Contains Nonbinding Recommendations 
Guidance for Industry
Demonstration of the Quality Factor 
Requirements Under 21 CFR 106.96(i) 
for Eligible Infant Formulas  
Additional copies are available from: 
Office of Nutrition, Labeling and Dietary Supplements, HFS-800 
Center for Food Safety and Applied Nutrition 
Food and Drug Administration 
5001 Campus Drive 
College Park, MD 20740 
(Tel) 240-402-2373 
http://www.fda.gov/FoodGuidances 
You may submit written comments regarding 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, rm. 1061, Rockville, MD 20852. All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal 
Register.  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
June 2014 
1  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
I.  Introduction 
 
II.  Questions and Answers 
1.  Which infant formulas are eligible? 
2.  What are the quality factors that an eligible infant formula must meet? 
3.  How can the quality factor of normal physical growth be met for an 
eligible infant formula? 
4.  What must I do if the data and information available do not show that 
the formulation meets the quality factor requirements for 
demonstrating normal physical growth? 
5.  How can the quality factor of sufficient biological quality of the 
protein be met for an eligible infant formula? 
6.  What records must I keep concerning an eligible infant formula?  
7.  Do I have to file a citizen petition? 
8.  Why should I file a citizen petition for an eligible infant formula? 
9.  How long do I have to file a citizen petition for an eligible infant 
formula? 
10. Do I need to submit a separate citizen petition for each form of an 
eligible infant formula? 
11. What does FDA recommend if I need to include proprietary 
information in support of a citizen petition?  
12. How do I submit a citizen petition?  
13. What should I request for the petition under A. Action requested (21 
CFR 10.30(b))?  
14. What information should I include under B. Statement of grounds 
(21 CFR 10.30(b))? 
15. How will FDA respond to the citizen petitions? 
 
III.  Conclusions 
 
 
  2  Contains Nonbinding Recommendations 
 
 
1
Guidance for Industry  
 
 
Demonstration of the Quality Factor Requirements Under  
21 CFR 106.96(i) for Eligible Infant Formulas 
 
 
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 may 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 FDA staff responsible for implementing this 
guidance.  If you cannot identify the appropriate FDA staff, call the telephone number 
listed on the title page of this guidance.  
 
 
I.  Introduction 
 
The Food and Drug Administration (FDA or we) regulates infant formula under the 
Federal Food, Drug, and Cosmetic Act and supporting regulations.  On June 10, 2014,  
we published a final rule that requires, among other things, that infant formulas satisfy 
the two quality factors of normal physical growth and sufficient biological quality of the 
protein component of the formula.  The regulations establish quality factor requirements 
for eligible infant formulas (21 CFR 106.96(i)).  Under 21 CFR 106.3, an eligible 
infant formula is an infant formula that could be lawfully distributed in the United States 
on December 8, 2014.   
 
This guidance provides FDAs current thinking about the requirements in the final rule 
for eligible infant formulas.  It answers questions about the quality factor requirements, 
record requirements, and voluntary submission of a citizen petition.  In addition to 
consulting this guidance, we encourage you to discuss the voluntary submission of a 
citizen petition with us.  
 
We recognize that you, the manufacturer of an eligible infant formula, may need time to 
develop the data and information needed to meet the specific quality factor requirements 
in the infant formula regulations.  In addition, we want to ensure the continued 
availability of infant formulas, an essential source of nutrition for infants fed infant 
formula.  Therefore, as discussed below, the final rule establishes a compliance date of 
November 12, 2015 for you to meet certain requirements related to quality factors.   
                                                 
1 This  guidance has been prepared by the Office of Nutrition, Labeling, and Dietary Supplements in the 
Center for Food Safety and Applied Nutrition at the U.S. Food and Drug Administration. 
  3  Contains Nonbinding Recommendations 
 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidance documents describe our current thinking on a topic 
and should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in FDA guidance means that 
something is suggested or recommended, but not required. 
II. Questions and Answers 
 
1.  Which infant formulas are eligible? 
 
Section 106.3 in the final rule defines eligible infant formula as an infant formula that 
could be lawfully distributed in the United States on December 8, 2014.   
 
