Guidance for FDA 
Reviewers and 
Sponsors 
 
Content and Review of Chemistry, 
Manufacturing, and Control (CMC) 
Information for Human Somatic Cell 
Therapy Investigational New Drug 
Applications (INDs) 
 
 
Additional copies of this 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 the Office of Cellular, Tissue, and Gene 
Therapies at 301-827-5102. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
April 2008 Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
I.  INTRODUCTION.............................................................................................................1 
A.  How will FDA Reviewers and Sponsors Use this Guidance?............................2 
B.  How is this Guidance Organized?.......................................................................2 
II.  ADMINISTRATIVE INFORMATION TO BE DOCUMENTED BY FDA 
REVIEWERS....................................................................................................................3 
III.  PRODUCT MANUFACTURING AND CHARACTERIZATION INFORMATION 
TO BE SUBMITTED BY SPONSORS AND DOCUMENTED BY FDA 
REVIEWERS....................................................................................................................4 
A.  Product Manufacturing  Components and Materials.....................................4 
1.  Cells............................................................................................................4 
2.  Reagents......................................................................................................7 
3.  Excipients..................................................................................................10 
4.  Additional Considerations........................................................................10 
B.  Product Manufacturing  Procedures..............................................................12 
1.  Preparation of Autologous or Allogeneic Cells........................................12 
2.  Process Timing and Intermediate Storage................................................13 
3.  Final Formulation.....................................................................................13 
IV.  PRODUCT TESTING....................................................................................................14 
A.  Microbiological Testing......................................................................................14 
1.  Sterility Testing (Bacterial and Fungal Testing)......................................14 
2.  Mycoplasma..............................................................................................17 
3.  Adventitious Agent Testing......................................................................17 
B.  Identity.................................................................................................................18 
C.  Purity....................................................................................................................18 
1.  Residual Contaminants.............................................................................18 
2.  Pyrogenicity/Endotoxin............................................................................19 
D.  Potency.................................................................................................................19 
E.  Other....................................................................................................................20 
1.  General Safety Testing..............................................................................20 
2.  Viability....................................................................................................20 
3.  Cell Number/Dose....................................................................................20 
V.  FINAL PRODUCT RELEASE CRITERIA TESTING..............................................20 
VI.  PRODUCT STABILITY................................................................................................20 
VII.  OTHER ISSUES.............................................................................................................22 
A.  Product Tracking................................................................................................22 
B.  Labeling...............................................................................................................22 
C.  Container/Closure...............................................................................................22 
i Contains Nonbinding Recommendations 
 
 
D.  Environmental Impact.......................................................................................23 
E.  Qualification of the Manufacturing Process....................................................23 
F.  Biostatistics..........................................................................................................24 
VIII.  PRECLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS........25 
IX.  CLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS................25 
A.  Protocol Title.......................................................................................................25 
B.  Subject Population..............................................................................................25 
C.  Route of Administration.....................................................................................25 
D.  Dose......................................................................................................................25 
E.  Frequency............................................................................................................25 
F.  Genetic, Biochemical, and Immunological Testing..........................................25 
G.  Informed Consent...............................................................................................26 
X.  RECOMMENDATION TO BE DETERMINDED BY FDA REVIEWERS............26 
XI.  COMMENTS TO SPONSOR GENERATED BY FDA REVIEWERS....................26 
A.  Clinical Hold........................................................................................................26 
B.  Non-Clinical Hold...............................................................................................26 
XII.  REFERENCES................................................................................................................27 
APPENDIX A  PRODUCT REVIEW TEMPLATE.............................................................30 
APPENDIX B  CONSIDERATIONS FOR DEVELOPMENT OF FINAL PRODUCT 
RELEASE CRITERIA SPECIFICATIONS AND STABILITY 
PROTOCOLS.................................................................................................35 
A.  Development of Release Acceptance Criteria..................................................35 
B.  Development of Acceptance Criteria Analytical Procedures.........................35 
C.  Development of Stability Protocols...................................................................36 
 
 
ii Contains Nonbinding Recommendations 
 
Guidance for FDA Reviewers and Sponsors 
 
Content and Review of Chemistry, Manufacturing, and Control 
(CMC) Information for Human Somatic Cell Therapy 
Investigational New Drug Applications (INDs) 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
 
I.  INTRODUCTION 
 
This guidance document provides to you, sponsors of a human somatic cell therapy 
investigational new drug application (IND), recommendations on the chemistry, manufacturing, 
and control (CMC) information to include in an original IND.  This guidance also applies to 
combination products that contain a human somatic cell therapy biological product in 
combination with a drug or device as part of the final product.  Also, this guidance instructs FDA 
CMC reviewers about the information to record and assess as part of an IND review, taking into 
consideration the various manufacturing challenges for these products.   
 
In order to deliver a safe and effective product, human somatic cell therapies present many 
manufacturing challenges.  Some of these challenges include the variability and complexity 
inherent in the components used to generate the final product, such as the source of cells (i.e., 
autologous or allogeneic), the potential for adventitious agent contamination, the need for aseptic 
processing, and the inability to sterilize the final product because it contains living cells.  
Distribution of these products can also be a challenge due to stability issues and the frequently 
short dating period of many cellular products, which may necessitate release of the final product 
for administration to a patient before certain test results are available.   
 
This guidance finalizes the draft guidance entitled, Guidance for Reviewers: Instructions and 
Template for Chemistry Manufacturing, and Control Reviewers of Human Somatic Cell Therapy 
Investigational New Drug Applications dated August 2003 (68 FR 49488; August 18, 2003).  
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
1 Contains Nonbinding Recommendations 
 
 
A.  How will FDA Reviewers and Sponsors Use this Guidance?  
 
FDAs primary objectives in the review of INDs are to help ensure the safety and rights 
of human subjects in all phases of an investigation and, in Phases 2 and 3, to help ensure 
that the quality of the scientific evaluation of the investigational product is adequate to 
permit an evaluation of its safety and effectiveness (21 CFR 312.22(a)).  This guidance 
will help sponsors and FDA reviewers to assess, given the phase of the investigation, 
whether sufficient information is provided to assure the proper identification (identity 
testing), quality, purity, and strength (one aspect of potency) of the investigational 
product (21 CFR 312.23(a)(7)(i)).  These principles apply to investigational biological 
products and drugs; however, specific terms, such as safety, identity, purity, and potency, 
are generally understood to be applicable to biological products and are used throughout 
this document.   
 
If you are a FDA reviewer, you will use this guidance as you assess the safety, identity, 
purity, and potency of an investigational product and you will use the format of the 
human somatic cell therapy CMC review template (Appendix A) in preparing your 
reviews.  Because of the wide variability of the contents of IND amendments, you are 
only expected to use the attached template during review of original IND submissions.  
However, you should consult this document for guidance throughout the investigational 
new drug development process.  
 
The human somatic cellular therapy CMC review instructions and template described in 
this guidance are tools to assist FDA in the review of human somatic cellular therapy 
INDs.  They are designed to serve as a guide to help ensure that all applicable regulatory 
requirements are reviewed at the appropriate stage of product development.  In addition 
to the CMC review instructions and template, some general considerations are discussed 
in Appendix B that should be helpful in assessing proposed release criteria testing and 
specifications.  Section 10.70 (21 CFR 10.70) provides further instruction to FDA 
reviewers regarding documentation of review decisions. 
 
If you are a sponsor of a human somatic cell therapy IND, you may use this guidance in 
developing an IND submission that will be adequate to permit FDA reviewers to make an 
assessment of the safety, identity, purity, and potency of your investigational product.  
Other regulatory documents that may be relevant are listed in the references (see Section 
XII below). 
 
B.  How is this Guidance Organized? 
 
This guidance is organized in a format that generally corresponds to the sections in the 
CMC review template provided in Appendix A.  In each section, where necessary, we 
(FDA) provide recommendations as to the information you may submit in your original 
IND submission.  As necessary throughout this document, we give specific instructions  
2 Contains Nonbinding Recommendations 
 
 
to FDA reviewers concerning their documentation and assessment of an IND submission 
during the CMC review.  Many of the instructions for FDA reviewers provided in this 
guidance are distinguished by the designation Note to FDA Reviewers. 
 
 
II.  ADMINISTRATIVE INFORMATION TO BE DOCUMENTED BY FDA 
REVIEWERS 
 
Note to FDA Reviewers:  Document in your review all of the IND information listed below.  
Most of this information should be available on Form FDA 1571, the sponsors cover letter, or 
the reviewer assignment notice from the Regulatory Project Manager (RPM) of the application 
division. 
 
  BB-IND Number (assigned by Center for Biologics Evaluation and Research (CBER) after 
receipt); 
  Date of submission; 
  30-day review due date; 
  Sponsor  name, address, title, phone, fax; 
  Sponsor point of contact (sponsors authorized representative)  name, address, title, phone, 
fax; 
  Title of IND; 
  Proposed use; 
  Product description; 
  Phase of study;  
  Cross-referenced INDs, investigational device exemptions (IDEs), and master files (MFs):  
List all regulatory files (IND, IDE, MF) that the sponsor has obtained permission to cross-
reference in support of this file.  The file under review must contain a letter signed by the 
person who submitted the cross-referenced file (21 CFR 312.23(b)), giving FDA permission 
to cross-reference the file.  This letter should identify the nature of the information being 
cross-referenced (e.g., pre-clinical, product manufacturing, and/or clinical) and where it is 
located within the file being cross-referenced.  You should verify that the cross-referenced 
information satisfies the IND requirement for which the information is cited.  If the letter of 
cross-reference is absent or inadequate, or the cross-referenced information is inadequate for 
the purpose cited, the RPM or the reviewer should notify the sponsor to obtain additional 
information; 
  Key words:  Include three to four words that can be used to identify the product, indication, 
and any materials, components, or devices that may be part of the final product or used in the 
manufacturing process.  These key words should be general enough to be used in a database 
search; 
  Introduction/rationale:  Summarize relevant information on the development of the product if 
the sponsor provides this information.  In addition, document and assess, as appropriate, the 
sponsors scientific rationale and justification for using the product for the indication under 
review; and  
  Study objectives. 
 
