comparability of cord blood units -...
TRANSCRIPT
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�� Draft Guidance document allows the CBB Draft Guidance document allows the CBB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
Quality ControlQuality Control
CryopreservationCryopreservation
1 (5), 2 (4)1 (5), 2 (4)
-- Manual Manual vsvs automatedautomated
-- RBC depletionRBC depletion
ProcessingProcessing
CollectionCollection
# Different Procedures Used# Different Procedures Used
Quality ControlQuality Control
1 (7), 2 (2)1 (7), 2 (2)
-- CRF CRF vsvs Mechanical B/UMechanical B/U
CryopreservationCryopreservation
ProcessingProcessing
CollectionCollection
# Different Procedures Used# Different Procedures Used
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)
Quality ControlQuality Control
CryopreservationCryopreservation
ProcessingProcessing
CollectionCollection
# Different Procedures Used# Different Procedures Used
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
3)3) Past __ yearsPast __ years
Cleaning documentation Cleaning documentation
(instruments and work (instruments and work
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
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………………4………………4
2)2) NeverNever……………….3……………….3
3)3) Past __ yearsPast __ years…….2…….2
Cleaning documentation Cleaning documentation
(instruments and work (instruments and work
area) between productsarea) between products
1)1) Always………………7Always………………7
2)2) NeverNever
3)3) Past __ years…….1Past __ years…….1
Complete documentation Complete documentation
of procedureof procedure
GMP Documentation p.1GMP Documentation p.1
1)1) AlwaysAlways………………7………………7
2)2) NeverNever
3)3) Past __ yearsPast __ years…….1…….1
Cleaning documentation Cleaning documentation
(instruments and work (instruments and work
area) daily, weekly, area) daily, weekly,
monthlymonthly
1)1) Always………………4Always………………4
2)2) Never……………….3Never……………….3
3)3) Past __ years…….2Past __ years…….2
Cleaning documentation Cleaning documentation
(instruments and work (instruments and work
area) between productsarea) between products
1)1) Always………………8Always………………8
2)2) NeverNever
3)3) Past __ years…….1Past __ years…….1
Complete documentation Complete documentation
of procedureof procedure
GMP Documentation p.1GMP Documentation p.1
1)1) AlwaysAlways
2)2) NeverNever
3)3) Past __ yearsPast __ years
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
3)3) Past __ yearsPast __ years
Environmental Environmental
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
3)3) Past __ yearsPast __ years…….3…….3
Materials management Materials management
(Quarantine, Release (Quarantine, Release
specifications, etc)specifications, etc)
GMP Documentation p.2GMP Documentation p.2
1)1) AlwaysAlways
2)2) NeverNever
3)3) Past __ yearsPast __ years
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………………..7………………..7
3)3) Past __ yearsPast __ years…….2…….2
-- occasionallyoccasionally
Environmental Environmental
Monitoring of Monitoring of NON NON
VIABLEVIABLE particles in the particles in the
Cell Processing LabCell Processing Lab
1)1) Always……………..6Always……………..6
2)2) NeverNever
3)3) Past __ years…….3Past __ years…….3
Materials management Materials management
(Quarantine, Release (Quarantine, Release
specifications, etc)specifications, etc)
GMP Documentation p.2GMP Documentation p.2
1)1) AlwaysAlways
2)2) NeverNever………………..7………………..7
3)3) Past __ yearsPast __ years……..2……..2
-- occasionallyoccasionally
Environmental Environmental
Monitoring of Monitoring of VIABLE VIABLE
particles in the Cell particles in the Cell
Processing LabProcessing Lab
1)1) AlwaysAlways
2)2) Never………………..7Never………………..7
3)3) Past __ years…….2Past __ years…….2
-- occasionallyoccasionally
Environmental Environmental
Monitoring of NON Monitoring of NON
VIABLE particles in the VIABLE particles in the
Cell Processing LabCell Processing Lab
1)1) Always……………..6Always……………..6
2)2) NeverNever
3)3) Past __ years…….3Past __ years…….3
Materials management Materials management
(Quarantine, Release (Quarantine, Release
specifications, etc)specifications, etc)
GMP Documentation p.2GMP Documentation p.2
1)1) AlwaysAlways
2)2) NeverNever
3)3) Past __ yearsPast __ years
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
3)3) Past __ yearsPast __ years
Quality review of all Quality review of all
deviationsdeviations
1)1) AlwaysAlways……………….9……………….9
2)2) NeverNever
3)3) Past __ yearsPast __ years
Training documentation Training documentation
of all personnel involved of all personnel involved
with CBBwith CBB
GMP Documentation p.3GMP Documentation p.3
1)1) AlwaysAlways
2)2) NeverNever
3)3) Past __ yearsPast __ years
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……………….7……………….7
2)2) NeverNever
3)3) Past __ yearsPast __ years……..2……..2
Quality review of all Quality review of all
deviationsdeviations
1)1) Always……………….9Always……………….9
2)2) NeverNever
3)3) Past __ yearsPast __ years
Training documentation Training documentation
of all personnel involved of all personnel involved
with CBBwith CBB
GMP Documentation p.3GMP Documentation p.3
1)1) AlwaysAlways……………….5……………….5
2)2) NeverNever………………..4………………..4
3)3) Past __ yearsPast __ years
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) Always……………….7Always……………….7
2)2) NeverNever
3)3) Past __ years……..2Past __ years……..2
Quality review of all Quality review of all
deviationsdeviations
1)1) Always……………….9Always……………….9
2)2) NeverNever
3)3) Past __ yearsPast __ years
Training documentation Training documentation
of all personnel involved of all personnel involved
with CBBwith CBB
GMP Documentation p.3GMP Documentation p.3
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
ComparabilityComparability
�� 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
ComparabilityComparability
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
CollectionCollection
�� 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
ProcessingProcessing
�� 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
CryopreservationCryopreservation
�� 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)
Quality ControlQuality Control
ComparabilityComparability
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
ComparabilityComparability
Additional Information (if available)Additional Information (if available)
�� EngraftmentEngraftment
�� ChimerismChimerism for single CB infusionsfor single CB infusions