CVM GFI #218 Cell-Based Products for Animal Use

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

#218
Guidance for Industry
Cell-Based Products for Animal Use
Submit comments on this guidance at any time. Submit electronic comments to
http://www.regulations.gov. 	Submit written comments to the Division of Dockets Management
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD
20852. 	All written comments should be identified with the Docket No. FDA-2014-D-0634.
For further information regarding this document, contact Lynne Boxer, Center for Veterinary
Medicine (HFV-114), Food and Drug Administration, 7500 Standish Place, Rockville, MD
20855, 240-402-0611, e-mail: lynne.boxer@fda.hhs.gov.
Additional copies of this guidance document may be requested from the Policy and Regulations
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish
Place, Rockville, MD 20855, and may be viewed on the Internet at either
http://www.fda.gov/AnimalVeterinary/default.htm or http://www.regulations.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
June 2015

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Table of Contents
I. 	INTRODUCTION...................................................................................................... 3
II. 	PURPOSE AND SCOPE............................................................................................ 3
III. 	WHAT IS AN ANIMAL STEM CELL-BASED PRODUCT (ASCP)?...................... 4
IV. 	STATUTORY AUTHORITY .................................................................................... 5
V. 	CATEGORIES OF ASCPS ........................................................................................ 6
A. 	Xenogeneic ...................................................................................................... 6
B. 	Allogeneic........................................................................................................ 6
C. 	Autologous ...................................................................................................... 6
1. 	Type I ......................................................................................................... 6
2. 	Type II........................................................................................................ 7
VI. 	PREAPPROVAL REQUIREMENTS........................................................................ 7
A. 	Xenogeneic, Allogeneic, and Autologous Type I ASCPs ................................. 7
1. 	New Animal Drug Application .................................................................... 7
2. 	Investigational Use ...................................................................................... 9
B. 	Autologous Type II (ATII) ASCPs for Nonfood-Producing Animals ........... 10
C. 	ASCPs for use in Food-Producing Animals .................................................. 11
VII. 	POST-APPROVAL RESPONSIBILITIES.............................................................. 11
VIII. 	DEFINITIONS ......................................................................................................... 13

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Guidance for Industry
Cell-Based Products for Animal Use
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency)
on this topic. It does not establish any rights for any person and is not binding on FDA or the public.
You can use an alternative approach if it satisfies the requirements of the applicable statutes and
regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance
as listed on the title page.
I. INTRODUCTION
The Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM, we) is
aware that many potential veterinary therapies may be produced using cell-based products.
Developers of such products for veterinary use have approached CVM for clarification regarding
the regulation of these products. This guidance for industry (GFI) describes CVM’s current
thinking on cell-based products for animal use that meet the definition of a “new animal drug.”
This guidance is for persons1 developing, manufacturing, or marketing cell-based products for
animal use, including “animal stem cell-based products” (ASCPs). CVM encourages all such
persons to contact the Center early in product development.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. 	Instead, guidances describe the Agency’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 Agency’s guidances means that something is suggested or
recommended, but not required.
II. PURPOSE AND SCOPE
This guidance is intended to:
• 	Clarify FDA’s position that it has jurisdiction over cell-based products meeting the
definition of a new animal drug
• 	Clarify FDA’s current thinking on how existing regulations apply to cell-based products
• 	Establish a common vocabulary for cell-based products
• 	Establish a risk-based category structure for cell-based products
• 	Encourage industry to communicate and interact with CVM early in product
development.
1 “Person’’ includes individuals, partnerships, corporations, and associations. FD&C Act, section 201(e).