3 Contains Nonbinding Recommendations 
 
 
 
III.  PRODUCT MANUFACTURING AND CHARACTERIZATION INFORMATION 
TO BE SUBMITTED BY SPONSORS AND DOCUMENTED BY FDA 
REVIEWERS 
 
As described in the following sections, you should provide a detailed description of where and 
how the cell therapy product is manufactured.  You should include all of the components and 
materials used during the manufacture of the cellular product, such as cells, cell bank systems, 
and any reagents or excipients.  In addition, you should describe all procedures used during the 
manufacturing process.  Examples of these procedures may include recovery and processing of 
tissues or cells, purification, and other preparation of cells, donor screening and testing, 
including final formulation of the product.  This information will allow us to assess the identity, 
quality, purity, and potency of your product.  For further information, refer to the Guidance for 
Human Somatic Cell Therapy and Gene Therapy (Ref. 1) and the guidance on Content and 
Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, 
Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (Ref. 2).  In 
addition, you may refer to the other documents listed in the references (see Section XII below). 
 
We also encourage sponsors to use the format and headings described in Appendix A to facilitate 
an efficient review by FDA.   
 
Note to FDA Reviewers:  Document and assess product manufacturing and characterization 
information in your IND reviews.  Organize the CMC review using the format and headings 
described in Appendix A and below, as appropriate.   
 
A.  Product Manufacturing  Components and Materials  
 
Note to FDA Reviewers:  Document the source of all materials and components and 
summarize the testing performed on those materials and components, and review the 
specific instructions and recommendations set out below.   
 
Your IND must include a list of all components used in manufacturing of your product 
(21 CFR 312.23(a)(7)(iv)(b)).  The sections below detail the information on 
manufacturing components that we recommend you submit in an IND. 
 
1.  Cells 
 
a.  Allogeneic and/or Autologous Cell Components 
 
You should describe the following information in your IND: 
 
  Cell source:  tissue and cell type (e.g., colon, hematopoietic, neuronal, T-
cells); 
  Mobilization protocol:  document whether or not donor cells are mobilized or 
activated in vivo in the donor;  
4 Contains Nonbinding Recommendations 
 
 
  Collection or recovery method:  state the procedure used to obtain cells (e.g., 
surgery or leukapheresis indicating the device used if possible), the name and 
location of the collection facility, and transport conditions if shipped to a 
processing facility for further manufacturing; and 
  Donor screening and testing:  the donor screening and testing that is 
performed to determine donor eligibility.  Requirements for screening and 
testing donors of human cells and tissues are described in 21 CFR Part 1271 
(see final rule, Eligibility Determination for Donors of Human Cells, Tissues 
and Cellular and Tissue-Based Products (HCT/Ps)) (Ref. 3).  When 
appropriate, you should document the donor safety testing that is performed.  
In addition, FDA has published a final Guidance for Industry:  Eligibility 
Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-
Based Products (HCT/Ps) (Ref. 4).  We recommend that you review this 
guidance to ensure that the donor qualification criteria described in your IND 
are consistent with current recommendations.     
 
1) Autologous  
 
You are not required to make a donor eligibility determination or to perform 
donor screening for cells and tissues for autologous use (21 CFR 
1271.90(a)(1)).  However, you should determine whether your manufacturing 
procedures increase the risk of propagation of pathogenic agents that may be 
present in the donor.  If so, you should document whether the donor is 
reactive for specific pathogens.  Also, you should describe precautions to 
prevent the spread of viruses or other adventitious agents to persons other 
than the autologous recipient (see Ref. 3).  
 
2) Allogeneic 
 
You must perform donor screening and testing as required in 21 CFR Part 
1271 for all allogeneic cells or tissues except those that meet the exceptions 
in 21 CFR 1271.90(a).  Donors of all types of cells and tissues must be 
screened and tested for HIV-1, HIV-2, hepatitis B virus (HBV, surface and 
core antigen), hepatitis C virus (HCV), Treponema pallidum (syphilis), and 
CJD (screening only).  Donors of viable leukocyte-rich cells or tissues should 
be screened and tested for human T-lymphotropic virus types 1 and 2 
(HTLV-1, HTLV-2) and CMV.  In addition, you should document whether 
FDA-licensed, cleared, or approved test kits are used in these detection 
assays and document which tests are used.  Include a description of the type 
of serological, diagnostic, and clinical history data obtained from the donor.  
You should consider other issues such as typing for polymorphisms and 
human leukocyte antigen (HLA) matching, where appropriate.  If cord blood 
or other maternally derived tissue is used, you should describe testing and 
screening performed on birth mothers.   
 
5 Contains Nonbinding Recommendations 
 
 
Note to FDA Reviewers:  Communicate with the clinical reviewer regarding any 
issues or concerns relating to the screening or testing of the donor cells. 
 
b.  Cell Bank System 
 
You should describe pertinent information, as described in sections 1) and 2) 
below, relating to the cell bank system (i.e., master cell bank (MCB), and working 
cell bank (WCB)) used in product manufacture.  In addition, you should describe 
the history, source, derivation, characterization of each cell bank (both MCB and 
WCB), and the frequency at which testing is performed.  For further information, 
refer to the document on Points to Consider in the Characterization of Cell Lines 
Used to Produce Biologicals (Ref. 5).  See also ICH document Q5D, Derivation 
and Characterization of Cell Substrates Used for Production of 
Biotechnological/Biological Products (Ref. 6), and, where applicable, Guidance 
for Industry:  Source Animal, Product, Preclinical, and Clinical Issues Concerning 
the Use of Xenotransplantation Products in Humans (Ref. 7) and the PHS 
Guideline on Infectious Disease Issues in Xenotransplantation (Ref. 8).1   
 
Note to FDA Reviewers:  Document and assess the testing that is performed on 
each cell bank.  Determine if the most relevant and critical testing for the 
particular cellular product has been performed.  Appropriate tests should be 
performed depending on the species of origin used to derive the cell bank.   
 
1) Master Cell Bank (MCB) 
 
You should include in the IND information regarding MCB history, source, 
derivation and characterization, including testing to adequately establish the 
safety, identity, purity, and stability of the cells.  This section will likely 
address: 
 
 Product microbiologic characteristics, including sterility, mycoplasma, in 
vivo and in vitro testing for adventitious viral agents, as appropriate (see 
Section IV below); 
 Freedom from the presence of specific pathogens, including, for human 
cells, testing for CMV, HIV-1 & 2, HTLV-1 & 2, EBV, B19, HBV, and 
HCV, as appropriate.  For cell lines that are exposed to bovine or porcine 
components (e.g., serum, serum components, trypsin), appropriate testing 
would include testing for bovine and/or porcine adventitious agents.  See 
further discussion of bovine components and reagents in Section III.A.2.a; 
 Identity of the cells, including tests to distinguish the specified cells 
through physical or chemical characteristics of the cell line (i.e., 
phenotype, genotype, or other markers); 
                                
 
1 If a feeder cell line of animal origin is used to propagate human cells (i.e., human and non-human animal cells are 
co-cultivated), the final product falls within the definition of a xenotransplantation product (see both Refs. 8 and 9). 
6 Contains Nonbinding Recommendations 
 
 
 Purity of bank cells, including identification and quantification of any 
contaminating cells; 
 Testing for activity of cells (e.g., activated lymphocytes, dopamine 
secretion, insulin secretion) and cell maturation (e.g., dendritic cells).  
This should be performed if activity is relevant to the therapeutic nature of 
the product; and 
 Processes critical to product safety, as applicable, including: 
  Culture conditions used, including documentation of all media, and 
reagents/components used during production, with copies of relevant 
certificates of analysis (COA);  
  Cryopreservation, storage, and recovery of the MCB, including 
information pertaining to cell density, number of vials frozen, storage 
temperature, and cell bank location; and 
  Genetic and phenotypic stability of the MCB after multiple passages as 
well as viability of cells after cryopreservation.  We recommend that, 
while the IND is in effect, you perform a stability assessment on the 
end of production cells (EOP) as a one-time test.  This testing is usually 
performed later in product development and would be included as part 
of the biologics license application (BLA).  
 
2) Working Cell Bank (WCB) 
 
WCB may have been derived from one or more vials of the MCB.  As 
discussed in the guidance documents referenced in Section III.A.2.b, the 
amount of information needed to document characterization of the WCB 
derived from the MCB is usually less extensive than that needed to document 
characterization of the MCB.  If there is a two-tiered cell bank system in 
place (MCB and WCB), we recommend that you test the WCB for: 
 
 In vitro adventitious viral agent testing;  
 Bacterial and fungal sterility; 
 Mycoplasma; and  
 Limited identity testing (e.g., Southern blot, flow cytometry). 
 
