BLA for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Biologics License Applications for Minimally
Manipulated, Unrelated Allogeneic
Placental/Umbilical Cord Blood Intended for
Hematopoietic and Immunologic Reconstitution
in Patients with Disorders Affecting the
Hematopoietic System
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-
1448, or by calling 1-800-835-4709 or 301-827-1800, or e-mail ocod@fda.hhs.gov, or from the
Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or e-mail
address listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
March 2014

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Table of Contents
I. 	INTRODUCTION............................................................................................................. 3
II. 	BACKGROUND ............................................................................................................... 4
A. 	Scope....................................................................................................................... 4
1. 	What Products Does this Guidance Cover? ...................................................... 4
2. 	What Products are Not Covered? ...................................................................... 4
B. 	How do I Use this Guidance to Apply for a Biologics License? ........................ 4
C. 	Am I Required to Use this Guidance when I Apply for a Biologics License
Application?........................................................................................................... 5
D. 	Historical Background.......................................................................................... 5
III. 	APPLICABLE REGULATORY REQUIREMENTS ................................................... 8
IV. 	LICENSE APPLICATION PROCEDURE .................................................................... 9
A. 	What Form Do I Submit with My Application? ................................................ 9
B. 	Where Should I Submit My License Application? ............................................ 9
C. 	What Information Do I Need to Include in My Application?........................... 9
D. 	What Action Will FDA Take? ........................................................................... 10
V. 	CHEMISTRY, MANUFACTURING, AND CONTROLS SECTION ...................... 10
A. 	Introduction ......................................................................................................... 10
B. 	HPC, Cord Blood Description and Characterization ...................................... 10
C. 	Manufacturer(s) .................................................................................................. 12
1. 	Identification ................................................................................................... 12
2. 	Floor Diagram(s) ............................................................................................. 12
3. 	Contamination Precautions ............................................................................. 12
D. 	Methods of Manufacturing ................................................................................ 13
1. 	SOPs to Submit with License Application...................................................... 13
2. 	Validation........................................................................................................ 14
3. 	Flow Charts ..................................................................................................... 14
4. 	Microbiology................................................................................................... 15
5. 	Control of Aseptic Manipulations ................................................................... 15
6. 	Batch Records ................................................................................................. 15
E. 	Container Closure System (21 CFR 211.94) ..................................................... 15
F. 	Methods Validation/Verification ....................................................................... 16
1. 	Infectious Disease Test Methods .................................................................... 16
2. 	Other Test Methods......................................................................................... 16
3. 	Validation Results ........................................................................................... 17
G. 	Labeling ............................................................................................................... 17
H. 	Environmental Assessment ................................................................................ 17
VI. 	ESTABLISHMENT DESCRIPTION SECTION ........................................................ 18
A. 	Introduction ......................................................................................................... 18
B. 	General Information ........................................................................................... 18
C. 	Specific Systems .................................................................................................. 18

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1. 	Source of Water Used in Processing (if applicable) ....................................... 18
2. 	Heating, Ventilation, and Air Conditioning.................................................... 18
3. 	Facility Controls.............................................................................................. 19
4. 	Computer Systems .......................................................................................... 19
D. 	Contamination/Cross-Contamination Issues.................................................... 20
1. 	Equipment Cleaning Procedures and Validation ............................................ 20
2. 	Containment Features ..................................................................................... 20
VII. 	GUIDANCE ON APPLICABLE REGULATIONS .................................................... 21
A. 	Establishment Registration and Listing............................................................ 21
B. 	Current Good Manufacturing Practice and Current Good Tissue Practice 21
1. 	Donor Eligibility ............................................................................................. 22
2. 	Prevention of the Introduction, Transmission, or Spread of Communicable
Diseases........................................................................................................... 23
3. 	Manufacturing Arrangements ......................................................................... 23
4. 	Exemptions and Alternatives .......................................................................... 23
5. 	Quality Control Unit (21 CFR 211.22) ........................................................... 23
6. 	Personnel ......................................................................................................... 24
7. 	Buildings and Facilities................................................................................... 25
8. 	Equipment ....................................................................................................... 27
9. 	Predistribution Shipments and Control of Components, Containers, and
Closures........................................................................................................... 28
10. 	Production and Process Controls (Process Validation) .................................. 30
11. 	Packaging and Labeling Control ..................................................................... 32
12. 	Label and Labeling Content to be Submitted with Your Application ............ 34
13. 	Holding and Distribution ................................................................................ 35
14. 	Laboratory Controls ........................................................................................ 36
15. 	Records and Reports ....................................................................................... 40
16. 	Failure Investigations ...................................................................................... 42
17. 	Tracking .......................................................................................................... 43
18. 	Complaints ...................................................................................................... 44
19. 	Returned and Salvaged HPC, Cord Blood Units ............................................ 45
VIII. 	POSTMARKETING ACTIVITIES .............................................................................. 45
A. 	Clinical Outcome Data Collection ..................................................................... 45
B. 	Changes to be Reported...................................................................................... 46
C. 	Adverse Experience Reporting .......................................................................... 46
D. 	Biological Product Deviation Reporting ........................................................... 46
IX. 	DEFINITIONS ................................................................................................................ 47
X. 	REFERENCES ................................................................................................................ 48

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Guidance for Industry
Biologics License Applications for Minimally Manipulated,
Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for
Hematopoietic and Immunologic Reconstitution in Patients with
Disorders Affecting the Hematopoietic System
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this
topic. It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public. You can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you want to discuss an alternative
approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff,
call the appropriate number listed on the title page of this guidance.
I. 	INTRODUCTION
We, the Center for Biologics Evaluation and Research (CBER), FDA, are recommending ways
that would allow you, the manufacturer, generally a cord blood bank, to apply for licensure of
minimally manipulated, unrelated allogeneic placental/umbilical cord blood, for hematopoietic
and immunologic reconstitution in patients with disorders affecting the hematopoietic system
that are inherited, acquired, or result from myeloablative treatment. This guidance document is
intended to assist you in obtaining a biologics license. It contains information about the
manufacture of minimally manipulated, unrelated allogeneic placental/umbilical cord blood and
how to comply with applicable regulatory requirements.
This guidance finalizes the draft guidance of the same title dated June 2013 (June 17, 2013, 78
FR 36196) and supersedes the guidance entitled “Guidance for Industry: Minimally
Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic
Reconstitution for Specified Indications” dated October 2009 (October 20, 2009, 74 FR 53753)
(2009 licensure guidance). The changes from the 2009 licensure guidance include replacing the
term “HPC-C” with the term “HPC, Cord Blood,” which is the proper name for these products,
expanding the clinical indication, clarifying the types of clinical information that should be
submitted for review, and adding additional references to other guidance documents on process
validation and methods validation.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.

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II. 	BACKGROUND
A. 	Scope
1. 	What Products Does this Guidance Cover?
This guidance document provides recommendations for the submission of a
biologics license application (BLA) under Title 21 of the Code of Federal
Regulations Part 601 (21 CFR Part 601) for placental/umbilical cord blood
products that are:
• 	Manipulated minimally; and
• 	Intended for use in unrelated donor hematopoietic progenitor cell
transplantation procedures in conjunction with an appropriate preparative
regimen for hematopoietic and immunologic reconstitution in patients
with disorders affecting the hematopoietic system that are inherited,
acquired, or result from myeloablative treatment.
For the purpose of this guidance, HPC, Cord Blood refers to the final drug
product (cryopreserved or thawed) of minimally manipulated hematopoietic
stem/progenitor cells from placental/umbilical cord blood, sourced from an
unrelated allogeneic cord blood donor and intended for hematopoietic and
immunologic reconstitution.
2. 	What Products are Not Covered?
This guidance applies only to those HPC, Cord Blood products described in
section II.A.1 of this guidance. If you manufacture peripheral blood or
placental/umbilical cord hematopoietic stem/progenitor cells other than those
described, (e.g., more than minimally manipulated, or for other indications) you
may need to submit an Investigational New Drug application (IND) or other
premarketing application appropriate for that product.
We encourage manufacturers of hematopoietic stem/progenitor cells from
placental/umbilical cord blood for autologous use, or use in a first- or second-
degree blood relative, to follow the recommendations concerning the manufacture
of these products and how to comply with applicable regulatory requirements,
even though their products may not require premarket review.
B. 	How do I Use this Guidance to Apply for a Biologics License?
You may demonstrate in your license application that you have followed the
recommendations in this guidance in order to meet the applicable regulatory requirements
for a license application. We intend to grant a license for products shown to follow these
recommendations and that meet applicable regulatory requirements in Title 21 of the
CFR. Also, you may modify any particular procedure in this guidance, provided that you

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present evidence in your application demonstrating that the modification will provide
assurances of the safety, purity, potency, and effectiveness of your product.
The license would apply to all units of HPC, Cord Blood manufactured in compliance
with all applicable requirements and standards, including current good manufacturing
practice (CGMP) requirements, as outlined in this guidance.
C. 	Am I Required to Use this Guidance when I Apply for a Biologics License
Application?
No, you are not required to use this guidance. However, you must submit a BLA for your
HPC, Cord Blood product containing data derived from nonclinical laboratory and
clinical studies which demonstrate that the manufactured product meets prescribed
requirements of safety, purity, and potency (21 CFR 601.2). This guidance provides
specific recommendations for those manufacturers who wish to rely on data submitted to
the docket for this guidance and data in docket number FDA-1997-N-0010 (Legacy
Docket number 1997N-0497)1. If you choose not to rely on these data, you should
consult with FDA about alternative approaches to satisfying applicable regulatory
requirements.
D. 	Historical Background
In 1997, we proposed a new regulatory framework for human cellular and tissue-based
products, including hematopoietic stem/progenitor cells. The proposed framework
provided a tiered approach to the regulation of human cellular and tissue-based products,
now referred to as human cells, tissues, and cellular and tissue-based products (HCT/Ps).
We implemented this approach by promulgating three final rules, which comprise
21 CFR Part 1271.
On January 19, 2001, we published the first final rule entitled “Human Cells, Tissues, and
Cellular and Tissue-Based Products; Establishment Registration and Listing” (66 FR
5447) (the registration and listing final rule).
On May 25, 2004, we published the second final rule entitled “Eligibility Determination
for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products” (69 FR
29786) (the donor eligibility final rule).
On November 24, 2004, we published the third final rule entitled “Current Good Tissue
Practice for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based
Products; Inspection and Enforcement” (69 FR 68612).
As of May 25, 2005, all three final rules were in effect. As described in the registration
and listing final rule,2 we are regulating as biological drugs or devices those HCT/Ps that:
1 “Request for Proposed Standards for Unrelated Allogeneic Peripheral and Placental/Umbilical Cord Blood
Hematopoietic Stem/Progenitor Cell Products” (January 20, 1998, 63 FR 2985).
2 66 FR 5447 at 5467, January 19, 2001. See also 21 CFR 1271.10.