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Cell-based products meeting the definition of a new animal drug are subject to the same statutory
and regulatory requirements as other new animal drugs. Although this guidance focuses on
ASCPs meeting the definition of a new animal drug, it also applies to other cell-based products
meeting the definition of a new animal drug.
Purified proteins derived from cells, such as monoclonal antibodies, and products produced by
fermentation are also regulated as new animal drugs, provided they meet the definition of a new
animal drug; however, this guidance is not intended to apply to such products.
Persons, including persons utilizing in-clinic cell/tissue processing systems, performing
operations required to produce a cell-based product are considered manufacturers. 2
Manufacturers of cell-based products meeting the definition of a new animal drug are subject to
the same statutory and regulatory requirements as manufacturers of other new animal drugs,
including current good manufacturing practices (cGMPs) and labeling requirements.
Cell-based products may incorporate, or be the product of, genetic engineering (GE)
technologies, including recombinant DNA (rDNA) constructs. Cell-based products that contain
rDNA constructs can result in the production of genetically engineered animals. 	If you intend to
produce genetically engineered cell-based products, or animals produced from them, there will
likely be additional risk-based questions regarding your product. 3 You should contact CVM for
more information early in product development if you are producing, or intend to produce,
genetically engineered cell-based products or animals produced from them.
III. WHAT IS AN ANIMAL STEM CELL-BASED PRODUCT (ASCP)?
In this guidance, the following terms apply:
• 	The term “cell-based products” means those articles containing, consisting of, or derived
from cells that are intended for implantation, transplantation, infusion, or transfer into an
animal recipient. In this guidance, the term “cell-based products” refers to those products
meeting the definition of a new animal drug.
• 	The term “animal stem cell-based products” (ASCPs) means articles containing,
consisting of, or derived from stem cells for use in animals. 	ASCPs are a subset of cell-
based products containing, consisting of, or derived from cells such as stem cells,
progenitor cells, precursor cells, stem cell-like cells, reprogrammed cells, and other cell
types with similar properties. In this guidance, the term ASCP refers to those products
meeting the definition of a new animal drug.
2 Examples of operations required to produce a cell-based product include, but are not limited to, processing,
packaging, holding, testing, analyzing or labeling.
3 As an example, see Guidance for Industry 187, "Regulation of Genetically Engineered Animals Containing
Heritable Recombinant DNA Constructs.” Guidance for Industry 187 pertains to genetically engineered animals
containing heritable rDNA constructs; however, much of this guidance may also be relevant to non-heritable rDNA
constructs.

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• 	The term “stem cell” means a non-terminally differentiated, self-renewing cell that
harbors the ability to produce mature, differentiated daughter cells. Stem cells serve to
regulate or participate in normal tissue homeostasis and embryonic and fetal
development.
Generally, cell-based products, including ASCPs, meet the definition of a new animal drug if,
among other things, those products are intended to diagnose, cure, mitigate, treat, or prevent
disease in animals, or are intended to affect the structure or function of the animal, and do not
meet any statutory exemptions.
IV. STATUTORY AUTHORITY
The following sections of the Food, Drug, and Cosmetic Act (FD&C Act) establish FDA’s
authority over new animal drugs:
• 	Section 201(g) defines a drug, in part, as “articles intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in man or other animals;” and “articles
(other than food) intended to affect the structure or any function of the body of man or
other animals.”
• 	Section 201(v) defines a “new animal drug,” in part, as any drug intended for use for
animals that is not generally recognized as safe and effective for use under the conditions
prescribed, recommended, or suggested in the drug's labeling.
• 	Section 512(a) states the conditions that render a drug “unsafe.” This section states, in
part, that a new animal drug is “deemed unsafe” for a particular use unless the use of the
drug is approved, conditionally approved, or indexed.
• 	Section 512(j) provides for an exemption from the requirements in section 512(a) for
products used solely for investigational use. 21 CFR part 511 describes the
responsibilities and obligations of sponsors qualifying for legal investigational use.
Cell-based products, including ASCPs, that are intended for use in the diagnosis, cure,
mitigation, treatment or prevention of disease or are intended to affect the structure or function of
the animal generally meet the definition of a new animal drug, and are regulated as new animal
drugs. Cell-based products require an approved or conditionally approved new animal drug
application or index listing in order to be legally marketed. Investigational use of cell-based
products used solely for research purposes is allowed, provided the requirements set forth in 21
CFR part 511 are met.
CVM encourages persons developing cell-based products, to visit the Center’s website at
http://www.fda.gov/AnimalVeterinary/ to learn more about the pathways to legal manufacture
and distribution of new animal drugs. Persons intending to, or currently, developing, marketing,
or distributing cell-based products should contact CVM to determine the regulatory status of
their products and to discuss any questions regarding new animal drug applications and approval
requirements.

