comparability of cord blood units -...

Comparability of Comparability of

Cord Blood UnitsCord Blood Units

John D. John D. McMannisMcMannis, Ph.D., Ph.D.Professor of Cancer MedicineProfessor of Cancer Medicine

Director, Cell Therapy LaboratoryDirector, Cell Therapy Laboratory

Technical Director, UT Technical Director, UT MDAndersonMDAnderson Cord Blood BankCord Blood Bank

Liaison Meeting, BethesdaLiaison Meeting, Bethesda

June 2007June 2007

SurveySurvey

�� Draft Guidance document allows the CBB Draft Guidance document allows the CBB

to present comparability data for units to present comparability data for units

previously collected by different methodspreviously collected by different methods

�� Snapshot of practices that have been used Snapshot of practices that have been used

by CBB for some of their inventoryby CBB for some of their inventory

–– Asked questions about numbers of different Asked questions about numbers of different

proceduresprocedures

–– Asked questions about “GMP” complianceAsked questions about “GMP” compliance

SurveySurvey

�� Number of centers:Number of centers: 2121

�� Number of responses:Number of responses: 99

�� Note: Last minute requestNote: Last minute request

Quality ControlQuality Control

CryopreservationCryopreservation

ProcessingProcessing

1(2), 2(5), 4(2)1(2), 2(5), 4(2)

-- in in uteroutero vsvs ex ex uteroutero

-- different collection bagsdifferent collection bags

-- donor screeningdonor screening

CollectionCollection

# Different Procedures Used# Different Procedures Used



1 (5), 2 (4)1 (5), 2 (4)

-- Manual Manual vsvs automatedautomated

-- RBC depletionRBC depletion





1 (7), 2 (2)1 (7), 2 (2)

-- CRF CRF vsvs Mechanical B/UMechanical B/U





1 (4), 2 (1), ? (4)1 (4), 2 (1), ? (4)

-- TNC/CFU onlyTNC/CFU only

-- NAT TestingNAT Testing

-- Anaerobic bottlesAnaerobic bottles

-- Missing data (CFU, CD34)Missing data (CFU, CD34)






1)1) AlwaysAlways

2)2) NeverNever

3)3) Past __ yearsPast __ years

Cleaning documentation Cleaning documentation

(instruments and work (instruments and work

area) daily, weekly, area) daily, weekly,

monthlymonthly

1)1) AlwaysAlways

2)2) NeverNever




area) between productsarea) between products

1)1) AlwaysAlways………………8………………8

2)2) NeverNever

3)3) Past __ yearsPast __ years…….1…….1

Complete documentation Complete documentation

of procedureof procedure

GMP Documentation p.1GMP Documentation p.1

1)1) AlwaysAlways

2)2) NeverNever





monthlymonthly

1)1) AlwaysAlways………………4………………4

2)2) NeverNever……………….3……………….3





1)1) Always………………7Always………………7

2)2) NeverNever

3)3) Past __ years…….1Past __ years…….1




1)1) AlwaysAlways………………7………………7

2)2) NeverNever





monthlymonthly

1)1) Always………………4Always………………4

2)2) Never……………….3Never……………….3





1)1) Always………………8Always………………8

2)2) NeverNever





1)1) AlwaysAlways

2)2) NeverNever


Environmental Environmental

Monitoring of VIABLE Monitoring of VIABLE

particles in the Cell particles in the Cell

Processing LabProcessing Lab

1)1) AlwaysAlways

2)2) NeverNever



Monitoring of NON Monitoring of NON

VIABLE particles in the VIABLE particles in the

Cell Processing LabCell Processing Lab

1)1) AlwaysAlways……………..6……………..6

2)2) NeverNever


Materials management Materials management

(Quarantine, Release (Quarantine, Release

specifications, etc)specifications, etc)


