Guidance for Industry

Minimally Manipulated, Unrelated, 

Allogeneic Placental/Umbilical Cord 

Blood Intended for Hematopoietic 

Reconstitution in Patients with 

Hematological Malignancies 

DRAFT GUIDANCE

This guidance document is for comment purposes only.

Submit comments on this draft guidance by the date provided in the Federal Register notice 

announcing the availability of the draft guidance. Submit written comments to the Division of 

Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. 

You should identify all comments with the docket number listed in the notice of availability that 

publishes in the Federal Register. 

Additional copies of this draft guidance are available from the Office of Communication, 

Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, 

MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at 

http://www.fda.gov/cber/guidelines.htm. 

For questions on the content of this guidance, contact Ellen Lazarus, M.D., at 301-827-6031. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Biologics Evaluation and Research 

December 2006 
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Table of Contents 

I. INTRODUCTION............................................................................................................. 1

A. Purpose................................................................................................................... 1

B. Scope....................................................................................................................... 1

1. What Products does this Guidance Cover?....................................................... 1 

2. What Products are not Covered?....................................................................... 2 

C. How do I use this Guidance to Apply for a Biologics License? ........................ 2

D. Am I Required to use this Guidance when I Apply for a Biologics License 

Application?........................................................................................................... 2

II. BACKGROUND ............................................................................................................... 3

III. APPLICABLE REGULATORY REQUIREMENTS ................................................... 5

IV. LICENSE APPLICATION PROCEDURE.................................................................... 6

A. What Form do I Submit with My Application?................................................. 6

B. Where Should I Submit My License Application? ............................................ 6

C. What Information Should I Include in My Application?.................................. 6

D. What Action will FDA Take?............................................................................... 7

V. CHEMISTRY, MANUFACTURING AND CONTROLS SECTION......................... 7

A. Introduction........................................................................................................... 7

B. HPC-C Description and Characterization.......................................................... 7

C. Manufacturer(s).................................................................................................... 9

D. Methods of Manufacturing ................................................................................ 10

E. Container Closure System.................................................................................. 13

F. Environmental Assessment................................................................................ 13

G. Methods Validation/Verification....................................................................... 13

H. Labeling ............................................................................................................... 14

VI. ESTABLISHMENT DESCRIPTION SECTION........................................................ 14

A. Introduction......................................................................................................... 14

B. General Information........................................................................................... 14

C. Specific Systems .................................................................................................. 15

D. Contamination/Cross-Contamination Issues.................................................... 16

VII. GUIDANCE ON APPLICABLE REGULATIONS .................................................... 17

A. Establishment Registration and Listing ........................................................... 17

B. Current Good Manufacturing Practice and Current Good Tissue Practice. 17

VIII. POSTMARKETING ACTIVITIES.............................................................................. 42

A. Clinical Outcome Data Collection..................................................................... 42

B. Changes to be Reported...................................................................................... 42

C. Adverse Experience Reporting .......................................................................... 43

D. Biologic Product Deviation Reporting .............................................................. 43

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IX. DEFINITIONS ................................................................................................................ 44

X. REFERENCES................................................................................................................ 46

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Guidance for Industry 

Minimally Manipulated, Unrelated, Allogeneic Placental/Umbilical 

Cord Blood Intended for Hematopoietic Reconstitution in Patients 

with Hematological Malignancies 

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) 

current thinking on this topic. It does not create or confer any rights for or on any person and 

does not operate to bind FDA or the public. You can use an alternative approach if the 

approach satisfies the requirements of the applicable statutes and regulations. If you want to 

discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the 

appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 

I. INTRODUCTION 

A. Purpose 

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 specified indications. This guidance document contains those recommendations and 

is intended to assist you in obtaining a biologics license by following those 

recommendations and applicable requirements in Title 21 of the Code of Federal 

Regulations (CFR). This guidance document also contains information about the 

manufacture of minimally manipulated, unrelated, allogeneic placental/umbilical cord 

blood and how to comply with applicable regulatory requirements. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and 

should be viewed only as recommendations, unless specific regulatory or statutory 

requirements are cited. The use of the word should in FDA’s guidances means that 

something is suggested or recommended, but not required. 

B. Scope 

1. What Products does this Guidance Cover? 

This guidance document provides recommendations for the submission of a 

biologics license application (BLA) (21 CFR Part 601) for placental/umbilical 

cord blood products that are: 

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• manipulated minimally; and 

• intended for hematopoietic reconstitution in patients with hematological 

malignancies; and 

• intended to be used in recipients unrelated to the donor. 

For the purpose of this guidance, these products will hereafter be referred to as 

hematopoietic progenitor cells, cord (HPC-C). 

2. What Products are not Covered? 

This guidance applies only to those HPC-C described in Section I.B.1 above. If 

you manufacture peripheral blood or cord hematopoietic stem/progenitor cells 

other than those described, you may need to submit an investigational new drug 

application (IND) or other premarketing application appropriate for that product. 

We encourage manufacturers of cord hematopoietic stem/progenitor cells for 

autologous use, or use in a first- or second-degree blood relative, to follow these 

recommendations, even though their products may not require premarket review. 

C. 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 

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 HPC-C manufactured after approval of the license 

application, as well as HPC-C previously manufactured in accordance with the 

information provided in the license application, where documentation is provided to 

demonstrate their comparability. 

D. 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-C 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 if 

you wish to rely on data in docket number 1997N-0497 (formerly docket number 97N0497). If you choose not to rely on these data, you should consult with us about 

alternative approaches to satisfying applicable regulatory requirements. 

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II. 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 Federal 

Register 5447) (the “registration and listing final rule”). The registration and listing final rule 

requires establishments that manufacture HCT/Ps to register and list their products with the 

agency. 