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V. 	CATEGORIES OF ASCPs
ASCPs may be collected, derived, harvested, or isolated from any embryonic, fetal, post-natal
somatic, or adult reproductive tissue. ASCPs may be classified according to the relationship
between the cell donor and ASCP recipient. The source of the cells, the relationship between
donor and recipient, the manufacturing process and the intended use of the cells can affect safety,
effectiveness, or quality of the ASCP. For the purposes of this guidance, CVM divides ASCPs
into the following categories:
A. Xenogeneic
Xenogeneic ASCPs are those in which the cells are collected from a donor animal of one
species and used in a recipient animal of a different species.
B. Allogeneic
Allogeneic ASCPs are those in which the cells are collected from a donor animal and
used in a recipient animal of the same species, but the donor and recipient animals are not
the same individual.
C. Autologous
Autologous ASCPs are those in which the cells are collected from, and the ASCP is
administered to, the same animal (the donor and recipient are the same individual
animal). 	CVM further divides this category into the following two types:
1. 	Type I
Autologous ASCPs are Type I products if they meet any of the following criteria:
a. 	The ASCP is more than minimally manipulated (see definition below).
b. 	The ASCP is for non-homologous use (see definition below).
c. 	The ASCP is for use in a food-producing animal.
d. 	The ASCP’s effect is dependent on the metabolic activity of its living cells.
e. 	The manufacture of the ASCP involves the combination of the cells with another
article, except for water, crystalloids, or a sterilizing, preserving, or storage
agent unless the addition of the agent raises new safety concerns with respect to
the product.
f. 	The finished ASCP is combined with or modified by the addition of a
component that is another drug or device.4
4 The term “device” is defined in section 201(h) of the FD&C Act.

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In this guidance, the following terms apply:
• 	The term “more than minimal manipulation” means processing that alters the
relevant biological characteristics of cells or tissues. Examples of more than
minimal manipulation include, but are not limited to, cell expansion, directed
cell differentiation, and addition of purified trophic factors.
• 	The term “homologous use” means the repair, reconstruction, replacement or
supplementation of a recipient's cells or tissues with a cell-based product that
performs the same basic function or functions in the recipient as in the donor
(for example, cartilage-derived cells intended to replace damaged cartilage in
the recipient). 	For the purposes of this document, homologous use refers to
the intended function of the ASCP in the recipient. 	Any product not meeting
this definition is considered to be for a non-homologous use.
2. 	Type II
Autologous ASCPs are Type II products if they meet all of the following criteria:
a. 	The ASCP is minimally manipulated.
b. 	The ASCP is for homologous use.
c. 	The ASCP is for use in nonfood-producing animals.
d. 	The manufacture of the ASCP does not involve the combination of the cells
with another article, except for water, crystalloids, or a sterilizing, preserving,
or storage agent, provided that the addition of water, crystalloids, or the
sterilizing, preserving, or storage agent does not raise new safety concerns with
respect to the product.
e. 	The finished ASCP is not combined with or modified by the addition of any
component that is a drug or device.
In this guidance, the term “minimal manipulation” means processing that does not
alter the relevant biological characteristics of cells or tissues. Examples of minimal
manipulation include, but are not limited to, centrifugation and cryopreservation.
You should contact CVM's Office of New Animal Drug Evaluation to discuss where
your ASCP fits within these categories.
VI. PREAPPROVAL REQUIREMENTS
A. Xenogeneic, Allogeneic, and Autologous Type I ASCPs
1. 	New Animal Drug Application
Xenogeneic, allogeneic, and autologous Type I ASCPs require premarket review to
be legally marketed. At this time, FDA believes that a New Animal Drug Application