1)1) AlwaysAlways

2)2) NeverNever



Monitoring of VIABLE Monitoring of VIABLE



1)1) AlwaysAlways

2)2) NeverNever………………..7………………..7


-- occasionallyoccasionally


Monitoring of Monitoring of NON NON

VIABLEVIABLE particles in the particles in the


1)1) Always……………..6Always……………..6

2)2) NeverNever






1)1) AlwaysAlways

2)2) NeverNever………………..7………………..7

3)3) Past __ yearsPast __ years……..2……..2



Monitoring of Monitoring of VIABLE VIABLE



1)1) AlwaysAlways

2)2) Never………………..7Never………………..7




Monitoring of NON Monitoring of NON

VIABLE particles in the VIABLE particles in the


1)1) Always……………..6Always……………..6

2)2) NeverNever






1)1) AlwaysAlways

2)2) NeverNever


Two person signTwo person sign--off of off of

critical steps of critical steps of

procedure (i.e. addition procedure (i.e. addition

of starch)of starch)

1)1) AlwaysAlways

2)2) NeverNever


Quality review of all Quality review of all

deviationsdeviations

1)1) AlwaysAlways……………….9……………….9

2)2) NeverNever


Training documentation Training documentation

of all personnel involved of all personnel involved

with CBBwith CBB


1)1) AlwaysAlways

2)2) NeverNever






1)1) AlwaysAlways……………….7……………….7

2)2) NeverNever

3)3) Past __ yearsPast __ years……..2……..2



1)1) Always……………….9Always……………….9

2)2) NeverNever




with CBBwith CBB


1)1) AlwaysAlways……………….5……………….5

2)2) NeverNever………………..4………………..4






1)1) Always……………….7Always……………….7

2)2) NeverNever

3)3) Past __ years……..2Past __ years……..2



1)1) Always……………….9Always……………….9

2)2) NeverNever




with CBBwith CBB


Cord Blood TechnologyCord Blood Technology(And HPC(And HPC--A) A)

�� Different than other therapeutic productsDifferent than other therapeutic products–– Half life is 50 years (?)Half life is 50 years (?)

–– Not end stage differentiationNot end stage differentiation

–– Take 20 Take 20 –– 40 days to detect in the periphery40 days to detect in the periphery

–– NonNon--engraftment engraftment �� Maybe due to poor Stem Cell ProductMaybe due to poor Stem Cell Product

�� Double cord transplantationDouble cord transplantation

�� Conditioning regimenConditioning regimen

�� Clinical course during engraftmentClinical course during engraftment

�� Previous chemotherapyPrevious chemotherapy

ComparabilityComparability

�� Based on Clinical utilityBased on Clinical utility

–– Difficult if not impossibleDifficult if not impossible

�� Similar to drug study requirementsSimilar to drug study requirements

�� Large numbers of infusions dilute out the clinical factors Large numbers of infusions dilute out the clinical factors

–– What is the endpointWhat is the endpoint

�� EngraftmentEngraftment

–– 30d, 6mo, 1, 2 5 year engraftment30d, 6mo, 1, 2 5 year engraftment

–– Inhibit new technologyInhibit new technology

�� 11--3% of inventory is used on a yearly basis3% of inventory is used on a yearly basis

–– Inhibit others from entering the fieldInhibit others from entering the field


�� Based on in vitro dataBased on in vitro data

–– Goal is to have the maximum number of CB Goal is to have the maximum number of CB

units available for clinical use balanced with units available for clinical use balanced with

protecting the safety of the patients receiving protecting the safety of the patients receiving

the productthe product

––Less data is betterLess data is better (within reason)(within reason)

–– What are the minimum requirements to What are the minimum requirements to

accomplish this goal accomplish this goal

Choosing a Cord Blood UnitChoosing a Cord Blood Unit

�� HLA: 6, then 5, then 4HLA: 6, then 5, then 4

�� TNCTNC

�� BankBank

�� CD34 NumbersCD34 Numbers

�� All other factors are reviewed but usually All other factors are reviewed but usually

at time of CB arrivalat time of CB arrival


Suggested ParametersSuggested Parameters

�� TNCTNC

�� HLAHLA

�� SterilitySterility

�� CFU (growth) OR CFU (growth) OR

�� Viable CD34 (presence)Viable CD34 (presence)