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 Federal Register

29786) (the “donor eligibility final rule”). This final rule requires, with certain exceptions, that a 

donor eligibility determination be made based on the results of HCT/P donor screening and 

testing for relevant communicable disease agents and diseases. 

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 Federal Register 68612). The Current Good Tissue Practice (CGTP) 

requirements govern the methods used in, and the facilities and controls used for, the 

manufacture of HCT/Ps, including but not limited to all steps in recovery (collection), donor 

screening, donor testing, processing, storage, labeling, packaging, and distribution. 

On May 25, 2005, the three final rules became effective. As described in the registration and 

listing final rule,1 we are regulating as biological drugs or devices those HCT/Ps that: 

• are more than minimally manipulated (processing alters the biological characteristics of 

the cells); 

• are for a use other than homologous use as reflected by the labeling, advertising, or other 

indications of the manufacturer’s objective intent; 

• the manufacture involves the combination of the cell or tissues with another article, to 

include water, crystalloids, or a sterilizing, preserving, or storage agent provided the 

addition of water, crystalloids, or the sterilizing, preserving, or storage agent raises new 

clinical safety concerns with respect to the HCT/P; or 

• has a systemic effect or is dependent upon the metabolic activity of living cells for its 

primary function, and is not for: 

 autologous use; 

 allogeneic use in a first- or second- degree blood relative; or 

 reproductive use. 

 

1

 66 Federal Register 5447 at 5467, January 19, 2001. See also, 21 CFR 1271.10. 

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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 (FDCA). 

On January 20, 1998 (63 Federal Register 2985), 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.” 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 

(65 Federal Register 20825, April 18, 2000). 

The Biological Response Modifiers Advisory Committee met on February 27, 2003, 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 the FDA regarding the safety and effectiveness 

of cord blood for hematopoietic reconstitution. Guest experts provided the most recent data on 

clinical studies of unrelated donor umbilical cord blood transplantation in children and adults. 

The committee’s deliberations focused on: 

1. factors the agency should consider in determining the safety and effectiveness of 

placental/umbilical cord blood transplantation for hematopoietic reconstitution; 

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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.2

We have reviewed and assessed the submitted information as well as the large body of published 

literature on this subject, and have determined that the data are sufficient to establish the safety 

and effectiveness of HPC-C. The data permit the development of recommendations for 

establishment and processing controls and product characteristics for these products. 

Accordingly, this document provides guidance on the content and format of information to be 

submitted in your BLA for HPC-C in the chemistry, manufacturing, and controls (CMC) section, 

and the establishment description section. 

III. APPLICABLE REGULATORY REQUIREMENTS 

You and your HPC-C are subject to all applicable regulatory requirements; and, when applying 

for a biologics license, this includes a prelicense inspection (42 U.S.C. § 262). Because we 

regulate HPC-C for unrelated allogeneic use as drugs under the FDCA and as biological products 

under the PHS Act, you must follow the applicable regulations promulgated under these acts. 

Regulations applicable to HPC-C include, but are not limited to, the following sections of the 

CFR: 

• 21 CFR Parts 210 and 211 – Current Good Manufacturing Practice Regulations (CGMP); 

• 21 CFR Part 600 – Biological Products: General; 

• 21 CFR Part 610 – General Biological Products Standards; 

• 21 CFR Parts 201, and 610 Subpart G – Labeling; and 

• 21 CFR Part 202 – Advertising. 

Cord blood and HPC-C are considered HCT/Ps, defined in 21 CFR 1271.3(d). In the collection 

of cord blood and the manufacture of HPC-C, the regulations promulgated for HCT/Ps in 21 

CFR Part 1271 apply. These regulations encompass registration and listing, donor eligibility, 

and good tissue practices. For the manufacture of HPC-C, 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 an HPC-C 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-C are HCT/Ps, these provisions are applicable to both cord blood and 

HPC-C. 

2

 Summary minutes of the meeting are available at our website at 

http://www.fda.gov/ohrms/dockets/ac/03/minutes/3924M1.htm. 

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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 FDCA as to safety, and 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-C. 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-C. We recommend that you 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 biologic products. We have indicated a section from 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.3 

B. Where Should I Submit My License Application? 

You should submit your completed application to: Document Control Center (HFM-99), 

Center for Biologics Evaluation and Research, Food and Drug Administration, Suite 

200N, 1401 Rockville Pike, Rockville, MD 20852-1448. (21 CFR 600.2(a)). 

 

C. What Information Should I Include in My Application? 

In accordance with Form FDA 356h, you should include, at a minimum, the following 

information: (Numbers in parentheses refer to items listed in Form FDA 356h) 

(1): Index; 

(2): Representative draft labeling for the product for which licensing is being 

sought; 

(3): A summary of the information submitted in the application; 

(4A): Chemistry, manufacturing and controls information (21 CFR 314.50(d); 21 

CFR 601.2). Include a full description of your manufacturing process and copies 

3

 See http://www.fda.gov/opacom/morechoices/fdaforms/FDA-356h.pdf. 

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of standard operating procedures (SOPs) for critical procedures and assays as 

listed in this guidance, Section V.D; 

(4C): Summary data demonstrating validation of critical processes and assays as 

listed in this guidance, Section V.G; 

(15): A description of your facility including personnel, physical establishment, 

and equipment (21 CFR 600.10) as described in this guidance, Section VI; and 

(20): Other attachments, including a citation to the data submitted to docket 

number 1997N-0497 (formerly docket number 97N-0497), which may be 

incorporated by reference. 

Under Establishment Information on page one of Form FDA 356(h), 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 Therapies, 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 prelicense 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-C 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-C (i.e., tests performed and the results) that were used to obtain the 

clinical data submitted to FDA in docket number 1997N-0497 (formerly docket number 

97N-0497). These clinical data demonstrate the safety, purity, and potency of HPC-C. 

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. 

