Contains Nonbinding Recommendations

Draft — Not for Implementation

March 2010

Table of Contents and Introduction (Part I)

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II. Elements Common to All Regulatory Submissions

1. General Information
2. Forms
3. Amendments, Updates, and Supplements
4. Table of Contents
5. Information that is Exempt from Disclosure under the Freedom of Information Act (FOIA)
6. Cover Letter
7. References

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A. General

1. Where can I find the definitions of the regulatory submissions and terms covered by this document?

   You can find the definitions of the regulatory submissions and terms covered by this guidance in Appendix 11.

2. Do any fees apply to my regulatory submission?

   As of the date of this document, fees only apply to the submission of a CAP for the listing of a color additive (see 21 CFR 70.19).

3. Where do I send my regulatory submission?

   Send all fully electronic submissions through FDA’s Electronic Submission Gateway (ESG).  For additional information about FDA’s ESG, see Section III.B of this document.

   Send a FCN, PNC, or FMF concerning a food contact substance (FCS) that is prepared in paper format, or prepared in electronic format but submitted on physical media (e.g., CD-ROM or DVD), to:

   Notification Control Assistant
   Office of Food Additive Safety
   HFS-275
   5001 Campus Drive
   College Park, MD 20740-3835

   Send all other regulatory submissions prepared in paper format, or prepared in electronic format but submitted on physical media (e.g., CD-ROM or DVD), to:

   Office of Food Additive Safety
   HFS-200
   5001 Campus Drive
   College Park, MD 20740-3835
    

4. May FDA refuse to accept my regulatory submission?

   Yes. FDA may refuse to accept any regulatory submission that is transmitted in electronic format, if it is either inaccessible or contaminated with malicious elements such as a computer virus. FDA may also refuse to file a new submission if it is incomplete or if any data are lacking or not set forth so as to be readily understood (see, e.g., 21 CFR 71.1(d), 21 CFR 171.1(d), and 21 CFR 170.104(b)(1)).

B. Forms

5. Should I include a specific form with my regulatory submission?

   Yes. You should include a specific form with any regulatory submission (including any new submission and any update, amendment, or supplement to a previous submission), regardless of whether you transmit the regulatory submission in electronic format or in paper format. You must use Form FDA 3480 when submitting a FCN (21 CFR 170.101(e)). If you are sending your submission in paper format, place your submission form at the beginning of the entire submission.

6. What is the purpose of the form I include with my regulatory submission?

   The form prompts you to include certain elements of the particular type of regulatory submission in a standard format. A form you transmit in electronic format improves the efficiency of our administration of your submission, because it provides data and information that our systems can extract and upload directly into our databases.

   The form also substitutes for the “Dear Sir” section of 21 CFR 71.1(c) (for a CAP) and 21 CFR 171.1(c) (for a FAP). However, the information on the form is not intended to substitute for the complete description of procedures, requirements, or recommendations included in the applicable regulation or guidance.

7. How do I find the correct form and applicable instructions for completing the form?

   Table II-1 identifies the correct form to include with each type of regulatory submission, the Appendices where you can find each form, and the Appendices where you can find instructions for completing each form.

   Table II-1
   Where to Find the Correct Form for Your Regulatory Submission

   Type of Submission	Form No.*	Where to Find the Instructions for Using the Form	Where to Find the Form
   FAP, FMF	3503	Appendix 1	Appendix 2
   CAP, CMF	3503	Appendix 1	Appendix 2
   FCN, FMF for FCS, PNC	3480	Appendix 3a	Appendix 4a
   Amendment to a FCN, PNC, or FMF for a FCS	3480-A	Appendix 3b	Appendix 4b
   GRAS Notice	3667	Appendix 5	Appendix 6
   Biotechnology Final Consultation	3665	Appendix 7	Appendix 8
   New Protein Consultation	3666	Appendix 9	Appendix 10

   * For all original submissions and any additional information to those submissions (except those concerning FCS) use the same submission form.

8. How should I organize a new master file submission?

   You should organize a new master file submission according to the items listed on the applicable form (i.e., Form FDA 3503 or Form FDA 3480).  A summary of these items is listed in Table IV-1 of this document (for Form FDA 3503) and Table V-1 of this document (for Form FDA 3480) and described in the applicable instructions for the form (see Appendices 1, 3a and 3b). 

C. Amendments, Updates, and Supplements

9. How are the terms “amendment,” “update,” and “supplement” used in the context of the regulatory submissions covered by this document?

   The terms “amendment,” update,” and “supplement” are used as shown in Table II-2.

