Share the Science FDA Licensure of HPC, Cord Blood: How Licensure Has Improved Cord Blood Banking

Transcription

1 Share the Science FDA Licensure of HPC, Cord Blood: How Licensure Has Improved Cord Blood Banking Presented by: Sharon Miller, MT(ASCP), CHS(ABHI) University of Colorado Cord Blood Bank Director of Regulatory Affairs, ClinImmune Labs

2 Share the Science Webinar Series + Educational Partnership + Focus on industry topics and trends + Research + Expert opinions + Industry news + Expert speakers

3 Introducing Mediware + History + Incorporated in Over 3,000 installed customer facilities + Over 400 employees and now a private company backed by Thoma Bravo private equity + Products and Solutions + Blood & Cellular Therapy Management + Medication Management + Performance Management + Home Care (a.k.a. Alternate Care ) + Installations across the world including + U.S., Canada, Ireland, U.K., South Africa, Holland, Belgium and Singapore + Locations - Headquarters: Kansas City + Chicago, Jacksonville, Atlanta, Providence (RI), Pittsburgh, Indianapolis, St. Louis, Chandler, AZ + Merged with Thoma Bravo in 2012 for the purpose of going private previously listed on NASDAQ

4 4 Mediware Solutions InSight Extensions

5 Transtem Cellular Therapy Software + Two Primary Component Offerings: + Transtem Lab: For Cellular Therapy Labs, Cord Blood Banks and Regenerative Medicine Programs + Transtem Patient: For Cancer Centers and Bone Marrow Transplant (BMT) Programs + Bridges donor, product and patient information into a single environment + Improves how we access and share information + Drives compliance with standards and regulatory bodies + Provides comprehensive management of stem cell transplants + Provides strong analytical tools for program quality improvement and to drive research + Allows for the management of multiple business lines through a single system 5

6 Introducing Save the Cord Foundation For more information about Save the Cord Foundation and saving cord blood, please visit

7 Introducing Sharon Miller Sharon Miller, MT(ASCP), CHS(ABHI) Director of Regulatory Affairs, ClinImmune Labs Supervisor of University of Colorado Cord Blood Bank

8 FDA Licensure of HPC, Cord Blood: How Licensure Has Improved Cord Blood Banking Sharon Miller, MT (ASCP), CHS (ABHI) Director of Regulatory Affairs ClinImmune Labs, UCCBB

9 Introduction This webinar will detail the positive effects of FDA licensure on HPC, Cord Blood products. Over a period of three years, since the 2012 FDA approval, the University of Colorado Cord Blood Bank has been licensed to cgmp manufacture the minimally manipulated allogeneic 351 products for distribution. This webinar will provide insight from a bank that has experienced the biologic license application (BLA) and distributed licensed products for infusion.

10 ClinImmune Labs-University of Colorado Cord Blood Bank FDA Biologic License # 1855 issued May 24, 2012 How does licensure affect transplant centers, search coordinators, collection sites, cord blood banks and the teams that consent, collect, evaluate and assess donor risk?

11 FDA 3356 HPC, Apheresis and HPC, Cord Blood Changes must be submitted within 5 days Renew each December or June

12 Positive changes in the Cord Blood Bank that resulted from FDA GMP licensure Cord Blood Collection Site/ Research Monitoring Many CB Collection Recovery sites (Hospitals) have opted NOT to require Internal Review Board (IRB) oversite for licensed cord blood banking of the de-identified waste product. While data tracking and reporting to the FDA 1 is required, the individual hospital specific annual IRB data reporting, consent updates, and submission deadlines are no longer required.

13 FDA Laws and Regulations: Donor risk/eligibility, Consenting and Shipment The FDA has moved from the collection and processing of HPC, Cord Blood to the Storage, Processing and Distribution. Fresh cord blood must be stored at C (59-77 F)- any deviation will not be licensed, unless validated.

