#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  Contains Nonbinding  Recommendations 
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 
 
2  Contains Nonbinding  Recommendations 
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 Administrations  (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 CVMs 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. 
 
FDAs guidance documents, including  this guidance, do not establish legally  enforceable 
responsibilities.   Instead, guidances describe the Agencys 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 Agencys guidances means that something is suggested or 
recommended, but not required. 
 
II.  PURPOSE AND SCOPE 
 
This guidance is intended to: 
 
  Clarify FDAs position  that it has jurisdiction  over cell-based products meeting the 
definition  of a new animal drug 
  Clarify FDAs 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). 
3  Contains Nonbinding  Recommendations 
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. 
4  Contains Nonbinding  Recommendations 
  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 FDAs 
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 Centers 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. 
   
5  Contains Nonbinding  Recommendations 
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 ASCPs 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. 
6  Contains Nonbinding  Recommendations 
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 
7  Contains Nonbinding  Recommendations 
(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).  CVMs 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. 
8  Contains Nonbinding  Recommendations 
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. 
9  Contains Nonbinding  Recommendations 
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). 
10  Contains Nonbinding  Recommendations 
  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. 
11  Contains Nonbinding  Recommendations 
  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: 
 
  Adverse events must be reported to FDA (21 CFR 514.80).  
o
(http://www.fda.gov/AnimalVeterinary/SafetyHealth/ReportaProblem/ucm21
2682.htm). 
 
  Complete records must be kept of all information  relevant to the safety and 
o
effectiveness of the ASCP that has not been previously  submitted to FDA (21 
CFR 514.80(a)(1)). 
 
  Sponsors must submit drug experience reports to CVM containing  reports of 
o
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). 
 
12  Contains Nonbinding  Recommendations 
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. 
13  Contains Nonbinding  Recommendations 
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. 
14