2.  What are the quality factors that an eligible infant formula must meet? 
 
The quality factors are (1) normal physical growth and (2) sufficient biological quality of 
the formulas protein component (adequate amounts of protein and in a form that can be 
utilized by infants).  The quality factors for an eligible infant formula are the same as for 
a new infant formula.  However, there are different requirements that apply to eligible 
infant formulas for demonstrating that the quality factors are met.  Additionally, the 
voluntary submission of a citizen petition in accordance with 21 CFR 106.96(i)(3) applies 
only to eligible infant formulas.  The requirements for eligible infant formulas are 
described below.  
 
3.  How can the quality factor of normal physical growth be met for an eligible 
infant formula? 
 
You must meet at least one of the following criteria under 21 CFR 106.96(i)(1):   
 
  According to 21 CFR 106.96(i)(1)(i), you can meet the quality factor of normal 
physical growth if you conduct a growth monitoring study (GMS) in accordance 
with the requirements under 21 CFR 106.96(b) for an infant formula that is not 
eligible.  
 
A manufacturer of an infant formula that is not an eligible infant formula must 
show that a formula supports normal physical growth in infants when fed as a sole 
source of nutrition by conducting, in accordance with good clinical practice, an 
adequate and well-controlled GMS of the infant formula that:  
 
(1) Is no less than 15 weeks in duration, enrolling infants no more than 2 weeks 
old at time of entry into the study;  
(2) Includes the collection and maintenance of data on formula intake and 
anthropometric measures of physical growth, including body weight, 
recumbent length, head circumference, average daily weight increment, and 
average daily recumbent length increment;  
  4  Contains Nonbinding Recommendations 
 
 
(3) Includes anthropometric measurements made at the beginning and end of the 
study, and at least four additional measurements made at intermediate time 
points with three of the six total measurements made within the first 4 weeks 
of the study and three measurements made at approximately 4-week intervals 
over the remaining 11 weeks of the study;  
(4) Compares the anthropometric data for the test group to a concurrent control 
group or groups at each time point and compares the anthropometric data for 
each infant (body weight for age, body length for age, head circumference for 
age, and weight for length) in the test group and the control group to the 2009 
Centers for Disease Control and Prevention (CDC) growth charts, which are 
incorporated by reference at 21 CFR 106.160;2 and  
(5) Compares the data on formula intake of the test group with a concurrent 
control group or groups and a scientifically appropriate reference. 
 
  According to 21 CFR 106.96(i)(1)(ii), consistent with the 1996 proposal3 you can 
meet the quality factor of normal physical growth if you conduct the GMS as 
follows: 
 
(1) The evidence is an adequate and well-controlled growth study, conducted in 
accordance with good clinical practice, to determine whether an infant 
formula supports normal physical growth in infants when the formula is fed as 
the sole source of nutrition;  
(2) The growth study is no less than 4 months in duration, enrolling infants no 
more than 1 month old at time of entry into the study;  
(3) The growth study collects from the study subjects data on anthropometric 
measures of physical growth, including body weight, recumbent length, head 
circumference, and average daily weight increment, and plots the data on 
National Center for Health Statistics reference percentiles for body weight, 
body length, and head circumference, which are incorporated by reference at 
21 CFR 106.160;4 and 
(4) The growth study collects anthropometric measurements at the beginning of 
the growth study, at 2 weeks, at 4 weeks, at least monthly thereafter, and at 
the end of the study. 
 
  According to 21 CFR 106.96(i)(1)(iii), you can meet the quality factor of normal 
physical growth if you use other scientific evidence to show the formula supports 
normal physical growth.  
 