14 Positive Changes for the Consent and Collection Team Cord Blood Collection Site/ Research Monitoring Although cord banking accrediting agencies (AABB, FACT) will maintain review of collection hospitals, the FDA does not inspect recovery sites (Labor and Delivery decks). Informed Donor consenting continues and review may still be requested for approval by the hospital. The plan is to keep informed consent simple!

15 Maternal Donor Testing for Communicable Diseases (b)maternal Test sample must be collected at, or up to 7 days before or after product cord blood collection (c) Infectious Disease Test Kits used must be licensed!

16 FDA and the Consent and Collection Team 2

17 HPC Donor Risk Assessment Screen for Communicable Diseases: History for BOTH Donor and Family Questionnaires and Hospital History and Physicals (For HPC, Cord Blood Both maternal and baby) 21 CFR Part of 1271 Subpart C

18 Positive changes for the Transplant Center that resulted from FDA GMP licensure FDA Defined and Standardized Donor Eligibility All FDA licensed products are donor eligible. There is no requirement to determine if the cord blood meets FDA licensed infectious disease testing requirements, or if there is CJD/WNV risk. You know that an Urgent Medical Need (UMN) is not required, testing and risk assessment are complete and there is no need to track down and confirm genetic screening for hemaglobinopathy.

19 Cord blood products have benefitted from licensed GMP manufacturing and distribution: 1) Standardizing sterility testing (14 days of incubation/ local environmental pathogens.) = safe and pure products. 1) Standardized TNC, CD34 and RBC content and complete documentation = potent, safe and pure products. 1) Limiting transient warming = potent products. 2) Expiration dating and annual stability testing = potent products. 3) Standardizing Labeling / Product Specific COI / PI. = safe products 4) Post Thaw QC Sample Release Criteria for COA = potent products. 5) Reserve Sample save one year after release = safe products. 6) Standardized, validated and quality controlled FDA approved excipient CB product components = pure products. 7) In 2007 it was predicted that We anticipate that the introduction of GMP will reduce the incidence of microbiological contamination in the future. 6 Disinfectant efficacy studies are no longer FDA required- COA only!

20 Cord blood products have benefitted from licensed manufacturing: Propionibacterium Acnes- Day 9,9,11. (3/125+) 1) Collecting a sterile cord blood from a vaginal birth requires careful decontamination and standardized validation of the sterility testing process. If you set an expected positive sterility rate (<10%), you do not need to test prior to processing- thereby saving valuable CB volume / TNC cells. Standardizing Sterility Testing: -14 days of incubation in detection systems is shown to detect organisms when Maternal donors are on antibiotics at birth (Resin Optimal.) -Standardized # bacterial colony CFU (<100). Also be sure to mix CB and CFU to spike BACTEC bottles under the same inoculation conditions as testing CB. -Testing with pathogens known to grow in the cord blood manufacturing Environment. (Note: you will be allowed to sterility test CB prior to freeze solution, if you validate Freeze solution sterility separately.)

21 Cord blood products have benefitted from licensed manufacturing: 1) Standardized TNC, CD34 and RBC content. TB Viability test now includes a standardized positive control. Mean Collected Volume(ml) % PreCryo Viability TNC Collected (x10e9) TNC Cryopreserv ed (x10e9) CD34 Cryopreserve d (x10e6) Volume RBC_POS T (ml) Range mL % x 10e x 10e x 10e ml

22 Complete Documentation in the HPC Master Batch Records

23 Since licensure, six hundred and fifty licensed Rx Only CBU Absolute TNC x 10e9 (Must be >0.5 x 10e9) FDA Licensed CBU 17/650 licensed CBU distributed Absolute CD34 x 10e6 (Must be >1.25 x 10e6)

24 What Does the Transplant Physician Want? An average TNC of 1.8 x 10 9 Lic CBU N=17 TNC x 10e9 Avg TNC 2.17 median 1.94 sd 0.55 range B Freed