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• 	Are more than minimally manipulated (processing alters the biological
characteristics of the cells);
• 	Are for a use other than homologous use as reflected by the labeling, advertising,
or other indications of the manufacturer’s objective intent;
• 	Involve for their manufacture the combination of the cell or tissues with another
article, excluding water, crystalloids, or a sterilizing, preserving, or storage agent
that does not raise new clinical safety concerns with respect to the HCT/P; or
• 	Have a systemic effect or are dependent upon the metabolic activity of living cells
for their primary function, and are not for:
o 	Autologous use;
o 	Allogeneic use in a first- or second-degree blood relative; or
o 	Reproductive use.
We consider unrelated allogeneic hematopoietic stem/progenitor cells to have a systemic
effect and are therefore regulating them as biological products and drugs under the Public
Health Service (PHS) Act and the Federal Food, Drug, and Cosmetic Act (FD&C Act).
On January 20, 1998, we issued a notice in the Federal Register entitled “Request for
Proposed Standards for Unrelated Allogeneic Peripheral and Placental/Umbilical Cord
Blood Hematopoietic Stem/Progenitor Cell Products; Request for Comments.” (63 FR
2985). In the notice, we explained that it may be possible to develop product standards
and establishment and processing controls of minimally manipulated unrelated allogeneic
hematopoietic stem/progenitor cell products intended for hematopoietic reconstitution,
based on existing clinical trial data, or data developed shortly thereafter, demonstrating
the safety and effectiveness of the cells. We further explained that if adequate
information were submitted to the docket, we intended to issue guidance in accordance
with good guidance practice regulations, 21 CFR 10.115, for establishment controls,
processing controls, and product standards. If such standards could be developed, we
suggested that, in lieu of reviewing individual applications containing clinical data, we
would propose granting licensure for products shown to meet the issued standards.
To provide a scientific basis for the proposed standards, we requested the submission of
comments proposing establishment controls, process controls, and product standards
designed to ensure the safety and effectiveness of minimally manipulated unrelated
allogeneic hematopoietic stem/progenitor cell products derived from peripheral and cord
blood for hematopoietic reconstitution. Submitted comments were to include supporting
clinical and nonclinical laboratory data and other relevant information. To allow
sufficient time for the development of data and standards for these products, the notice
also announced our intention to phase in implementation of an IND and license
application requirements for these products. We provided a period of two years, until
January 20, 2000, for interested persons to submit proposed product standards and
establishment and processing controls with supporting clinical and nonclinical data. At
the request of industry, we reopened the comment period for 90 days until July 17, 2000
(April 18, 2000, 65 FR 20825).

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The Biological Response Modifiers Advisory Committee (Committee) met on February
27, 20033, to discuss issues related to the use of unrelated allogeneic hematopoietic
stem/progenitor cells derived from placental/umbilical cord blood for hematopoietic
reconstitution. At the meeting, FDA provided an analysis of clinical outcome data
submitted to FDA regarding the safety and effectiveness of cord blood for hematopoietic
reconstitution. Guest experts provided the most recent data on clinical studies of
unrelated donor umbilical cord blood transplantation in children and adults.
The Committee’s deliberations focused on:
1. 	Factors the agency should consider in determining the safety and effectiveness of
placental/umbilical cord blood transplantation for hematopoietic reconstitution;
2. 	The role of CD34+ cell count in selection of cord blood units for transplantation;
and
3. 	Other measures of quality that should be considered.
We reviewed and assessed the submitted information as well as the large body of
published literature on this subject, and determined that the data were sufficient to
establish the safety and effectiveness of HPC, Cord Blood for the following indications:
hematological malignancies; certain lysosomal storage and peroxisomal enzyme
deficiency disorders including Hurler Syndrome (MPS I); Krabbe Disease (Globoid
Leukodystrophy), and X-linked Adrenoleukodystrophy; primary immunodeficiency
diseases; bone marrow failure; and beta thalassemia. The data permitted the development
of recommendations for establishment and processing controls and product characteristics for
these products. Accordingly, in October 2009, we published the 2009 licensure guidance.
The guidance provided recommendations on the content and format of information to be
submitted in BLAs for HPC, Cord Blood in the chemistry, manufacturing, and controls
(CMC) section, and the establishment description section. In the Federal Register notice
announcing the 2009 licensure guidance, FDA also stated that it planned to end the
phased-in implementation period for IND and BLA requirements for HPC, Cord Blood,
after October 20, 2011.
The indication contained in this guidance differs from the indications listed in the scope
of the 2009 licensure guidance. This difference is a result of the Agency’s re-
examination of the legacy docket data and the Agency’s consideration of the proceedings
of the September 2011 meeting of the Cellular, Tissue, and Gene Therapies Advisory
Committee (Ref. 1).
This document provides guidance on the content and format of information to be
submitted in your BLA for HPC, Cord Blood in the CMC section, and the establishment
description section.
3 Summary minutes of the meeting are available on the FDA website at
http://www.fda.gov/ohrms/dockets/ac/03/minutes/3924M1.htm.

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III. 	APPLICABLE REGULATORY REQUIREMENTS
You and your HPC, Cord Blood product are subject to all applicable regulatory requirements;
and, when applying for a biologics license, this includes a prelicense inspection (42 U.S.C. § 262
of the PHS Act). Because we regulate HPC, Cord Blood for unrelated allogeneic use as a drug
under the FD&C Act and as a biological product under the PHS Act, you must follow the
applicable regulations promulgated under these acts.
Regulations applicable to HPC, Cord Blood include, but are not limited to, the following sections
of the CFR:
• 	21 CFR Parts 201 and 610 Subpart G – Labeling;
• 	21 CFR Part 202 – Prescription Drug Advertising;
• 	21 CFR Parts 210 and 211 – Current Good Manufacturing Practice Regulations (CGMP);
• 	21 CFR Part 600 – Biological Products: General; and
• 	21 CFR Part 610 – General Biological Products Standards.
Cord blood and HPC, Cord Blood are considered HCT/Ps, defined in 21 CFR 1271.3(d). In the
collection of cord blood and the manufacture of HPC, Cord Blood, the regulations promulgated
for HCT/Ps in 21 CFR Part 1271 apply. These regulations encompass registration and listing,
donor eligibility, and current good tissue practices. For the manufacture of HPC, Cord Blood, in
the event that a regulation in 21 CFR Part 1271 is in conflict with a requirement in 21 CFR Parts
210, 211, 600, or 610, the regulations more specifically applicable to HPC, Cord Blood will
supersede the more general.
The current good tissue practice (CGTP) requirements govern the methods used in, and the
facilities and controls used for, the manufacture of HCT/Ps to prevent the introduction,
transmission, or spread of communicable diseases by HCT/Ps (21 CFR 1271.150(a)). Because
cord blood and HPC, Cord Blood are HCT/Ps, these provisions are applicable to both cord blood
and HPC, Cord Blood.
The CGMP requirements, in 21 CFR Parts 210 and 211, govern the methods to be used in, and
the facilities or controls to be used for, the manufacture, processing, packing, or holding of a
drug to ensure that such drug meets the requirements of the FD&C Act as to safety, has the
identity and strength, and meets the quality and purity characteristics that it purports or is
represented to possess. Due to the broader scope of these regulations, most of the CGMP
regulations under 21 CFR Parts 210 and 211 would be applicable to your HPC, Cord Blood.
Additionally, due to the broad scope of the regulations, for the most part, CGTP would be
subsumed under the broader CGMP requirements. Compliance with these CGMP requirements
would result in compliance with applicable CGTP requirements.
Section VII. of this guidance contains recommendations for application of the appropriate
regulations for establishment registration and listing, and specific recommendations for
manufacturing HPC, Cord Blood. You should use section VII. as a reference for compiling
information for submission of your BLA. We have referenced the appropriate CGMP sections of
the regulations that apply to biological products. We have indicated a section from

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21 CFR Part 1271 only when there is not a corresponding section in the CGMP requirements, in
order to bring that CGTP section to your attention.
IV. 	LICENSE APPLICATION PROCEDURE
A. 	What Form Do I Submit with My Application?
You should submit a Form FDA 356h - Application to Market a New Drug, Biologic, or
an Antibiotic Drug for Human Use.4
B. 	Where Should I Submit My License Application?
Pursuant to 21 CFR 600.2(a), you must submit your completed application to:
Document Control Center (HFM-99)
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448.5
C. 	What Information Do I Need to Include in My Application?
In accordance with Form FDA 356h, at a minimum, you must include all of the following
information:
• 	Form FDA 356h Item 31.2: Representative draft labeling for the product for
which licensing is being sought (21 CFR 601.2).
• 	Form FDA 356h Item 31.4A: Chemistry, manufacturing, and controls
information (21 CFR 601.2). Include a full description of your manufacturing
process and copies of standard operating procedures (SOPs) for critical
procedures and assays as listed in this guidance.
• 	Form FDA 356h Item 31.4C: Summary data demonstrating validation of
critical processes and assays as listed in this guidance, (21 CFR 601.2).
• 	Form FDA 356h Item 31.15: A description of your facility including
personnel, physical establishment, and equipment (21 CFR 600.10) as
described in this guidance.
You should also provide the following:
• 	Form FDA 356h Item 31.1: An index.
• 	Form FDA 356h Item 31.3: A summary of the information submitted in the
application.
• 	Form FDA 356h Item 31.8: Clinical data section including summaries of any
4 See http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM082348.pdf.
5 Please check the FDA website for the most up-to-date address information.

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available efficacy and safety data on your HPC, Cord Blood product and a
citation to the data submitted to docket number FDA-1997-N-0010 (Legacy
Docket number 97N-0497), which may be incorporated by reference.
• 	Form FDA 356h Item 31.11: Case report form tabulations of any available
clinical experience with your HPC, Cord Blood product, including datasets in
SAS transport files.
• 	Form FDA 356h Item 31.12: Case report forms, including narratives of any
serious adverse events (SAEs) reported for your HPC, Cord Blood product.
Under Establishment Information on page one of Form FDA 356h, please indicate if you
are ready for inspection.
You may consider submitting to FDA a validation plan for review prior to submitting
your application. You may also request a pre-BLA meeting with the Office of Cellular,
Tissue, and Gene Therapy, to discuss your validation plan.
D. 	What Action Will FDA Take?
Upon receiving your submission we will review your license application, including the
submitted SOPs and validation data. As soon as possible after receiving a complete
application, we will schedule a pre-license inspection to verify that you are in compliance
with the applicable regulations. If the submitted application is not complete, we will
identify/advise you of the additional information that you will need to submit.
V. 	CHEMISTRY, MANUFACTURING, AND CONTROLS SECTION
A. 	Introduction
This section provides guidance on the content and format of information to be submitted
in the CMC section of your BLA.
B. 	HPC, Cord Blood Description and Characterization
This section of the application should contain a description of the specific tests and
expected results that will provide information regarding the safety, purity, potency, and
identity of the product. Table A provides the description and characteristics of the cord
blood and HPC, Cord Blood (i.e., tests performed and the results) used to obtain the
clinical data submitted to FDA in docket number FDA-1997-N-0010 (Legacy Docket
number 97N-0497). These clinical data demonstrate the safety, purity, and potency of
HPC, Cord Blood. You would be expected to obtain similar test results using the
recommended or other appropriate tests in order to rely on these clinical data in support
of your BLA. In addition, release specifications as described in section VII.B.14.a. of
this guidance should be included in this section.