   Table II-2
   Use of the Terms “Amendment,” Update,” and “Supplement”

   Submission	Amendment	Update	Supplement
   FAP	Any data or information you submit to a filed FAP in response to a request from us for additional information or clarification	Any data or information submitted to a filed FAP on the initiative of the submitter (i.e., without a request from FDA)	N/A*
   CAP	Any data or information you submit to a filed CAP in response to a request from us for additional information or clarification	Any data or information submitted to a filed CAP on the initiative of the submitter (i.e., without a request from FDA)	N/A
   FCN	Any data or information you submit to an FCN	N/A	N/A
   PNC	Any data or information you submit to a PNC	N/A	N/A
   GRAS notice	Any data or information you submit regarding a filed GRAS notice before we respond to it	N/A	Any data or information you submit regarding a GRAS notice after we respond to it
   Biotechnology Final Consultation	Any data or information you submit regarding a Biotechnology Final Consultation before we respond to it	N/A	Any data or information you submit regarding a Biotechnology Final Consultation after we respond to it
   New Protein Consultation	Any data or information you submit regarding a New Protein Consultation before we respond to it	N/A	Any data or information you submit regarding a New Protein Consultation after we respond to it
   FMF	Any data or information you submit to an FMF established for a FCS	Any data or information you submit to an FMF established for a substance other than a FCS	N/A
   CMF	N/A	Any data or information you submit to an established CMF	N/A

   *N/A means “Not applicable.”

D. Table of Contents

10. Should I include a Table of Contents with my regulatory submission?

    You should include a Table of Contents:

    • With any submission regarding a GRAS notice, Biotechnology Final Consultation, or New Protein Consultation (whether the submission is a new submission or an amendment or supplement to a previous submission), regardless of whether the submission is transmitted in paper or electronic format;
    • With any other regulatory submission transmitted in paper format; and
    • Within individual Studies submitted as part of a regulatory submission.
11. How should I paginate a regulatory submission in paper format?

    You should paginate a regulatory submission in paper format using continuous pagination.  For an example of continuous pagination, see the example Table of Contents in Table II-3 in the next question.

12. How should I format the Table of Contents in a regulatory submission I transmit in paper format?

    You should format the Table of Contents in a regulatory submission in paper format to show the overall page numbers for the entire submission.  When there is more than one volume, the Table of Contents should include the volume number.   Below, we provide examples of a Table of Contents for a FAP (Table II-3) and a safety study (Table II-4), respectively.

    Table II-3
    Example of a Table of Contents for a FAP Submitted in Paper Format

    Title	Volume	Page No.
    Proposed Regulation	I	1-2
    Chemistry Information	I - VII	3-2560
    Identity	I	3-203
    Use and Technical Effect	I - III	204-1342
    Labeling	III	1343-1350
    Manufacturing Method	III	1351-1377
    Specifications	III	1378-1379
    Stability Studies	III - IV	1380 - 1753
    Studies Regarding Intended Effect	IV - V	1754 -2109
    Analytical Methods	V - VI	2110 -2531
    Chemistry References	VI	2532 -2560
    Safety Information	VI - XXXI	2561-11671
    Toxicology Narrative	VI	2561-2575
    Genetic Toxicity Studies	VI	2576-2848
    Short Term Toxicity Studies in Rodents	VII	2849-3120
    Short Term Toxicity Studies in Non-Rodents	VII - VIII	3121-3170
    Subchronic Toxicity Studies in Rodents	VIII - IX	3171- 3552
    Subchronic Toxicity Studies in Non-Rodents	IX	3553-3853
    One Year Toxicity Studies in Non-Rodents	X	3854 - 4104
    Combined Chronic Toxicity/Carcinogenicity Studies in Rodents	X - XIX	4105-9948
    Multi-Generation Reproduction Study	XIX - XXX	9949-10970
    Immunotoxicity Studies	XXX	10971-11021
    Neurotoxicity Studies	XXX	11022-11202
    Metabolism and Pharmacokinetic Studies	XXX - XXXI	11203-11673
    Safety References	XXXI	11674-11678
    Environmental Assessment	XXXI	11679-11792

    Table II-4
    Example of a Table of Contents for a One Year Toxicity Study
    in Non-Rodents Submitted in Paper Format

    Title	Volume	Page No.
    Authentication	X	1
    Quality Assurance	X	2-3
    Summary and Conclusions	X	4-10
    Study Organization	X	11-13
    Information on the Test and Control Article	X	14-18
    Experimental Procedure	X	19-29
    Evaluation of Data	X	30 - 40
    Archives	X	41-43
    Schedule of the Study	X	44-48
    Comments and Deviations from The Original Protocol and Amendments	X	49- 51
    Results	X	52-200
    Tables of Mean Values	X	201-225
    Appendices (individual results)	X	226 -245
    Addenda	X	246 -249
    Statement of Compliance	X	250

E. Information that is Exempt from Disclosure under the Freedom of Information Act (FOIA)

13. Should I designate in my regulatory submission information that I view as exempt from disclosure under the Freedom of Information Act?