25 In-Process and Final Release Criteria Characteristics of HPC Products 21 CFR HPC, Cord Blood Testing Infectious disease Tested (21 CFR through ) Sample (Type and Timing) Maternal peripheral blood obtained within 7 days of cord blood collection Type and Timing-see Table D below (21 CFR (a) and (b)) Results of Product Testing All tests negative except non-treponemal test for syphilis when confirmatory test is negative. (Cytomegalovirus (CMV) results are recorded). Sterility - Bacterial and fungal cultures Testing Required. (21 CFR (b), and 21 CFR ) Hemoglobin HPC-C (pre- cryopreservation) Fresh Baby blood or frozen CB donor RBC sample obtained at time of cord blood recovery No growth at 14 days No homozygous hemoglobinopathy Total nucleated cells (TNC=WNC + NRBC) HPC-C (pre-cryopreservation) 5.0 x 10 8 TNC/ unit HPC-C Viable nucleated cells HPC-C (pre-cryopreservation) 85% viable nucleated cells tested by trypan blue Viable CD34+ cells (flow cytometry) HPC-C (pre-cryopreservation) 1.25 x 10 6 viable CD34+ cells/unit HPC-C Human leukocyte antigen (HLA) Typing ABO Rh Human leukocyte antigen (HLA) Typing Cord Blood Cord Blood Attached segment of HPC-C Report & Search Class I Serologic HLA- A, B and Class II HLA-DRB1 Molecular High Resolution Report Report and Confirm Class I Molecular HLA- A, B Moderate resolution and Class II HLA- DRB1 Molecular High Resolution

26 Cord blood products have benefitted from licensed manufacturing: 1) Limiting transient warming: Licensed banks have to validate training to establish and limit acceptance criteria for time of transient warming during product storage transfers and integrity checks. 2) EXPIRATION: Although it has been published that HPC, Cord blood products stored a < -150 C for more than 25 years are stable and do not expire, FDA has required individual bank expiration dating based on products processed in the exact same way and with the same materials as licensed CBU. 3) Stability: FDA requires annual individual bank stability testing to confirm that the expiration date is reliable to release potent products. 4) Inventory Control: Standardized, validated and quality controlled FDA approved equipment (510K), excipient and material components.

27 HPC Critical Equipment, Supplies, Containers and Closures 21CFR K, NDA, BK listing ID # Use Container Manufacturer name and address Primary collection bags #1 Collection bag: 250 ml blood Baxter Fenwal The bag and tubing is made of PL 146 collection bag #4R0837MC 120, RLP Plastic Container. This is a less 35 ml of Anticoagulant permeable plastic and is Polyvinyl Citrate Phosphate Dextrose Chloride (PVC) two sealed access stoppers for processing and one (CPD) Solution attached collection port. Automated sterile processing system- SEPAX representative has not released kit composition, but ETO sterilization is noted. #3. Contains one access port for collection bag and one processing port for Cryo bag. Sepax Cell Separation System System CS-530 with attached buffy coat cryo bag-(cryo bag not used.) CS-430 without attached Cryo buffy coat bag BioSafe SA Rte du Petit-Eysins 1262 Eysins FDA NDA or 510(k) # and weblink to clearance NDA BloodVaccines/BloodBloodProducts/Ap provedproducts/newdrugapplicationsn DAs/UCM pdf PDF Ref: 4R0837 and BN BK BloodBloodProducts/ApprovedProducts/Sub stantiallyequivalent510kdeviceinformation/u cm htm PDF Ref: BK #1 #3 21 CFR Parts of 1271, 211

28 Five HPC-C split in two and stored. Long term thawed at 8 months Long Term 8 months Thawed Origen Thawed Miltenyl Thawed Baxter %TNC Rec %TNC Rec %TNC Rec %TNC Rec %TNC Rec Mean % TNC Recovery NS %CFU-GM Rec %CFU-GM Rec %CFU-GM Rec %CFU-GM Rec %CFU-GM Rec Mean % CFU Recovery median %CD34 Rec %CD34 Rec %CD34 Rec %CD34 Rec %CD34 Rec Mean CD34% Recovery NS TB % Viab TB % Viab TB % Viab TB % Viab TB % Viab Mean TB % Viability NS 7AAD % Viab AAD % Viab AAD % Viab AAD % Viab AAD % Viab Mean 7AAD % Viability NS Long Term Mean Cryo Bag Review HPC, Cord Blood Potency N=5 % TNC Recovery % CD34 Recovery % CFU Recovery TB % Viability 7AAD % Viability Origen Miltenyi Baxter

