T R A N S P L A N T A T I O N A N D C E L L U L A R E N G I N E E R I N G

Establishment of an unrelated umbilical cord blood bankqualification program: ensuring quality while meeting Food and

Drug Administration vendor qualification requirements

Fran Rabe, Diane Kadidlo, Lisa Van Orsow, and David McKenna

BACKGROUND: Qualification of a cord blood bank(CBB) is a complex process that includes evaluation ofmultiple aspects of donor screening and testing, pro-cessing, accreditation and approval by professional celltherapy groups, and results of received cord bloodunits. The University of Minnesota Medical Center CellTherapy Laboratory has established a CBB vendorqualification process to ensure the CBB meets estab-lished regulatory and quality requirements.STUDY DESIGN AND METHODS: The deployed quali-fication of CBBs is based on retrospective and prospec-tive review of the CBB.RESULTS: Forty-one CBBs were evaluatedretrospectively: seven CBBs were disqualified based onfailed quality control (QC) results. Eight CBBs did notmeet the criteria for retrospective qualification becausefewer than 3 cord blood units were received and theCBB was not accredited. As of March 2012, three USand one non-US CBBs have been qualified prospec-tively. One CBB withdrew from the qualification processafter successful completion of the comprehensivesurvey and subsequent failure of the provided QC unitto pass the minimum criteria. One CBB failed the pro-spective qualification process based on processingmethods that were revealed during the paper portion ofthe evaluation.CONCLUSIONS: A CBB qualification process is neces-sary for a transplant center to manage the qualificationof the large number of CBBs needed to support aumbilical cord blood transplantation program. A trans-plant center that has utilized cord blood for a number ofyears before implementation of a qualification processshould use a retrospective qualification process alongwith a prospective process.

In May 2005 the US Food and Drug Administration(FDA) mandated the regulation of the manufactureof unrelated umbilical cord blood (UCB).1 To ensurecompliance with the Current Good Tissue Practices

(cGTPs), 21 CFR 1271.210, as it relates to control of the“material” used in manufacture, a comprehensive unre-lated cord blood bank (CBB) vendor qualification systemhas been implemented by Molecular and Cellular Thera-peutics (MCT)2 on behalf of the University of MinnesotaMedical Center, Fairview, and the University of MinnesotaBlood and Marrow Transplant Program.

Due to the nature of unrelated UCB transplantation,which includes consideration for HLA match and celldose, transplant centers must access multiple CBBs toensure optimal outcome. While finding the best unit forthe patient is the transplant physician’s primary concern,ensuring that the cord blood unit comes from a bank thatproduces high-quality cord blood units and complies withall applicable regulations is essential as well. CBBs arevendors and as such should be evaluated by the consumerto ensure that specified requirements are met. Performingan in-person audit of a supplier is a common method toqualify a vendor; this approach is not practical from eithera staffing or a financial standpoint. In-person audits canimpede patient care especially when a new bank hasbeen identified as having the only possible UCB unit for a

ABBREVIATIONS: CBB = cord blood bank; FACT = Foundation

for the Accreditation of Cellular Therapy; MCT = Molecular and

Cellular Therapeutics; UCB = umbilical cord blood.

From Molecular and Cellular Therapeutics, University of

Minnesota, St Paul, MN; and University of Minnesota Medical

Center, Fairview, Minneapolis, MN.

Address correspondence to: Fran Rabe, MS, Molecular &

Cellular Therapeutics, University of Minnesota, 1900 Fitch

Avenue, St Paul, MN 55108; e-mail: rabex022@umn.edu.

Received for publication June 13, 2012; revision received

November 9, 2012, and accepted November 19, 2012.

doi: 10.1111/trf.12085

TRANSFUSION 2013;53:2243-2247.

Volume 53, October 2013 TRANSFUSION 2243

specific patient. Considering these limitations, we devel-oped a paper-based vendor qualification process forCBBs.