�� In In uteroutero vsvs ex ex uteroutero

–– Published studies showing no difference in vitro or in Published studies showing no difference in vitro or in

vivovivo

�� Collection bagsCollection bags

–– Qualification/validation runs of the different bagsQualification/validation runs of the different bags

�� Viability and sterility of cellsViability and sterility of cells

�� Donor screeningDonor screening

–– License products as is with requirement of a callback License products as is with requirement of a callback

at time of CT. If unreachable, then label at time of CT. If unreachable, then label

appropriatelyappropriately

1(2), 2(5), 4(2)1(2), 2(5), 4(2)

-- in in uteroutero vsvs ex ex uteroutero

-- different collection bagsdifferent collection bags

-- donor screeningdonor screening


�� Manual Manual vsvs automatedautomated

–– In vitro split runs comparing productsIn vitro split runs comparing products

�� Sterility, viability, CFUSterility, viability, CFU

–– Minimum number Minimum number -- ??????

�� RBC depletion RBC depletion vsvs no depletionno depletion

–– Same comparisonSame comparison

1 (5), 2 (4)1 (5), 2 (4)

-- Manual Manual vsvs automatedautomated

-- RBC depletionRBC depletion


�� Validate your methodValidate your method

–– Viability and yieldViability and yield

–– Sterility….yes but how?Sterility….yes but how?

�� Two methodsTwo methods

–– Split runs and compare viability and yieldSplit runs and compare viability and yield

1 (7), 2 (2)1 (7), 2 (2)

-- CRF CRF vsvs Mechanical B/UMechanical B/U


�� Minimum QC of TNC, HLA, Sterility and Minimum QC of TNC, HLA, Sterility and either CFU or CD34either CFU or CD34

�� NAT testing/Anaerobic microNAT testing/Anaerobic micro

–– Products licensed with requirement that NAT Products licensed with requirement that NAT (or Sterility) be done at time of CT(or Sterility) be done at time of CT�� NAT and Cord BloodNAT and Cord Blood

�� Missing dataMissing data

–– Product licensed with requirement that test be Product licensed with requirement that test be performed on segment (vial) at time of CTperformed on segment (vial) at time of CT

1 (4), 2 (1), ? (4)1 (4), 2 (1), ? (4)

-- TNC/CFU onlyTNC/CFU only

-- NAT TestingNAT Testing

-- Anaerobic bottlesAnaerobic bottles

-- Missing data (CFU, CD34)Missing data (CFU, CD34)



GMP Manufacturing ConditionsGMP Manufacturing Conditions

�� Require analysis for all of the “GMP” Require analysis for all of the “GMP”

requirements that have not been performedrequirements that have not been performed

–– Quality review of the effect of this deficiency on the Quality review of the effect of this deficiency on the

potential safety of the product as part of Licensure potential safety of the product as part of Licensure

submission submission

–– Example: No documentation of cleaning between Example: No documentation of cleaning between

productsproducts

�� Overall contamination rate before and after implementing Overall contamination rate before and after implementing

this documentationthis documentation

�� Review all positives and look upstream and downstream in Review all positives and look upstream and downstream in

manufacturing process to see if any other contaminationmanufacturing process to see if any other contamination

�� Viral screening on products processed in the same time Viral screening on products processed in the same time

periodperiod


Additional Information (if available)Additional Information (if available)

�� EngraftmentEngraftment

�� ChimerismChimerism for single CB infusionsfor single CB infusions

Questions for discussionQuestions for discussion

�� BackBack--up proceduresup procedures

�� New technologiesNew technologies

�� Donor HistoryDonor History

comparability of cord blood units -...

Documents