2.  Reagents 
 
You must list in your IND any reagents used in manufacturing the product (21 CFR 
312.23(a)(7)(iv)(b)).  For the purpose of this guidance, reagents are those materials 
that are used for cellular growth, differentiation, selection, purification, or other 
critical manufacturing steps but are not intended to be part of the final product.  
Examples include fetal bovine serum, trypsin, digestion enzymes (e.g., collagenase, 
DNAse) growth factors, cytokines, monoclonal antibodies, antibiotics, cell 
separation devices, and media and media components.  These reagents can affect the 
safety, potency, and purity of the final product, especially by introducing 
adventitious agents.  For monoclonal antibodies, refer to the guidance on Points to 
7 Contains Nonbinding Recommendations 
 
 
Consider in the Manufacture and Testing of Monoclonal Antibody Products for 
Human Use (Ref. 9) for further information. 
 
a.  Tabulation of Reagents Used in Manufacture 
 
We recommend that you provide the following information on all reagents used 
during product manufacturing: 
 
  concentration of the reagent at the manufacturing step at which it is used;   
  vendor/supplier; 
  source:   
o  human:  If human albumin is used, you should have procedures in place 
to ensure that no recalled lots were used during manufacture or 
preparation of the product.  If using human AB serum, ensure serum is 
obtained from an approved blood bank and meets all blood donor 
criteria.  For all other reagents that are human derived you should 
identify whether it is a licensed product, or clinical or research grade, 
and provide a COA or information regarding testing of the donor and/or 
reagent. 
o  porcine:  If porcine products are used, a COA or other documentation 
that the products are free of porcine parvovirus. 
o  bovine:  If a reagent is derived from bovine material, you should 
identify the bovine material, the source of the material, information on 
the location where the herd was born, raised, and slaughtered, and any 
other information relevant to the likelihood that the animal may have 
ingested animal feed prohibited under 21 CFR 589.2000.  It may be that 
bovine material is introduced at different points in production of a 
reagent; the information described above should be provided for all 
bovine materials used.  For more information see, Proposed Rule: Use 
of Materials Derived from Cattle in Medical Products Intended for Use 
in Humans and Drugs Intended for Use in Ruminants, (72 FR 1581; 
January 12, 2007) found at 
http://www.fda.gov/cber/rules/catruminant.htm.  In addition, you 
should provide a COA to document that bovine materials are compliant 
with the requirements for the ingredients of animal origin used for 
production of biologics described in 9 CFR 113.53.   
 
Note to FDA Reviewers:  For all animal derived products, enter the following 
information in the animal components database:  source organism, 
supplier/vendor, country of origin, and stage of manufacture.  Additionally, the 
information provided on bovine materials should be evaluated to determine 
whether, for informed consent that is adequate under 21 CFR Part 50, the subject 
should be informed of the potential risk that TSE agents have been introduced 
into the final product.  
 
8 Contains Nonbinding Recommendations 
 
 
  Reagent quality:  We recommend that you use FDA-approved or cleared, or 
clinical grade reagents whenever they are available. 
 
Note to FDA Reviewers:  If the reagent is regulated as a biological product, drug, 
or device, consider whether a consultative review should be obtained.  See 
Section III.A.4.b below for further information about consultative review process.   
 
  COA or cross-reference letters:  If you are using a research grade (not FDA-
approved or cleared) reagent as part of the manufacturing process, we 
recommend that you provide information verifying the source, safety, and 
performance of the reagent.  If the vendor of the reagent has a regulatory file 
with the FDA, a cross-reference letter from the sponsor may be provided in 
the IND.  If a COA from the reagent manufacturer is used, you may assess 
whether the testing performed is adequate (see Qualification Program 
below) and provide that information in the IND.  
 
Note to FDA Reviewers:  For letters of cross-reference, include the regulatory file 
number and consider the need for a consultative review to determine whether 
there are any safety concerns or other outstanding issues. 
 
b.  Qualification Program 
 
If the reagent is not FDA-approved or cleared, additional testing may be needed 
to ensure the safety and quality of the reagent.  We recommend that you establish 
a qualification program that includes safety testing (sterility, endotoxin, 
mycoplasma, and adventitious agents), functional analysis, purity testing, and 
assays (e.g., residual solvent testing) to demonstrate absence of potentially 
harmful substances.  The extent of testing will depend on how the specific reagent 
is used in the manufacturing process.   
 
c.  Determination of Removal of Reagents from Final Product  
 
You should test the final product for residual manufacturing reagents with known 
or potential toxicities and describe the test procedures you use to detect residual 
levels of these reagents in the final product.  We recommend that you determine 
whether a qualification study is sufficient to document their removal, or whether 
lot release testing is appropriate prior to initiation of clinical trials.   
 
d.  Other Concerns 
 
Because some patients may be sensitive to penicillin, we recommend that you do 
not use beta-lactam antibiotics during the manufacturing of a therapeutic product 
for humans.  If beta-lactam antibiotics are used, we recommend that you provide a 
rationale for their use and describe precautions to prevent hypersensitivity 
reactions. 
9 Contains Nonbinding Recommendations 
 
 
 
Note to FDA Reviewers:  If beta-lactam antibiotics are used during 
manufacturing, consult with the clinical reviewer concerning appropriate 
exclusion criteria for the study and proper informed consent to address potential 
patient sensitivity.  Discuss with the sponsor the rationale for using beta-lactam 
antibiotics and whether an alternative to beta-lactam antibiotics can be used as an 
appropriate substitute.  
 
3.  Excipients 
 
For the purpose of this guidance, an excipient is any component that is intended to 
be part of the final product, such as human serum albumin or Dimethyl Sulfoxide 
(DMSO).  You must list in your IND all excipients used during manufacture of the 
product that are intended to be present in the final product.  (21 CFR 
312.23(a)(7)(iv)(b)).  You should include the concentration and source of the 
excipients.  Also, you must provide information regarding the qualification of all 
excipients that are present in the final product (21 CFR 211.84(a)).  For further 
information, please see Sections III.A.2 above on reagents. 
 
4.  Additional Considerations 
 
a.  Combination Products 
 
This guidance also applies to combination products that contain a human somatic 
cell therapy biological product in combination with a drug or device as part of the 
final product.2  When intended for a different use, the drug or device component 
may already have FDA marketing approval or clearance (e.g., new drug 
application (NDA), a premarket approval application (PMA), or a premarket 
notification (510(k)), or it may be previously unstudied.   
 
If information describing the drug or device component has already been 
submitted to FDA (e.g., in another IND, IDE, or Master File), you may submit a 
letter of authorization authorizing FDA to reference the previous submission for 
CMC or other information related to the drug or device component of your 
product. 
 
Note to FDA Reviewers:  Determine the regulatory status of the drug or device 
either by contacting the RPM from the center with jurisdiction for the drug or 
device or the sponsor directly, if necessary.  If the drug or device has been 
approved for any use, confirm and document this in your review.  In most cases, 
                                
 
2 Regulations on combination products are found in 21 CFR Part 3, which describes how we will determine which 
component of FDA has primary jurisdiction for the premarket review and regulation of a combination product.  
Note to FDA Reviewers:  If you have any concerns regarding the appropriateness of the jurisdictional assignment or 
regulatory mechanism, you should contact the Office of Cellular, Tissues, and Gene Therapies jurisdictional 
officer. 
10 Contains Nonbinding Recommendations 
 
 
request a consultative or collaborative review from the Center for Drug 
Evaluation and Research (CDER) or the Center for Devices and Radiological 
Health (CDRH) even if the drugs or device components were previously approved 
for another use.  Confer with your supervisor if it is unclear whether a 
consultative or collaborative review is needed.  Once an adequate letter of 
authorization is submitted, verify that the referenced file contains the needed 
information.  Inform the consultative or collaborative reviewer that the 
information referenced in the letter of authorization should be reviewed as part of 
the application. 
 
b.  Consultative Reviews 
 
Note to FDA Reviewers:  Follow the standard operating procedures and policies 
(SOPP) on the Intercenter Consultative/Collaborative Review Process (Ref. 
10).  Specify the questions the consultative reviewer should address, identify the 
specific sections of the IND applicable to those questions, and request a date for 
completion of the consultative review.  The requested date should be determined 
by coordinating with the consulting review center and be based on timeframes 
mandated by statute, the priority of the consultative review request, and the 
workload of the designated reviewer.  The RPM will request the consultative or 
collaborative review from the appropriate Center/Division using the form in 
Appendix 1 of the SOPP.  Given the tight IND deadlines, work with the RPM to 
contact the appropriate Center/Division before sending the consult request to 
identify the appropriate reviewer and ensure that the review can be completed 
within the time requirements.  Also, as described in the SOPP, the RPM should 
send to the Office of Combination Products a copy of the 
consultative/collaborative request for monitoring/tracking purposes.  The RPM 
should follow up with the consultative reviewer to confirm that essential 
documents are received along with the consultative review request.  If problems 
that affect the timeliness of the consultative review occur during the consult 
review period, discuss with your supervisor how to share these experiences with 
the Office of Combination Products, which is responsible for monitoring the 
efficiency and effectiveness of the intercenter consultative/collaborative review 
process.   
 
