaw, remove the HPC, Cord Blood from the water bath and clamp off the leaking portion of the bag with a hemostat. If the HPC, Cord Blood is still frozen, continue to thaw the product with the leaking site clamped tightly. Once thawed, remove the HPC, Cord Blood from the water bath, recover cells in the sterile thawing bag if there are any, and contact the appropriate transplant center staff immediately for further instruction. Document all findings on Form E8.102 and fax it to the ClinImmune Labs, University of Colorado Cord Blood Bank at 303-724-1849

Distributed by:
ClinImmune Labs
University of Colorado Cord Blood Bank (UCCBB)
1999 North Fitzsimmons Parkway, Suite 160
Aurora, CO 80045
US License #1855

Issued: 05/2012

Principal Display Panel – Bag Label

HPC, Cord Blood
Approx & VOL.: mL
Additives & Vol.: mL DMSO
DEXTRAN. < mL HESPAN
< mL CPD. EtO may persist
For Intravenous Infusion
Do Not Irradiate
Do Not Use Leukoreduction Filters
Store at <= -150C

Caution: Federal Law prohibits
distribution without a prescription

ClinImmune Labs – UCCBB
12635 E. Montview Blvd.
Aurora, CO 80045