MATERIALS AND METHODS

Qualification of a CBB is a complex process thatincludes, but is not limited to, evaluation of multipleaspects of operations, facility management, qualitysystems and process controls, donor screening andtesting, technical aspects of processing, regulatory com-pliance, and accrediting status. The MCT has developedan algorithm that drives the CBB qualification process.The factors that impact the algorithm path are: 1) thenumber of units historically received by our facility fromthe CBB, 2) historical results of the postthaw quality ofthe UCB from the CBB, 3) the CBB accreditation statuswith professional organizations (e.g., AABB or theNetCord-Foundation for the Accreditation of CellularTherapy [NetCord-FACT]). The AABB’s accreditationprocess is based on compliance with the most currentedition of their Standards for Cellular Therapy ProductServices.3 The FACT accreditation process is based oncompliance with the most current edition of that organi-zation’s NetCord-FACT International Standards for CordBlood Collection, Processing, Testing, Banking, Selection,and Release.4 Both sets of standards are comprehensiverequirements, which require that the CBB have the exist-ence of policies, processes, and procedures that bothdirectly and indirectly address elements of a facility’sday-to-day operations, quality processes, product safety,and purity. The standards also include many elements ofthe FDA’s Current Good Tissue Practices. Accreditationby AABB or FACT requires the CBB to have successfullycompleted an application and an on-site audit by quali-fied inspectors and assessors.

The algorithm we have applied to the qualificationprocess is described in the retrospective evaluation and inthe prospective evaluation and is depicted in Fig. 1. Table 1summarizes the qualification process based on theaccreditation status of the CBB.

Retrospective evaluationAt the time the qualification process was initiated, the CellTherapy Laboratory of the University of MinnesotaMedical Center had greater than 15 years of experiencewith the receipt, processing, and storage of unrelated UCBunits for transplant. During this time frame the facilityreceived UCB units from 43 CBBs. Twenty-two of the 43(51%) CBBs are located outside of the United States. Thetwo primary US CBBs provided 26 and 21% of the cordblood units while the two non-US primary banks provided3 and 2% of the total number of units distributed to theCell Therapy Laboratory. Postthaw product characteristicsfrom 1172 UCB units were evaluated for total nucleated

cell count recovery, viability, and colony-forming units(CFUs)–granulocyte-macrophage. The values were thebasis or benchmark for retrospective evaluation of the 43CBBs. While we monitor engraftment results on anongoing basis, a decision was made not to include engraft-ment analysis as a part of the retrospective evaluation dueto the complex nature of double cord blood transplantengraftment, which comprises a large portion of our cordblood transplant data.5 Minimum quality control (QC)indices were derived from a 2 standard deviation (SD) ofhistorical data. The results were:

• Postthaw total nucleated cell count recovery ofgreater than 51%.

• Postthaw viability (by acridine orange/propidiumiodide) of greater than 48%.

• Postthaw CFUs/million cells of greater than 448.

Based on the qualification algorithm, if at least 1 unitwas received where all QC data were acceptable, and theCBB was accredited by one of the professional groups, thebank was qualified. CBBs that had provided 1 to 2 UCBunits, and were not accredited, were required to completea “short” survey related to donor screening and testing,processing methods, and quality systems in addition tohaving acceptable QC results from the previously receivedUCB units. The two groups were handled differently due tothe assumption that those CBBs that were accredited hadappropriate quality systems in place (accrediting organi-zation standards and applications are quality systembased). CBBs that had provided at least 3 cord blood unitsand were not accredited were approved if their QC resultswere acceptable. If the QC results were not acceptable, theCBB was disqualified.

Prospective qualificationNew CBBs, those that have never been used by the trans-plant program, are qualified prospectively. If the bank isaccredited, they must complete the 2.5-page short surveyand must also provide a QC unit for testing without reim-bursement. Both of these sets of criteria must be foundacceptable for the bank to be qualified. New CBBs that arenot accredited must complete a three-page comprehen-sive survey, which includes additional quality systemcomponents beyond those in the short survey.

The broad categories covered in both surveys arequality and regulatory, collection, donor screening andtesting, product processing, and storage. The comprehen-sive survey, required to be completed by the CBBs that arenot accredited, includes elements associated with qualitysystems beyond those in the short survey, such as stafftraining, quality plan, and equipment management.Details related to survey content are shown in Table 2. Thephilosophy we have incorporated within our algorithmis the assumption that the accredited CBBs have

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2244 TRANSFUSION Volume 53, October 2013

experienced and successfully completed a comprehensiveCBB on-site audit.