c.  Review of Device Components    
 
Note to FDA Reviewers:  In the device consultative/collaborative review request, 
describe the device component, and where to find relevant information in the 
submission.  You should ask the consultative reviewer to identify concerns with 
how the device component will be used, to determine whether appropriate types 
of biocompatibility and other device testing were performed adequately, and to 
assess testing of any hardware and software controlling the hardware.  In addition, 
if the sponsor asserts barrier or performance claims, identify information relative 
to these claims for the consultative reviewer to assess.  Document in the review 
11 Contains Nonbinding Recommendations 
 
 
basic information concerning the device, such as the device name, vendor or 
source, purpose, regulatory status, and a brief description of the device.  When the 
consultative/collaborative review is completed, and signed off by the appropriate 
CDRH supervisory chain, attach it to your review and communicate any 
outstanding issues to the sponsor. 
 
d.  Review of Drug Components  
 
Note to FDA Reviewers:  In the drug consultative/collaborative review request, 
describe the drug component of the combination product and state where to find 
relevant information on the component in the submission.  Ask the 
consultative/collaborative reviewer to identify any concerns with how the drug 
will be used and also to evaluate the methods of manufacturing and the adequacy 
of results from testing of the drug substance and/or drug product.  Document in 
your review basic information concerning the drug component, such as the drug 
name, vendor or source, purpose, regulatory status, and a brief description of the 
use of the drug.  When the consultative/collaborative review is completed and 
signed off by appropriate CDER supervisory chain, attach it to your review and 
communicate any outstanding issues to the sponsor.  
 
e.  Summarize Any Areas of Concern to be Addressed 
 
Note to FDA Reviewers:  Summarize any areas of concern identified during the 
review of the product components.  Discuss these concerns with the sponsor 
and/or communicate them in a letter to the sponsor, as described in Section XI, 
Comments to Sponsor Generated by FDA Reviewers.   
 
B.  Product Manufacturing  Procedures 
 
You should include a detailed description (list or summary) of all procedures used during 
the collection, production, and purification of the cellular therapy product.  We believe 
that a schematic of the production and purification process, and in-process and final 
product testing, helps to provide more clearly this information. 
 
Note to FDA Reviewers:  If provided by the sponsor, append a copy of the process 
schematic to the IND review.  If a schematic is not included, briefly summarize the 
processing steps used during product manufacturing.  In addition, summarize any areas of 
concern identified during the review of any submitted product manufacturing procedures.  
Discuss these concerns with the sponsor and/or communicate to the sponsor in a letter, as 
described in Section XI, Comments to Sponsor Generated by FDA Reviewers.   
 
1.  Preparation of Autologous or Allogeneic Cells 
 
We recommend that you describe the following procedures:  
 
12 Contains Nonbinding Recommendations 
 
 
a.  Method of Cell Collection/Processing/Culture Conditions 
 
You should describe the volume and number of cells collected.  You should 
include any mechanical or enzymatic digestion steps used, and describe the use of 
any cell selection device or separation device, including density gradients, 
magnetic beads, or fluorescence activated cell sorting (FACS).  You should 
include a description of culture systems (flasks, bags, etc.) and state whether the 
system is closed or open.  Also, you should describe any in-process testing that 
will be performed during these procedures. 
 
b.  Irradiation 
 
If the autologous or allogeneic cell product is irradiated before injection, you 
should provide data to demonstrate that the cells are rendered replication-
incompetent, but still maintain their desired characteristics after irradiation.  You 
should describe the documentation of calibration of the cell irradiator source. 
 
c.  Final Harvest 
 
You should provide a detailed description of the final harvest.  You should inform 
FDA whether the final cell harvest is centrifuged prior to final formulation, and if 
so, describe the wash conditions and media used.  You should also inform FDA in 
your IND submission whether the cells are cryopreserved after formulation or 
formulated immediately and given to the patient.  If the final harvest is stored, 
you should describe the storage conditions and the length of storage, and provide 
appropriate supporting data (see Section VI below). 
 
2.  Process Timing and Intermediate Storage 
 
You should report the approximate time elapsed for each step from cell collection to 
final harvest.  It is important to know the time limit of each step in production to 
determine what, if any, in-process testing to perform.  If cells are cryopreserved 
before injection into patients, you should include this information along with any 
stability studies initiated (see Section VI.A.1 below).  Also, you should describe the 
time and conditions of storage prior to patient administration.   
 
Note to FDA Reviewers:  Describe and assess the procedures in place to ensure the 
stability of the bulk harvest while in storage. 
 
3.  Final Formulation 
 
You must describe the formulation of the final product, including excipients such as 
growth factors or human serum albumin (21 CFR 312.23(a)(7)(iv)(a)).  You should 
state the source of these components (see Section III.A.3 above).  You should 
identify the vendor and final concentration of these excipients and describe the cell 
13 Contains Nonbinding Recommendations 
 
 
density or cell concentration used in the final product.  If the final product is 
delivered to the clinical site frozen, you should include a description of how the 
product will be shipped and data to show that the product can be thawed with 
consistent results.  In addition, if the product is shipped, you should provide data on 
product stability during shipping (see Section VI.A.2 below). 
 
 
IV.  PRODUCT TESTING  
 
We recommend that product testing for cellular therapies include, but not be limited to, 
microbiological testing (including sterility, mycoplasma, and adventitious viral agent testing) to 
ensure safety and assessments of other product characteristics such as identity, purity (including 
endotoxin), viability, and potency.  We recommend that you perform this testing throughout the 
manufacturing process, including on the manufacture of cell banks, to evaluate the 
manufacturing process itself and to ensure the quality and consistency of the product.  You 
should describe the specifications used for intermediate acceptance criteria and final product 
release criteria.  Specifications are the quality standards (i.e., tests, analytical procedures, and 
acceptance criteria) that confirm the quality of products and other materials used in the 
production of a product.  Acceptance criteria mean numerical limits, ranges, or other attributes or 
variables for the tests described.  Specifications should be appropriate to the stage of product 
development, because release criteria should be refined and tightened as product development 
progresses toward licensure (see Appendix B).  You should submit test results related to lot 
release, characterization testing, MCBs, and WCBs in tabular form including the lot number or 
identifier, date of manufacture, test, test method, the sensitivity and specificity of test methods 
and, when appropriate, release criteria. 
 
Product testing is an integral part of ensuring control of the manufacturing process and lot to lot 
consistency.  Therefore, it is important to identify critical parameters in the manufacturing 
process and critical product attributes to ensure the desired clinical effect of the final product.  
Refer to the FDA Guidance Concerning Demonstration of Comparability of Human Biological 
Products, Including Therapeutic Biotechnology-Derived Products (Ref. 11) for additional 
information.   
 
Note to FDA Reviewers:  Document the testing performed.  Assess the appropriateness of that 
testing and the acceptance criteria, based on any results previously obtained by the sponsor. 
 
A.  Microbiological Testing 
 
We recommend that you perform microbiological testing on cell banks, in-process 
intermediates, and the final product, as appropriate. 
 
1.  Sterility Testing (Bacterial and Fungal Testing) 
 
Current practices for sterility testing.  
 
14 Contains Nonbinding Recommendations 
 
 
a.  Test Method 
 
Suitable sterility tests include the test described in 21 CFR 610.12 and the test 
described in United States Pharmacopoeia (USP) <71> Sterility Tests (23rd 
edition, 1995) (Ref. 12).  Later versions of the USP<71> are also suitable.  If you 
are using another test method, you should describe its suitability.  Note that under 
21 CFR 610.9, prior to product licensing, the alternative method must be shown 
to provide assurances of the safety, purity, potency and effectiveness of the 
biological product equal to or greater that the assurances provided by the method 
or process specified in the 21 CFR 610.12 method.   
 
If you use antibiotics in manufacturing, you should provide documentation that 
the antibiotics were removed prior to sterility testing.  If the antibiotics cannot be 
removed from the final product, we recommend that you assess the validity of the 
sterility assay using the bacteriostasis and fungistasis testing as described in USP 
<71> Sterility Tests.  Use of this assay is designed to ensure that any residual 
antibiotic present in the product does not interfere with the results of sterility 
testing. 
 
b.  Note to FDA Reviewers:  If the Sponsor proposes to use an alternative method 
in place of the traditional sterility methods described in 21 CFR 610.12, then 
you will need to assess the adequacy of this alternative test method and the 
data provided to provide assurances of the safety, purity, potency and 
effectiveness of the biological product equal to or greater than the assurances 
provided by the method or process specified in the general standard (21 CFR 
610.9).  The completeness of the validation study for the alternative method 
used during the product development should reflect an assessment of risk 
associated with the application of the method (e.g., stage of the manufacturing 
process).  
 
c.  Test Timing 
 
Sponsors frequently perform in-process sterility testing at critical points during 
manufacturing, such as during extended culture periods, or after cells have 
undergone activation or other modification.  You should identify when in-process 
sterility testing is performed during manufacturing and the test method used.  The 
test method that you choose for in-process sterility testing should be adequate to 
provide assurance of product sterility. 
 
If you freeze the final product before its use, we recommend that you perform 
testing on the product prior to cryopreservation, so that results will be available 
before the product is administered to a patient.  However, if the product 
undergoes manipulation (e.g., washing, culturing) after thawing, particularly if 
procedures are performed in an open system, you may need to repeat sterility 
testing.  You should incorporate the results of in-process sterility testing into your 
15 Contains Nonbinding Recommendations 
 
 
acceptance criteria for final product specifications. 
 
