[Federal Register Volume 83, Number 176 (Tuesday, September 11, 2018)]
[Notices]
[Pages 45944-45945]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-19666]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-D-3151]


Postapproval Changes to Drug Substances; Draft Guidance for 
Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a draft guidance for industry entitled 
``Postapproval Changes to Drug Substances.'' This draft guidance 
provides recommendations to holders of approved new drug applications, 
abbreviated new drug applications, new animal drug applications, 
abbreviated new animal drug applications, and holders of drug master 
files and veterinary master files who may want to make a change to the 
drug substance manufacturing process during the drug product 
application postapproval period. The draft guidance applies to 
synthetic drug substances and the synthetic steps involved in the 
preparation of semisynthetic drug substances. The draft guidance covers 
facility, scale, and equipment changes associated with all steps of 
drug substance manufacturing; specification changes to starting 
materials, raw materials, intermediates, and the unfinished and final 
drug substance; synthetic manufacturing process changes; changes in the 
source of drug substance; and change to container closure system of the 
drug substance.

DATES: Submit either electronic or written comments on the draft 
guidance by November 13, 2018 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

Electronic Submissions

    Submit electronic comments in the following way:
    <bullet> Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
    <bullet> If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
    <bullet> Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    <bullet> For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2018-D-3151 for ``Postapproval Changes to Drug Substances.'' 
Received comments will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday.
    <bullet> Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the

[[Page 45945]]

``Search'' box and follow the prompts and/or go to the Dockets 
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the draft guidance to 
the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10001 New Hampshire Ave., 
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002, or the 
Office of Communication, Outreach, and Development, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave, Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. 
Send one self-addressed adhesive label to assist that office in 
processing your requests. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Carolyn Cohran, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm 4151, Silver Spring, MD 20993-0002, 240-
402-8612; Stephen Ripley, Center for Biologics Evaluation and Research, 
Food and Drug Administration, 10903 New Hampshire Ave., Bldg.71, Rm. 
7301, Silver Spring, MD 20993-0002, 240-402-7911; or Dennis Bensley, 
Center for Veterinary Medicine, Food and Drug Administration, 7500 
Standish Place, Rm. E334, Rockville, MD 20855, 240-402-0696.

SUPPLEMENTARY INFORMATION: 

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Postapproval Changes to Drug Substances.'' As part of the 
reauthorization of the Generic Drug User Fee Amendments (GDUFA II), FDA 
committed to issuing a guidance on postapproval changes to Type II 
Active Pharmaceutical Ingredients Drug Master Files (DMFs) and 
submission mechanisms for abbreviated new drug application holders who 
reference such DMFs (see GDUFA Reauthorization Performance Goals and 
Program Enhancements Fiscal Years 2018-2022, known as the GDUFA II 
Commitment Letter, at https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM525234.pdf). This draft guidance is 
intended to fulfill that commitment by describing the documentation for 
master file holders or drug substance manufacturers, as appropriate. 
The documentation to be submitted by the approved application holder is 
also outlined, and references to the appropriate pathways for such 
submissions are provided.
    A letter of authorization must be provided for an applicant to 
reference a DMF for the proposed drug substance Sec.  314.420(b) (21 
CFR 314.420(b)). Any addition, change, or deletion of information in 
the master file must be submitted to the master file in the form of an 
amendment (see Sec.  314.420(c)). Further, the master file holder must 
notify each person authorized to reference the DMF of the nature of the 
changes, and should provide as much detail as is consistent with the 
confidentiality agreement between the master file holder and the 
authorized person, so that the authorized person can determine how to 
report the changes in the approved application (see Sec.  314.420(c)). 
In turn, application holders must notify FDA of each change in each 
condition established in an approved application, excluding the 
variations already provided for in the application (Sec. Sec.  314.70, 
314.97, 514.8).
    When drug substance information is contained in an application, 
rather than in a referenced DMF, such changes must be submitted to FDA 
in the form of a supplement to the approved application or in an annual 
report (Sec. Sec.  314.70, 314.97, 514.8).
    This draft guidance addresses how the risk of one or more change(s) 
to the drug substance should be assessed and provides recommendations 
regarding the documentation needed to support such changes for the drug 
substance, and where applicable, for the drug product made with 
modified drug substance. The draft guidance covers the following 
changes: (1) facility, scale, and equipment changes associated with all 
steps of drug substance manufacturing; (2) specification changes to 
starting materials, raw materials, intermediates, and the unfinished 
and final drug substance; (3) synthetic manufacturing process changes; 
(4) changes in the source of drug substance; and (5) change to 
container closure system of the drug substance.
    This draft guidance does not address postapproval changes to 
peptides, oligonucleotides, radiopharmaceuticals; or drug substances 
isolated from natural sources or produced by procedures involving 
biotechnology; or nonsynthetic steps (such as fermentation) for 
semisynthetic drug substances. This draft guidance also does not 
address complex active ingredients as defined in the GDUFA II 
Commitment Letter.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on Postapproval 
Changes to Drug Substances. It does not establish any rights for any 
person and is not binding on FDA or the public. You can use an 
alternative approach if it satisfies the requirements of the applicable 
statutes and regulations. This guidance is not subject to Executive 
Order 12866.

II. Paperwork Reduction Act of 1995

    This draft guidance refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
collections of information in Sec.  314.70 have been approved under OMB 
control number 0910-0001; the collections of information in 21 CFR part 
211 have been approved under OMB control number 0910-0139; and the 
collections of information in 21 CFR 514.8 have been approved under OMB 
control number 0910-0032. In accordance with the PRA, prior to 
publication of any final guidance document, FDA intends to solicit 
public comment and obtain OMB approval for any information collections 
recommended in this draft guidance that are new or that would represent 
material modifications to those previously approved collections of 
information found in FDA regulations or guidances.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm, or https://www.regulations.gov.

    Dated: September 4, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-19666 Filed 9-10-18; 8:45 am]
 BILLING CODE 4164-01-P