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Table A. Required and Recommended Tests and Test Results 1 

Product 

Characteristics 2 Testing Sample 

(Type and Timing) 

Results of Product 

Testing 

All tests negative 

except non-treponemal 

test for syphilis when 

confirmatory test is 

negative. 

(Cytomegalovirus 

(CMV) results are 

recorded). 

Infectious diseases – 

Testing Required. 

(21 CFR 1271.45 

through 1271.90) 

Maternal peripheral 

blood obtained within 

7 days of cord blood 

collection – Type and 

Timing Required. 

(21 CFR 1271.80(a) 

and (b)) 

CMV - Report 

Sterility - Bacterial and 

fungal cultures – 

Testing Required. 

(21 CFR 211.165(b), 

and 21 CFR 610.12) 

Cord blood * and 

HPC-C (precryopreservation) ** Negative 

Safety 

Hemoglobin Cord blood * No homozygous 

hemoglobinopathy 

Total nucleated cells 

(TNC) 

HPC-C (precryopreservation) ≥ 5.0 x 108 TNC ***/ 

unit HPC-C 

Viable nucleated cells HPC-C (precryopreservation) 

≥ 85% viable nucleated 

cells Purity and 

Potency 

Viable CD34+ cells 

(flow cytometry) 

HPC-C (precryopreservation) 

≥ 1.25 x 106

 viable 

CD34+ cells ****/ unit 

HPC-C 

Human leukocyte 

antigen (HLA) Typing Cord blood Report 

Confirmatory HLA 

typing 

Attached segment of 

HPC-C Confirms initial typing Identity 

Blood Group and Rh 

Type Cord blood Report 

1 Testing, Sample (Type and Timing), and Results are recommended unless specifically noted as required. 2 The PHS Act requires a demonstration that the product is safe, pure, and potent. 

* Cord blood = cord blood before undergoing volume reduction. 

** Sample may be obtained before or after addition of the cryoprotectant. 

*** Based on 20 kg recipient @ ≥ 2.5 x 107 nucleated cells/kg & ≥ 70% post-thaw recovery = 1.7 x 107

 nucleated 

 cells/kg. 

****Based on CD34+ cells ≥ 0.25% of TNC prior to freezing. 

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C. Manufacturer(s) 

1. Identification 

This section should include the name(s), address(es), telephone number(s), FDA 

registration number(s), and other pertinent organizational information for each 

manufacturer, including those under contract, agreement, or other arrangement 

with you to perform a manufacturing step. These organizations include, but are 

not limited to, all collection sites that act as your agent(s) and laboratory(ies) 

performing testing of donor samples for relevant communicable disease agents 

and product sterility testing. 

2. Floor Diagram(s) 

For each processing location, a description of the area(s) used for processing of 

HPC-C 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-C 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 avoid the 

simultaneous manipulation of more than one HPC-C in a single area or the 

use of any piece of equipment for more than one HPC-C; and, you should 

discuss measures to prevent cross-contamination; 

• A brief, narrative description of the procedures and/or facility/equipment 

design features for the control of contamination, cross-contamination, and 

aseptic manipulations; and 

• A brief, narrative description of the area where the manufacturing is 

performed, including collection, volume reduction, packaging, labeling, 

cryopreservation, storage, and shipping. 

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D. Methods of Manufacturing 

This section should contain a detailed description of the manufacturing and controls. In 

accordance with Form FDA 356(h), you should submit all relevant SOPs including donor 

selection and cord blood collection, cord blood transport to the processing facility, 

processing, testing, storage, recipient matching, and HPC-C 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 screening 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; 

• criteria for accepting cord blood for further processing; and 

• cord blood collection, storage, and transport to the processing facility. 

b. Processing 

• volume reduction and cell concentration; 

• cryopreservation; 

• frozen storage; and 

• lot release. 

c. Selection 

• data management; 

• search request; 

• donor matching to candidate recipients; and 

• selection of HPC-C. 

d. HPC-C Shipping and Handling 

• shipping to transplant center; 

• thawing and preparation for administration; and 

• emergency product recovery in the event of a container failure, 

including plan for sterility testing of the compromised product and 

notification of the appropriate individuals and regulatory authorities. 

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2. Validation 

We recommend that you submit a validation data summary for the following 

manufacturing and administration steps: 

• cord blood collection; 

• cord blood processing, including volume reduction and cryopreservation; 

• storage; 

• shipping; and 

• thawing and cryoprotectant removal. 

We recommend that the validation summary include data from the manufacture, 

as well as the thawing and cryoprotectant removal of a minimum of three 

consecutive, separate HPC-Cs to demonstrate that you are able to consistently 

manufacture and thaw the HPC-C that meet the product characteristics described 

previously in section V.B of this document. 

A separate validation summary should be submitted for those HPC-C that were 

manufactured using different procedures than those you use currently. The 

summary should include data demonstrating comparability between the 

previously manufactured HPC-C and HPC-C manufactured currently and 

evidence that the methods, facilities, and controls used for manufacture of these 

products were operated in conformity with CGMP and other applicable regulatory 

requirements. The comparability data could include product characteristics such 

as: 

• TNC count; 

• viable CD34+ cell content; and 

• colony forming unit content. 

Establishments may include data describing other product attributes obtained 

from stability or other studies. Information from the medical literature could also 

be cited to support comparability, if available. Additionally, we recommend that 

you submit any available clinical outcome data to support comparability of your 

HPC-C manufactured using different procedures than those you use currently.4

4

 You may find additional information on comparability in the following publications: 

• Guidance for Industry: Q5E Comparability of Biotechnological/Biological Products Subject to Changes in 

Their Manufacturing Process, June 2005 (http://www.fda.gov/cber/gdlns/ichcompbio.pdf). 