If your product has a short dating period and must be administered to patients 
before sterility test results of the final product are available, then you will need to 
develop an alternate approach to provide sterility assurance.  As an alternative 
approach, we recommend that you perform all of the following tests: 
 
  in-process sterility testing on a sample taken 48 to 72 hours prior to final 
harvest or after the last re-feeding of the cell cultures  
  a rapid microbial detection test such as a Gram stain or other procedure  
on the final formulated product  
  sterility testing compliant with 21 CFR 610.12 on the final formulated 
product. 
 
Under this alternative approach the release criteria for sterility would be based on 
a negative result of the Gram stain and a no-growth result from the 48 to 72 hour 
in-process sterility test.  Although in this situation the results of the sterility 
culture performed on the final product will not be available for product release, 
this testing will provide useful data.  A no-growth result will provide assurance 
that aseptic technique was maintained.  A positive result will provide information 
for the medical management of the subject, and trigger an investigation of the 
cause of the sterility failure.  The sterility culture on the final formulated product 
and when possible the in-process culture should be continued to obtain the full 14 
day sterility test result even after the product has been given to the patient. 
 
In all cases where product release is prior to obtaining results from a full 14 day 
sterility test, the investigational plan should address the actions to be taken in the 
event that the 14 day sterility test is determined to be positive after the product is 
administered to the subject.  You should report the sterility failure, results of 
investigation of cause and any corrective actions, in an information amendment 
submitted to your IND in a timely manner, within 30 calendar days after initial 
receipt of the positive culture test result (21 CFR 312.31). 
 
The investigator should evaluate the subject for any signs of infection that may be 
attributable to the product sterility failure.  If the patient experiences any serious 
and unexpected adverse drug experience that could be from administration of the 
sterility failure of the cellular product, then you must report this information to 
FDA in an IND safety report no more than 15 calendar days after your initial 
receipt of the information (21 CFR 312.32).  If you determine that an 
investigational drug presents an unreasonable and significant risk to subjects, you 
must discontinue those investigations that present the risk, notify FDA, all 
Institutional Review Boards, and all investigators (21 CFR 312.56(d)).   
 
16 Contains Nonbinding Recommendations 
 
 
2.  Mycoplasma  
 
There are several potential sources of mycoplasma contamination.  Two major 
sources include animal serum products used in culture and the culture facility 
environment, particularly with open culture systems.  We recommend that you 
perform mycoplasma testing on the product at the manufacturing stage when the test 
is most likely to detect contamination, such as after pooling of cultures for harvest 
but prior to cell washing.  Testing should be conducted on both cells and 
supernatant.  We recommend that you inform FDA whether there is in-process 
testing for mycoplasma during extended culture procedures.  Due to the limited 
dating period of many cellular products, it is frequently not feasible for a sponsor to 
perform the recommended culture-based assay (see Ref. 5) for release testing.  In 
those cases, we recommend the use of polymerase chain reaction (PCR)-based 
mycoplasma assays or another rapid detection assay during product development.  
As part of your BLA, you should submit appropriate data to demonstrate that the 
PCR or alternative test has adequate sensitivity and specificity.  
 
3.  Adventitious Agent Testing 
 
As appropriate, you should perform and describe in your IND adventitious agent 
testing as set out below.  For more information on adventitious agent testing, refer to 
Points to Consider in the Characterization of Cell Lines Used to Produce 
Biologicals and ICH guidance Q5A:  Guidance on Viral Safety Evaluation of 
Biotechnology Products Derived From Cell Lines of Human or Animal Origin 
(Refs. 5 and 13). 
 
a.  In Vitro Viral Testing 
 
When cell lines are used, you should describe the cell lines and perform in vitro 
viral testing.  In vitro viral testing should be performed on the MCB, WCB, and 
as a one time test on the EOP cells.  Testing should be conducted by inoculating 
the test sample (MCB) onto various susceptible indicator cell lines such as the 
human cell line MRC-5 or Vero cells which are primate in origin.  The choice of 
cells used would depend on the species of origin of the product to be tested.  An 
appropriate test should include monolayer cultures of the same species and tissue 
as that used for production of the product, as well as a human and a non-human 
primate cell line susceptible to human viruses.  In addition, the test should include 
a measure of both cytopathic and hemadsorbing viruses.   
 
b.  In Vivo Viral Testing  
 
When cell lines are used, we recommend that you perform and submit data on in 
vivo viral assays carried out by inoculating the test sample (MCB) into animals 
such as adult and suckling mice and embryonated hen eggs.  You should consider 
whether to include additional testing of guinea pigs, rabbits, or monkeys.  Such 
17 Contains Nonbinding Recommendations 
 
 
studies would assess the test animals for any indication of illness.  If such 
additional testing is appropriate, you should describe and explain the suitability of 
the animals used.   
 
c.  Selected Species-Specific Testing for Adventitious Viruses  
 
We recommend that you test your MCB for appropriate, species-specific viruses.  
You should describe the testing that is performed, the different stages of 
manufacturing where those tests are performed (e.g., cell banks, final product), 
and the test methods used.  If human cell lines are used in the therapeutic product, 
we recommend that you perform testing for human pathogens (CMV, HIV-1 & 2, 
HTLV-1 & 2, EBV, HBV, HCV, B19), and other human viral agents, as 
appropriate.  We recommend such testing because these cells are manipulated 
(cultured for extended time periods) and human pathogens can be introduced or 
propagated during the extended culture periods.  Human viral agents may be 
tested using a PCR-based test system.  (Refer to Section III.A.1.b.1) 
 
B.  Identity 
 
We recommend that you verify the identity of the MCB, WCB, and the final product by 
assays that will identify the product and distinguish it from other products being 
processed in the same facility.  For the final product, identity testing is important to 
ensure that the contents of the vial are labeled appropriately.  For additional information 
on labeling, refer to Section VII.B below.   
 
If the final product consists of one or more cell lines, we recommend that you establish 
identity tests and/or controls that distinguish between the multiple cell lines used, and 
describe those tests and/or controls.  Tests may include assays for cell surface markers or 
genetic polymorphisms (see Ref. 1 for additional information).   
 
C.  Purity  
 
Product purity is defined as relative freedom from extraneous material in the finished 
product, whether or not harmful to the recipient or deleterious to the product (21 CFR 
600.3(r)).  Purity testing includes assays for pyrogenicity/endotoxin (see below), residual 
proteins or peptides used to stimulate or pulse cells, reagents/components used during 
manufacture, such as cytokines, growth factors, antibodies, and serum, and unintended 
cellular phenotypes.   
 
1.  Residual Contaminants  
 
The appropriate purity testing should include assays for residual peptides, and 
proteins used during production and purification, and reagents used during 
manufacture, such as cytokines, growth factors, antibodies, beads, and serum.  
Appropriate purity testing should include a measurement of contaminating cell types 
18 Contains Nonbinding Recommendations 
 
 
or cell debris.  For further information, refer to ICH Q3 on Impurities (Ref. 14).  
You should describe in your IND the purity testing you conduct and your 
specifications for release. 
 
2.  Pyrogenicity/Endotoxin 
 
The rabbit pyrogen test method is the currently required method for testing 
biological products for pyrogenic substances (21 CFR 610.13).  Although the 
pyrogenicity test is required, there may be specific cases where this test method can 
not be performed for release due to properties of the cellular product (i.e., short 
product shelf life, toxicity of product in rabbits).  Under these circumstances, a test 
method such as the Limulus Amebocyte Lysate test method (LAL) may be used as 
an alternative method, but prior to licensure must be shown to provide equal or 
greater assurances of safety, purity, and potency (see 21 CFR 610.9).  The 1987 FDA 
Guideline on Validation of the Limulus Amebocyte Lysate (LAL) Test as End-
Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological 
Products, and Medical Devices sets forth acceptable conditions for use of LAL.   
 
For any parenteral drug, except those administered intrathecally, we recommend that 
the upper limit of acceptance criterion for endotoxin be 5 EU/kg body weight/hour.  
For intrathecally-administered drugs, we recommend an upper limit of acceptance 
criterion of 0.2 EU/kg body weight/hour.  You should describe in your IND the 
pyrogenicity/endotoxin testing you conduct, and your acceptance criterion for 
release.   
 
Note to FDA Reviewers:  Document in your review the specification for 
pyrogenicity/endotoxin testing and verify that testing is on the final product and that 
results are available prior to lot release. 
 
D.  Potency 
 
You should describe and justify all assays you will use to measure potency.  We 
recommend that these assays be quantitative, but in addition, they may include a 
qualitative biological assay.  By the end of Phase 2, we recommend that the potency 
assay consist of in vivo or in vitro tests that measure an appropriate biological activity.  If 
development of a quantitative biological assay is not possible, then a quantitative 
physical assay which correlates with and is used in conjunction with a qualitative 
biological assay can be used.  Note that potency assays are part of lot release and should 
be validated prior to licensure. 
 
19 Contains Nonbinding Recommendations 
 
 
E.  Other 
 
1.  General Safety Testing 
 
Cellular therapy products are exempt from general safety testing under 21 CFR 
610.11(g)(1).    
 
2.  Viability 
 
You should establish minimum release criteria for viability.  For somatic cellular 
therapies, the minimum acceptable viability specification is generally set at 70 
percent.  If this level cannot be achieved, we recommend that you submit data in 
support of a lower viability specification, demonstrating, for example, that dead cells 
and cell debris do not affect the safe administration of the product and/or the 
therapeutic effect.  For further information, see Ref. 1. 
 
3.  Cell Number/Dose 
 
You should develop specifications for the minimum number of viable and functional 
cells as part of product testing and release.  We recommend that you inform FDA 
whether a maximum number/dose of cells to be administered has been established 
and the basis for that level. 
 