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Table A. Required and Recommended Tests and Test Results1
Product
Characteristics2 	Testing Sample
(Type and Timing)
Results of Product
Testing
Safety
Infectious diseases –
Testing required.
(21 CFR 1271.45
through 1271.90)
Maternal peripheral
blood obtained within
7 days of cord blood
collection – Type and
Timing Required.
(21 CFR 1271.80(a)
and (b))
All tests negative;
except, non-treponemal
test for syphilis when
specific treponemal
confirmatory test is
negative.
(Cytomegalovirus
(CMV) results are
recorded).
CMV – Report
Sterility - Bacterial and
fungal cultures –
Testing required.
(21 CFR 211.165(b),
and 21 CFR 610.12)
HPC, Cord Blood (pre-
cryopreservation)* No growth
Hemoglobin
Cord blood** or
appropriate donor
sample obtained at
time of cord blood
recovery
No homozygous
hemoglobinopathy
Purity and
Potency3
Total nucleated cells
(TNC)
HPC, Cord Blood (pre-
cryopreservation)
≥ 5.0 x 108 TNC***/
unit HPC, Cord Blood
Viable nucleated cells HPC, Cord Blood (pre-
cryopreservation)
≥ 85% viable nucleated
cells
Viable CD34+ cells
(flow cytometry)
HPC, Cord Blood (pre-
cryopreservation)
≥ 1.25 x 106 viable
CD34+ cells****/unit
HPC, Cord Blood
Identity
Human leukocyte
antigen (HLA) typing Cord blood 	Report
Confirmatory HLA
typing
Attached segment of
HPC, Cord Blood Confirms initial typing
Blood Group and Rh
Type Cord blood 	Report
1 Testing, Sample (Type and Timing), and Results are recommended unless specifically noted as required.
2 The PHS Act requires a demonstration that the product is safe, pure, and potent.
3 Other purity and potency assays may be considered under the BLA.
* Sample may be obtained before or after addition of the cryoprotectant.
** Cord blood = a sample of unmanipulated cord blood. A red cell sample or other cord blood aliquot obtained after volume reduction may be
used for testing with appropriately validated reagents or test systems.
*** Based on 20 kg recipient, a target dose of ≥ 2.5 x 107 nucleated cells/kg and ≥ 70% post-thaw recovery = 1.7 x 107 nucleated cells/kg.
**** Based on CD34+ cells ≥ 0.25% of TNC prior to freezing.

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C. 	Manufacturer(s)
1. 	Identification
This section should include the name(s), address(es), telephone number(s), FDA
registration number(s), and other pertinent organizational information for each
manufacturer, including those under contract, agreement, or other arrangement
with you to perform a manufacturing step. These organizations include, but are
not limited to, all collection sites that act as your agent(s) and laboratory(ies)
performing testing of donor samples for relevant communicable disease agents
and product sterility testing.
2. 	Floor Diagram(s)
For each processing location, a description of the area(s) used for processing of
HPC, Cord Blood should be provided. A floor diagram of the general layout of
the facility should be submitted along with the narrative description. The floor
diagram(s) should be sufficiently clear to enable the visualization of the
production flow and to identify adjacent operations that may create particular
concerns (potential impact on product quality). Submission of a floor diagram is
not necessary for collection sites.
3. 	Contamination Precautions
For all areas in which operations for the processing of HPC, Cord Blood are
performed, you should provide the following information concerning precautions
taken to prevent contamination or cross-contamination:
• 	A description of the in-process controls performed to prevent or to identify
contamination or cross-contamination. You should take appropriate
precautions to prevent cross-contamination when the same area or
equipment is used to process more than one HPC, Cord Blood unit at a
time (e.g., several HPC, Cord Blood units in a centrifuge bucket
simultaneously).
• 	A brief, narrative description of the procedures and/or facility/equipment
design features for the control of contamination, cross-contamination, and
aseptic manipulations.
• 	A brief, narrative description of the area where the manufacturing is
performed, including collection, volume reduction, packaging, labeling,
cryopreservation, storage, and shipping.

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D. 	Methods of Manufacturing
In accordance with 21 CFR 601.2, you must submit a detailed description of the
manufacturing and controls. In this section of Form FDA 356h, you should submit all
relevant SOPs, including donor selection and cord blood collection, cord blood transport
to the processing facility, processing, testing, storage, registry listing and HPC, Cord
Blood selection management, and HPC, Cord Blood shipping and handling.
1. 	SOPs to Submit with License Application
You should submit with your license application detailed SOPs for performance
of the following critical operations:
a. 	Collection
• 	Maternal risk and family history questionnaires;
• 	Maternal screening6 and obtaining informed consent;
• 	Donor eligibility – donor screening and donor testing;
• 	Notification of mothers or their responsible physicians of positive or
indeterminate test results according to local or national regulations;
• 	Positive identification of birth mother and donor;
• 	Cord blood collection, storage, and transport to the processing facility;
• 	Criteria for accepting cord blood for further processing; and
• 	Eliciting and handling of post-donation information.
b. 	Processing
• 	Plasma reduction, red cell sedimentation, and/or other nucleated cell
concentration methods;
• 	Cryopreservation;
• 	Frozen storage; and
• 	Lot release.
c. 	Selection
• 	Registry listing; and
• 	Search and selection request management.
6 For further information on Centers for Disease Control and Prevention maternal screening recommendations see
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm and
http://www.cdc.gov/hepatitis/HBV/PerinatalXmtn.htm.

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d. 	HPC, Cord Blood shipping and handling
• 	Shipping to transplant center;
• 	Thawing and preparation for administration; and
• 	Emergency product recovery in the event of a container failure,
including plans for sterility testing of the compromised product and
notification of the appropriate individuals and regulatory authorities.
2. 	Validation
You should submit a detailed validation data summary for the following
manufacturing and administration steps:
• 	Cord blood collection;
• 	Cord blood processing, including volume reduction and cryopreservation;
• 	Storage;
• 	Shipping;
• 	Thawing; and
• 	Cryoprotectant removal (for use in transplant centers that perform this
step).
The detailed validation summary should include data from the manufacture, as
well as the thawing and cryoprotectant removal of a minimum of three
consecutive, separate HPC, Cord Blood units to demonstrate that you are able to
consistently manufacture and thaw those HPC, Cord Blood units that meet the
product characteristics described previously in section V.B. of this guidance.
Additional information on process validation is in section VII.B.10. of this
guidance.7
3. 	Flow Charts
In this section, a complete visual representation of the manufacturing process flow
should be provided. The flow chart should show the steps in production,
equipment and materials used; room or area where the processing is performed
(may make reference to diagrams in other sections of the application); and a
complete list of the in-process controls and tests performed on the product at each
step. In-process holding steps should be included, with time and temperature
limits indicated.
The flow chart should also include information (or be accompanied by a
descriptive narrative) on the methods used to transfer the product between steps,
7 You may find additional information on process validation in the FDA guidance entitled, “Guidance for Industry:
Process Validation: General Principles and Practices” dated January 2011 (January 25, 2011, 76 FR 4360)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf).

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such as open transfers under laminar flow units. Reference may be made to other
sections of the application for more detailed process information. If equipment is
dedicated to specific areas, it should be identified.
4. 	Microbiology
If presterilized equipment and containers are going to be used, you should provide
a description of the item, whether it is single-use, and how the item is sterilized.
If equipment is going to be sterilized in-house, you should provide a description
and documentation of the validation studies for any processes used for equipment
sterilization. The procedures followed should be listed. Information should be
submitted as described in FDA’s “Guidance for Industry: For the Submission
Documentation for Sterilization Process Validation in Applications for Human
and Veterinary Drug Products” dated November 1994 (Ref. 2).
5. 	Control of Aseptic Manipulations
This section should contain descriptions of:
• 	How transfers and additions are performed;
• 	Precautions to control contamination; and
• 	In-process testing.
You should provide a brief description of all process parameters that are
monitored. A description should be provided of the precautions taken to maintain
aseptic conditions and prevent contamination during collection, concentration,
and cryopreservation. A description of the procedures used to monitor
bioburden/sterility should be included. You should also provide a description of
the conditions and time limits for process steps.
6. 	Batch Records
A completed batch record of the process of production of the biologic product
should be included.
E. 	Container Closure System (21 CFR 211.94)
The container closure system refers to the packaging components that together contain
and protect the product, including, but not limited to, storage bags, seals, stoppers and
administration ports, overwraps, administration accessories, and container labels (Ref. 3).
You should submit a description of the container and closure system, and its
compatibility with the HPC, Cord Blood. The license application should include detailed
information concerning the supplier(s), address(es), and the results of compatibility,
toxicity, and biological tests. Alternately, a new drug application, 510(k) premarket

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notification, or drug master file may be referenced for this information. Evidence of
container and closure integrity should be provided for the duration of the proposed dating
period.
F. 	Methods Validation/Verification
1. 	Infectious Disease Test Methods
Appropriate FDA licensed, approved, or cleared donor screening tests must be
used to test for relevant communicable disease agents and diseases in accordance
with the manufacturer’s instructions. The required testing must be performed by a
laboratory that either is certified to perform such testing on human specimens
under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C.
263a) (CLIA) and 42 CFR Part 493, or has met equivalent requirements as
determined by the Centers for Medicare and Medicaid Services
(21 CFR 1271.80(c)). In this section of your application, you should list the
assays that you (or your contract laboratory) perform to test the maternal sample
for relevant communicable disease agents and diseases, including the name and
manufacturer of the FDA licensed, approved, or cleared test kits used. You
should also identify and provide information regarding the certification of the
testing laboratory (e.g., CLIA certification number).
2. 	Other Test Methods
In this section of your application, you should provide a description of all other
test methods selected to ensure the identity, purity, strength and/or potency, as
well as the lot-to-lot consistency of the finished product and the specifications
used for the HPC, Cord Blood. Certificates of analysis and analytical results for
at least three consecutive batches should be provided. You should use FDA
approved, licensed, or cleared test kits and reagents, where available. Examples
of the other test methods that you should describe in your application include:
• 	Sterility (bacterial and fungal cultures): You should provide a description
of the sterility test method used which is appropriate to the material being
tested, sample types tested, and include a description of your validation
protocol and summary validation data (21 CFR 610.12);
• 	Hemoglobin testing: Provide a description of the tests used to evaluate the
cord blood donor for hemoglobinopathies;
• 	TNC counts;
• 	Nucleated cell viability assay(s);
• 	CD34+ cell viability (flow cytometry);
• 	HLA typing: Provide a description of the serologic and DNA-based
testing performed, sample types used (e.g., cord blood, processed cord
blood discard fractions, and maternal samples, if used) and the name and
location of the laboratory that performs the initial and the confirmatory
HLA typing of the final product;

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• 	ABO blood group and Rh type; and
• 	Other tests you may perform to evaluate your HPC, Cord Blood units,
such as colony-forming unit assays, nucleated red blood cell counts, and
cell phenotype analysis.
3. 	Validation Results
You should provide the results of studies validating the specificity, sensitivity,
and variability of each method used for determining whether a product can be
made available for distribution. Where applicable, this should include
descriptions of reference standards and their validation. For analytical methods in
compendial sources, you should provide the appropriate citations.
Additional information on methods validation is found in section VII.B.14. of this
guidance.8
G. 	Labeling
In this section you should provide representative draft labeling for your HPC, Cord Blood
product. A description of the required labels and labeling for HPC, Cord Blood is
provided in this guidance in section VII.B.12.
H. 	Environmental Assessment
An environmental assessment, as outlined in 21 CFR Part 25, or a request for a
categorical exclusion with the basis for the exclusion, should be submitted. If an
environmental assessment is appropriate, it should include a description of the action that
is being considered and should address all the components involved in the manufacture
and disposal of the product.
8 You may find additional information on methods validation in the FDA draft guidance entitled, “Guidance for
Industry: On Analytical Procedures and Methods Validation: Chemistry, Manufacturing, and Controls
Documentation” dated August 2000 (August 30, 2000, 65 FR 52776)
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070489.pdf.
When finalized, this guidance will represent FDA’s current thinking on this topic. In addition, you may find
additional information in the ICH Harmonised Tripartite Guideline Q2(R1): Validation of Analytical Procedures:
Text and Methodology. Available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm.