Evidence that FDA would consider in determining whether the requirements of 21 
CFR 106.96(i)(1)(iii) are met might include a series of shorter studies that used 
                                                 
2 Information about the 2009 CDC growth charts, based on the World Health Organizations Child Growth 
Standards, is available at http://www.cdc.gov/growthcharts/who_charts.htm.   
3 61 FR 36154 (July 9, 1996). 
4 Physical growth: National Center for Health Statistics percentiles, Hamill, P.V.V., T.A. Drizd, C.L. 
Johnson, R.B. Reed, A.F. Roche, and W.M. Moore,  American Journal of Clinical Nutrition, vol. 32, pp. 
607-614, dated March 1979. 
  5  Contains Nonbinding Recommendations 
 
 
the formulation at issue and had growth measurements during the first 4 months 
of life, and that when viewed collectively, show normal physical growth.  For 
example, studies in which the primary purpose of the study had a different 
objective than growth (e.g., immune responses to the addition of nucleotides) 
might be useful if the study was conducted using human infants in the appropriate 
age range and anthropometric measurements were obtained at sufficient 
frequency during the first 4 months of life to show normal physical growth.  It is 
also critical that the formula used in such a study, as either the test formula or the 
control formula, is the formulation for which the manufacturer is seeking to show 
normal physical growth.   
 
As another example, if the manufacturer conducted a GMS for the formulation 
consistent with 21 CFR 106.96(i)(1)(ii) but demonstrated normal physical growth 
when charting length, weight, and head circumference against the 2000 CDC 
growth charts5 or using the 2009 CDC growth charts, we would consider the use 
of these sources to be an appropriate means by which to establish that scientific 
evidence exists that demonstrates the formula supports normal physical growth.  
 
You are required to keep records to demonstrate that an eligible infant formula supports 
normal physical growth under 21 CFR 106.96(i)(5).  If you plan to submit a voluntary 
citizen petition under 21 CFR 106.96(i)(3), we recommend that you include a copy of 
these records in the citizen petition or a citation to any notification(s) in which these data 
were reported to FDA. 
 
4.  What must I do if the data and information available do not show that the 
formulation meets the quality factor requirements for demonstrating normal 
physical growth? 
 
Although there is likely to be some existing scientific evidence relating to quality factor 
status of many eligible formulas, you may need to design, conduct, and analyze the 
results of a GMS to meet the quality factor of normal physical growth.   
 
Because we recognize that you may need to design, conduct, and analyze the results of a 
GMS to develop evidence of the formulas ability to support normal physical growth, we 
established a separate compliance date for certain quality factor provisions that apply to 
eligible infant formulas.  Specifically, manufacturers must comply with 21 CFR 
106.96(a), 106.96(e), 106.96(i)(5), 106.100(p)(2), and 106.100(q)(2) as of November 12, 
2015.   
 
This means that eligible infant formulas must be in compliance with the quality factor 
and applicable recordkeeping requirements, as of November 12, 2015.  This compliance 
date should provide you sufficient time to develop the required data and information and 
submit the data and information through the voluntary citizen petition process discussed 
                                                 
5 Available at http://www.cdc.gov/growthcharts/.   
  6  Contains Nonbinding Recommendations 
 
 
in this guidance document.  The same date also applies to filing a citizen petition, as 
discussed under question 9. 
 
5.  How can the quality factor of sufficient biological quality of the protein be met 
for an eligible infant formula? 
 
You must meet at least one of the following criteria under 21 CFR 106.96(i)(2):   
 
  According to 21 CFR 106.96(i)(2)(i), you can meet the quality factor of sufficient 
biological quality of the protein if you conduct a protein efficiency ratio (PER) rat 
bioassay in accordance with the requirements under 21 CFR 106.96(f) that apply 
to an infant formula that is not an eligible infant formula. 
 
  According to 21 CFR 106.96(i)(2)(ii), you can meet the quality factor of sufficient 
biological quality of the protein if you conduct a PER rat bioassay for the 
formulation consistent with the 1996 proposal.  That is, the scientific evidence on 
such infant formula is a study that establishes the biological quality of the protein 
in an infant formula by showing that the protein source supports adequate growth 
using the PER rat bioassay described in the Official Methods of Analysis of the 
Association of Official Analytical Chemists, 16th ed., sections 45.3.04 and 
45.3.05, AOAC Official Method 960.48 Protein Efficiency Ratio Rat Bioassay. 
 