 
V.  FINAL PRODUCT RELEASE CRITERIA TESTING 
 
The final product is the final formulated product used for administration to human subjects.  
Final product release criteria testing should be performed on each lot of product manufactured.  
In some situations, each dose could be considered a single lot, depending on the manufacturing 
process.  The results from final product release criteria testing should be available prior to 
administration to a human subject.  If results from final product testing will not be available prior 
to release, we recommend that you clearly indicate this in the IND, together with your 
specifications, and include a description of the reporting notification process if the acceptance 
criteria are not met.  We recommend that you provide, in table format, all of your proposed 
specifications (tests for safety, purity, potency, and identity as described in Section IV, test 
methods, and acceptance criteria), including test sensitivity and specificity, where appropriate, 
for the final product.  (Note that, before the product may be licensed, these parameters must be 
validated (21 CFR 211.165(e)). 
 
 
VI.  PRODUCT STABILITY 
 
Stability testing must be performed during early phases of the clinical trial to establish that the 
product is sufficiently stable for the time period required by the study (21 CFR 312.23(a)(7)(ii)).  
Data supporting a final formulation and dating period will be necessary for licensure.  You 
20 Contains Nonbinding Recommendations 
 
 
should describe the stability measures you will use to support your studies.  For further 
information, refer to ICH Q5C:  Quality of Biotechnological Products:  Stability Testing of 
Biotechnological/Biological Products, (Ref. 16), ICH Guideline Q1A(R):  Stability Testing of 
New Drugs and Products (revised guideline) (Ref. 17), ICH Guideline Q1E:  Evaluation of 
Stability Data (Ref. 18). 
 
Note to FDA Reviewers:  Assess the product development plan in the IND review to determine 
how much stability data are needed for the current phase of investigation and whether sufficient 
data are included in the submission.  If submitted, include preliminary data in your review.  
Assess whether proposed expiration dating is appropriate. 
 
Stability Testing 
 
Under 21 CFR 312.23(a)(7)(ii), you must conduct stability testing in all phases of the 
IND, to demonstrate that the product is within acceptable chemical and physical limits 
for the planned duration of the proposed clinical investigation.  If a very short term 
clinical investigation is proposed, the stability data submitted may be correspondingly 
limited.  You should submit a stability protocol and data for both in-process material and 
the final cellular product.  A proposed stability protocol should include a measure of 
product sterility, identity, purity, quality, and potency.  For each test conducted, you 
should describe the test method, sampling time points (there should be a zero-time point), 
testing temperature, and other appropriate information, including your justification of the 
assays used to indicate product stability, measuring those parameters for the duration of 
storage required by the clinical protocol.  We recommend sterility testing be performed at 
zero-time, end of stability study, and at an intermediate point during the study.  
 
Note to FDA Reviewers:  If the sponsor plans to use the product past the duration of the 
clinical trial (e.g., for a separate trial being conducted after the initial trial), verify that 
testing establishes stability throughout the relevant time period. 
 
1)  In-Process Stability Testing  
 
If cells are cryopreserved, you should describe the stability protocol that will be 
used to ensure that the product is stable during the period of cryopreservation, 
measuring the parameters described in Section VI.A, as appropriate.  A 
comparison is often made of analyses carried out pre-freeze and post-thaw.  You 
should describe any stability testing performed on the product during the holding 
steps, such as cryopreservation of cells and storage of bulk product.   
 
2)  Final Product Stability Testing 
 
You should include any data that demonstrate that the product is stable between 
the time of product formulation and infusion to subjects to aid in establishing an 
expiration-dating period.  We recommend that you conduct the testing at the 
appropriate temperatures and at time points consistent with predicted storage 
21 Contains Nonbinding Recommendations 
 
 
times.  If the product is shipped from the manufacturing site to the clinical site, 
describe the time and shipping conditions (e.g., packaging, temperature).  Your 
stability protocol should be adequate to demonstrate that product integrity, 
sterility, and potency are maintained under the proposed shipping conditions.  We 
further recommend that validation studies using conditions that stress the system 
be initiated by Phase 3 and completed prior to submission of a BLA. 
 
 
VII.  OTHER ISSUES 
 
A.  Product Tracking  
 
For all products, you should establish a product tracking and segregation system.  An 
adequate system should allow identification of the therapeutic product from collection to 
administration of the product and should include procedures to ensure that the product is 
segregated from other products in incubators, hoods, and cryopreservation units.  You 
must establish and maintain a system of tracking that enables the tracking of all products 
from the donor to the consignee or final disposition, and from consignee or final 
disposition to donor (21 CFR 1271.290(b)).  In INDs for somatic cell therapy products, 
typically the processor would consign the product to the investigator, thus the 
investigator is the consignee. 
 
B.  Labeling 
 
You should describe the product labeling used throughout the manufacturing process and 
on the final product container.  As described in 21 CFR 312.6(a), the label for an 
investigational product must contain the following statement:  Caution:  New Drug  
Limited by Federal law to Investigational Use.  To minimize the potential for mix-ups 
for products manufactured in multi-use facilities and for patient-specific products, we 
recommend that the product label contain the date of product manufacture, storage 
conditions, expiration date and time (if appropriate), product name, and two non-personal 
patient identifiers.  As HCT/Ps, labeling for somatic cell therapy products must meet the 
requirements in 21 CFR 1271.250.  For autologous donors and other situations described 
in 21 CFR 1271.90(a) for which a donor eligibility determination is not required, you 
must include the applicable required labeling in 21 CFR 1271.90(b).  For example, for 
autologous cells intended for autologous use you must label the product FOR 
AUTOLOGOUS USE ONLY (21 CFR 1271.90(b)(1)), and NOT EVALUATED FOR 
INFECTIOUS SUBSTANCES if donor testing and screening is not performed (21 CFR 
1271.90(b)(2)).  For more information, refer to Ref. 4.  
 
C.  Container/Closure 
 
You should describe the types of container and closure used, and that you have 
determined that the containers and closures are compatible with the product.  For more 
information, refer to Guidance for Industry:  Container Closure Systems for Packaging 
22 Contains Nonbinding Recommendations 
 
 
Human Drugs and Biologics; Chemistry, Manufacturing, and Controls Documentation 
(Ref. 19) and Guidance for Industry:  Container Closure Systems for Packaging Human 
Drugs and Biologics, Questions and Answers (Ref. 20).
 
D.  Environmental Impact 
 
Under 21 CFR 312.23(a)(7)(iv)(e), you must submit either a claim for categorical 
exclusion under 21 CFR 25.30 or 25.31, or an environmental assessment under 21 CFR 
25.40.  Such categorical exclusion is ordinarily granted, absent extraordinary 
circumstances indicating that the specific proposed action might significantly affect the 
quality of the human environment.  Extraordinary circumstances are described in 40 CFR 
1508.27 and may include actions that create a potential for serious harm to the 
environment and actions that adversely affect a species or the critical habitat of a species 
determined to be endangered, threatened, or entitled to special protection (21 CFR 
25.21).  See the Guidance for Industry:  Environmental Assessment of Human Drug and 
Biologics Applications (Ref. 21) for additional information. 
 
Note to FDA Reviewers:  Document in your review whether the sponsor has claimed a 
categorical exclusion or evaluate the sponsors assessment of any extraordinary 
circumstances using this product.   
 
E.  Qualification of the Manufacturing Process  
 
The manufacturing process for somatic cell therapy products entails the use of reagents 
and source materials of differing complexity, variability and risk for introduction of 
adventitious agents.  Qualification of reagents and source materials, as well as ensuring 
that appropriate controls are in place for monitoring manufacturing consistency and 
product quality, are key elements in ensuring that subjects receive a product that is 
consistently safe, pure, and potent.  We recommend that, prior to production of clinical 
lots and initiation of clinical studies, you establish and implement written procedures to 
ensure proper manufacturing oversight.  This includes the responsibilities and procedures 
applicable to the quality control unit.  We recommend that you establish a quality control 
(QC) plan and document that plan in writing.  For example, a sound QC plan must 
provide for the following functions: 
 
  Responsibility for examining the various components used in the production 
of a product (e.g., containers, closures, in-process materials) to ensure that 
they are appropriate and meet defined, relevant quality standards (21 CFR 
211.84(a)); 
  Responsibility for review and approval of production procedures, testing 
procedures and acceptance criteria (21 CFR 211.22(c)); 
  Responsibility for releasing or rejecting each clinical batch based on a 
cumulative review of completed production records and other relevant 
information (21 CFR 211.22(a), 21 CFR 211.165, 21 CFR 211.192); and 
23 Contains Nonbinding Recommendations 
 
 
  Responsibility for investigating and initiating corrective actions if unexpected 
results or errors occur during production (21 CFR 211.22(a), 21 CFR 
211.192). 
 
You should summarize the QC plan that is in place to prevent, detect, and correct 
deficiencies that may compromise product integrity or function, or that may lead to the 
possible transmission of adventitious infectious agents.  We recommend that QC 
responsibilities be performed independently from production responsibilities by 
dedicated QC personnel who are familiar with QC principles.  You should conduct 
internal audits at planned intervals to evaluate effective implementation of the quality 
plan and to determine if processes and products meet established parameters.  You should 
develop and document audit procedures to ensure that the planned audit schedule takes 
into account the relative risk of the various QC activities, the results of previous audits 
and corrective actions, and the need to audit the entire operation at least annually.   
 