New CBBs that have never been used by the trans-plant program but hold an FDA license are required to

provide only a QC unit for testing. Completion of a surveyis not required. Less scrutiny for these CBBs is based onthe assumption that the CBB’s Current Good Manufactur-ing Practices, 21 CFR 210 and 211, and Current Good

CBB

Accredited/Approved

AABB, NetCord-FACT

CBUs Received

Previously?

(≥1)

QC

Acceptable?

Complete Short

Survey

QC Unit

Acceptable?

Complete

Comprehensive

Survey

Survey

Acceptable

Get 1 QC Unit

NO

YES

YES

YES

YES

NO

Yes

NO

Ongoing Monitoring

Adverse CBB or

product postqualification

findings that could impact

future cord blood products

CBUs

Received

Previously?

YES ≥ or 3

NO

YES

NO

NO

START

BANK

DISQUALIFIED

BANK

QUALIFIED

QC

Acceptable?YES

YES.

Less < 3

Survey

Acceptable?

Get 1 QC

Unit

QC Unit

Acceptable?

YES

YES

NO

NO

MCTUnrelated

Cord BloodBank

QualificationProcess

NO

NO

retrospective evaluation

retrospectiveevaluation

retrospectiveevaluation

prospectiveevaluation

prospectiveevaluation

New CBB

Licensed Units

Only

Fig. 1. MCT unrelated CBB qualification process. CBU = cord blood unit.

CBB QUALIFICATION PROCESS

Volume 53, October 2013 TRANSFUSION 2245

Tissue Practices, 21 CFR 1271, have been reviewed duringthe FDA pre–Biologics License Application process byFDA personnel.

Future qualification plansThe CBBs that have been retrospectively qualified do notprovide sufficient HLA diversity to meet all our transplantprogram needs, thus requiring expanded access to addi-tional qualified CBBs. Non-US regions, such as Asia, thatare underrepresented with regard to ethnic diversity

within the currently qualified CBBs, will be targeted forfuture qualification.

DisqualificationDisqualification of the CBB after previously acceptabledesignation of the bank may occur at any time after quali-fication of the CBB. The disqualification may be a result ofinformation obtained during ongoing monitoring of UCBproduct performance or may be a result of, but not limitedto the following circumstances:

TABLE 1. Qualification based on accreditation statusCBB qualification algorithm accredited vs. not accredited

Receipt of CBUs for transplantationCBB AABB or NetCord-FACT

accreditedCBB not AABB or NetCord-FACT

accredited

Received 1 or 2 CBUs in past. Met QC criteria. CBB is qualified Complete short survey, FF-169Received �3 CBUs and met QC criteria. CBB is qualified CBB is qualifiedNew bank—never used (received 0 CBU) Short survey, FF-169

Get QC unitComprehensive survey, FF-171Get QC unit

New bank—never used (received 0 CBU) andholds an FDA license for CB

Get QC unit Get QC unit

CBU = cord blood unit.

TABLE 2. Comparison of CBB surveys (short vs. comprehensive)Process Short survey* Comprehensive*

Quality or regulatory and administrativeProvide FDA establishment registration number ✓ ✓Non-US facilities: are you governed by government cord blood regulations? ✓Quality plan ✓AABB or NetCord-FACT accreditation ✓Standard operating procedure table of contents ✓ ✓Procedures for handling patient adverse events ✓Procedures for handling event deviations ✓

StaffProcedures for training ✓

EquipmentProcedures for calibration and maintenance ✓

CollectionTotal number of UCBs collected and available ✓ ✓Cross over from private units to public units ✓ ✓

Donor qualificationProvide donor health history questionnaire ✓ ✓List donor infections disease testing ✓ ✓Donor testing laboratory CMS approved ✓Donor testing kits FDA approved and cleared for donor screening ✓ ✓FDA registration of infectious disease laboratory ✓ ✓

Product processing and storageDescribe processing methods ✓ ✓Describe QC prefreeze requirement ✓ ✓Describe postthaw expected QC results ✓ ✓Describe freezing methods ✓ ✓Describe product storage temperature requirements ✓ ✓Describe product storage monitoring devices ✓ ✓Validation of product shipping containers ✓ ✓Number of units used clinically ✓ ✓Monitoring of engraftment results ✓ ✓

* ✓ = component is required to be addressed by the CBB.CMS = Centers for Medicare & Medicaid Services.

