Storage of Cellular Therapy Products:

Issues Related to Duration, Discard

and Quarantine

Co-Chairs:
Leigh Sims Poston, BS, MT(ASCP)
Michele W. Sugrue, MS, MT(ASCP)SBB

Speakers:
Dr. Phyllis I. Warkentin
Director, Transfusion and Transplantation
University of Nebraska Medical Center
Dr. Linda L. Kelley
Director, Cell Therapy Facility
University of Utah Cell Therapy Facility

Dr. Vincent F. La Russa

Director, Cytotherapy Laboratory
Memorial Sloan-Kettering Cancer Center

Learning Objectives:
1. Review points to consider in developing storage duration and
product disposal policies/documents.
2. Review the QC/QA aspects of product disposal to include
product traceability, accountability and cross check.
3. Identify/Review GTP/GMP requirements for product quarantine.
4. Provide guidance for inventory management strategies.

Cellular Therapy Products

Storage, Disposal, Standards
Phyllis I. Warkentin, MD
University of Nebraska Medical Center
Foundation for the Accreditation of Cellular
Therapy
October 22, 2008

Objectives
Points to consider in HCT/P storage
duration and product disposal policies
Scientific considerations
Legal and Ethical issues
Practical considerations

Review applicable professional standards

Example

Cellular Therapy Product Storage

Scope of Policies
HPC, Apheresis; HPC, Marrow; TC
Autologous; Allogeneic products
Variable quantities:

Whole collection(s) not used; back-up

Left-over portions large and small
Aliquots
Residual cells from testing

HPC, Cord Blood; not unique CB Bank issues

Laboratory perspective
6

CT Product Disposal
Common reasons for product disposal:

Death of the intended recipient

No further need for product
Compliance with Registry agreements
Poor quality product / contaminated

Common product dispositions:

Offer to patient to relocate product
Discard to biohazard waste according to applicable
laws and regulations
Release to research
Reassign to allogeneic donor
Indefinite storage
7

CTP Storage Duration Policies

Scientific considerations:
Viability maximum storage time unknown
Cryopreservation theory
Observations:
At least 15 years as measured by flow cytometry,
clonogenic assays, and hematopoietic reconstitution in
NOD/SCID mice and in patients

Contamination
Positive infectious disease marker tests in donor
Microbial contamination
Malignant cell contamination

CTP Storage Duration Policies

Legal considerations
US Regulatory authority: 45CFR 46: A-D
Should be under oversight by local IRB for research
Written informed consent should be documented,
including type of research, conditions for release of
tissues, and procedures to maintain confidentiality
Without exculpatory language through which donors
may appear to waive any legal rights
Residual cells from testing excluded

State, Federal, National, Provincial regulations

apply to discard of products / aliquots
9

CTP Storage Duration Policies

Central ethical principles:
Respect for the donor/recipient and families
Importance of informed consent and refusal

Unused CTPs may be:

Used in research or teaching
Used in laboratory quality control, process
development, stability studies, other
Discarded Discard is not ethically neutral

Use of CTPs in absence of informed consent:

Anonymised
Respect outright denial of consent
Withdrawal from research does not affect samples
already obtained
10

CTP Storage Duration Policies

Practical considerations:
Integrated policies and procedures across the CTP
program (clinical, collection, laboratory)
Final disposition of products consistent with consent
obtained prior to collection- requires communication
Inventory size
Available storage space and resources
Pattern of product usage average storage duration
Preference Is there a research market?

11

CTP Storage Duration Policies

Common Disposal Issues:
Older products stored before agreements required
No aliquots available to assess viability
Patients lost to follow-up; survival can not be
confirmed or death verified
Ownership of product
Usually considered to belong to recipient
Legal counsel recommended

How to document death

US Social Security Administration - http://www.ssa.gov
Many companies/services

12

Applicable Standards

13

FACT-JACIE CTP Standards

Fourth Edition, 2008
Disposal (D11) Standards
Pre-collection agreement; storage facility and designated recipient
Length of storage
Conditions for discard
Option to transfer CTP to another facility

Document recipient death or no further need before discard

Laboratory Med Director and recipients physician approve
disposition and method
Follow applicable laws and regulations for biohazardous waste
If obtained through Registry, follow Registry policies
If no prestorage agreement:
Communicate with recipients physician
Make document effort to contact recipient

Complete tracking records when, where, how

14

AABB Standards for Cellular

Therapy Product Services
Third Edition, 2008

Disposition Agreements:
Terms / length of storage; disposition; possible transfer
Donor, recipient, recipients physician

Informed Consent:
Ownership, transfer, and/or disposition of the CTP

Stability During Storage:

(21CFR 211.166) Stability of each type of CTP during
storage shall be monitored; sampling and evaluation at
least annually

15

National Marrow Donor Program

Standards and Policies 2008
Unrelated donor products whole products
Expectation: HPC, Apheresis; HPC, Marrow, TC are
collected for immediate infusion
If cryopreserved, notify NMDP
Notify NMDP when cryopreserved unit infused or discarded

To use product in anonymous research:

NMDP DC informed consent from donor

TC notify local IRB
Donor consent OK for research
Donor refuses consent discard

Partial unused products and aliquots

Cryopreserve, discard or use in anonymous research
Notify local IRB, not NMDP

16

National Marrow Donor Program

Standards and Policies 2008
Unrelated donor cord blood units
Expectation: HPC, Cord Blood units are
transported to TC for planned infusion
If discarded, notify NMDP
To use product in anonymous research:
NMDP CBB ? Policies prohibit research
Yes discard
(maternal donors only consented to transplant)
No No further consent required
TC notify local IRB

17

CTP Storage and Disposal

An Example
FACT and AABB accredited
Informed consent agreement:
Store indefinitely until death or no further need
No guarantee re: long term viability of cells
If no further need and recipient is alive, recipient will be offered
opportunity to relocate cells
If recipient doesnt want them, cells are offered to donor
Use of up to 5 mL per product for research repository
Small quantities may be used for IRB-approved research
At product disposal, all remaining cells available

Clinical staff documents consent on prescription form

Do not use for research if +IDM; contaminated

18

[email protected]
www.factwebsite.org

19

Storage of Cellular Therapy Products:

Issues Related to Duration, Discard and
Quarantine
Linda Kelley, PhD
Director, Cell Therapy Facility
University of Utah
October 22, 2008

20

Objectives
Identify/review GTP/GMP requirements for
product quarantine

21

FDA Rules and Guidance

21 CFR Part 1271 (subparts A, C)
21 CFR Part 210 and 211
CGMP for Phase 1 Investigational Drugs

22

Quarantine
FDA Primary Concern

To prevent the likelihood of cross

contamination of HCTP/s with virus,
bacteria, fungus, mycoplasma or other
infectious agents.
To prevent product distribution when
release is not approved

23

Quarantine
(Definition)
1271.3 (q) The storage or identification of
an HCT/P, to prevent improper release, in
a physically separate area clearly
identified for such use.
or through use of other procedures,
such as automated designation

24

Quarantine
(Receipt and Storage)

211.82 (b) Components, drug product

containers, and closures shall be stored
under quarantine until they have been
tested or examined, as appropriate, and
released.

25

Quarantine at Receipt
Segregated area for receipt

26

Quarantine
(Prior to Donor Eligibility)
1271.60 (a) You must keep an HCTP/P in
quarantine until completion of the donor
eligibility determination.
1271.60 (b) You must clearly identify as
quarantined an HCT/P that is in quarantine
pending completion of a donor-eligibility
determination. The quarantined HCT/P must be
easily distinguishable from HCT/Ps that are
available for release and distribution.

27

Quarantine During
Processing/Manufacture
GLP
GMP

28

Quarantine
Labeling

29

Quarantine During Storage

Cryopreserved HCTP/s

Physical separation (separate freezers)

Use of vapor phase storage
Protective outer coverings over the
primary freezing bag
Use of mechanical freezer storage

30

Quarantine During Storage

Cryopreserved HCTP/s

Short Term Storage

31

Quarantine During Storage

Cryopreserved HCTP/s

Long Term Storage

32

Quarantine During Storage

Cryopreserved HCTP/s
Over wrapping

33

Quarantine During Storage

Cryopreserved HCTP/s

Mechanical Freezer Storage

34

Quarantine
Transport

1271.60 (c) If you ship an HCT/P that is in

quarantine before completion of donoreligibility determination, you must keep it
in quarantine during shipment.

35

Quarantine
Transport

36

Management Strategies for Cryostorage of

Clinical Stem Cell Products

Vincent F. La Russa, PhD

Director, Cytotherapy Laboratory
MSKCC

37

HPC Cryopreserved Units

38

Problem

No pre-existing agreement describing

conditions for storage
The number of LN2 storage units are not
suitably located to facilitate the operations
safely.
Additional space is needed for
cryopreservation procedures and storage
and retrieval operations.
39

Objectives

Identify concepts of active storage and

long term storage

Historical perspective
Data analysis of inventory
Identify LN2 Tanks to keep
Identify LN2 Tanks to Off-Site