• Draft Guidance for Industry; Comparability Protocols - Chemistry, Manufacturing, and Controls 

Information, February 2003 (http://www.fda.gov/cber/gdlns/cmprprot.pdf). When finalized, this guidance 

will represent FDA’s current thinking on the topic. 

• Draft Guidance for Industry; Comparability Protocols Protein Drug Products and Biological Products - 

Chemistry, Manufacturing and Controls Information, September 2003 

(http://www.fda.gov/cber/gdlns/protcmc.pdf). When finalized, this guidance will represent FDA’s current 

thinking on the topic. 

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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, 

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 the “Guidance for Industry for the Submission 

Documentation for Sterilization Process Validation in Applications for Human 

and Veterinary Drug Products,” dated November 1994.5

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. 

5

 See http://www.fda.gov/cber/gdlns/sterval.pdf. 

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E. Container Closure System 

You should submit a description of the container and closure systems used during cord 

blood collection and for final storage of HPC-C, and their compatibility with the HPC-C. 

The submission should include detailed information concerning the supplier, address, and 

the results of any compatibility, toxicity, and biological tests. Alternately, a new drug 

application, 510(k) premarket notification, or drug master file may be referenced for this 

information. Evidence of container and closure integrity for the duration of the proposed 

expiration period should be provided. 

F. 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. 

G. Methods Validation/Verification 

1. Infectious Disease Test Methods 

Appropriate FDA licensed, approved, or cleared donor screening tests must be 

used to test for relevant communicable disease agents and diseases in accordance 

with the manufacturer’s instructions (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 cord blood donor for relevant communicable disease agents 

and diseases, including the name and manufacturer of the FDA 

licensed/approved/cleared test kits used. 

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-C. Certificates of analysis and analytical results for at least 

three consecutive batches should be provided. 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 21 CFR 610.12, United States Pharmacopeia, or alternative 

methodologies used, sample types tested, and if applicable, include a 

description of your validation protocol and summary validation data for 

alternative methods, such as automated microbiologic testing systems 

adapted for this use; 

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• 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 molecular testing 

performed, sample types used (including maternal and cord blood 

samples) and the name and location of the laboratory that performs the 

initial and the confirmatory HLA typing of the final product; 

• ABO blood group and Rh type (we recommend that you use FDA-licensed 

reagents for performing these tests); and 

• other tests you may perform to evaluate your HPC-C, such as colonyforming 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 release testing. Where applicable, this 

should include descriptions of reference standards and their validation. For 

analytical methods in compendial sources, you should provide the appropriate 

citations. 

H. Labeling 

In this section you should provide representative draft labeling for your HPC-C. A 

description of the required labels and labeling for HPC-C is provided in this guidance in 

Section VII.B.12. 

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: 

 

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• 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 crosscontamination, 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 

• 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; 

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• 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-C and associated samples; automated 

systems for controlled-rate freezing, storage, and retrieval; and any other 

automated systems you use to manufacture your HPC-C. 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 summary for each of these systems, 

which includes: 

• 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 crosscontamination 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. 

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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. 

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). This means that you 

are required to register and list at the time of BLA approval, prior to commercial 

distribution. 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-C. FDA considers umbilical 

cord blood collected for further processing into HPC-C 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 section 

501(a)(2)(B) of the FDCA is required. Accordingly, for collection of cord blood for 

further processing into HPC-C, section 501(a)(2)(B) or statutory CGMP would be 

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applied. This section of the FDCA 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-C, the “Guidance for Industry Q7A Good Manufacturing Practice 

Guidance for Active Pharmaceutical Ingredients” (Ref. 2), provides recommendations for 

good manufacturing practice for the manufacture of intermediates, drug substances, and 

active pharmaceutical ingredients. 

For the collection of cord blood as well as manufacture of HPC-C, the CGTP and other 

applicable provisions in 21 CFR 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-C, 

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 1271, and applicable regulations 

for biologics contained in 21 CFR Parts 600 through 680. For the most part, in the 

manufacture of HPC-C, the CGMP regulations will be applied because they are more 

broadly drafted and subsume the CGTP regulation. 

The CGMP regulations applicable to the manufacture of your HPC-C are contained in 

eleven subparts in 21 CFR Part 211, and this guidance is formatted to follow these 

subparts: 

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-C are contained in two subparts in 21 CFR Part 1271, and this 

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-C. However, 21 CFR Part 

1271 Subpart E – Additional Requirements for Establishments Described in § 1271.10 

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(reporting requirements and labeling), and Subpart F – Inspection and Enforcement of 

Establishments Described in § 1271.10, are not applicable to HPC-C products described 

in this guidance. 

As the applicable regulations contain many requirements for written procedures 

(hereafter “SOPs” for standard operating procedures), you may want to consider 

establishing an SOP manual so that all SOPs are found in one location available to 

personnel. 

The following guidance is provided to assist you in complying with section 501(a)(2)(B) 

of the FDCA as well as regulations applicable to the manufacture of your HPC-C. This 

guidance may not include all the regulations that would apply to you, so we recommend 

that you 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 

seven 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). 

2. Prevention of the Introduction, Transmission, or Spread of Communicable 

 Diseases 

You must recover, process, store, label, package, and distribute your HPC-C, 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 Part 1271 that apply (21 CFR 1271.155). 

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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; and 

• responsibilities and procedures in writing and the written procedures 

must be followed. 

c. The QCU has the following responsibilities (21 CFR 211.22): 

• responsibility and authority to approve/reject all components, drug 

product containers and closures, in-process materials, packaging, 

labeling, and HPC-C (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-C (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 

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-C 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-C 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 

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relating to communicable disease transmission, such as donor 

eligibility determination. For HPC-C, we recommend audits 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 21 CFR 

600.10). 

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 21 CFR 

600.10). 

Personnel who perform HPC-C 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). 

We recommend that you develop a system for education and training of 

transplant center personnel to ensure appropriate handling, testing, and 

administration of the HPC-C. 

b. Medical Director 

We recommend that you 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 

We recommend that you 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. 