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VI. 	ESTABLISHMENT DESCRIPTION SECTION
A. 	Introduction
This section provides guidance on the content and format of information to be submitted
in the establishment description section of your BLA.
B. 	General Information
For each manufacturing location, a floor diagram should be included that indicates the
general layout of the facility. The following information should be provided on each
floor diagram and/or in an accompanying narrative:
• 	A layout of the physical facility and the processing that takes place in each area,
including receipt and testing activities. A floor diagram should be submitted,
indicating the room number and location of major equipment;
• 	A general description of the processing areas, including a description of the floor,
ceiling, and equipment surfaces used for cord blood processing;
• 	Activities in adjacent areas to the processing areas; and
• 	Product, personnel, equipment and waste flows.
A floor diagram of the collection site(s) is not necessary.
C. 	Specific Systems
1. 	Source of Water Used in Processing (if applicable)
If the water for production is being purchased for manufacturing, you should
provide a description of the water quality used in manufacturing (at each stage in
the process) and rinsing of product contact equipment and containers/closures.
This includes bottled/packaged water.
If the water is being manufactured on site, you should provide a general
description of the water system(s), including the validation summary and routine
monitoring program.
2. 	Heating, Ventilation, and Air Conditioning
You should include the following information:
• 	A description of the controls used to prevent contamination and cross-
contamination, including air handling units, pressure differentials, whether
air is once-through or recirculated, and air changes per hour;
• 	A description of the environmental quality of each room and each aseptic
processing area (laminar flow unit); and

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• 	A validation summary for the system, including a narrative on the
validation utilized, acceptance criteria, and explanation of failures and
excursions, including deviation reports and results of investigations.
3. 	Facility Controls
This section should contain information on the various controls and monitoring
for the collection and processing of cord blood at the manufacturing locations,
including:
• 	A description of the area and cleaning/sanitization procedures;
• 	A description of the personnel gowning practices for the manufacturing
areas;
• 	A description of the measures used to prevent unauthorized access into the
manufacturing areas (card key readers, etc.); and
• 	A brief description of any environmental monitoring program, including
monitoring for airborne viable and nonviable particles, surface sampling,
frequency of the monitoring, and alert and action levels that have been
established for each area.
4. 	Computer Systems
This section should contain information on computer systems that control critical
manufacturing processes. For example, you should provide information for
computer systems used for recording results of donor eligibility screening and
testing; tracking the distribution of HPC, Cord Blood units and associated
samples; automated systems for controlled-rate freezing, storage, and retrieval;
and any other automated systems you use to manufacture your HPC, Cord Blood.
The developer of the system should be identified, whether in-house or
contractor/vendor. The information provided should also include a brief
description of procedures for making changes to the computer system. For each
of these systems a list of manufacturing steps that are computer-controlled should
be provided.
This section should also contain a validation/verification summary for each of
these systems, which includes9:
9 For information on software regulation and validation, you should refer to the FDA guidance entitled “General
Principles of Software Validation: Guidance for Industry and FDA Staff” dated January 2002 available at
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126954.htm. Section 6, “Validation of Automated
Process Equipment and Quality System Software” of the guidance may be particularly helpful to you in validating
the software for use in your establishment. In addition, the CGMP regulations at 21 CFR 211.68(a), (b), and (c)
describe requirements that apply to the validation of automatic, mechanical, and electronic equipment, including
computers.

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• 	A narrative description of the validation/verification process or protocol,
including acceptance criteria;
• 	Certification that installation qualification and operation qualification have
been completed;
• 	An explanation of the parameters monitored and tests performed;
• 	A validation/verification data summary; and
• 	An explanation of all excursions or failures, deviation reports, and result
of investigations for all excursions or failures.
D. 	Contamination/Cross-Contamination Issues
The following information regarding methods to prevent contamination and cross-
contamination should be provided to supplement the information requested in the CMC
section of the application.
1. 	Equipment Cleaning Procedures and Validation
You should provide a brief description of the cleaning procedures and cleaning
reagents used. This section should also contain a certification that the cleaning
validation for removal of product residues has been successfully completed.
2. 	Containment Features
This section should contain a description of segregation and containment
procedures for areas, manufacturing operations, personnel, equipment and waste
materials designed to prevent contamination of products. You should discuss the
features that are employed to maintain segregation and containment. These
features might include but are not limited to:
a. 	Air Handling (where appropriate)
• 	Air pressure differentials between adjacent manufacturing areas;
• 	Segregation of air handling units;
• 	Air supply and return (recirculated, once-through, high efficiency
particulate air (HEPA) filters, etc.); and
• 	Use of airlocks.
b. 	Decontamination and Equipment Cleaning
Procedures for decontamination and cleaning of equipment used to
process material in closed containers when there is a breach in the
container integrity and leakage of product onto the equipment.

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VII. 	GUIDANCE ON APPLICABLE REGULATIONS
A. 	Establishment Registration and Listing
Within five days after beginning of operations, you must register and submit a list of
every HCT/P that your establishment manufactures, following the registration and listing
procedures in 21 CFR Part 1271 Subpart B (see 21 CFR 1271.21). If you, the registered
establishment, contract with or have an agreement or other arrangement with an
individual to collect and send to you cord blood for processing, that individual does not
have to register or list independently; however, that individual must comply with all other
applicable requirements (21 CFR 1271.15(f)).
B. 	Current Good Manufacturing Practice and Current Good Tissue Practice
As previously noted in this guidance, you, the manufacturer, must follow all regulations
applicable to cord blood collection and manufacture of HPC, Cord Blood. FDA
considers umbilical cord blood collected for further processing into HPC, Cord Blood to
be an intermediate product. While there are no specific regulations governing the
manufacture of intermediates, drug substances or what are termed active pharmaceutical
ingredients, compliance with statutory CGMP (Section 501(a)(2)(B) of the FD&C Act) is
required. Accordingly, for collection of cord blood for further processing into HPC, Cord
Blood, Section 501(a)(2)(B) or statutory CGMP would be applied. This section of the
FD&C Act mandates that methods used in, or the facilities or controls used for the
manufacture, processing, packing, or holding of a drug must conform or be administered
in conformity with CGMP. Though not specifically applicable to HPC, Cord Blood, the
FDA guidance entitled “Guidance for Industry: Q7A Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients” dated August 2001 (Ref. 4), provides
recommendations for good manufacturing practices for the manufacture of intermediates,
drug substances, and active pharmaceutical ingredients.
For the collection of cord blood as well as manufacture of HPC, Cord Blood, the CGTP
and other applicable provisions in 21 CFR Part 1271 apply. The CGMP regulations in
21 CFR Parts 210 and 211 are applicable to the manufacture of a drug product, which is
defined as the finished dosage form (21 CFR 210.3(b)(4)). Accordingly, for the
manufacture of HPC, Cord Blood, applicable regulations include, but are not limited to,
the CGMP in 21 CFR Parts 210 and 211, CGTP and other applicable provisions in
21 CFR Part 1271, and applicable regulations for biologics contained in
21 CFR Parts 600 through 680. For the most part, in the manufacture of HPC, Cord
Blood, the CGMP regulations will be applied because they are more broadly drafted and
subsume the CGTP regulations.
The CGMP regulations applicable to the manufacture of your HPC, Cord Blood are
contained in eleven subparts in 21 CFR Part 211, and this section of the guidance is
formatted to follow these subparts:

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Subpart A – General Provisions
Subpart B – Organization and Personnel
Subpart C – Buildings and Facilities
Subpart D – Equipment
Subpart E – Control of Components and Drug Product Containers and Closures
Subpart F – Production and Process Controls
Subpart G – Packaging and Labeling Controls
Subpart H – Holding and Distribution
Subpart I 	– Laboratory Controls
Subpart J 	– Records and Reports
Subpart K – Returned and Salvaged Drug Products
The CGTP regulations applicable to the collection of the cord blood as well as the
manufacture of HPC, Cord Blood are contained in two subparts in 21 CFR Part 1271, and
this section of the guidance is formatted to follow these subparts:
Subpart C 	– Donor Eligibility
Subpart D 	– Current Good Tissue Practice
In addition, 21 CFR Part 1271 Subpart A – General Provisions, and Subpart B –
Procedures for Registration and Listing, are applicable to HPC, Cord Blood. However,
21 CFR Part 1271 Subpart E – Additional Requirements for Establishments Described in
§ 1271.10 (reporting requirements and labeling), and Subpart F – Inspection and
Enforcement of Establishments Described in § 1271.10, are not applicable to HPC, Cord
Blood products described in this guidance.
As the applicable regulations contain many requirements for written procedures
(hereafter “SOPs”), you may consider establishing an SOP manual so that all SOPs are
found in one location available to personnel.
The following recommendations are provided to assist you in complying with section
501(a)(2)(B) of the FD&C Act, as well as regulations applicable to the manufacture of
your HPC, Cord Blood. This guidance may not include all the regulations that would
apply to you, so you should carefully review all the regulations to ensure that you are in
compliance.
1. 	Donor Eligibility
You must comply with the donor eligibility requirements contained in
21 CFR 1271.45 through 1271.90. You must perform communicable disease
testing using a peripheral blood sample taken from the mother of the cord blood
donor within 7 days of collection (21 CFR 1271.80(b)).
Once a donor eligibility determination has been made, you must create and retain
specific records (21 CFR 1271.55).

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2. 	Prevention of the Introduction, Transmission, or Spread of Communicable
Diseases
You must recover, process, store, label, package, and distribute your HPC, Cord
Blood, and screen and test donors in a way that prevents the introduction,
transmission, or spread of communicable diseases (21 CFR 1271.145).
3. 	Manufacturing Arrangements
If you engage another establishment under a contract, agreement, or other
arrangement to perform any step in the manufacture, then that establishment must
comply with applicable requirements for that manufacturing step
(21 CFR 1271.150(c)(1)(ii)).
4. 	Exemptions and Alternatives
You may request an exemption from or alternative to any requirement in Subparts
C and D of 21 CFR Part 1271 that apply (21 CFR 1271.155).
5. 	Quality Control Unit (21 CFR 211.22)
a. 	You must have a Quality Control Unit (QCU). The QCU may be any
person or organizational element responsible for the duties relating to
quality control (21 CFR 210.3(b)(15)).
b. 	The QCU must have:
• 	Adequate laboratory facilities for testing (21 CFR 211.22(b)); and
• 	Responsibilities and procedures in writing and the written procedures
must be followed (21 CFR 211.22(d)).
c. 	The QCU has the following responsibilities:
• 	Responsibility and authority to approve/reject all components, drug
product containers and closures, in-process materials, packaging,
labeling, and HPC, Cord Blood units (21 CFR 211.22(a));
• 	Authority to review records to ensure that no errors have occurred and
that those that do occur are fully investigated (21 CFR 211.22(a));
• 	Responsibility to approve/reject procedures/specifications affecting
identity, strength, quality, and purity of the HPC, Cord Blood
(21 CFR 211.22(c);
• 	Responsibility to review and approve written procedures for
production and process control, including any changes to these
procedures (21 CFR 211.100(a));
• 	Responsibility to review and approve the establishment of any
specifications, standards, sampling plans, test procedures, or other

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laboratory control mechanisms, including any changes in such
specifications, standards, sampling plans, test procedures, or other
laboratory control mechanisms (21 CFR 211.160(a));
• 	Responsibility to review and approve all HPC, Cord Blood production
and control records to determine compliance with all established,
approved, written procedures before a lot is released or distributed.
Any discrepancies must be thoroughly investigated (21 CFR 211.192);
• 	Responsibility to establish and follow written procedures describing
the handling of all written or oral complaints, including provisions for
QCU review of any complaint related to HPC, Cord Blood failures;
investigation of any complaint; evaluation of whether the complaint
represents an adverse drug experience and, if so properly reporting it
(21 CFR 211.198); and
• 	Responsibility for periodically conducting an internal quality audit for
management review. You should document these independent reviews
(21 CFR 1271.160(c)). Quality audit is defined in 21 CFR 1271.3(gg),
and must be performed for activities of core CGTP requirements
relating to communicable disease transmission, such as donor
eligibility determination. For HPC, Cord Blood, audits should be
performed more broadly to encompass CGMP.
6. 	Personnel
a. 	General
You must have an adequate number of personnel with the education, training,
and experience, or any combination thereof, required to perform their assigned
functions. Personnel must be trained in the specific operations they perform
and the CGMP that relate to their functions (21 CFR 211.25, and 600.10(b)).
Personnel should be properly gowned and practice good sanitation practices.
Only personnel authorized by supervisory personnel should enter limited
access areas of your facility. Anyone with an apparent illness that could
adversely affect the product should report the condition to their supervisor and
be excluded from direct product contact (21 CFR 211.28, and 600.10(c)).
Personnel who perform cord blood collection as your agents must be trained
according to the applicable CGMP and CGTP requirements
(21 CFR 211.25(a)). (See also 21 CFR 1271.170).
You should develop a system for providing information and other resources
that could be used for education and training of transplant center personnel to
ensure appropriate handling, testing, and administration of the HPC, Cord
Blood.