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(NADA) will be the most appropriate pathway for legally marketing most ASCPs.5
The requirements for NADAs are described in 21 CFR part 514. The requirements
for approval of an NADA include, for example, a demonstration of safety,
effectiveness, and manufacturing quality.6
Due to the nature of ASCPs, the information provided to meet the requirements for
approval of an NADA for an ASCP may differ from traditional drug products. CVM
evaluates ASCPs using a risk-based approach that examines the risks and benefits to
the treated animal, as well as the likelihood of harm to other populations that may be
affected by the treated animal (for example, transmission of communicable disease
that may spread beyond the recipient animal). 	CVM’s evaluation is conducted on a
case-by-case basis because the potential hazards and risks are likely to be unique to
each ASCP. General considerations for evaluating the safety, effectiveness and
manufacturing quality of ASCPs are described below.
a. Safety and Effectiveness
Preapproval safety assessments of ASCPs should address the risks of the
individual product. In addition to evaluating the general safety of the product in
the target animal, the completion of other safety evaluations depends on the
specific characteristics of the product and may include, but are not limited to,
evaluation of the following:
• 	Tumorigenicity
• 	Immunogenicity
• 	Donor selection criteria
• 	Transmission of adventitious agents
• 	Long term-safety
• 	Cell survival
• 	Biodistribution
• 	Ectopic tissue formation
Preapproval effectiveness evaluations must demonstrate substantial evidence of
effectiveness.7 Adequate and well-controlled studies are required to demonstrate
that the ASCP has its intended effect.8
5 Indexing and conditional approval are also pathways to legal marketing of products under certain specified
circumstances involving minor species and minor uses in major species; however, FDA believes that at this time the
indexing and conditional approval requirements may be difficult to meet for most cell-based products due to the
novel nature of the products, the inter-related nature of safety, effectiveness, and manufacturing, and the current
state of the science.
6 Safety includes target animal safety, human user safety, human food safety, and safety to other animals and
humans in contact with the recipient animal. The requirements for approval of an NADA also include evaluation of
the labeling and all other information pertinent to the product. In addition, as required by the National
Environmental Policy Act, FDA assesses the impact an approval decision may have on the environment.
7 FD&C Act, section 512(d)(1)(E); 21 CFR 514.4.
8 FD&C Act, section 512(d)(3); 21 CFR 514.117.

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We recommend that you contact CVM early in your development process to
discuss what types of evidence will be required to demonstrate the safety and
effectiveness of your product.
b. Chemistry, Manufacturing, and Controls
In the Chemistry, Manufacturing, and Controls (CMC) technical section you must
include information regarding the production and manufacture of ASCPs.9
Controlled practices and procedures should be employed in the manufacture of
the ASCP to ensure that tissue handling and cellular isolation are reliable,
consistent, preserve cellular function and integrity, and prevent contamination of
the product.10 All finished new animal drug products, including ASCPs, are
required to meet cGMPs.11
We recommend that you contact CVM early in your development process to
discuss how to provide data and information to support the CMC technical section
of your NADA.
2. 	Investigational Use
The requirements for investigational use of new animal drugs are provided in 21 CFR
511. There are two categories of investigational exemptions; one for tests in vitro and
in laboratory research animals and one for clinical investigations.
If you intend to investigate ASCPs in client-owned animals you should contact CVM
for information on how to establish an Investigational New Animal Drug (INAD) file
prior to conducting clinical investigations. 	The “investigational exemption” provided
for in 21 CFR part 511 allows sponsors to ship or deliver the product for use in client-
owned animals.
a. 	Investigational use in vitro and in laboratory research animals
New animal drug products, including ASCPs, intended solely for in vitro studies
or tests in laboratory research animals used solely for research purposes may be
eligible for an “investigational exemption” under 21 CFR 511.1(a). This
regulation allows a sponsor to deliver the product for investigational use in vitro
and in laboratory research animals, provided that it is labeled as described in the
regulation.
9 FD&C Act, section 512(b)(1); FD&C Act, section 512(d)(1)(C).
10 The current good tissue practices (GTPs) in 21 CFR part 1271 apply to human cellular and tissue-based products.
While these regulations only apply to human products, the principles described in GTPs may provide a basic
reference for the handling of cells and tissues used in the manufacture of ASCPs.
11 For the purposes of this document, Good Manufacturing Practice regulations refers to 21 CFR part 210, Current
Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs and 21 CFR part 211,
Current Good Manufacturing Practices for Finished Pharmaceuticals.