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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-C, 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-C 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-C must be of suitable 

size, construction, and/or 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)); 

• Equipment for adequate control over air pressure, microorganisms, 

dust, humidity, and temperature must be provided, when appropriate 

(21 CFR 211.46(b), and 21 CFR 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: 

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o receipt, identification, storage, and withholding from use, of 

components, product containers, closures, and labeling pending 

sampling, testing, or examination by the QCU before release 

for manufacturing; 

o holding of rejected, and storage of released components, 

product containers, closures, and labeling before disposition; 

o storage of in-process materials; 

o manufacturing and processing operations; 

o quarantine storage before release of products; 

o control and laboratory operations; and 

o aseptic processing, including, when appropriate, an 

environmental monitoring system, a room and equipment 

cleaning/disinfecting system, and a maintenance system for 

equipment used to maintain aseptic conditions (21 CFR 

211.42(c)). 

e. Sanitation of the Building; Cleaning and Sanitizing Agents 

Buildings used in the manufacture of HPC-C must be maintained in a clean 

and sanitary condition (21 CFR 211.56(a)). There should 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)). 

8. Equipment 

a. Adequacy of Equipment Design, Size, and Location 

Equipment used in the manufacture of HPC-C must be of appropriate 

design, adequate size, and/or suitably located for its intended use and/or 

for its cleaning and maintenance (21 CFR 211.63). 

b. Cleaning and Maintenance 

• Equipment and/or utensils must be cleaned, maintained, and sanitized 

at appropriate intervals to prevent malfunctions or contamination that 

would alter the safety, identity, strength, quality, or purity of the HPCC (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)). 

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c. Automatic, Mechanical and Electronic Equipment 

• Equipment must be routinely calibrated, inspected, or checked 

according to a written program designed to ensure proper performance 

(21 CFR 211.68(a)); 

• SOPs for calibration and maintenance should conform to the 

equipment manufacturers’ recommendations and/or user’s manual; 

• Written records of calibration checks and inspections must be 

maintained (21 CFR 211.68(a)); 

• The liquid nitrogen freezers you use for storage of HPC-C should be 

qualified to maintain the desired temperature and to permit insertion 

and removal of HPC-C without compromising the quality of other 

HPC-C 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)). 

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(a)). 

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-C 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)). 

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b. Identification, Inventory, and Storage of Components, Containers and 

 Closures 

• The components and HPC-C 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(a) and (b)); and 

• Each container or grouping of containers for components or HPC-C 

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, and released 

(21 CFR 211.82(b)); and 

• The product containers and/or closures must be sampled and tested by 

the quality control unit before release (21 CFR 211.84(a)). 

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. The testing performed 

should be based on the intended use of the component and the 

reliability of the vendor (21 CFR 211.84(b)); 

• Each component must be tested for conformance with appropriate 

written specifications for purity, strength, and quality. For example, 

components that come into direct contact with an HPC-C should be 

sterile. Acceptance may be based on a Certificate of Analysis, as long 

as at least one specific identity test is performed and the reliability of 

the vendor’s results has been established (21 CFR 211.84(d)); 

• 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); 

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• 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 quality control unit (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-C (21 CFR 211.94(a)); 

• The container closure system used for HPC-C must provide adequate 

protection against unforeseeable 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-C must be clean and must be 

sterilized and processed to remove pyrogenic properties to ensure they 

are suitable for the intended use (21 CFR 211.94(c)); 

• Specifications for the containers and closures, testing and/or 

examination methods, and, where applicable, the methods for cleaning, 

sterilization, and depyrogenation must be contained in SOPs and 

followed (21 CFR 211.94(d)); 

• During collection of cord blood, we recommend that you use an 

appropriate closed, sterile container sealed in a manner that prevents 

cell loss and contamination. We recommend that you use only citratebased anticoagulants; 

• We recommend that you transport cord blood in a shipping container 

designed to contain any leakage from the collection container and to 

minimize temperature changes during transportation; and 

• We recommend that you 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-C and establish inprocess controls and final product specifications to ensure that your HPC-C have 

the identity, strength, quality, and purity necessary for the products to be safe and 

effective. Whenever an established, validated procedure is modified, you should 

perform new validation studies. Because HPC-C are subject to microbiological 

contamination, you should have procedures in place to ensure that sterility of the 

product is maintained. 

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a. Written Procedures; Deviations 

• You must have SOPs for production and process controls designed to 

assure that HPC-C 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 quality control unit (21 

CFR 211.100(a)); and 

• SOPs must be followed and deviations from the SOPs must be 

recorded and justified. Documentation should be done at the time of 

performance (21 CFR 211.100(b)). 

b. Pre-Cryopreservation Processing 

• We recommend that your manipulation of the cord blood 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. 

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 to permit recovery of at least 70% of viable nucleated 

cells present in the product before freezing. 

d. Thawing 

• You should validate a thawing process demonstrated to permit 

recovery of at least 70% of the viable nucleated cells present in the 

product before freezing; and 

• If thawing is to be performed at a separate facility, you should provide 

that facility with instructions for performing the validated thawing 

process. 

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e. Implementation and Documentation of In-Process Controls, Tests, and 

 Examinations (21 CFR 211.110(b)) 

• You should 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; and 

• In-process controls must be consistent with product final 

specifications. 

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-C. 

Deviations from these limits may be acceptable if the deviation does 

not compromise the quality of the HPC-C. Deviations must be 

justified and documented (21 CFR 211.111); 

• We recommend that you begin processing of HPC-C within 48 hours 

of collection; and 

• Your SOPs should be designed to minimize the transit time of the 

HPC-C 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. 