29 Standardized CRF Graph review Validate and define in your SOP the critical limits for CRF graph issues Phase 2A Glass Phase transition to - 55 o C. Check to see that chamber temperature equals the programmed temperature as defined by the cryopreservation program. Maximum chamber cooling rate must not exceed C/min. Once the product has reached -15 o C, make sure that it does not warm up beyond -8 o C. Program 1. Wait at 5.0 o C 2. Ramp 1.0 o C/min. until Sample = -9.0 o C 3. Ramp 30.0 o C/min. until Chamber = o C 4. Ramp 15.0 o C/min. until Chamber = o C 5. Ramp 1.0 o C/min. until Chamber = o C 6. Ramp 10.0 o C/min. until Sample = o C 7. End

30 Transplant centers have benefitted from licensed distribution: 1) Standard Labeling: Licensed products require a product specific package insert (PI) which replaces the generalized AABB COI. This gives TC the background on adverse infusion reactions for the specific manufactured product. 2) Certification of Acceptabililty/Analysis: Licensed products require post thaw QC for product release for distribution. FDA approved COA have set reference ranges for HPC, Cord Blood product shipment. 3) Reserve Sample: Licensed product manufacturer s are required to retain product samples for at least 1 year after the distribution of he product, thus giving the transplant center the ability to re-test samples, if needed. 4) FDA (PAERS) safety reports for adverse events reported with distributed licensed products: 0/17.

31 21 CFR Subpart J Subopart D subpart E Complaint Files and Reports of Adverse Infusion Experiences UCCBB data: Most Common AIE HTN Nausea fever chills bradycardia ANC Engrafted DOC DNE slide 31

32 UCCBB Package Insert for Cord Blood Injection Licensed products require a package insert from the manufacturer which lists all components of the product, dose instructions and possible adverse events associated with infusion. Also required: Instructions for wash and emergency protocol in case of bag break.

33 IND HPC-C Product Complaints Lic # 1855 HPC-C Product Complaints NMDP cord blood advisory group: Quality subcommittee reviewed 44 TC complaints from July December (approx total distributed) Although 14/44 were related to transport problems and could happen with either IND or Licensed CBU, the rest were associated with improper labeling (13), poor product quality (15) and distribution without infectious disease testing (2). One case out of seventeen reported a case of an expected AIE of hypertension. There have been no reports of licensed HPC-C product complaints.

34 Transplant Centers have benefitted from licensed manufacturing and distribution: 1) Standardized Donor Eligibility (DE): Licensed products must be DE. 2) Standardized Infectious disease testing: Meet FDA requirements. 3) Standardized CD34: FDA approved Flow cytometric techniques. 4) Standardized Viability Potency Assay: FDA required viability assay controls to reduce the subjectivity of interpretation and confirm consistent reproducibility.

35 Percent CBU Post Thaw Potency assays Figure Transplant Centers ClinImmune Labs Viability Recovery Viability Recovery B Freed

36 Percent Engrafted FDA Annual Report 1 : Must include Licensed HPC-C Product Potency Review Absolute Neutrophil Count(ANC) Figure Median = 26 days Percent Engrafted = 94.2% Days After Infusion

37 Ways to improve consistent manufacture of HPC, Cord Blood products that are safe, pure and potent. Licensed HPC, Cord Blood are manufactured ONLY under FDA approved processes. If a critical reagent is in short supply, an emergency validation of a close enough replacement, would need complete FDA prior approval supplement (PAS) to be used for licensed product manufacture. Any SOP deviation, no matter how minor to the manufacturer, does not result in a licensed product the transplant center no longer has to worry about the manufacturer s subjective interpretation of the deviation.