  According to 21 CFR 106.96(i)(2)(iii), you can meet the quality factor of 
sufficient biological quality of the protein if the scientific evidence on such infant 
formula otherwise demonstrates that the protein in such infant formula is of 
sufficient biological quality. 
 
Conducting PER studies has been a requirement since 1982.  Therefore, you should have 
already conducted a PER study on the formulation and have PER study results in your 
files.  You are required to keep records of your PER study results under 21 CFR 
106.96(i)(5).  If you plan to submit a voluntary citizen petition under 21 CFR 
106.96(i)(3), we recommend that you include a copy of these records in the citizen 
petition or a citation to any notification(s) in which these data were reported to FDA. 
 
6.  What records must I keep concerning an eligible infant formula?  
 
  7  Contains Nonbinding Recommendations 
 
 
Under 21 CFR 106.96(i)(5), you must maintain records that show your eligible infant 
formula supports normal physical growth in infants when fed as the sole source of 
nutrition and that the protein is of sufficient biological quality.  The records must include 
(1) all relevant scientific data and information and a narrative explaining why the data 
and information show that the formula supports normal physical growth and (2) a 
narrative explaining why the data and information show that the protein in the infant 
formula is of sufficient biological quality.  These records must be available for FDAs 
review during an inspection, as required under 21 CFR 106.100(l).  Under the final rule, 
failure to have the quality factor records for a specific formulation renders that 
formulation adulterated.   
 
7.  Do I have to file a citizen petition? 
 
No, submission of a citizen petition under 21 CFR 106.96(i)(3) is voluntary; however, 
meeting the quality factor requirements for an eligible infant formula under 21 CFR 
106.96(i) is mandatory.   
 
If you choose not to submit a citizen petition, you must still retain records demonstrating 
that you have met the quality factor requirements, as required by 21 CFR 106.96(i)(5). 
   
8.  Why should I file a citizen petition for an eligible infant formula? 
 
This voluntary process allows infant formula manufacturers to show the public that their 
formulations meet the quality factor requirements. The process also allows an infant formula 
manufacturer to be aware of FDAs view of the manufacturers determination that their 
formulation meets the quality factor requirements.  
 
Additionally, the public, including competitors, purchasers for retail stores, and 
individual consumers, will indirectly benefit from this process because they will have 
access to scientific evidence and other information on the quality factor status of eligible 
infant formulas as well as FDAs view of that evidence, subject to the limitation on the 
disclosure of proprietary information discussed in the response to Question 11.  We plan 
to establish a Web page on which we will post petitions submitted under 21 CFR 
106.96(i)(3) and our responses to the petitions.  This Web page will let the public know 
(1) if you have taken the opportunity to show that the formula meets the quality factors 
and (2) our view as to whether outstanding questions remain regarding your 
determination that the quality factors have been met. 
 
9.  How long do I have to file a citizen petition for an eligible infant formula? 
 
Under 21 CFR 106.96(i)(3), you have until November 12, 2015 to submit a petition to 
FDA.  You can find specific requirements for a citizen petition in 21 CFR 10.30 and on 
the FDA website.  You may submit the petition electronically (see 78 FR 76748; 
December 19, 2013) or in a hard copy by mail. 
 