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b. 	Clinical investigations (e.g., use in client-owned animals)
New animal drug products, including ASCPs, used in clinical investigations
(e.g., studies in client-owned animals) may be eligible for an investigational
exemption under 21 CFR 511.1(b). This exemption allows a sponsor to legally
deliver the product for investigational use in clinical studies if the sponsor meets
certain conditions. 	These conditions include using the product only for bona
fide scientific investigations, submission of notices of claimed investigational
exemption (drug delivery notices) to FDA, retaining all reports received from
investigators, providing for current monitoring of investigations, and use of the
labeling statements provided in the regulation. 12 Sponsors must also report any
findings that may suggest significant safety hazards to FDA and all
investigators. 13 These conditions also prohibit commercial distribution and test
marketing, unduly prolonging distribution, or representing that the product is
safe and effective. 14 For a complete list of requirements refer to 21 CFR
511.1(b) and 21 CFR 511.1(d)(2).
CVM encourages sponsors of investigational new animal drugs to establish an
INAD file prior to beginning clinical investigations in client-owned animals. 	In
order to meet the requirements for an investigational exemption, sponsors must
submit a notice of claimed investigational exemption (NCIE) to CVM prior to
clinical investigations in client-owned animals. 15 If a sponsor has not previously
contacted CVM to request an INAD, CVM will establish one upon receipt of an
NCIE. 16
B. Autologous Type II (ATII) ASCPs for Nonfood-Producing Animals
Although ATII ASCPs require an approved NADA, conditional approval, or index
listing to be legally marketed, FDA recognizes that these products pose a lower risk to
human and animal safety than other categories of ASCPs when used in nonfood-
producing animals and are, therefore, a lower enforcement priority. 	However, persons
marketing such products should be aware that the agency may take enforcement action
against them at any time when the agency concludes it is necessary to further the
purposes of the FD&C Act.
FDA expects all ASCPs to comply with the manufacturing standards and post-marketing
responsibilities listed below:
12 21 CFR 511.1(d)(2), 21 CFR 511.1(b)(4), 21 CFR 511.1(b)(8)(i), 21 CFR 511.1(b)(8)(ii), 21 CFR 511.1(b)(1).
13 21 CFR 511.1(b)(8)(ii).
14 21 CFR 511.1(b)(8)(iii)-(v).
15 21 CFR 511.1(b)(4).
16 Under the Animal Drug User Fee Act of 2003 (ADUFA), user fees are assessed at the time the INAD file is
established unless the sponsor qualifies for a fee waiver. For guidance on these user fees and how to request waivers
and reductions from these fees, see GFI #170 “Animal Drug User Fees and Fee Waivers and Reductions” and GFI
#173 “Animal Drug Sponsor Fees under the Animal Drug User Fee Act (ADUFA).”

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• 	The finished ASCP is required to meet cGMPs in 21 CFR parts 210 and 211.
Controlled practices and procedures should be employed in the manufacture
of the ASCP to ensure that tissue handling and cellular isolation are reliable,
consistent, preserve cellular function and integrity and prevent contamination
of the product.17 We recommend that you contact CVM with questions
regarding appropriate manufacturing standards.
• 	All ASCP manufacturing facilities must register with the agency and drug list
their products prior to marketing (21 CFR part 207).
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Drug
RegistrationandListing/ucm078801.htm)
• 	All labeling and promotion must be truthful and not misleading (section
502(a) FD&C Act and section 201(n) FD&C Act).
• 	Manufacturers of ATII ASCPs should report adverse events to FDA.
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/An
imalDrugForms/ucm048817.pdf).
C. ASCPs for use in Food-Producing Animals
FDA expects manufacturers of all ASCPs meeting the definition of a new animal drug
and intended for use in food-producing animals to obtain approval for these products. In
addition, FDA reminds sponsors that they must comply with 21 CFR part 511 for
investigational use of their ASCP.
New animal drug products, including ASCPs, intended for use in food-producing
animals have the potential to affect edible tissues entering the human food supply. 	As
with any investigational use of a new animal drug in food-producing animals, edible
products of investigational animals are not to be used for food unless authorization has
been granted by FDA (21 CFR 511.1(b)(5), 21 CFR 511.1(b)(4)(v)(a)).
VII. POST-APPROVAL RESPONSIBILITIES
Post-approval responsibilities for ASCPs as set forth in the applicable regulations include, but
are not limited to, the following:
• 	All ASCP manufacturing facilities must register with the agency and drug list their
products prior to marketing (21 CFR part 207).
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegistr
ationandListing/ucm078801.htm)
17 The current Good Tissue Practices (GTPs) in 21 CFR part 1271 apply to human cellular and tissue-based
products. While these regulations only apply to human products, the principles described in GTPs may provide a
basic reference for the handling of cells and tissues used in the manufacture of ASCPs.