38 University Of Colorado Cord Blood Bank Cord Blood Processing Chart FDA Licensed #1855 Registered # AABB Accredited Denver Health Hospital, Exempla St Joseph Hospital, Phoenix Baptist St Joseph Phoenix Consent, Donor Eligibility, Cord Blood and Maternal Sample Collection Cord Blood Transport w/in 24 hours Storage and shipping temperature C ClinImmune Labs University of Colorado Cord Blood Bank Determine Cord Blood Storage & Shipping Temperature, Weight, Volume and TNC Storage temp C TNC > 2.0 x 10 9 Screen Consent Forms and Donor Eligibility History Storage temperature C CB<44 hours old Not Donor Eligible or >48hrs old BioHazard Discard Contracted services UH Clinical Lab: Pre 0.5 ml : STAT ABO/Rh 0.5 ml : Sterility CAP # FDA # CLIA # 06D C Freezer LN 2 Freezer < -150 C UC Cord Blood Bank: Reference Aliquots 4 ml CB Plasma 2 ml CB Red Blood Cells 1.8 ml maternal plasma 1.8 ml maternal RBC 2 ml Viable CB TNC QC vials, 3-4 attached CB Segments Clean Room Cord Blood Processing Samples Pre Processing Red Blood Cell Depletion Plasma Reduction Adding Freezing Solution 3-4 attached segments ClinImmune Stem Cell Laboratory: Post 0.2 ml FTA 0.5 ml TNC & Viability 0.5 ml CFU FDA # CLIA # 06D CAP# FACT Accredited UH Clinical Lab: Post 0.5 ml: CD 34, 7AAD 5.0 ml Product waste: Sterility 0.5 ml: ABO/Rh Controlled Rate Cryo Freezer LN 2 Vapor Quarantine Freezer < -150 C Bonfils Blood Center Maternal Infectious Disease 2 Maternal EDTA Samples 1 Maternal Red Top Sample AABB Accredited FDA # CAP # CLIA # 06D LN 2 Permanent Storage Freezer < -150 C ClinImmune HLA Lab: 0.2 ml HLA Typing CLIA # 06D CAP# ASHI#02-4-CO-12-1

39 GMP Clean Room Processing with Monitored Environments

40 UCCBB Processing and Clean Room Cleanroom Filter HVAC Layout ClinImmune Labs University of Colorado Cord Blood and Stem Cell Laboratory BioScience Place E Montview Blvd Suite 300 and 360 Aurora, CO Supply Roof Top Unit 3 Air Supply Return air Plenum Space 10% Outside Air Return Air Exhaust Flue 3 1 Hep a 3 Hepa 4 Hepa 5 Hepa RM Hepa 6 Hepa 2 Ceiling Return 7 Hepa Low wall returns Air Return Ceiling Return Gwn Rm Hepa Filters RM 312A 1 Hepa 1 Fan Powered Hepas 2 Hepa 1 Hepa Hematology Lab Rm 305 RM Hepa 4 Hepa RM Hepa 6 Hepa Low wall returns RTU Processed Air 7 Hepa 8 Hepa RM 311A 1 Hep a Ceiling Return Gowning 103 ft^ M^2 94 Ceiling ft^3 Room ft^2 30 M^2 95 Ceiling ft^3 Room 311A ft^ M^2 95 Ceiling ft^3 Room ft^ M^2 91 Ceiling ft^3 Room 312A ft^ M^2 101 Ceiling ft^3

41 Unlimited TC Access to a Licensed FDA Biologic HPC, Cord Blood Off- label Use: Injecting a Licensed Cord blood for purposes other than For use in unrelated donor hematopoietic progenitor 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. If the CBU is a great HLA match and TNC dose, the TC may distribute under IND Use: this is required for injection of an unlicensed minimally manipulated cord blood.