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b. 	Medical Director
You should have a medical director who is qualified by education, training
and/or experience to have responsibility and authority for all medical aspects
of the cord blood bank. Where a remote collection facility ships cord blood to
a central cord blood bank, the medical director of the central cord blood bank
may serve as medical director of the remote collection facility.
c. 	Laboratory Director
You should have a laboratory director who is qualified by education, training
and/or experience and is responsible for all technical aspects of the cord blood
bank.
If you choose to designate a medical or laboratory director to perform any
authorization activities, we remind you that the QCU has the ultimate
responsibility for approval and/or rejection of the product, in addition to its
other responsibilities (see section VII.B.5. of this guidance).
7. 	Buildings and Facilities
You should design and maintain your buildings and facilities to provide adequate
environmental conditions for the manufacture of HPC, Cord Blood, adequate
segregation of operations to prevent mix-ups, and adequate sanitation SOPs to
prevent contamination and cross-contamination. The following should be
considered:
a. 	Maintenance
Buildings used in the manufacture of HPC, Cord Blood must be maintained in
a state of good repair (21 CFR 211.58).
b. 	Facility Design and Air Handling Systems for Prevention of Cross-
Contamination
• 	Building(s) used in the manufacture of HPC, Cord Blood must be of
suitable size, construction, and location to facilitate cleaning,
maintenance, and proper operations (21 CFR 211.42(a)); and
• 	Operations must be performed within specifically defined areas of
adequate size (21 CFR 211.42(c)).
c. 	General Air Handling Systems
• 	Adequate ventilation must be provided (21 CFR 211.46(a));

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• 	Equipment for adequate control over air pressure, microorganisms,
dust, humidity, and temperature must be provided, when appropriate
(21 CFR 211.46(b) and 600.11(a)); and
• 	Air filtration systems must be used, when appropriate, on air supplies
to manufacturing areas (21 CFR 211.46(c)).
d. 	Prevention of Mix-ups, Contamination and Cross-Contamination
• 	Buildings must have adequate space for the orderly placement of
equipment and materials to prevent mix-ups and/or contamination
between different components, product containers, closures, labeling,
in-process materials, and/or products (21 CFR 211.42(b)); and
• 	Separate or defined areas or other control systems must be in place for
the operations as necessary to prevent contamination or mix-ups,
including:
o 	Receipt, identification, storage, and withholding from use of
components, product containers, closures, and labeling pending
sampling, testing, or examination by the QCU before release
for manufacturing;
o 	Holding of rejected, and storage of released components,
product containers, closures, and labeling before disposition;
o 	Storage of in-process materials;
o 	Manufacturing and processing operations;
o 	Quarantine storage before release of products;
o 	Control and laboratory operations; and
o 	Aseptic processing, including, when appropriate, an
environmental monitoring system, a room and equipment
cleaning/disinfecting system, and a maintenance system for
equipment used to maintain aseptic conditions
(21 CFR 211.42(c)).
e. 	Sanitation of the Building; Cleaning and Sanitizing Agents
Buildings used in the manufacture of HPC, Cord Blood must be maintained in
a clean and sanitary condition (21 CFR 211.56(a)). There must be SOPs for
facility sanitation designed to prevent the contamination of equipment,
components, product containers, closures, packaging, labeling materials, or
products (21 CFR 211.56(c)).

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8. 	Equipment
a. 	Adequacy of Equipment Design, Size, and Location
Equipment used in the manufacture of HPC, Cord Blood must be of
appropriate design, adequate size, and suitably located for its intended use and
for its cleaning and maintenance (21 CFR 211.63).
b. 	Cleaning and Maintenance
• 	Equipment and/or utensils must be cleaned, maintained, and, as
appropriate for the nature of the drug, sanitized and/or sterilized at
appropriate intervals to prevent malfunctions or contamination that
would alter the safety, identity, strength, quality, or purity of the HPC,
Cord Blood (21 CFR 211.67(a));
• 	SOPs for cleaning and maintenance of equipment, including utensils,
must be established and followed (21 CFR 211.67(b)); and
• 	Records of equipment maintenance, cleaning, sanitizing, and
inspection must be kept (21 CFR 211.67(c)).
c. 	Automatic, Mechanical and Electronic Equipment
• 	Equipment must be routinely calibrated, inspected, or checked
according to a written program designed to ensure proper performance
(21 CFR 211.68(a));
• 	SOPs for calibration and maintenance should conform to the
equipment manufacturers’ recommendations and/or user’s manual;
• 	Written records of calibration checks and inspections must be
maintained (21 CFR 211.68(a));
• 	The liquid nitrogen freezers you use for storage of HPC, Cord Blood
should be qualified to maintain the desired temperature and to permit
insertion and removal of HPC, Cord Blood unit(s) without
compromising the quality of other HPC, Cord Blood units stored in the
same freezer;
• 	Input to and output from the computer or related system of formulas or
other records or data must be checked for accuracy
(21 CFR 211.68(b));
• 	Appropriate controls must be exercised over computer or related
systems to ensure that only authorized personnel institute changes in
records (21 CFR 211.68(b)); and
• 	Hard copy or alternative systems, such as duplicates, tapes, or
microfilm, must be designed to ensure that backup data are exact and
complete and that they are secure from alteration, inadvertent erasures,
or loss (21 CFR 211.68(b)).

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d. 	Equipment Identification Practices (where appropriate)
Major equipment must be properly identified in the production records to
show the specific equipment used in the manufacture (21 CFR 211.105(b)).
9. 	Predistribution Shipments and Control of Components, Containers, and
Closures
You must have SOPs describing in sufficient detail the receipt, identification,
storage, handling, sampling, testing, and approval or rejection of components
(including cord blood that you receive for processing) and HPC, Cord Blood
containers and closures. These procedures must be followed (21 CFR 211.80(a)).
a. 	Predistribution Shipments
If you ship cord blood within your establishment or between establishments
(e.g., collector to processor) and the cord blood is not available for
distribution as described in 21 CFR 1271.265(c), you must first determine and
document whether pre-established criteria designed to prevent communicable
disease transmission have been met, and you must ship the cord blood in
quarantine (21 CFR 1271.265(b)).
b. 	Identification, Inventory, and Storage of Components, Containers and
Closures
• 	The components and HPC, Cord Blood containers and closures must
be handled and stored in a manner to prevent contamination. Bags and
boxes should be stored above the floor and in such a way as to permit
cleaning and inspection (21 CFR 211.80(b) and (c)); and
• 	Each container or grouping of containers for components or HPC,
Cord Blood containers or closures must be identified with a distinctive
code for each lot in each shipment received. You must use this code in
recording disposition of the lot. Each lot must be properly identified
as to its status (e.g., quarantined, released) (21 CFR 211.80(d)).
c. 	Storage of Components, Containers, and Closures under Quarantine until
Tested or Examined, and Released
• 	The components, product containers, and/or closures must be stored
under quarantine until they have been tested or examined, whichever is
appropriate, and released (21 CFR 211.82(b)); and
• 	The product containers and/or closures must be sampled and tested by
the QCU before release (21 CFR 211.84(a)).

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29
d. 	Representative Samples Collected, Tested, or Examined Using
Appropriate Means; Approval and Rejection Activities
• 	The product containers and/or closures must be visually inspected for
container damage or broken seals upon receipt and before acceptance
(21 CFR 211.82(a));
• 	A representative sample of each shipment of each lot of components
must be collected for testing or examination (21 CFR 211.84(b)). The
testing performed should be based on the intended use of the
component and the reliability of the vendor;
• 	Each component must be tested for conformance with appropriate
written specifications for purity, strength, and quality
(21 CFR 211.84(d)). For example, components that come into direct
contact with an HPC, Cord Blood unit must be sterile. Acceptance
may be based on a Certificate of Analysis, as long as at least one
specific identity test is performed and the reliability of the vendor’s
results has been established;
• 	Lots of components, and product containers and closures that meet the
appropriate written specifications may be released for use. Those that
do not must be rejected (21 CFR 211.84(e));
• 	Components, and product containers and closures released for use
must be used on a first in first out basis, i.e., the oldest lots used first
(21 CFR 211.86);
• 	If components and product containers and closures are stored for long
periods of time under conditions that may adversely affect their
performance, they must be re-tested and/or re-examined and approved
or rejected by the QCU (21 CFR 211.87); and
• 	Rejected components and product containers and closures must be
identified and controlled under a quarantine system intended to
prevent their use in manufacturing (21 CFR 211.89).
e. 	Containers and Closures
• 	Product containers and closures must not be reactive, additive or
absorptive so as to alter the safety, identity, strength, quality, or purity
of the HPC, Cord Blood (21 CFR 211.94(a));
• 	The container closure system used for HPC, Cord Blood must provide
adequate protection against foreseeable external factors in storage and
use that can cause deterioration or contamination of the product
(21 CFR 211.94(b));
• 	Containers and closures used for HPC, Cord Blood must be clean and
must be sterilized and processed to remove pyrogenic properties to
ensure they are suitable for the intended use. Such depyrogenation
processes must be validated (21 CFR 211.94(c));
• 	Specifications for the containers and closures, testing and/or
examination methods, and, where applicable, the methods for cleaning,

Contains Nonbinding Recommendations
30
sterilization, and depyrogenation must be contained in SOPs and
followed (21 CFR 211.94(d));
• 	During collection of cord blood, you should use an appropriate closed,
sterile container sealed in a manner that prevents cell loss and
contamination. You should use only citrate-based anticoagulants;
• 	You should transport cord blood in a shipping container designed to
contain any leakage from the collection container and to minimize
temperature changes during transportation; and
• 	You should store unprocessed cord blood in a secure location and in
containers monitored to maintain the desired temperature range.
10. 	Production and Process Controls (Process Validation)
You should validate the processes used to manufacture HPC, Cord Blood and
establish in-process controls and final product specifications to ensure that your
HPC, Cord Blood units have the identity, strength, quality, and purity necessary to
be safe and effective. Whenever an established, validated procedure is modified,
you should perform new validation studies. Because HPC, Cord Blood is subject
to microbiological contamination, you should have procedures in place to ensure
that sterility of the product is maintained.
a. 	Written Procedures; Deviations
• 	You must have SOPs for production and process controls designed to
assure that HPC, Cord Blood units have the identity, strength, quality,
and purity they purport or are represented to possess
(21 CFR 211.100(a));
• 	SOPs, including changes to SOPs, must be approved by the
appropriate organizational units and by the QCU (21 CFR 211.100(a));
and
• 	SOPs must be followed and deviations from the SOPs must be
recorded and justified. Documentation must be done at the time of
performance (21 CFR 211.100(b)).
b. 	Pre-Cryopreservation Processing
• 	Your manipulation of the cord blood should be restricted to volume
reduction by depletion of red cells and plasma, followed by
cryopreservation by controlled rate freezing or an alternative validated
technique; and
• 	You should use an aseptic method of reducing cord blood volume
known to preserve viability and potency and to allow acceptable
recovery of the original number of hematopoietic progenitor cells.