Note to FDA Reviewers:  Document that you have reviewed the summary of the QC 
plan.  Note each individual who has authority over the QC unit and the individuals 
assigned duties.  Document the date of the most recent internal audits of the 
manufacturing operations and those of contract manufacturers, vendors, or other parties. 
 
You should describe the changeover procedures that are followed to ensure that no cross-
contamination occurs among cells intended for an individual subject and other products 
stored or produced in the same facility.  You should describe the use of PCR assays for 
detecting area clearance, cleaning and decontamination reagents and segregation of 
activities, and the qualification of aseptic processing steps.  Because most cellular 
therapy products are not subject to final sterile filtration prior to infusion, you should 
manufacture these products under aseptic conditions.  A media fill is an appropriate 
method to qualify that the process produces a sterile product.  Refer to the Guidance for 
Industry:  Sterile Drug Products Produced by Aseptic Processing  Current Good 
Manufacturing Practice (Ref. 22) for further information.   
 
Note to FDA Reviewers:  Obtain consultative reviews from the Division of 
Manufacturing and Product Quality, CBER, to assess any data submitted by the sponsor 
on facilities and environmental issues such as decontamination and cleaning validation. 
 
F.  Biostatistics 
 
Note to FDA Reviewers:  Obtain consultative reviews for relevant portions of the CMC 
section from the Division of Biostatistics to ensure the adequacy of proposed 
experimental designs and analytic plans.  There are many significant design and analysis 
issues in the areas of assay validation, establishing specifications, evaluation of product 
potency, and evaluation of product stability.  Proper statistical design and analysis of 
such studies are essential to ensure reliable documentation of the safety, purity, and 
potency of the product.  If applicable, document in your review recommendations from 
the Biostatistics consult. 
24 Contains Nonbinding Recommendations 
 
 
 
 
VIII.  PRECLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS 
 
Note to FDA Reviewers:  Document information provided by the sponsor to support the 
scientific rationale underlying the proposal.  Include a brief summary of preclinical data that was 
generated using in vivo animal studies and/or in vitro studies to assess the products activity, 
efficacy, and any safety issues observed during the study.  Also include the route of 
administration and dosage used in the proof of concept studies.  
 
 
IX.  CLINICAL STUDIES TO BE DOCUMENTED BY FDA REVIEWERS 
 
Note to FDA Reviewers:  Provide a brief description of the following in the CMC review: 
 
A.  Protocol Title 
 
Name of the protocol. 
 
B.  Subject Population 
 
Define the population; e.g., size, gender, race, age, etc. 
 
C.  Route of Administration 
 
Define; e.g., oral, intravenous, intramuscular, etc. 
 
D.  Dose 
Include the dosing regimen and whether there is a dose escalation.  Document the dosing 
range and number of subjects enrolled in each dose.  Describe the plans for dose 
escalation and what time interval/data evaluations occur between dose increases. 
 
E.  Frequency  
 
Include the frequency of dose injections per treatment cycle and the number of proposed 
cycles. 
 
F.  Genetic, Biochemical, and Immunological Testing 
 
Assess, in conjunction with the clinical reviewer, whether all genetic and/or product-
specific biochemical and immunological testing of subjects is appropriate for the stage of 
clinical investigation.  Evaluate the sensitivity and specificity of the test methods used to 
demonstrate biological activity (e.g., immunological assay, PCR) and document this 
information in your review. 
 
25 Contains Nonbinding Recommendations 
 
 
G.  Informed Consent  
 
If the informed consent document is submitted for your review, verify that the product is 
described accurately and completely. 
 
 
X.  RECOMMENDATION TO BE DETERMINDED BY FDA REVIEWERS 
 
Note to FDA Reviewers:  Describe any information that is missing or incomplete, and issues that 
require additional clarification.  Provide an overall assessment from the CMC perspective of 
whether the trial may proceed or should be placed on clinical hold.  Document all information 
obtained from the sponsor through telephone conversations or faxes.  Note this documentation in 
the Recommendation Section of the Product Review Template, throughout the review document, 
or as an attachment to the review, as appropriate.  Upon completion, sign and date the review 
and then obtain concurrence from your supervisor.  
 
 
XI.  COMMENTS TO SPONSOR GENERATED BY FDA REVIEWERS 
 
Note to FDA Reviewers:  Draft letter comments on unresolved issues as discussed below.  Refer 
to SOPP 8201, Issuance of and Response to Clinical Hold Letters for Investigational New Drug 
Applications (Ref. 23), for additional information.  After you have obtained supervisory 
concurrence on your review, forward your comments to the RPM for inclusion in a letter to the 
sponsor. 
 
A.  Clinical Hold 
 
Clinical hold comments are comments that the sponsor must satisfactorily address prior 
to allowing clinical studies to proceed after FDA has imposed a clinical hold.  These 
comments must meet the criteria listed in 21 CFR 312.42(b). 
 
B.  Non-Clinical Hold 
 
Non-clinical hold comments are comments that the sponsor should address as product 
development progresses.  In some cases, a sponsor may need to address specific 
manufacturing issues by a certain point in clinical development, such as prior to initiation 
of Phase 3 studies.   
26 Contains Nonbinding Recommendations 
 
 
 
XII.  REFERENCES 
 
1.  Guidance for Industry:  Guidance for Human Somatic Cell Therapy and Gene Therapy, 
March 1998, http://www.fda.gov/cber/gdlns/somgene.pdf.  
 
2.  Guidance for Industry:  Content and Format of Investigational New Drug Applications 
(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, 
Biotechnology-Derived Products, November 1995, 
http://www.fda.gov/cder/guidance/phase1.pdf.  
 
3.  Final Rule:  Eligibility Determination for Donors of Human Cells, Tissues, and Cellular 
and Tissue-Based Products, (69 FR 29786, May 25, 2004), 
http://www.fda.gov/cber/rules/suitdonor.pdf. 
 
4.  Guidance for Industry:  Eligibility Determination for Donors of Human Cells, Tissues, and 
Cellular and Tissue-Based Products (HCT/Ps), August 2007, 
http://www.fda.gov/cber/gdlns/tissdonor.pdf. 
 
5.  Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals, July 
12, 1993, http://www.fda.gov/cber/gdlns/ptccell.pdf. 
 
6.  ICH Guidance on Quality of Biotechnological/Biological Products:  Derivation and 
Characterization of Cell Substrates Used for Production of Biotechnological/Biological 
Products, (63 FR 50244, September 21, 1998), http://www.fda.gov/cber/gdlns/qualbiot.pdf. 
 
7.  Guidance for Industry:  Source Animal, Product, Preclinical and Clinical Issues 
Concerning the Use of Xenotransplantation Products in Humans, April 2003, 
http://www.fda.gov/cber/gdlns/clinxeno.htm. 
 
8.  PHS Guideline on Infectious Disease Issues in Xenotransplantation, January 19, 2001, 
http://www.fda.gov/cber/gdlns/xenophs0101.htm.  
 
9.  Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for 
Human Use, February 28, 1997, http://www.fda.gov/cber/gdlns/ptc_mab.pdf.  
 
10.  Manual of Standard Operating Procedures and Policies: Intercenter 
Consultative/Collaborative Review Process, Version 4, dated June 18, 2004, 
http://www.fda.gov/oc/ombudsman/intercentersop.pdf.  
 
11.  FDA Guidance Concerning Demonstration of Comparability of Human Biological Product, 
Including Therapeutic Biotechnology-derived Products, April 1996, 
http://www.fda.gov/cber/gdlns/comptest.pdf.  
 
27 Contains Nonbinding Recommendations 
 
 
12.  United States Pharmacopoeia (USP), Chapter <71> Sterility Tests, 23th Edition, 1995, 
http://www.usp.org. 
 
13.  ICH Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell 
Lines of Human or Animal Origin, (63 FR 51074, September 24, 1998), 
http://www.fda.gov/cber/gdlns/virsafe.pdf.  
 
14.  ICH Topic Q3.  Impurities.  
  Guidance for Industry:  Q3A Impurities in New Drug Substances, February 2003, 
http://www.fda.gov/cber/gdlns/ichq3a.pdf.  
  Guidance for Industry:  Q3B(R2) Impurities in New Drug Products, July 2006, 
http://www.fda.gov/cber/gdlns/ichq3br.pdf. 
  Guidance for Industry:  Q3C Impurities: Residual Solvents, December 1997, 
http://www.fda.gov/cber/gdlns/q3cresolvent.pdf.   
 
15.  Guideline on Validation of the Limulus Amebocyte Lysate test as an End-Product 
Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products and Medical 
Devices, 1987, http://www.fda.gov/cber/gdlns/lal.pdf.   
 
16.  Guideline for Industry:  Quality of Biotechnological Products: Stability Testing of 
Biotechnological/Biological Products, July 1996 (ICH Q5C), 
http://www.fda.gov/cder/guidance/ichq5c.pdf.  
 
17.  Guidance for Industry:  Q1A(R2): Stability Testing of New Drug Substances and Products 
(Revision 2), November 2003, http://www.fda.gov/cber/gdlns/ichstab.pdf. 
 
18.  Guidance for Industry:  Q1E:  Evaluation of Stability Data, June, 2004, 
http://www.fda.gov/cber/gdlns/ichstabdta.pdf. 
 
19.  Guidance for Industry:  Container Closure Systems for Packaging Human Drugs and 
Biologics; Chemistry, Manufacturing, and Controls Documentation, May 1999, 
http://www.fda.gov/cber/gdlns/cntanr.pdf. 
 
