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

1
 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

2
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.

3
 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

4
 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

5
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

8
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
pwarkent@unmc.edu
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 donor-
eligibility 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

1400 Total Units Frozen

Infused
Remained in Storage
1200

1000
Units

800

600

400

200

0
94 95 96 97 98 99 00 01 02
02 03
03 04
04 05 06 07
Years
Years

41
 Yearly Cumulative Rate of
Cryopreserved units

7000

6000

5000 Units that remain every year

Units that accumulate every year
4000
Units

3000

2000

1000

83 85 87 89 91 93 95 97 99 01 03 05 07

42
 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

80
% Units

60

40

20

0
94 95 96 97 98 99 00 01 02 03 04 05 06 07

43
 The Number of TX and Units Infused Yearly
Stored Frozen <1,<5 & >5yrs

Infused Units Infused Units Infused Units

Stored frozen Stored frozen Stored frozen Average # of Average # of
< 1yr >1& <5yrs >5yr TX per Units infused
month per month Total Units
# of # Units # of # Units # of # Units (using units (using units Remain in
Year TX Infused TX Infused TX Infused frozen >1yr) frozen >1yr) the year
1994 178 430 8 9 0 0 0.67 0.75 183

1995 229 428 4 7 0 0 0.33 0.58 195

1996 247 408 7 11 0 0 0.58 0.92 241

1997 244 400 13 19 1 1 1.17 1.67 250

1998 206 352 11 12 0 0 0.92 1.00 258

1999 193 363 17 24 0 0 1.42 2.00 295

2000 175 451 8 8 0 0 0.67 0.67 518

2001 163 512 19 35 0 0 1.58 2.92 478

2002 150 436 9 28 0 0 0.75 2.33 367

2003 168 403 13 23 1 1 1.17 2.00 501

2004 141 362 20 43 0 0 1.67 3.58 663

2005 199 459 18 41 1 1 1.58 3.50 716

2006 168 424 22 31 4 9 2.17 3.33 682

2007 171 377 13 24 4 9 1.42 2.75 758

44
 INVENTORY OF LN2 TANKS AND PRODUCTS
FOR OFF-SITE
# Units
# Units Stored # Units Stored # Units Stored Total Units Proposed
Freezer # Frozen <1yr Frozen >1 & <5yrs Frozen >5yrs in Freezer Purge

49 0 14 (5%) 273 (95%) 287 86

51 0 4 (2%) 265 (99%) 269 76

52 0 14 (5%) 250 (95%) 264 61

53 0 7 (2%) 318 (98%) 325 82

55 0 35 (9%) 337 (91%) 372 105

56 0 278 (34%) 532 (66%) 810 271

57 0 184 (36%) 324 (64%) 508 129

59 0 0 86 (100%) 86 7

69 0 4 (2%) 253 (98%) 257 28

70 0 24 (9%) 256 (91%) 280 74

80 0 3 (1%) 285 (99%) 288 74

Total = 11 0 567 3179 3746 993

45
 LN2 TANKS AND PRODUCT
INVENTORY THAT REMAINS MSKCC

# Units
# Units Stored # Units Stored # Units Stored Total Units Proposed
Freezer # Frozen <1yr Frozen >1 & <5yrs Frozen >5yrs in Freezer Purge

54 0 645 (75%) 210 (25%) 855 210

58 0 443 (97%) 14 (3%) 457 129

65 0 168 (75%) 55 (25%) 223 55

66 114 (15%) 647 (81%) 34 (4%) 795 143

67 0 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

Data Manager Sent to Clinical Information Center Deceased patient list

Patients List Data Line with expired date

Sent back to Lab

If vital status conflict with Data manager
HIS, go back to confirm Confirms Healthcare Information System
Confirm
Conflicting
Primary
Vital
Confirmed physician
status
Patients Deceased

List for physician List for physician List for physician

in Medicine in Pediatrics unknown or left

Physicians

Confirm pt Discard Research

vital status permission permission

Data
manager

A discard Update
worksheet Inventory

Lab Discard
technologists expired Completed
products discard
Release worksheet
expired
products for
research

47
 Expired Units Purging Status

# Units Proposed # Units Actual % Units Discarded # Expired Units

to Discard Discarded from tanks 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

1119 (Medicine)

452 (Peds)

Purge 4 226 (physician

(2008-2009) unknown) NA NA NA

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 1

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 2

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 3

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, Ad-Hoc Committee

Xiaoshe , PhD Farid Boulad, MD
Data Manager
Hugo Castro-Malaspina, MD
Jo-ann Tonon, H (ASCP) BB, SBB
Supervisor
Ray Comenzo,MD
Sharon Bleau, BS, MA Martin Fleisher,PhD
Allison Schaible, MT (ASCP) Creg Moskowitz,MD
Edward Hoefer, MT (ASCP) Steven Nimer, MD
Melany Centeno, MT (ASCP) Richard OReilly, MD
David Rice, PhD
Office of Clinical research
Lee McDonald, PhD
Marcel van den Brink, MD PhD
Manager, Manufacturing QA David Wuest, MD
Veronica Negron-Almache, Ph.D. James Young, MD
Coordinator, Manufacturing QA Ms. Reilly, SBB
Office of Clinical Research, Investigational Products Ms. Russell
Division
Mr. Parker

60
 Q&A Session
We Welcome Your Questions!

Chat box questions will be addressed first.

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