Contains Nonbinding Recommendations
31
c. 	Cryopreservation
• 	Your cryopreservation SOPs should specify the cryoprotectant to be
used and its final concentration, as well as the nucleated cell
concentration, method of freezing, endpoint temperature of cooling,
cooling rate, and storage temperature; and
• 	You should use a cryopreservation process validated to preserve
potency and maintain at least 70% viability.
d. 	Thawing
• 	You should validate a thawing process demonstrated to maintain at
least 70% viability; and
• 	If thawing is to be performed at a separate facility, you should provide
that facility with instructions for performing the validated thawing
process.
e. 	Implementation and Documentation of In-Process Controls, Tests, and
Examinations
• 	You must have SOPs that describe the in-process controls, and tests or
examinations to be conducted on appropriate samples of in-process
materials of each batch (21 CFR 211.110(a)); and
• 	In-process controls must be consistent with product final specifications
(21 CFR 211.110(b)).
f. 	Time Limitations on Production
• 	When appropriate, you must establish time limits for the completion of
each phase of production to assure the quality of the HPC, Cord Blood.
Deviations from these limits may be acceptable if the deviation does
not compromise the quality of the HPC, Cord Blood. Deviations must
be justified and documented (21 CFR 211.111);
• 	You should begin processing of HPC, Cord Blood within 48 hours of
collection; and
• 	Your SOPs should be designed to minimize the transit time of the
HPC, Cord Blood between freezing and storage devices.
g. 	Prevention of Microorganisms in Sterile Products
• 	Appropriate written procedures (SOPs) designed to prevent
microbiological contamination must be established and followed
(21 CFR 211.113(a)). Such procedures must include validation of all
aseptic and sterilization processes (21 CFR 211.113(b)). (See also
21 CFR 600.11(b));

Contains Nonbinding Recommendations
32
• 	During collection, you should use validated aseptic methods to provide
maximum assurance of sterile products (Ref. 5); and
• 	Your cryopreservation process should employ aseptic techniques and
not permit introduction of microbial contaminants or other
adventitious agents.
h. 	Pooling
Cord blood from two or more donors must not be pooled (placed in physical
contact or mixed in a single receptacle) during manufacturing
(21 CFR 1271.220(b)).
11. 	Packaging and Labeling Control
a. 	Acceptance Operations for Packaging and Labeling Materials;
Examination, Storage, and Usage
• 	SOPs describing the receipt, identification, storage, handling,
sampling, examination, and/or testing of labeling and packaging
materials must be written and followed (21 CFR 211.122(a));
• 	Labeling and packaging materials must be representatively sampled,
examined, and/or tested upon receipt and before use in packaging or
labeling of the product (21 CFR 211.122(a)); and
• 	Labeling and/or packaging materials not meeting appropriate written
specifications must not be approved and released for use
(21 CFR 211.122(b)).
b. 	Control of Labeling Issuance, Examination of Issued Labels, and
Reconciliation of Used Labels
• 	Labeling issued for use in product labeling operations must be strictly
controlled (21 CFR 211.125(a)) and must be carefully examined for
identity and conformity to the labeling specified in the master or HPC,
Cord Blood production records (21 CFR 211.125(b));
• 	The quantities of labeling issued, used, and returned must be
reconciled, and discrepancies between the quantity of finished product
and the quantity of labeling issued must be evaluated
(21 CFR 211.125(c)); and
• 	All excess labeling bearing lot or control numbers must be destroyed
(21 CFR 211.125(d)).

Contains Nonbinding Recommendations
33
c. 	Packaging and Labeling Operations, Line Clearance, Inspection and
Documentation Including Validation and Security of Computerized
Processes
• 	SOPs designed to ensure that correct labels, labeling, and packaging
materials are used must be established and followed
(21 CFR 211.130). Such procedures must incorporate the following
features:
o 	Prevention of mix-ups and/or cross-contamination by physical
or spatial separation from operations on other products
(21 CFR 211.130(a));
o 	HPC, Cord Blood units must be labeled with a distinct
identification code (e.g., alphanumeric, that relates the product
to the donor and to all records pertaining to the product)
(21 CFR 1271.290(c)); and
o 	The label must include information designed to facilitate
effective tracking, using the distinct identification code, from
the donor to the recipient and from the recipient to the donor.
You must create such a code specifically for tracking, and it
may not include an individual’s name, social security number,
or medical record number. You may adopt a distinct
identification code assigned by another establishment engaged
in the manufacturing process or you may assign a new code. If
you assign a new code to an HPC, Cord Blood unit, you must
establish and maintain procedures for relating the new code to
the old code (21 CFR 1271.290(c)).
• 	Equipment used in computerized packaging and/or labeling processes
must be routinely calibrated, inspected, or checked according to a
written program designed to ensure proper performance
(21 CFR 211.68(a));
• 	Changes in the computers and related systems must be appropriately
controlled to ensure only authorized personnel perform them
(21 CFR 211.68(b)); and
• 	The following information should accompany HPC, Cord Blood
during shipping:
o 	Emergency contact information; and
o 	Instructions for receiving and handling HPC, Cord Blood,
including interim storage, thawing, and cryoprotectant
removal.

Contains Nonbinding Recommendations
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d. 	Expiration Dating (21 CFR 211.137(a) through (d)); and 21 CFR
1271.260(c))
The HPC, Cord Blood container label or other labeling must:
• 	Bear an expiration date determined by appropriate stability testing; and
• 	Have expiration dates related to any storage conditions stated in the
labeling, as determined by stability studies; for example,
cryopreserved and post-thaw expiration dates (and times, when
appropriate).
e. 	Examination of the Labeled Finished Product (21 CFR 211.134(a) and (c))
Labeled HPC, Cord Blood units must be examined during the finishing
operations to ensure that the containers and/or packages have the correct label.
The results of the examination must be documented in the production or
control records.
f. 	Packaging and Shipping (21 CFR 1271.265(d))
Packaging and shipping containers must be designed and constructed to
protect the HPC, Cord Blood from contamination and other harmful effects of
environmental exposure.
You must establish appropriate shipping conditions to be maintained during
transit. Cryopreserved HPC, Cord Blood units should be transported in a
liquid nitrogen-cooled dry shipper validated to maintain temperature for the
appropriate time period.
12. 	Label and Labeling Content to be Submitted with Your Application
a. 	Prescription Drug Labeling (21 CFR 201.56 and 201.57)
HPC, Cord Blood is a prescription drug product subject to the labeling
requirements in 21 CFR 201.56 and 201.57. Clearly inapplicable sections,
subsections, or specific information may be omitted from the labeling
(21 CFR 201.56(d)(4)). The “Guidance for Industry: Labeling for Human
Prescription Drug and Biological Products — Implementing the Physician
Labeling Rule Content and Format Requirements” dated February 2013,
contains guidance for implementing these labeling provisions (Ref. 6).
b. 	Package Label (21 CFR 610.60 and 610.61)
In addition to the labeling requirements in 21 CFR 201.56 and 201.57, HPC,
Cord Blood is subject to the label requirements in 21 CFR 610.60 – Container
label; and 21 CFR 610.61 – Package label. A full container label is the label

Contains Nonbinding Recommendations
35
affixed to the immediate container of a product capable of bearing a full label
(21 CFR 610.60). A partial label may be used if the immediate container is
incapable of bearing a full label (21 CFR 610.60(c)). Partial labels must bear
at a minimum specific information described in 21 CFR 610.60(c).
Immediate containers bearing partial labels must be placed in a package that
bears all of the items required for a package label (21 CFR 610.60(c)). The
package label must bear the items listed in 21 CFR 610.61. This label must be
affixed to each package containing an HPC, Cord Blood product.
c. 	Bar Code (21 CFR 201.25)
Because HPC, Cord Blood is a prescription drug product, it is subject to the
bar code label requirements in 21 CFR 201.25. You may request, in writing,
an exemption from the bar code label requirements (see 21 CFR 201.25(d)).
d. 	Current Good Tissue Practice – Labeling (21 CFR 1271.55)
Licensed HPC, Cord Blood units must be accompanied by certain records at
all times after a donor has been determined to be eligible (21 CFR 1271.55(a)
and (b)). These accompanying records must not contain the donor’s name or
other personal information that might identify the donor (21 CFR 1271.55(c)).
The recommended extent of HLA match between the donor and recipient and
the recommended HPC, Cord Blood cell dose are important considerations for
HPC, Cord Blood dosage and administration and therefore, this information
should be provided in the labeling.
13. 	Holding and Distribution
SOPs describing the distribution of HPC, Cord Blood must be established and
followed and include a system by which the distribution of each lot of HPC, Cord
Blood can be readily determined to facilitate its recall if necessary
(21 CFR 211.150). You should:
• 	Store unprocessed cord blood in a secure location and in containers
monitored to maintain the desired temperature range;
• 	Visually examine the final product containers and all attached
containers for damage or possible contamination prior to use and
immediately after filling;
• 	Cryopreserve and store HPC, Cord Blood in liquid nitrogen in
containers appropriate for long-term storage;
• 	Place the cryopreserved final product in metal canisters, or use a
validated alternative method to protect HPC, Cord Blood from damage
due to mechanical trauma during cryopreservation, transport within the
laboratory, removal from storage, transfer to a shipping container, and
shipping to the transplant center;

Contains Nonbinding Recommendations
36
• 	Store the cryopreserved HPC, Cord Blood in a device that has been
qualified to maintain the desired temperature and that permits insertion
and removal of an HPC, Cord Blood unit without compromising the
quality of other HPC, Cord Blood units stored in the same freezer;
• 	Store HPC, Cord Blood at the following temperatures or at other
acceptable temperatures validated to maintain equivalent product
quality:
o 	liquid: 15 - 25˚C
o 	frozen: ≤ -150˚C (liquid or vapor phase of liquid nitrogen)
• 	Confirm that temperature controls were maintained throughout the
storage period prior to product release. Excursions in storage
temperature should be investigated; and
• 	Not store HPC, Cord Blood with nonhuman material.
You must maintain and record storage temperatures and periodically review
recorded temperatures to ensure that HPC, Cord Blood storage temperatures are
consistently within acceptable limits (21 CFR 1271.260(e)).
14. 	Laboratory Controls
You should establish scientifically sound and appropriate specifications,
standards, sampling plans, and test procedures designed to ensure that
components, drug product containers and closures, in-process materials, labeling,
and HPC, Cord Blood products conform to appropriate standards of identity,
strength, quality, and purity. All such procedures must be reviewed and approved
by your QCU, and any deviation should be recorded and justified
(21 CFR 211.160(a) and (b)).
a. 	Availability for Distribution and Testing and Release for Distribution
An HPC, Cord Blood unit that is in quarantine, is contaminated, is recovered
from a donor who has been determined to be ineligible or for whom a donor-
eligibility determination has not been completed, or that otherwise does not
meet release criteria designed to prevent communicable disease transmission
cannot be licensed and cannot be made available for distribution under the
approved BLA.10
For each lot of HPC, Cord Blood, there must be appropriate laboratory
determination of satisfactory conformance to final specifications
(21 CFR 211.165).
10 HPC, Cord Blood units that meet the criteria in 21 CFR 1271.60 and 1271.65 may be made available for use
under an IND in effect.