  8  Contains Nonbinding Recommendations 
10.Do I need to submit a separate citizen petition for each form of an eligible infant
formula?
No, you can submit one petition for formulas with the same formulation but different 
forms (e.g., liquid and powdered forms).  You need a separate citizen petition for each 
formulation as described in 21 CFR 106.96(i)(4).  The citizen petition should contain 
information regarding both quality factors for each formulation.   
11. What does FDA recommend if I need to include proprietary information in
support of a citizen petition?  
FDA will protect the confidentiality of information submitted through the citizen petition 
process in accordance with the Freedom of Information Act (5 U.S.C.  552) and FDAs 
regulations.  Under 21 CFR 20.61(c), we do not disclose confidential commercial or trade 
secret information.  However, if you intend to submit a citizen petition under 21 CFR 
106.96(i)(3), we recommend you include only public information in the citizen petitions 
you submit to show that you meet the quality factor requirements for an eligible infant 
formula.  If you need to submit confidential commercial or trade secret information as 
part of your evidence to show that you meet the quality factors, you may do so, but we 
recommend that you identify any confidential commercial or trade secret information in 
the materials submitted and that you segregate such information to the extent possible.   
The following options are also available to ensure the confidentiality of certain 
information submitted with a citizen petition:   
 Cite in your citizen petition to information contained in a previous notification; or
 Submit a supplement to the citizen petition directly to Infant Formula and Medical
Foods Staff at the address below that contains the information you wish to keep
confidential. Clearly mark the supplement as confidential and associated with the
citizen petition.  Cite the supplement in the citizen petition and send to:
Infant Formula and Medical Foods Staff 
Office of Nutrition, Labeling, and Dietary Supplements  
Center for Food Safety and Applied Nutrition (HFS-850) 
Food and Drug Administration 
5001 Campus Drive
College Park, MD 20740 
For manufacturers who have published research on their formulations, if you can show 
that you meet the quality factors using only publicly available information, such as 
published journal articles, then we will review the petition based on publicly available 
information that you cite in your citizen petition, and you would not need to cite a 
previous notification or submit a supporting supplement.     
9  Contains Nonbinding Recommendations 
 
 
FDA files its response to a citizen petition in the public docket, and we routinely post our 
responses to citizen petitions on our website.  We intend to follow this practice for citizen 
petitions submitted under 21 CFR 106.96(i)(3).   
 
12. How do I submit a citizen petition?  
 
You should follow the process described in 21 CFR 10.20 and submit the information 
in the format shown in 21 CFR 10.30. There is also an opportunity to file the citizen 
petition electronically through the regulations.gov website (see 78 FR 76748; 
December 19, 2013).  In addition, we encourage you to contact us at 240-402-1450 
with your questions about submitting a citizen petition, but we suggest that you do so 
well before the November 12, 2015 deadline to provide us with ample opportunity to 
respond. 
   
13. What should I request for the petition under A. Action requested (21 CFR 
10.30(b))?  
 
For a citizen petition submitted under 21 CFR 106.96(i)(3), you should ask FDA to 
evaluate your determination that your eligible formula meets the quality factor of normal 
physical growth and the quality factor of sufficient biological quality of the protein, based 
on the criteria you relied on for both factors.   
 
14. What information should I include under B. Statement of grounds (21 CFR 
10.30(b))? 
 
For a citizen petition submitted under 21 CFR 106.96(i)(3), we recommend you include 
the following information in a well-organized narrative: 
  The formulation (e.g., cow-milk based infant formula containing nucleotides, 
arachidonic acid (ARA), docosahexaenoic acid (DHA), and 
galactooligosaccharides). 
  The marketed name(s) used for the formulation. 
  A description of the factual and legal grounds you relied on, such as all relevant 
information and views, that provides the scientific basis for your conclusion that the 
formula meets the quality factors of normal physical growth and sufficient 
biological quality of the protein.  
15. How will FDA respond to the citizen petitions? 
 
We will follow the requirements under 21 CFR 10.30 and issue a response letter 
indicating whether we have questions about your determination that the data and 
information in the citizen petition show that the formulation meets one or more of the 
criteria in both 21 CFR 106.96(i)(1) and 21 CFR 106.96(i)(2).  
 
III. Conclusions 
  10  Contains Nonbinding Recommendations 
 
 
 
We encourage manufacturers planning to file a citizen petition under 21 CFR 
106.96(i)(3) to contact the Infant Formula and Medical Food Staff at 240-402-1450 to 
discuss any questions, and to use this guidance to help formulate specific questions 
regarding their eligible infant formula.   
 
 
  11