20.  Guidance for Industry:  Container Closure Systems for Packaging Human Drugs and 
Biologics, Questions and Answers, May 2002, 
http://www.fda.gov/cber/gdlns/cntanrq&a.pdf. 
 
21.  Guidance for Industry:  Environmental assessment of Human Drug and Biologics 
Applications, Revision 1, July 1998, http://www.fda.gov/cber/gdlns/environ.pdf. 
 
22.  Guidance for Industry:  Sterile Drug Products Produced by Aseptic Processing  Current 
Good Manufacturing Practice, September 2004, 
http://www.fda.gov/cber/gdlns/steraseptic.htm. 
 
28 Contains Nonbinding Recommendations 
 
 
23.  Manual of Standard Operating Procedures and Policies Investigational New Drug; Issuance 
of and Response to Clinical Hold Letters for Investigational New Drug Applications, SOPP 
8201, Version #3, April 27, 1999, http://www.fda.gov/cber/regsopp/8201.htm.  
29 Contains Nonbinding Recommendations 
 
 
APPENDIX A  PRODUCT REVIEW TEMPLATE (SOMATIC CELL THERAPY) 
 
 Supervisor Concurrence/Date 
IND:   XXXX  Sponsors Submission Date:   Month DD, YYYY   
  30 Day Review Due Date:   Month DD, YYYY   
  STATUS:   Pending   
 
 DATE:    Month DD, YYYY 
 
 REVIEWER:    Your Name 
  Your Title, OCTGT/DCGT/Your Branch 
 THROUGH:    Branch Chief Name 
  Branch Chief, OCTGT/DCGT/Branch 
 
 SPONSOR:   Name: 
 Address: 
 Title:  
 Phone: 
 Fax: 
 
 SPONSOR POINT OF CONTACT: 
   Name: 
 Address: 
 Title: 
 Phone: 
 Fax: 
 
 TITLE OF IND:   
 
 PROPOSED USE:   
 
 REVIEW TEAM:   Clinical:   
 Pharm-Tox: 
 RPM: 
 Consults: 
   
 PRODUCT DESCRIPTION:   
 
 PHASE OF STUDY:   
 
 CROSS-REFERENCED INDS, IDES, MFS:   
 
 KEY WORDS:   
 
INTRODUCTION / RATIONALE:   
30 Contains Nonbinding Recommendations 
 
 
 
STUDY OBJECTIVES: 
 
PRODUCT MANUFACTURING AND CHARACTERIZATION: 
 
Product Manufacturing - Components 
 
Cells 
 
Allogeneic or Autologous Cell Components 
 
Cell Source: 
 
Method of Collection: 
 
      Donor Screening: 
      Description 
 
      Tabulation of Testing 
 
Cell Bank System - If Applicable 
 
      Master Cell Bank (MCB)  
      Description 
 
      Tabulation of Testing 
 
    Working Cell Bank (WCB)  
      Description 
 
      Tabulation of Testing 
 
Reagents 
 
Tabulation of Reagents Used in Manufacture 
 
Reagent/Excipient  Concentration at use  Source  Grade  Vendor  COA 
 
    Qualification Program 
 
Determination of Removal of Reagents from Final Product 
 
Combination Products - If Applicable 
 
    Drug or Device Components - If Applicable 
31 Contains Nonbinding Recommendations 
 
 
 
Consult Review Issues: 
 
Areas of Concern for Components: 
 
Product Manufacturing - Procedures 
 
Preparation of Autologous or Allogeneic Cells 
 
Method of Cell Collection/Processing/Culture Conditions 
 
Irradiation - If Applicable 
 
Process Timing & Intermediate Storage 
 
Final Harvest 
 
    Timing/Methods/Wash Procedure 
 
Final Formulation 
 
    Formulation/Infusion Buffer  
 
    Excipients  
 
  Cell Density/Concentration in the Final Product 
    Storage Method Prior to Use 
 
Areas of Concern for Manufacturing 
 
PRODUCT TESTING 
 
In-Process Testing and Criteria 
 
Tabulation of Tests, Manufacturing Step, Test Methods, Criteria, and Test Sensitivity & 
Specificity 
 
32 Contains Nonbinding Recommendations 
 
 
Test  Manufacturing  Method  Criteria  Sensitivity  Specificity 
  Step Where 
Performed 
Sterility           
Mycoplasma           
Purity          
(endotoxin) 
Purity (other          
contaminants) 
Identity           
Potency           
Others (cell          
dose) 
Others (cell          
viability) 
Description of Test Methods 
 
FINAL PRODUCT RELEASE CRITERIA/SPECIFICATIONS 
 
Tabulation of Final Product Release Criteria Tests, Test Methods, Criteria, Test 
Sensitivity & Specificity 
   
Test  Method  Criteria  Sensitivity  Specificity  Results Available 
Prior to Release 
Description of Test Methods 
 
PRODUCT STABILITY 
 
  In-Process Stability Testing  
 
    Cryopreserved Cells  
 
    Other Intermediate Holding Steps  
 
  Final Product Stability Testing 
 
Product Formulation to Patient Infusion 
 
Shipping Conditions 
 
OTHER ISSUES 
 
Product Tracking  
 
33 Contains Nonbinding Recommendations 
 
 
Labeling and Containers 
In-Process Labeling 
 
Final Product Labeling 
   
Container Closure & Integrity  
 
Environmental Impact 
 
Validation and Qualification of the Manufacturing Process  
 
  QA/QC Program 
   
  Manufacturing Process Validation 
 
Biostatistics 
     
PRECLINICAL STUDIES 
 
CLINICAL STUDIES 
 
Protocol Title 
 
Subject Population 
 
Route of Administration 
 
Dose 
 
Frequency 
 
Genetic, Biochemical, and Immunological Testing 
 
Informed Consent 
 
RECOMMENDATION 
 
COMMENTS TO SPONSOR 
 
Clinical Hold 
Non-Clinical Hold 
 
     Signature           Date:____________________ 
Reviewer Name 
34 Contains Nonbinding Recommendations 
 
 
APPENDIX B  CONSIDERATIONS FOR DEVELOPMENT OF FINAL PRODUCT 
RELEASE CRITERIA SPECIFICATIONS AND STABILITY PROTOCOLS 
 
Specifications are the quality standards (i.e., tests, analytical procedures, and acceptance criteria) 
that confirm the quality of products and other materials used in the production of a product.  
Acceptance criteria are the numerical limits, ranges, or other criteria for the tests described.  For 
additional information, see ICH Guideline Q6B:  Test Procedures and Acceptance Criteria for 
Biotechnological/Biological Products.3  We believe that certain release specifications, such as 
those related to product safety, should be in place prior to initiating Phase 1 clinical studies.  As 
product development proceeds, additional specifications for product quality and manufacturing 
consistency are developed and implemented.  For additional discussion of manufacturing quality 
control, see Guidance for Industry: Guideline on the Preparation of Investigational New Drug 
Products4 and Guidance for Industry: IND Meetings for Human Drugs and Biologics; 
Chemistry, Manufacturing and Controls Information.5  
 
A.  Development of Release Acceptance Criteria  
 
We recommend that proposed release acceptance criteria for the final product be based 
on scientific data and manufacturing experience obtained during development of the 
product as described below: 
 
  Phase 1  Based on data from lots used in preclinical studies. 
  Phase 2  Refine and tighten based on data generated during Phase 1. 
  Phase 3  Based on information collected during product development.  
  Licensure  Based on information collected during product development using 
validated assays. 
 
B.  Development of Acceptance Criteria Analytical Procedures 
 
We recommend that proposed analytical procedures be based on scientific data and 
manufacturing experience as described below: 
 
  Phase 1-3  Usually based on Code of Federal Regulation (CFR) methods or 
alternative methods, if appropriate.  
  Phase 2  If an alternative to the CFR method is used, we recommend that the 
sponsor initiate validation of the alternative by Phase 3. 
  Licensure  The product specification should be in place and established 
under a validated assay. 
 
                                
 
3 Guidance for Industry:  Q6B Specifications:  Test Procedures and Acceptance Criteria for 
Biotechnological/Biological Products, August 1999, http://www.fda.gov/cder/guidance/Q6Bfnl.pdf. 
4 Guidance for Industry:  Guideline on the Preparation of Investigational New Drug Products (Human and Animal), 
dated March 1991, reprinted November 1992, http://www.fda.gov/cder/guidance/old042fn.pdf. 
5 Guidance for Industry: IND Meetings for Human Drugs and Biologics; Chemistry, Manufacturing and Controls 
Information, May 2001, http://www.fda.gov/cber/gdlns/ind052501.htm 
35 Contains Nonbinding Recommendations 
 
 
C.  Development of Stability Protocols 
 
In order to develop adequate stability data for timely submission in a license application, 
we recommend that a sponsor implement and expand the stability program as described 
below: 
 
  Phase 1 - 3  Preliminary data on product stability must indicate whether the 
product or components are likely to remain stable for the duration of the 
clinical trial.  Note:  the regulations require that the IND contain these data at 
each stage of the clinical trial (21 CFR 312.23(a)(7)(ii)). 
  Phase 2  We recommend that the sponsor initiate a stability protocol to 
accumulate additional data.  
  Phase 3  We recommend that the sponsor begin to establish the dating 
period, storage conditions, and shipping conditions based on data derived 
from the stability protocol. 
36