Such procedures must include validation of any sterilization (or 

aseptic) process (21 CFR 211.113(b)). (See also 21 CFR 600.11(b)); 

• During collection, we recommend that you use validated aseptic 

methods to provide maximum assurance of sterile products;6

 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)). 

6

 See “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good 

Manufacturing Practice.” Available at http://www.fda.gov/cber/gdlns/steraseptic.pdf. (Ref. 3). 

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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-C 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)). 

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. Such procedures 

must incorporate the following features (21 CFR 211.130): 

o prevention of mixups and/or cross-contamination by physical 

or spatial separation from operations on other products (21 

CFR 211.130(a)); 

o HPC-C must be labeled with a distinct identification code, e.g., 

alphanumeric, that relates the product to the donor and to all 

records pertaining to the product (21 CFR 1271.290(c)); and 

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o the label must include information designed to facilitate 

effective tracking, using the distinct identification code, from 

the donor to the recipient and from the recipient to the donor. 

Except in the case of autologous or directed donations as 

described in 21 CFR 1271.55(a)(1), you must create such a 

code specifically for tracking, and it may not include an 

individual’s name, social security number, or medical record 

number. You may adopt a distinct identification code assigned 

by another establishment engaged in the manufacturing process 

or you may assign a new code. If you assign a new code to an 

HPC-C, 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 

• We recommend that the following information accompany the HPC-C 

during shipping: 

 

o emergency contact information; and 

o instructions for receiving and handling the HPC-C, including 

interim storage, thawing, and cryoprotectant removal. 

d. Expiration Dating (21 CFR 211.137(a) and (d); and 21 CFR 1271.260(c)) 

The HPC-C container label or other labeling must: 

• bear an expiration date determined by appropriate stability testing; and 

• have expiration dates related to storage conditions on the label. 

e. Examination of the Labeled Finished Product (21 CFR 211.134(a) and 

 (c)) 

Labeled HPC-C 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. 

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f. Packaging and Shipping (21 CFR 1271.265(d)) 

Packaging and shipping containers must be designed and constructed to 

protect the HPC-C from contamination and other harmful effects of 

environmental exposure. 

You must establish appropriate shipping conditions to be maintained during 

transit. We recommend that cryopreserved HPC-C 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-C 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 January 2006 draft “Guidance for Industry: Labeling for Human 

Prescription Drug and Biological Products — Implementing the New Content 

and Format Requirements” contains guidance for implementing these labeling 

provisions.7

 

b. Package Label (21 CFR 610.60 and 610.61) 

In addition to the labeling requirements in 21 CFR 201.56 and 201.57, your 

HPC-C is subject to the label requirements in 21 CFR 610.60 – Container 

label; and 610.61 – Package label. A full container label is the label 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 a HPC-C product. 

c. Bar Code (21 CFR 201.25) 

HPC-C, as a prescription drug product, is also subject to the bar code label 

requirements in 21CFR 201.25(b)(2). The HPC-C label must have a bar code 

that contains, at a minimum, the appropriate National Drug Code (NDC) 

7

 See http://www.fda.gov/cber/gdlns/lbcontform.pdf. When finalized, this guidance will represent FDA’s thinking 

on this topic. 

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number in a linear bar code that meets European Article Number/Uniform 

Code Council (EAN.UCC) or Health Industry Business Communications 

Council (HIBCC) standards (21 CFR 201.25(c)). For additional information 

about the bar code label requirements, we recommend that you reference the 

October 2006, “Guidance for Industry: Bar Code Label Requirements – 

Questions and Answers.” 8

d. Current Good Tissue Practice – Labeling (21 CFR 1271.55) 

CGTPs require that cord blood and HPC-Cs be accompanied by certain 

records at all times after a donor eligibility determination has been made (21 

CFR 1271.55(a)). These accompanying records, a statement of donor 

eligibility or ineligibility, and a summary of the records used to make the 

donor eligibility determination (21 CFR 1271.55(b)), must not contain the 

donor’s name or other personal information that might identify the donor (21 

CFR 1271.55(c)). 

The recommended extent of HLA match between the donor and recipient and 

the recommended HPC-C cell dose are important considerations for HPC-C 

dosage and administration and therefore, this information should be provided 

in the labeling. 

13. Holding and Distribution 

• SOPs describing the distribution of HPC-C must be established and followed 

and include a system by which the distribution of each lot of HPC-C can be 

readily determined to facilitate its recall if necessary (21 CFR 211.150(a) and 

(b)); 

• We recommend that you store unprocessed cord blood in a secure location and 

in containers monitored to maintain the desired temperature range; 

• We recommend that you visually examine the final product containers and all 

attached containers for damage or possible contamination prior to use and 

immediately after filling; 

• We recommend that you cryopreserve and store the HPC-C in liquid nitrogen 

in containers appropriate for long-term storage; 

• We recommend that you place the cryopreserved final product in metal 

canisters, or use a validated alternative method to protect the HPC-C 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; 

8

 See http://www.fda.gov/cber/gdlns/barcode.pdf. 

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• We recommend that you store the cryopreserved HPC-C in a device that has 

been qualified to maintain the desired temperature and that permits insertion 

and removal of an HPC-C without compromising the quality of other HPC-C 

stored in the same freezer; 

• We recommend that you store HPC-C at the following temperatures or at 

other acceptable temperatures validated to maintain equivalent product 

quality: 

o liquid: 15 - 25 ̊C 

o frozen: ≤ -150 ̊C (liquid or vapor phase of liquid nitrogen) 

• You must maintain and record storage temperatures and periodically review 

recorded temperatures to ensure that HPC-C storage temperatures are 

consistently within acceptable limits (21 CFR 1271.260(e)); 

• Prior to product release, we recommend that you confirm that temperature 

controls were maintained throughout the storage period. Excursions in 

storage temperature should be investigated; and 

• HPC-C should not be stored with nonhuman material. 