    Yes. We recommend that you designate information that you consider exempt from disclosure in writing (21 CFR 20.61(d)).  However, if we disagree that the designated information satisfies the criteria for exemption from disclosure (see 21 CFR 20.27 and 21 CFR Part 20 Subparts D and E), the procedures in 21 CFR 20.61(e) will apply.

14. How should I designate information that I consider exempt from disclosure?

    You should designate this information in a manner that will unambiguously communicate your view. 

    We recommend that you:

    • Describe the information that you consider exempt from disclosure in a separate document (for the purposes of this guidance we are calling this document “Designation of Nondisclosable Information”). For example, the Designation of Nondisclosable Information included with a FAP could identify a particular quantitative formula you view as exempt from disclosure within the meaning of 21 CFR 171.1(h)(2)(iii).  This would ensure that we know your view on this quantitative formula each and every time it appears.  Such a separate document could, for example, both identify a quantitative formula you view as confidential and provide a list of places in the submission where the formula occurs.
    • Identify information as exempt from disclosure at the place where it occurs in a submission (e.g., by highlighting).  You may mark an entire page or set of pages as confidential (e.g., by a stamp at the top of each page) when you consider entire pages or multi-page documents as trade secret or confidential information (e.g., when describing a manufacturing process in a food additive petition).  You should not mark an entire page or set of pages as confidential when the page or pages contain both confidential and non-confidential information.  If you are unable to mark information on the electronic submission form as confidential (e.g., by highlighting), you should describe the information entered on the form you consider nondisclosable in a Designation of Nondisclosable Information document, as described above. 
15. May I provide a redacted copy of some or all of my regulatory submission?

    Yes.  You may provide a redacted copy of your complete submission, or a redacted copy of only those parts of your submission containing information you view exempt from disclosure.  If you provide a redacted copy of some or all of your regulatory submission, we nonetheless recommend that you also designate information exempt from disclosure as described above. This will help to ensure that we are aware of your view if, for example, you inadvertently did not redact all nondisclosable information.

16. Will FDA use my redacted copy when FDA responds to a request, under the FOIA, for a disclosable copy of my submission?

    FDA may or may not use your redacted copy depending on whether the redacted copy satisfies the criteria for exemption under FOIA (see 21 CFR Part 20 at 20.27 and Subparts D and E) and on whether using your redacted copy will be the most efficient means for us to respond to FOIA requests (e.g., because of formatting issues).

17. Are the data and information in a master file submission available for public disclosure?

    Whether the data and information in a master file submission are available for public disclosure is a case-by-case determination that we make in accordance with our regulations in 21 CFR part 20 and (when applicable) in submission-specific regulations such as 21 CFR 171.1(h).  Whether specific data and information are exempt from disclosure depends on circumstances and, thus, may change as circumstances change. 

F. Cover Letter

18. Should I include a cover letter with my regulatory submission?

    We do not ask you to include a cover letter if you use the applicable form for the regulatory submission. If you choose not to use the applicable form, you should include a cover letter regardless of whether you transmit the submission in electronic format or in paper format and regardless of whether your submission is a new submission or an amendment, update, or supplement to an existing submission.

19. What should a cover letter include?

    A cover letter should include the administrative information that would have been included with the applicable form.  For FCN submissions, this information can be found in Part I of Forms 3480 and 3480-A.  For all other regulatory submissions, this information can be found in Parts I, II, and III of the applicable form.

    Examples of this administrative information include:

    • The type of regulatory submission (e.g., FAP, New Protein Consultation);
    • Whether the submission is a new submission or an amendment, update or supplement to a previous submission;
    • The applicable regulation or guidance associated with the submission (e.g., a FAP is submitted in accordance with 21 CFR 171.1 and a New Protein Consultation is submitted in accordance with our Guidance to Industry entitled "Recommendations for the Early Food Safety Evaluation of New Non-Pesticidal Proteins Produced by New Plant Varieties Intended for Food Use" (22));
    • The format and mode of transmission (e.g., electronic format transmitted on physical media) and the number of any enclosed physical media (e.g., three CD-ROMs); and
    • A statement that any electronic files have been checked and found to be virus-free. 

    In addition, when your submission is a CAP or a FAP, the cover letter should include the elements specified in the opening of 21 CFR 71.1(c) (for a CAP) or 21 CFR 171.1(c) (for a FAP). 

G. References

20. How should I provide the Web site address when I refer to information available on the Internet?

    You should provide the Web site address for information available on the Internet by including it in a list of references or web-based documents.  For additional information on providing Web site addresses in electronic submissions, see Section III.E in this document.