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• 	All labeling and promotion must be truthful and not misleading (section 502(a)
FD&C Act, and section 201(n) FD&C Act). The labeling associated with an ASCP
may only prescribe, recommend, or suggest use under the conditions approved in the
labeling that was submitted as part of the approval (section 512(a)(1) FD&C Act).
This labeling must use the same language and emphasis as in the approval, including
descriptions of relevant hazards and precautions (21 CFR 201.105(d)).
• 	Manufacturers of ASCPs must comply with all record and reporting requirements set
forth in 21 CFR 514.80. 	Examples of these requirements include, but are not limited
to:
o 	Adverse events must be reported to FDA (21 CFR 514.80).
(http://www.fda.gov/AnimalVeterinary/SafetyHealth/ReportaProblem/ucm21
2682.htm).
o 	Complete records must be kept of all information relevant to the safety and
effectiveness of the ASCP that has not been previously submitted to FDA (21
CFR 514.80(a)(1)).
o 	Sponsors must submit drug experience reports to CVM containing reports of
data, studies and other information related to experience with the ASCP (21
CFR 514.80(a)(2).
• 	Sponsors must submit to CVM information on all proposed changes or changes that
have been made to the ASCP (21 CFR 514.8(b)). The nature and timing of the
reporting may be different depending on the risk that could be introduced by the
change. We recommend that you contact CVM regarding any post-approval changes
to your product prior to filing.
• 	Sponsors must submit supplemental applications for changes affecting the safety or
effectiveness of a product. These supplements require approval by CVM prior to
marketing (section 512(e)(1)(F) FD&C Act).

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VIII. DEFINITIONS
The following are definitions for terms used in this guidance document.
Adventitious Agent: Foreign agents that have been unintentionally introduced into the
manufacturing process of a product. Examples of adventitious agents include, but are not limited
to, bacteria, viruses, fungi, mycoplasmas, rickettsia, protozoa, parasites, and prions.
Allogeneic Use: The implantation, transplantation, infusion, or transfer of cells from a donor
animal into a recipient animal of the same species where the donor and recipient animals are not
the same individual.
Animal Stem Cell-Based Products (ASCPs): Articles containing, consisting of, or derived
from stem cells for use in animals. 	ASCPs include cell-based products containing, consisting of,
or derived from cells such as stem cells, progenitor cells, precursor cells, stem cell-like cells,
reprogrammed cells, and other cell types with similar properties.
Autologous Use: The implantation, transplantation, infusion, or transfer of cells back into the
individual animal from which the cells were recovered.
Cell-Based Products: Articles containing, consisting of, or derived from cells that are intended
for implantation, transplantation, infusion, or transfer into an animal recipient.
Combined Cell-Based Product: A cell-based product that is combined with or modified by the
addition of any component that is a drug or device or a cell-based product where the
manufacture of the product involves the combination of the cells with another article, except for
water, crystalloids, or a sterilizing, preserving, or storage agent.
Differentiation: The developmental maturation process occurring when a cell or tissue
increases its level of organization or complexity and acquires a more specialized form, function,
or both.
Homologous Use: The repair, reconstruction, replacement or supplementation of a recipient's
cells or tissues with a cell-based product that performs the same basic function or functions in the
recipient as in the donor. For the purposes of this document, homologous use refers to the
function of the cells in the cell-based product. Any product not meeting this definition for
homologous use is considered to be for a non-homologous use.
Minimal Manipulation: Processing that does not alter the relevant biological characteristics of
cells or tissues. Examples of minimal manipulation include, but are not limited to, centrifugation
and cryopreservation.

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More Than Minimal Manipulation: Processing that alters the relevant biological
characteristics of cells or tissues. Examples of more than minimal manipulation include, but are
not limited to, cell expansion, directed cell differentiation, addition of purified trophic factors,
and intentional manipulation of the DNA of the cell including the introduction of rDNA
constructs.
Progenitor Cell: A progenitor cell is an early specialized descendant of a stem cell that retains
the ability to differentiate, but in general, has lost the ability to self-renew. A progenitor cell
often may only produce more limited or specialized cell types than that of a stem cell. In this
guidance, ASCPs include progenitor cells and transiently-amplifying populations.
Self-Renewal: The mechanism by which subsequent generations of daughter stem cells retain
the molecular and phenotypic identity (a quality termed ‘stemness’) as well as the functional
characteristics of the parent stem cell provided that appropriate conditions are present or
supplied.
Stem Cell: A non-terminally differentiated, self-renewing cell that has the ability to produce
mature, specialized daughter cells. Stem cells serve to regulate or participate in normal adult
tissue homeostasis as well as embryonic and fetal development.
Xenogeneic Use: The implantation, transplantation, infusion, or transfer of cells from a donor
animal of one species into a recipient animal of a different species.