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2246 TRANSFUSION Volume 53, October 2013

• Failure or negative laboratory or clinical results ofUCB units received.

• Patient-associated adverse events either from ourtransplant center or reported by other transplantcenters.

• Voluntary or FDA recalls directly associated with theCBB.

• FDA-associated actions, such as FDA Form 483s orWarning Letters or similar actions from other non-USgovernment authorities.

• Non–US government–associated regulatory compli-ance actions.

• Removal of AABB or FACT approval of the CBB.• Other quality and regulatory issues associated with

the CBB.

RESULTS

Forty-one CBBs were evaluated retrospectively: The distri-bution among US versus non-US CBBs was 19 (46%) and22 (54%), respectively. Seven CBBs were disqualified basedon failed QC results. These seven CBBs consisted of four(57%) US CBBs and three (43%) non-US CBBs.

Eight CBBs did not meet the criteria for retrospectivequalification because less than three UCBs were receivedand the CBB was not accredited. They were thereforeautomatically eliminated from the qualification process.However, the eight CBBs are eligible to be prospectivelyqualified if they successfully complete the short survey,should the MCT choose to pursue their qualification.

As of March 2012, three US and one non-US CBBshave been qualified prospectively. One CBB withdrewfrom the qualification process after successful completionof the comprehensive survey and subsequent failure of theprovided QC unit to pass the minimum criteria. One CBBfailed the prospective qualification process based on pro-cessing methods that were revealed during the paperportion of the evaluation.

DISCUSSION

A CBB qualification process is necessary for a transplantcenter to manage the qualification of the large number ofCBBs needed to support a UCB transplantation program.A transplant center that has utilized UCB for a number of

years before implementation of a qualification processshould employ a retrospective qualification process alongwith a prospective process. We did this by establishingminimum QC indices based on UCB units transplanted atour institution. We also decided to consider professionalassociation (AABB, NetCord-FACT) accreditation status,as we felt this to be a strong indicator of quality practices.Finally, we included a quality-based survey in the qualifi-cation process. Depending on accreditation status andexperience with UCB units from the CBB, a short or com-prehensive survey would be sent to a CBB in the process ofqualification. Our program transplants a significantnumber of unrelated UCB units (>140 per year) and, there-fore, requires access to many CBBs (over 30 US and non–US-based banks). The program process discussed hereallows us to qualify perhaps the most important ofvendors involved in the process of hematopoietic stemcell transplantation. We encourage other programs to ini-tiate such a process.

CONFLICT OF INTEREST

The authors have no conflicts of interest.

REFERENCES

1. Code of federal regulation. Federal Register, Volume 70, No.

100/Wednesday, May 25, 2005. Washington, DC: US

Government Printing Office.

2. McKenna DH, Kadidlo DM, Miller JS, Orchard PJ, Wagner

JE, McCullough J. The Minnesota Molecular and Cellular

Therapeutics Facility: a state of the art biotherapeutics

engineering laboratory. Transfus Med Rev 2005;19:217-28.

3. American Association of Blood Banks. Standards for cellu-

lar therapy product services. 5th ed. Bethesda (MD):

American Association of Blood Banks; 2011.

4. NetCord-FACT. NetCord-FACT international standards for

cord blood collection, processing, testing, banking, selec-

tion and release. 4th ed. Omaha (NE): NetCord-FACT; 2008.

5. Ramirez P, Wagner JE, DeFor TE, Blazar BR, Verneris MR,

Miller JS, McKenna DH, Weisdorf DJ, McGlave PB, Brun-

stein CG. Factors predicting single-unit predominance

after double umbilical cord blood transplantation. Bone

Marrow Transplant 2012;47:799-803.

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