Criteria for identifying a candidate facility

Ad-Hoc Committee
Quality Management Plan
Institution QA team on site inspection

40

Historical Perspective
Units Frozen, Infused, and Remained In Storage

Total Units Frozen

Infused
Remained in Storage

1400

1200

Units

1000

800

600

400

200

94 95

96 97

98 99

02 03
00 01 02
03 04
04

Years
Years

41

05 06

07

Yearly Cumulative Rate of

Cryopreserved units

7000
6000

Units

5000

Units that remain every year

Units that accumulate every year

4000
3000
2000
1000
0

83

85

87

89

91

93

95

42

97

99

01

03

05

07

Age of Frozen Products Infused Yearly

fro z e n < 1 2 m o n th s
fro z e n > 1 yr & < 5 y rs
fro z e n > 5 y rs
120

100

% Units

80

60

40

20

94

95

96

97

98

99

00

43

01

02

03

04

05

06

07

The Number of TX and Units Infused Yearly

Stored Frozen <1,<5 & >5yrs
Infused Units
Stored frozen
< 1yr

Infused Units
Stored frozen
>1& <5yrs

Infused Units
Stored frozen
>5yr

Year

# of
TX

# Units
Infused

# of
TX

# Units
Infused

# of
TX

# Units
Infused

Average # of
TX per
month
(using units
frozen >1yr)

1994

178

430

0.67

0.75

183

1995

229

428

0.33

0.58

195

1996

247

408

11

0.58

0.92

241

1997

244

400

13

19

1.17

1.67

250

1998

206

352

11

12

0.92

1.00

258

1999

193

363

17

24

1.42

2.00

295

2000

175

451

0.67

0.67

518

2001

163

512

19

35

1.58

2.92

478

2002

150

436

28

0.75

2.33

367

2003

168

403

13

23

1.17

2.00

501

2004

141

362

20

43

1.67

3.58

663

2005

199

459

18

41

1.58

3.50

716

2006

168

424

22

31

2.17

3.33

682

2007

171

377

13

24

1.42

2.75

758

44

Average # of
Units infused
per month
(using units
frozen >1yr)

Total Units
Remain in
the year

INVENTORY OF LN2 TANKS AND PRODUCTS

FOR OFF-SITE

Freezer #

# Units Stored
Frozen <1yr

# Units Stored
Frozen >1 & <5yrs

# Units Stored
Frozen >5yrs

Total Units
in Freezer

# Units
Proposed
Purge

49

14 (5%)

273 (95%)

287

86

51

4 (2%)

265 (99%)

269

76

52

14 (5%)

250 (95%)

264

61

53

7 (2%)

318 (98%)

325

82

55

35 (9%)

337 (91%)

372

105

56

278 (34%)

532 (66%)

810

271

57

184 (36%)

324 (64%)

508

129

59

86 (100%)

86

69

4 (2%)

253 (98%)

257

28

70

24 (9%)

256 (91%)

280

74

80

3 (1%)

285 (99%)

288

74

Total = 11

567

3179

3746

993

45

LN2 TANKS AND PRODUCT

INVENTORY THAT REMAINS MSKCC

Freezer #

# Units Stored
Frozen <1yr

# Units Stored
Frozen >1 & <5yrs

# Units Stored
Frozen >5yrs

Total Units
in Freezer

# Units
Proposed
Purge

54

645 (75%)

210 (25%)

855

210

58

443 (97%)

14 (3%)

457

129

65

168 (75%)

55 (25%)

223

55

66

114 (15%)

647 (81%)

34 (4%)

795

143

67

63 (48%)

69 (52%)

132

38

68

1 (0.001%)

783 (99.8%)

1 (0.001%)

785

229

Total = 6

115

2749

383

3247

804

46

Cytotherapy Laboratory Purge

Process For Deceased Patients
Sent to

Data Manager
Patients List

Clinical Information Center

Data Line

If vital status conflict with

HIS, go back to confirm
Conflicting
Vital
status

List for physician

in Medicine

Deceased patient list

with expired date

Sent back to Lab

Data manager
Confirms Healthcare Information System

Confirmed
Patients Deceased

List for physician

in Pediatrics

Confirm
Primary
physician

List for physician

unknown or left

Physicians

Confirm pt
vital status

Discard
permission

Research
permission

Data
manager
A discard
worksheet
Lab
technologists

Discard
expired
products
Release
expired
products for
research

47

Update
Inventory

Completed
discard
worksheet

Expired Units Purging Status

# Units Proposed
to Discard

# Units Actual
Discarded

% Units Discarded
from tanks

# Expired Units
remained in tank

Purge 1
(2002-2003)

716

426

59.50

290

Purge 2
(2004-2005)

617

268

43.44

349

Purge 3
(2006-2007)

966

326

33.75

640

NA

NA

NA

1119 (Medicine)
452 (Peds)
Purge 4
(2008-2009)

226 (physician
unknown)