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-C 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 

You must not make available for distribution an HPC-C 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 (except as provided under 21 CFR 1271.60, 1271.65, and 1271.90), 

or that otherwise does not meet release criteria designed to prevent 

communicable disease transmission (21 CFR 1271.265(c)(2)). 

For each lot of HPC-C, there must be appropriate laboratory determination of 

satisfactory conformance to final specifications (21 CFR 211.165). 

• 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)); 

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• Acceptance criteria for the sampling and testing conducted by the quality 

control unit must be adequate to assure that HPC-C 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. The methods validation and 

documentation may be accomplished in accordance with 21 CFR 

211.194(a)(2). 

• Results of release testing on the HPC-C 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-C 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, and 21 CFR Part 1271, Subpart C) 

i. Infectious Disease Testing 

• You may not release an HPC-C for transplantation unless all infectious 

disease testing has been completed and the test results are negative, or 

in the case of syphilis testing, the appropriate confirmatory test is 

negative, except for conditions of documented urgent medical need (21 

CFR 1271.60(d)) with a signature of the establishment’s medical 

director and appropriate labeling, as described in 21 CFR Part 1271, 

Subpart C; 

• HPC-C with reactive tests for CMV may be released at the request of 

the prospective recipient’s physician (see 21 CFR 1271.85(b)(2)); 

• You should perform sterility testing on a sample of the HPC-C taken 

before cryopreservation. Testing must be performed as specified in 21 

CFR 610.12 or with an equivalent method that has been validated or 

verified for use with your HPC-C (21 CFR 610.9); and 

• You must not release an HPC-C for transplantation that fails sterility 

testing (21 CFR 1271.265(c)(2), and 21 CFR 211.165(f)). 

ii. Hemoglobin Testing 

You should obtain hemoglobin screening results that indicate whether an 

HPC-C expresses a homozygous hemoglobinopathy and you should not 

release for transplantation, an HPC-C with this abnormality. 

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c. Product Potency (21 CFR 610.10) 

i. Total Nucleated Cells 

• The total number of nucleated cells in the HPC-C 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, we recommend that you store HPC-C that contain at least 

5.0 x 108

 total nucleated cells per product.9 

ii. Viable Nucleated Cells 

You should demonstrate by a validated assay that at least 85% of the 

nucleated cells in the HPC-C 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-C 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 – We recommend that the cord blood bank 

utilize an HLA testing laboratory certified by CLIA (Clinical 

Laboratory Improvement Amendments of 1988) and accredited by the 

American Society for Histocompatibility and Immunogenetics or 

equivalent accrediting body for initial and confirmatory typing of 

HPC-C; 

• Typing Methods – The HPC-C should be typed by serologic or DNAbased 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; 

9

 We base this number upon a hypothetical recipient of 20 kg and a minimum nucleated cell recovery of 70% after 

freezing and thawing. 

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• HLA Confirmatory Testing of Potential Recipient – Prior to releasing 

an HPC-C for transplantation, we recommend that you obtain or 

perform confirmatory HLA typing of the potential recipient’s blood, 

unless this typing has been confirmed and updated on an independent 

sample by the original laboratory or by an independent HLA 

laboratory; and 

• HLA Confirmatory Testing of HPC-C – Once an HPC-C is identified 

for potential use, we recommend that you 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-C. 

e. Stability Testing (21 CFR 211.166) 

There must be a written testing program designed to assess the stability 

characteristics of HPC-C. 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. The written program must be followed and must 

include: 

• sample size and test intervals based on statistical criteria for each attribute 

examined to ensure valid estimates of stability (21 CFR 211.166(a)(1)); 

• storage conditions for HPC-C 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-C in the same container-closure system as that in which 

the HPC-C is marketed (21 CFR 211.166(a)(4)); and 

• an adequate number of HPC-C must be tested to determine an appropriate 

expiration date and a record of such data must be maintained (21 CFR 

211.166(b)). 

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f. Reserve Samples (21 CFR 211.170) 

An appropriately identified reserve sample that is representative of each 

HPC-C must be retained. The reserve sample consists of at least twice the 

quantity necessary for all tests required to determine whether the HPC-C 

meets its established specifications, except for sterility testing. 

While reserve samples consisting of small aliquots of plasma, sera, and 

nucleated cells are appropriate for most infectious disease tests and HLA 

typing, they may not be optimal for testing product potency (e.g., viability 

assays) because the results of such assays performed on small product aliquots 

may not directly correlate with results of potency tests performed using 

samples obtained directly from the original product. Where possible, we 

recommend that you reserve product aliquots determined to yield comparable 

results to those obtained using thawed samples of entire HPC-C for each 

specification tested. 

You must retain appropriately identified representative samples of the HPC-C 

for one year after the expiration date (21 CFR 211.170(b)(1)). 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)). You are required, 

however, to retain records pertaining to a particular HPC-C 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)). 

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-C involved (21 CFR 1271.270(a)). 

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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)). 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 1271.150(c)). 

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-C 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-C, 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-C, 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)). 

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). 

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c. Master Production and Control Records 

Master production and control records must include (21 CFR 211.186(b)(9)), 

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-C and 

must include complete information relating to the manufacture and control of 

each HPC-C (21 CFR 211.188, 21 CFR 600.12(a), and 21 CFR 1271.270). 

We expect these records to include, among others: 

• documentation that each significant step in the manufacture, processing, 

packing, or holding of the HPC-C 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)); 

• accompanying records (21 CFR 1271.55(a)(1) through (3)); and 

• if applicable, documentation of the urgent medical need when an HPC-C 

is released before the donor eligibility determination is complete, or an 

HPC-C from an ineligible donor is released (21 CFR 1271.60(d)(1), and 

21 CFR 1271.65(b)(1)(iii)). 

16. Failure Investigations 

Any unexplained discrepancy or the failure of an HPC-C or any of its components 

to meet any of its specifications must be thoroughly investigated, whether or not 

the HPC-C has already been distributed. All HPC-C 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-C is released or distributed. The investigation must extend 

to other HPC-C that may have been associated with the specific failure or 

discrepancy. A written record of the investigation must be made and must include 

the conclusions and followup (21 CFR 211.192). 