42 Quality Improvement details that may be implemented in the laboratory

43 Sterility & Tips for Cleaning the Umbilical Cord Prior to birth of the placenta, select a cord venipuncture site. Wipe cord with the gauze to remove excess fluid. Clean area with Chloroprep swab provided in kit. Swipe up with one side of the swab and down with the other. Wait 30 seconds for the Chloroprep to dry before venipuncture. Please * Do not allow maternal blood to contaminate venipuncture site. * Do not apply excessive traction to the cord. * In-Vivo collection: Do not manually remove the placenta. 43

44 FDA Requires Complete Validation FDA approval requires that validations must be robust and rigorous. Be sure to list the requirements for Installation Qualification (IQ), Operation qualification (OQ), and Performance qualification (PQ). Acceptance criteria should list requirements for validation of Assay/Process specificity, sensitivity, reproducibility, linearity, robustness and ruggedness. 21 CFR Parts of 1271

45 Expiration Dating and Stability Testing Expiration dates should be related to storage conditions in your own facility with established critical materials. The number of samples used to validate an assigned expiration date (N=31 UCCBB) should undergo a power analysis to determine validation sample size. Annual re-validation and a SOP for stability review must be established to confirm expiration dating. For HPC, Cord Blood a BLA supplement can be submitted to extend product storage expiration CFR Parts of 1271, ,

46 HPC-C Validation Recommendations 5 FDA recommended that the Controlled Rate Freezer be validated for demonstration of maximum capacity for freeze. The Media Fill validation for demonstration of aseptic processing should be performed during maximum capacity processing and should be performed after extensive growth promotion studies on this media and all media used for environmental monitoring. Computer Software must be fully validated and in compliance with BOTH Part 11 and GMP guidelines.

47 HPC-C Master Batch Records and Review The HPC Master Batch record is not complete if it contains only a record of your receipt, processing, and storage. We combined the processing record with all EM records, donor eligibility, hemoglobin, equipment SN, a checklist of each hold time and temperature, SOP versions used, temperature checks, details of % of each reagent used, and a quality unit approval for in-process release. This Batch record and all distribution records must be final released by the quality unit -AFTER medical director review. 21 CFR Parts of 211

48 Summary By standardizing the sterility testing for licensed banking of CBU, requiring GMP compliance and 14 days of incubation, the FDA has improved the likelyhood of infusing a safe and pure product. By requiring the standardized and trained staff definition of transient warming, cell content, quality controlled viability assays, freezing curve review, and fresh storage temperatures, the FDA has improved the likelihood of infusing a potent product. All in all, establishing these checkpoints may seem like a lot of extra work and result in the same quality products we have always banked, however it does also seem to prevent the unlikely event of a compromised unit from being released.

49 How to keep Improving. We do it for them! The donor and patient come first! Watch the data, produce a potent product. Listen to the transplant physician needs. Keep up with the regulations.

50 1. Mediware White Paper: Licensing Your Cord Blood- A Guide to Getting FDA Approval for Marketing your Public Bank s Lifesaving Product as a Prescription Drug, 2015, 2. FDA Guidance for Industry: Eligibility Determination for Donors of Human cells, Tissues and Cellular and Tissue-Based Products, August FDA Guidance for Industry, Process Validation: General Principles and Practices, January, FDA Guidance for Industry, Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellualr and Tissue-Based Products (HCT/Ps), December, FDA Guidance for Industry, Biologics License Applications for Minimally Manipulated, Unrelated Allogeneic Placental / Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System, March, How much GMP do we need to infuse contaminated HPC and DLI products?, Forte, et al, Bone Marrow Transplantation (2007) 40,

51 FDA Licensed Banking Costs per Unit (1,500 units per 25% of collections) Collections $ 694 Processing $ 412 Post processing $ 415 Testing $ 432 Space, equipment, maintenance $ 490 Regulatory and informatics $ 202 Indirect costs $ 185 Total $2,829 HRSA funding $1,282 Net -$1,547

52 Questions?

53 Contact: Mediware: Grace Godsey Save the Cord Foundation: Charis Ober