48

Facility Qualification Process

49

Multidisciplinary Ad-Hoc Committee

To provide guidance and establish vendor

qualifications for storage of cryopreserved
clinical stem cell products
Processing Facility Director
Processing Facility Medical Director
BMT Program Director
BMT Faculty representing each program
Manufacturing QA Manager
Office of General Counsel
Administration

50

Vendor Qualifications Verification

On-Site Inspection by OCR Manufacturing QA Manager

The vendor qualification verification process

assess whether a vendor under consideration
provides
related services, store, or transport clinical stem cell
products
is qualified with respect to experience and
compliance with applicable regulations, in our case
FDA, Good Tissue Practice, Regulation and FACT
Accreditation standards.

51

Organizational Structure

Name and address of parent company

Name and address of manufacturing (storage) site
Contact information and physical location
Reporting organizational structure

Medical Director
Scientific Director
Storage facility manager
QA/QC manager

52

GMP General
Claimed staff competency for GMP-GTP compliant
manufacturing and/or storage of cryopreserved HPC
clinical products
Examples of FDA-regulated products manufacturing and
/ or storage of Cryopreserved clinical HPC products
When were the last several FDA visits to your site and
what was inspected?
Provide details as to FDA findings (483 forms)
Describe experience with clinical trials products
Describe approach to GMP compliance for clinical trials
products compared to commercial products.
53

GMP To Store Clinical Products

Are the products for our project being stored in dedicated

rooms/areas?
What other products are made in the same facility as our
product?
Are any of the following products being made or stored
at this location: beta-lactams, cytotoxins, steroids,
agrochemicals, pesticides, herbicides, biologicals, other
potent actives? If so, what cross-contamination control
procedures are in place?
Who will transfer our process and conduct process
validation?
How will validation be documented and reviewed?
54

GMP To Store Clinical Products

Who will prepare SOPs, forms, and Master Batch
Record?
Who reviews and approves process documents?
Is any of the manufacturing (storage) anticipated to be
outsourced? Describe.
Describe the materials control procedures used in our
projects facility.
Describe the equipment control procedures used in our
projects facility.

55

GMP To Store Clinical Products

Describe the environmental control and monitoring
procedures used in our projects facility.
Describe equipment and facility cleaning before our
project begins.

56

Licensure and Accreditations

Names of the Scientific Director and Medical Director of
the facility for our project. Define their Responsibilities
vis--vis FACT standard definitions.
Do you have previous experience with the storage,
inventory, retrieval, and transfer of cryopreserved human
hematopoietic progenitor cell products for clinical use to
transplant centers/hospitals? If so, can you provide
references who we may contact?
Do you have the following registrations or accreditations:
FDA registered HCT/P facility, FACT accreditation,
AABB accreditation, tissue-banking or blood-banking
licenses?

57

Standard Operations
How many trained staff would be available to respond in
the event of a catastrophic equipment failure, requiring,
for example the transfer of the contents of one full LN2
freezer to a backup freezer? How many backup LN2 or
other ultralow (<-125C) freezers are available?
Review SOPs related to temperature monitoring.
Alarm response plan.
Describe the facility validation plan for the storage area.
Describe the inventory tracking system you will use for
our products, and how data correctness will be verified.

58

Standard Operations
Describe security for the facility that would house our
products.
Describe the backup electricity and LN2 for the facility
that would house our products.
As per FACT accreditation standards, a quarterly
independent audit of the facility will be required.
Describe whether you have this audit program in place
or how we might work together to make this program
happen.

59

Acknowledgments

Cytotherapy Laboratory StaffChen,

Xiaoshe , PhD
Data Manager
Jo-ann Tonon, H (ASCP) BB, SBB
Supervisor
Sharon Bleau, BS, MA
Allison Schaible, MT (ASCP)
Edward Hoefer, MT (ASCP)
Melany Centeno, MT (ASCP)
Office of Clinical research
Lee McDonald, PhD
Manager, Manufacturing QA
Veronica Negron-Almache, Ph.D.
Coordinator, Manufacturing QA
Office of Clinical Research, Investigational Products
Division

Ad-Hoc Committee

Farid Boulad, MD

Hugo Castro-Malaspina, MD

Ray Comenzo,MD

Martin Fleisher,PhD

Creg Moskowitz,MD

Steven Nimer, MD

Richard OReilly, MD

David Rice, PhD

Marcel van den Brink, MD PhD

David Wuest, MD

James Young, MD

Ms. Reilly, SBB

Ms. Russell

Mr. Parker

60

Q&A Session
We Welcome Your Questions!
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Afterwards, the operator will come on the line to ask
the audience if they would like to ask live
questions.
To do so, please press * followed by 1.

61