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  Contains Nonbinding Recommendations 
 
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 
i  Contains Nonbinding Recommendations 
 
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 
ii  Contains Nonbinding Recommendations 
 
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 Administrations (FDAs) 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.   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs 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 FDAs guidances means that something is suggested or 
recommended, but not required. 
3  Contains Nonbinding Recommendations 
 
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 
4  Contains Nonbinding Recommendations 
 
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. 
5  Contains Nonbinding Recommendations 
 
 
  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 manufacturers 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: 
 
  Autologous use;   
o
  Allogeneic use in a first- or second-degree blood relative; or  
o
  Reproductive use. 
o
 
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). 
6  Contains Nonbinding Recommendations 
 
 
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 Committees 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 Agencys re-
examination of the legacy docket data and the Agencys 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.  
7  Contains Nonbinding Recommendations 
 
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  
8  Contains Nonbinding Recommendations 
 
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.  
9  Contains Nonbinding Recommendations 
 
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. 
10  Contains Nonbinding Recommendations 
 
   
Table A.  Required and Recommended Tests and Test Results1  
Product  Sample   Results of Product 
Testing 
Characteristics2  (Type and Timing)  Testing 
All tests negative; 
except, non-treponemal 
Maternal peripheral  test for syphilis when 
blood obtained within  specific treponemal 
Infectious diseases  
7 days of cord blood  confirmatory test is 
Testing required.  
collection  Type and  negative.  
(21 CFR 1271.45 
Timing Required.  (Cytomegalovirus 
through 1271.90) 
(21 CFR 1271.80(a)  (CMV) results are 
 
and (b))   recorded). 
   
 
Safety  CMV  Report 
 
Sterility - Bacterial and 
fungal cultures   HPC, Cord Blood (pre-
No growth 
Testing required.  cryopreservation)* 
 
(21 CFR 211.165(b),   
and 21 CFR 610.12) 
Cord blood** or 
appropriate donor 
No homozygous 
Hemoglobin  sample obtained at 
hemoglobinopathy 
time of cord blood 
recovery 
Total nucleated cells   HPC, Cord Blood (pre-  5.0 x 108 TNC***/ 
(TNC)  cryopreservation)  unit HPC, Cord Blood 
 85% viable nucleated 
Purity and  HPC, Cord Blood (pre-
Viable nucleated cells  cells 
Potency3   cryopreservation) 
 
 
 1.25 x 106 viable 
Viable CD34+ cells  HPC, Cord Blood (pre-
CD34+ cells****/unit 
(flow cytometry)  cryopreservation) 
HPC, Cord Blood 
Human leukocyte 
Cord blood  Report 
antigen (HLA) typing 
Identity  Confirmatory HLA  Attached segment of 
Confirms initial typing 
  typing  HPC, Cord Blood 
Blood Group and Rh 
Cord blood  Report 
Type 
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. 
11  Contains Nonbinding Recommendations 
 
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. 
 
12  Contains Nonbinding Recommendations 
 
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. 
13  Contains Nonbinding Recommendations 
 
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). 
14  Contains Nonbinding Recommendations 
 
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 FDAs 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 
15  Contains Nonbinding Recommendations 
 
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 manufacturers 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; 
16  Contains Nonbinding Recommendations 
 
  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 FDAs 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. 
17  Contains Nonbinding Recommendations 
 
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 
18  Contains Nonbinding Recommendations 
 
  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.  
 
19  Contains Nonbinding Recommendations 
 
  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. 
 
 
 
20  Contains Nonbinding Recommendations 
 
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: 
 
 
21  Contains Nonbinding Recommendations 
 
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). 
 
22  Contains Nonbinding Recommendations 
 
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 
23  Contains Nonbinding Recommendations 
 
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. 
 
 
24  Contains Nonbinding Recommendations 
 
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)); 
25  Contains Nonbinding Recommendations 
 
  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: 
 
  Receipt, identification, storage, and withholding from use of 
o
components, product containers, closures, and labeling pending 
sampling, testing, or examination by the QCU before release 
for manufacturing;  
  Holding of rejected, and storage of released components, 
o
product containers, closures, and labeling before disposition; 
  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 
o
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)). 
 
 
 
 
 
 
26  Contains Nonbinding Recommendations 
 
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 users 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)). 
 
 
27  Contains Nonbinding Recommendations 
 
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)). 
 
28  Contains Nonbinding Recommendations 
 
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 vendors 
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, 
29  Contains Nonbinding Recommendations 
 
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. 
 
 
 
30  Contains Nonbinding Recommendations 
 
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)); 
31  Contains Nonbinding Recommendations 
 
  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)). 
 
 
 
 
32  Contains Nonbinding Recommendations 
 
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: 
 
  Prevention of mix-ups and/or cross-contamination by physical 
o
or spatial separation from operations on other products  
(21 CFR 211.130(a)); 
  HPC, Cord Blood units must be labeled with a distinct 
o
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 
  The label must include information designed to facilitate 
o
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 individuals 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: 
 
  Emergency contact information; and 
o
  Instructions for receiving and handling HPC, Cord Blood, 
o
including interim storage, thawing, and cryoprotectant 
removal. 
 
 
 
33  Contains Nonbinding Recommendations 
 
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 
34  Contains Nonbinding Recommendations 
 
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 donors 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; 
35  Contains Nonbinding Recommendations 
 
  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: 
 
  liquid:  15 - 25 C  
o
  frozen:   -150 C (liquid or vapor phase of liquid nitrogen) 
o
 
  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. 
 
36  Contains Nonbinding Recommendations 
 
  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. 
37  Contains Nonbinding Recommendations 
 
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. 
38  Contains Nonbinding Recommendations 
 
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 
recipients 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  
39  Contains Nonbinding Recommendations 
 
(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)). 
 
40  Contains Nonbinding Recommendations 
 
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)). 
 
41  Contains Nonbinding Recommendations 
 
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 
42  Contains Nonbinding Recommendations 
 
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 individuals 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)). 
 
 
 
43  Contains Nonbinding Recommendations 
 
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  
44  Contains Nonbinding Recommendations 
 
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)). 
 
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)). 
 
19.  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. 
 
45  Contains Nonbinding Recommendations 
 
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 CBERs 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.   
46  Contains Nonbinding Recommendations 
 
 
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. 
 
 
47  Contains Nonbinding Recommendations 
 
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).   
 
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