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17. Tracking 

a. Product Handling 

If you perform any step in the manufacture of an HPC-C in which you handle 

the HPC-C, you must track each such HPC-C 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-C 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-C 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-C, provided 

that the tracking system complies with all the requirements of 21 CFR 

1271.290. 

b. Distinct Identification Code 

As part of your tracking system, you must ensure that each HPC-C that you 

manufacture is assigned and labeled with a distinct identification code, e.g., 

alphanumeric, that relates the HPC-C to the donor and to all records 

pertaining to the HPC-C. 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. Except in the case 

of autologous or directed donations, you must create such a code specifically 

for tracking, and it may not include an individual’s name, social security 

number, or medical record number. You may adopt a distinct identification 

code assigned by another establishment engaged in the manufacturing process, 

or you may assign a new code. If you assign a new code to an HPC-C, you 

must establish and maintain procedures for relating the new code to the old 

code (21 CFR 1271.290(c)). 

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c. Tracking from Consignee to Donor 

As part of your tracking system, you must establish and maintain a method for 

recording the distinct identification code and type of each HPC-C 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-C, 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-C, if any 

(21 CFR 1271.290(e)). 

e. Written Confirmation of Requirements 

At or before the time of distribution of an HPC-C 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 an 

HPC-C 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-C to meet any of its specifications (21 CFR 211.192); 

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-C Complaints 

A written record of each complaint must be maintained in a file designated for 

HPC-C complaints. The file regarding HPC-C complaints must be maintained 

at the establishment where the HPC-C 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)). 

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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-C 

• We recommend that you have a procedure for product recovery in the 

event of a container failure; 

• We recommend that you 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-C 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, we recommend that you analyze 

information that you receive from the transplant centers on clinical outcomes of 

individuals who receive from your facility HPC-C released for transplantation. 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. 

B. Changes to be Reported 

Requirements for reporting changes to your approved BLA are contained in 21 CFR 

601.12. 

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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 explained in 21 

CFR 600.80 using the FDA Form 3500A.10 You may find clarification of what to report 

in the guidance document “Guidance for Industry: Postmarketing Adverse Experience 

Reporting for Human Drug and Licensed Biological Products – Clarification of What to 

Report.” 11 

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 the HPC-C, and delayed or 

failed engraftment that may relate to the HPC-C manufacturing. 

D. Biologic 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. 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 with holding or distribution. Product deviations can be reported 

electronically on CBER’s website at http://www.fda.gov/cber/aereporting.htm. 

10 Available at: www.fda.gov/medwatch. 11 Available at: http://www.fda.gov/medwatch/report/guide2.htm. 

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IX. DEFINITIONS 

CFR: Code of Federal Regulations. 

Cord blood: A unit of blood collected generally by venipuncture of the placental and umbilical 

cord vessels under aseptic conditions into a sterile container. 

CGMP: Current good manufacturing practice. 

CGTP: Current good tissue practice. 

Engraftment, failure of: 

• Neutrophil: Neutrophil engraftment is an absolute neutrophil count greater than or 

equal to 500 cells/uL for three consecutive measurements on different days. The first of 

the three days is designated as the day of neutrophil engraftment. 

o Failure of neutrophil engraftment is the lack of neutrophil engraftment by day 

42. 

o Secondary graft failure: An initial neutrophil engraftment followed by 

subsequent decline in the absolute neutrophil count to less than 500 cells/uL, or 

absence of donor cells in the marrow or blood as demonstrated by a chimerism 

assay without subsequent improvement occurring either spontaneously or after 

growth factor therapy. Improvement is defined as an absolute neutrophil count 

consistently greater than or equal to 500 cells/uL. Severe neutropenia with 

marrow cellularity greater than or equal to 25% is not secondary graft failure. 

• Platelet: Platelet engraftment is described as the first of three days that the transfusionindependent platelet count is equal to or greater than 20,000 platelets/uL. 

o Failure of platelet engraftment is the lack of platelet engraftment by day 180. 

Histocompatibility: Refers to the similarity of tissues between different individuals. The bestknown histocompatibility antigens are those of the major histocompatibility complex, termed 

HLA in humans. 

HLA: Human leukocyte antigen. 

HPC-C: Minimally manipulated hematopoietic stem/progenitor cells from placental/umbilical 

cord blood. For the purposes of this guidance, HPC-C refers to the final drug product 

(cryopreserved HPC-C), sourced from an unrelated allogeneic cord blood donor and intended for 

hematopoietic reconstitution in patients with hematological malignancies. 

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. 

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Minimal manipulation: For cells or nonstructural tissue - Processing that does not alter the 

relevant biological characteristics of cells or tissues. 

TNC: Total nucleated cells. 

Validation: The confirmation by examination and provision of objective evidence that 

particular requirements can consistently be fulfilled. Validation of a process, or process 

validation, means establishing by objective evidence that a process consistently produces a result 

or product meeting its predetermined specifications. 

Verification: The confirmation by examination and provision of objective evidence that 

specified requirements have been fulfilled. 

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X. REFERENCES 

1. Food and Drug Administration, Center for Biologics Evaluation and Research, 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/cder/guidance/cmc2.pdf). 

2. Guidance for Industry: Q7A Good Manufacturing Practice Guidance for Active 

Pharmaceutical Ingredients, August 2001 (http://www.fda.gov/cber/gdlns/ichactive.pdf). 

3. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current 

Good Manufacturing Practice, September 2004 

(http://www.fda.gov/cber/gdlns/steraseptic.pdf).

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