Contains Nonbinding Recommendations
37
• 	Any sampling and testing plans must be described in written
procedures that must include the method of sampling and the volume
to be tested; such written procedure must be followed
(21 CFR 211.165(c));
• 	Acceptance criteria for the sampling and testing conducted by the
QCU must be adequate to assure that HPC, Cord Blood meet each
appropriate specification and appropriate statistical quality control
criteria as a condition for their approval and release
(21 CFR 211.165(d));
• 	The statistical quality control criteria must include appropriate
acceptance levels and/or appropriate rejection levels
(21 CFR 211.165(d));
• 	The accuracy, sensitivity, specificity, and reproducibility of test
methods must be established and documented (21 CFR 211.165(e)).
The methods validation and documentation may be accomplished in
accordance with 21 CFR 211.194(a)(2);
• 	Results of release testing on HPC, Cord Blood must meet established
specifications or acceptance criteria before the unit is released for
patient administration (21 CFR 211.165(d), 1271.265(c), and
1271.50(a)); and
• 	HPC, Cord Blood units failing to meet established specifications and
any other relevant quality control criteria must be rejected
(21 CFR 211.165(f)).
b. 	Product Safety (21 CFR 610.11(g) and 21 CFR Part 1271 Subpart C)
i. 	Infectious Disease Testing
You must perform all required infectious disease tests (see
21 CFR 1271 Subpart C), and all test results must be negative, or in case
of syphilis testing, the appropriate confirmatory test must be negative prior
to the release of an HPC, Cord Blood unit for transplantation.11
You must establish and maintain a procedure governing the release of an
HPC, Cord Blood unit from a donor whose maternal blood sample tests
reactive for CMV (see 21 CFR 1271.85(b)(2)).
ii. 	Sterility
You should perform sterility testing on a sample of the HPC, Cord Blood
taken before cryopreservation. Testing must be performed in accordance
with 21 CFR 610.12 or with an equivalent method that has been validated
or verified for use with your HPC, Cord Blood (21 CFR 610.9); and you
11 HPC, Cord Blood units that meet the criteria in 21 CFR 1271.60 and 1271.65 may be made available for use
under an IND that is in effect.

Contains Nonbinding Recommendations
38
must not release an HPC, Cord Blood unit for transplantation that fails
sterility testing (21 CFR 1271.265(c)(2) and 21 CFR 211.165(f)).
iii. Hemoglobin Testing
You should obtain hemoglobin screening results that indicate whether an
HPC, Cord Blood donor expresses a homozygous hemoglobinopathy, and
you should not release for transplantation an HPC, Cord Blood unit with
this abnormality. In some situations it may be appropriate to include
testing for heterozygous hemoglobinopathies, at the request of the
transplant physician.
c. 	Product Potency (21 CFR 610.10)
i. 	Total Nucleated Cells
• 	The total number of nucleated cells in the HPC, Cord Blood should
be adequate to provide, after thawing, at least 1.7 x 107 nucleated
cells/kg of body weight of the prospective recipient; and
• 	Because the weight of the prospective recipient is unknown at the
time of storage, you should store HPC, Cord Blood units that
contain at least 5.0 x 108 total nucleated cells per product.12
ii. 	Viable Nucleated Cells
You should demonstrate by a validated assay that at least 85% of the
nucleated cells in the HPC, Cord Blood unit are viable after volume
reduction and before cryopreservation (see 21 CFR 211.165(a) and (e)).
iii. Viable CD34+ Cells
The percent of viable nucleated cells expressing the hematopoietic
progenitor cell marker CD34+ in a normal HPC, Cord Blood unit should
be at least 0.25% of the total viable nucleated cell content after volume
reduction and before cryopreservation.
d. 	Product Identity (21 CFR 610.14)
i. 	Histocompatibility Testing
• 	Accredited Laboratory – The cord blood bank should utilize an
HLA testing laboratory certified by CLIA and accredited by the
American Society for Histocompatibility and Immunogenetics or
12 We base this number upon a hypothetical recipient of 20 kg and a minimum nucleated cell recovery of 70% after
freezing and thawing.

Contains Nonbinding Recommendations
39
equivalent accrediting body for initial and confirmatory typing of
HPC, Cord Blood;
• 	Typing Methods – HPC, Cord Blood should be typed by serologic
or DNA-based methods for HLA Class I (A and B) loci, and by
DNA-based methods for HLA Class II (DRB1) loci. A
precryopreservation sample should be used for the initial HLA
typing if serologic methods are used;
• 	HLA Confirmatory Testing of Potential Recipient – Prior to
releasing an HPC, Cord Blood unit for transplantation, you should
obtain or perform confirmatory HLA typing of the potential
recipient’s blood, unless this typing has been confirmed and
updated on an independent sample by the original laboratory or by
an independent HLA laboratory; and
• 	HLA Confirmatory Testing of HPC, Cord Blood – Once an HPC,
Cord Blood unit is identified for potential use, you should test a
sample of that unit to confirm the HLA type using a contiguous
segment. The confirmatory testing record should include a list of
the alleles tested and methodology used.
ii. 	Blood Grouping and Rh Typing
You should identify and record the ABO and Rh of the HPC, Cord Blood
unit.
e. 	Stability Testing (21 CFR 211.166)
You must establish a written testing program designed to assess the stability
characteristics of HPC, Cord Blood (21 CFR 211.166(a)). Stability programs
should include, but are not limited to, analyses of product potency, integrity,
and sterility. These studies should also include analyses of products stored at
appropriate temperatures and at specific time intervals. Non-clinical
laboratory data, such as in vitro colony forming assays, may be used as part of
your stability testing program, supported by clinical transplant data where
available. The results of such stability testing must be used in determining
appropriate storage conditions and expiration dates (21 CFR 211.166(a)). The
written program must be followed and must include:
• 	Sample size and test intervals based on statistical criteria for each
attribute examined to assure valid estimates of stability
(21 CFR 211.166(a)(1));
• 	Storage conditions for HPC, Cord Blood and other product samples
retained for testing (21 CFR 211.166(a)(2));
• 	Reliable, meaningful, and specific test methods
(21 CFR 211.166(a)(3));
• 	Testing of the HPC, Cord Blood in the same container-closure system
as that in which the HPC, Cord Blood is marketed

Contains Nonbinding Recommendations
40
(21 CFR 211.166(a)(4)); and
• 	An adequate number of HPC, Cord Blood units must be tested to
determine an appropriate expiration date and a record of such data
must be maintained (21 CFR 211.166(b)).
f. 	Reserve Samples (21 CFR 211.170)
An appropriately identified reserve sample that is representative of each HPC,
Cord Blood unit must be retained (21 CFR 211.170(a)). You may retain
multiple samples. The reserve sample or samples taken together consist of at
least twice the quantity necessary for all tests required to determine whether
the HPC, Cord Blood meets its established specifications, except for sterility
testing.
While reserve samples consisting of small aliquots of plasma, serum,
nucleated cells, and genomic DNA are appropriate for most infectious disease
tests, HLA typing, and genetic testing, they may not be optimal for testing
product potency (e.g., viability assays) because the results of such assays
performed on small aliquots of various cord blood fractions may not directly
correlate with results of potency tests performed using samples obtained
directly from the original product. You should reserve product aliquots
determined to yield results comparable to those obtained using thawed
samples of an entire HPC, Cord Blood unit for each potency specification
tested.
You must retain appropriately identified representative samples of the HPC,
Cord Blood for one year after the expiration of the HPC, Cord Blood
(21 CFR 211.170(b)(1)). You may use the post-thaw expiration date to
determine the length of time the reserve samples must be retained. These
samples must be retained and stored at temperatures and under conditions that
will maintain their identity and integrity and are consistent with product
labeling (21 CFR 211.170(b)).
15. 	Records and Reports
a. 	General Requirements
You are required to maintain all records for 10 years after their creation
(21 CFR 1271.270(d)), with the exception of facility cleaning records, which
are to be maintained for 3 years (21 CFR 1271.190(d)(2)). You are required,
however, to retain records pertaining to a particular HPC, Cord Blood unit at
least 10 years after the date of its administration, or if the date of
administration is not known, then at least 10 years after the date of
distribution, disposition or expiration, whichever is latest
(21 CFR 1271.270(d)).

Contains Nonbinding Recommendations
41
Records must be maintained concurrently with the performance of each step
of manufacture (21 CFR 211.188, and 21 CFR 1271.270), including donor
screening and testing and recovery (collection) (21 CFR 1271.270(a); see
21 CFR 1271.150(a)) and must be accurate, indelible, and legible
(21 CFR 1271.270(a)). The records must include the identity of the individual
performing the work and the dates of the various entries
(21 CFR 1271.270(a)). The records must be as detailed as necessary to
provide a complete history of the work performed and to relate the records to
the particular HPC, Cord Blood unit involved (21 CFR 1271.270(a)).
All required records or copies of the records must be readily available for
FDA inspection at the establishment where the activities described in such
records occurred, or must be immediately retrieved from another location by
computer or other electronic means for review during inspection
(21 CFR 211.180(c)). Paper records retrieved via fax or courier from another
location are acceptable. If you are under contract, agreement, or other
arrangement with a collection facility that acts as your agent and is covered
under your registration, the collection records should be made available for
review at your establishment (21 CFR 1271.270(b)).
Required records may be maintained electronically, as original paper records,
or as true copies such as photocopies, microfiche, or microfilm
(21 CFR 1271.270(c)). Suitable equipment to retrieve these documents must
be readily available (21 CFR 211.180(d)).
Written records required by 21 CFR Part 211 must be maintained so that data
therein can be used for evaluating, at least annually, the quality standards of
HPC, Cord Blood to determine the need for changes in product specifications
or manufacturing or control procedures (21 CFR 211.180(e)). SOPs must be
established and followed for such evaluations and must include provisions for:
• 	A review of a representative number of batches of HPC, Cord Blood,
whether approved or rejected, and, where applicable, records
associated with the batch (21 CFR 211.180(e)(1)); and
• 	A review of complaints, recalls, returned or salvaged HPC, Cord
Blood, and investigations conducted under 21 CFR 211.192 for each
product (21 CFR 211.180(e)(2)).
Procedures must be established to assure that the responsible officials of the
firm, if they are not personally involved in or immediately aware of such
actions, are notified in writing of any investigations conducted under
21 CFR 211.198, 211.204, or 211.208, any recalls, reports of inspectional
observations issued by the FDA, or any regulatory actions relating to good
manufacturing practices brought by the FDA (21 CFR 211.180(f)).

Contains Nonbinding Recommendations
42
b. 	Equipment Cleaning and Use Logs
A written record of major equipment cleaning, maintenance (except routine
maintenance such as lubrication and adjustments), and use must be included in
individual equipment logs that show the date, time, product, and lot number of
each batch processed (21 CFR 211.182). For example, equipment logs must
include the date, time, product, and lot number of each HPC, Cord Blood unit
manufactured.
c. 	Master Production and Control Records
Under 21 CFR 211.186(b)(9), master production and control records must
include, among others:
• 	Complete manufacturing and control instructions;
• 	Sampling and testing procedures;
• 	Specifications; and
• 	Special notations and precautions to be followed.
You must have SOPs for preparing the master production and control records
(21 CFR 211.186(a)).
d. 	Batch Production and Control Records
Batch production and control records must be prepared for each HPC, Cord
Blood unit and must include complete information relating to the manufacture
and control of each HPC, Cord Blood unit (21 CFR 211.188, 21 CFR
600.12(a), and 21 CFR 1271.270). These records must include, among others:
• 	Documentation that each significant step in the manufacture,
processing, packing, or holding of the HPC, Cord Blood was
accomplished (21 CFR 211.188(b));
• 	Complete labeling control records, including specimens or copies of
all labeling used (21 CFR 211.188(b)(8)); and
• 	Accompanying records (21 CFR 1271.55(a)(1) through (a)(3)).
16. 	Failure Investigations
Any unexplained discrepancy or the failure of an HPC, Cord Blood unit or any of
its components to meet any of its specifications must be thoroughly investigated,
whether or not the HPC, Cord Blood unit has already been distributed. All HPC,
Cord Blood production and control records, including those for packaging and
labeling, must be reviewed and approved by the QCU to determine compliance
with all established, approved SOPs before the HPC, Cord Blood is released or
distributed. The investigation must extend to other HPC, Cord Blood units that
may have been associated with the specific failure or discrepancy. A written

Contains Nonbinding Recommendations
43
record of the investigation must be made and must include the conclusions and
follow-up (21 CFR 211.192).
17. 	Tracking
a. 	Product Handling
If you perform any step in the manufacture of an HPC, Cord Blood unit in
which you handle the HPC, Cord Blood, you must track each such HPC, Cord
Blood unit in accordance with 21 CFR 1271.290, to facilitate the investigation
of actual or suspected transmission of communicable disease and take
appropriate and timely corrective action.
You must establish and maintain a system of tracking that enables the tracking
of all HPC, Cord Blood from:
• 	The donor to the consignee or final disposition
(21 CFR 1271.290(b)(1)(i)); and
• 	The consignee or final disposition to the donor
(21 CFR 1271.290(b)(1)(ii)).
Alternatively, if you perform some but not all of the steps in the manufacture
of an HPC, Cord Blood unit in which you handle the product, you may
participate in a system of tracking established and maintained by another
establishment responsible for other steps in the manufacture of the same HPC,
Cord Blood unit, provided that the tracking system complies with all the
requirements of 21 CFR 1271.290.
b. 	Distinct Identification Code (21 CFR 1271.290(c))
As part of your tracking system, you must ensure that each HPC, Cord Blood
unit that you manufacture is assigned and labeled with a distinct identification
code (e.g., alphanumeric) that relates the HPC, Cord Blood unit to the donor
and to all records pertaining to the HPC, Cord Blood unit. This labeling must
include information designed to facilitate effective tracking, using the distinct
identification code, from the donor to the recipient and from the recipient to
the donor. You must create such a code specifically for tracking, and it may
not include an individual’s name, social security number, or medical record
number. You may adopt a distinct identification code assigned by another
establishment engaged in the manufacturing process, or you may assign a new
code. If you assign a new code to an HPC, Cord Blood unit, you must
establish and maintain procedures for relating the new code to the old code
(21 CFR 1271.290(c)).

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c. 	Tracking from Consignee to Donor
As part of your tracking system, you must establish and maintain a method for
recording the distinct identification code and type of each HPC, Cord Blood
unit distributed to a consignee to enable tracking from the consignee to the
donor (21 CFR 1271.290(d)).
d. 	Tracking from Donor to Consignee or Final Disposition
As part of your tracking system, you must establish and maintain a method for
documenting the disposition of each of your HPC, Cord Blood units, to enable
tracking from the donor to the consignee or final disposition. The information
you maintain must permit the prompt identification of the consignee of the
HPC, Cord Blood, if any (21 CFR 1271.290(e)).
e. 	Written Confirmation of Requirements
At or before the time of distribution of an HPC, Cord Blood unit to a
consignee, you must inform the consignee in writing of the requirements in
21 CFR 1271.290 and of the tracking system that you have established and are
maintaining to comply with the regulations (21 CFR 1271.290(f)).
18. 	Complaints
a. 	SOPs for Handling Complaints
SOPs describing the handling of all written and oral complaints regarding
HPC, Cord Blood must be established and followed (21 CFR 211.198(a)).
SOPs must include:
• 	Provisions for review by the QCU of any complaint involving the
possible failure of an HPC, Cord Blood unit to meet any of its
specifications (21 CFR 211.198(a)); and
• 	Provisions for review to determine whether the complaint represents a
serious and unexpected adverse experience that is required to be
reported to the FDA in accordance with 21 CFR 600.80
(21 CFR 211.198(a)).
b. 	File for Written HPC, Cord Blood Complaints
A written record of each complaint must be maintained in a file designated for
HPC, Cord Blood complaints. The file regarding HPC, Cord Blood
complaints must be maintained at the establishment where the HPC, Cord

Contains Nonbinding Recommendations
45
Blood unit(s) involved was manufactured, processed, or packed, or such file
may be maintained at another facility if the written records in such files are
readily available for inspection at that other facility (21 CFR 211.198(b)).
1
c. 	Findings of Investigation and Follow-Up
Where an investigation under 21 CFR 211.192 is conducted, the written
record must include the findings of the investigation and follow-up. The
record or copy of the record of the investigation must be maintained at the
establishment where the investigation occurred in accordance with
21 CFR 211.180(c) (21 CFR 211.198(b)(2)).
d. 	Reasons for Not Investigating
Where an investigation under 21 CFR 211.192 is not conducted, the written
record must include the reason that an investigation was found not to be
necessary and the name of the responsible person making such a
determination (21 CFR 211.198(b)(3)).
9. 	Returned and Salvaged HPC, Cord Blood Units
• 	You should have a procedure for product recovery in the event of a
container failure;
• 	You should have a plan for sterility testing of the compromised
product and notification of the appropriate individuals and regulatory
authorities; and
• 	You must establish and maintain procedures to determine if a unit of
HPC, Cord Blood that is returned to your establishment is suitable to
be returned to inventory (21 CFR 1271.265(f)).
VIII. 	POSTMARKETING ACTIVITIES
A. 	Clinical Outcome Data Collection
As an indicator of the quality of your products, you should analyze information that you
receive from the transplant centers on product-related clinical outcomes of individuals
who receive from your facility HPC, Cord Blood released for transplantation. Examples
of product-related clinical outcomes include graft failure or delayed engraftment, infusion
reactions, and transmission of infections. You should evaluate these data to determine
whether any adverse experiences or other unexpected outcomes identified may be due to
problems with product manufacture, and whether corrective actions are needed.

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46
B. 	Changes to be Reported
Requirements for reporting changes to your approved BLA are contained in
21 CFR 601.12.
C. 	Adverse Experience Reporting
You must report to FDA adverse experiences that are both serious and unexpected that
result in any outcomes such as death, a life-threatening adverse experience, inpatient
hospitalization or prolongation of existing hospitalization (21 CFR 600.80). These
adverse experiences must be promptly reviewed and reported to FDA as required under
21 CFR 600.80. You may find clarification of what to report in the guidance documents
entitled “Guidance for Industry: Postmarketing Adverse Experience Reporting for
Human Drug and Licensed Biological Products – Clarification of What to Report” dated
August 1997 (August 27, 1997, 62 FR 45425), and “Guidance for Industry:
Postmarketing Safety Reporting for Human Drug and Biological Products Including
Vaccines” dated March 2001 (March 12, 2001, 66 FR 14391).13
You must maintain for a period of 10 years records of all adverse experiences
(21 CFR 600.80(i)). This includes toxicity associated with infusion of HPC, Cord Blood,
and delayed or failed engraftment that may relate to HPC, Cord Blood manufacturing.
D. 	Biological Product Deviation Reporting
Product deviations from CGMP, applicable regulations, applicable standards or
established specifications that may affect the safety, purity, or potency of a distributed
product should be reported to FDA as soon as possible but you must report at a date not
to exceed 45 calendar days from the date you acquire information reasonably suggesting
that a reportable event occurred (21 CFR 600.14(c)). You must report on Form FDA
3486 as described in 21 CFR 600.14(d). These product deviations can be due to testing,
processing, packing, labeling, or storage, or withholding or distribution. Product
deviations can be reported electronically on CBER’s website at
http://www.fda.gov/cber/biodev/biodev.htm.
13 Available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071981.htm
and
http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccines/ucm074
850.htm. When finalized, the draft guidance will replace the August 1997 guidance.

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IX. 	DEFINITIONS
CFR: Code of Federal Regulations.
CGMP: Current good manufacturing practice.
CGTP: Current good tissue practice.
Cord blood: A unit of blood collected generally by venipuncture of the placental and umbilical
cord vessels under aseptic conditions into a sterile container.
Histocompatibility: Refers to the similarity of tissues between different individuals. The best-
known histocompatibility antigens are those of the major histocompatibility complex, termed
HLA in humans.
HLA: Human leukocyte antigen.
HPC, Cord Blood: For the purposes of this guidance, HPC, Cord Blood refers to the final drug
product (cryopreserved or thawed) of minimally manipulated hematopoietic stem/progenitor
cells from placental/umbilical cord blood, sourced from an unrelated allogeneic cord blood donor
and intended for hematopoietic and immunologic reconstitution in patients with disorders
affecting the hematopoietic system that are inherited, acquired, or result from myeloablative
treatment.
Manufacture: Means, but is not limited to, any or all steps in the recovery, processing, storage,
labeling, packaging, or distribution of any human cell or tissue, and the screening or testing of
the cell or tissue donor.
Minimal manipulation: For cells or nonstructural tissue - Processing that does not alter the
relevant biological characteristics of cells or tissues.
TNC: Total nucleated cells.
Validation: The confirmation by examination and provision of objective evidence that
particular requirements can consistently be fulfilled. Validation of a process, or process
validation, means establishing by objective evidence that a process consistently produces a result
or product meeting its predetermined specifications.
Verification: The confirmation by examination and provision of objective evidence that
specified requirements have been fulfilled.

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X. 	REFERENCES
1. 	Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) Meeting #53
September 22-23, 2011. Transcripts available at
(http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesand
OtherBiologics/CellularTissueandGeneTherapiesAdvisoryCommittee/ucm280554.htm).
2. 	Guidance for Industry: For the Submission Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products, November 1994
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/UCM072171.htm).
3. 	Guidance for Industry: Container Closure Systems for Packaging Human Drugs and
Biologics, May 1999 (July 7, 1999, 64 FR 36694)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/UCM070551.htm).
4. 	Guidance for Industry: Q7A Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients, August 2001 (September 25, 2001, 66 FR 49028)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/ucm073497.htm).
5. 	Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current
Good Manufacturing Practice, September 2004 (October 4, 2004, 69 FR 59258)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/UCM070342.htm).
6. 	Guidance for Industry: Labeling for Human Prescription Drug and Biological Products —
Implementing the Physician Labeling Rule Content and Format Requirements, February
2013 (February 25, 2013, 78 FR 12760)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/ucm075082.htm).