83 FR 45944 - Postapproval Changes to Drug Substances; Draft Guidance for Industry; Availability
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration Federal Register Volume 83, Issue 176 (September 11, 2018)
Food and Drug Administration
Federal Register Volume 83, Issue 176 (September 11, 2018)
| Page Range | 45944-45945 | |
| FR Document | 2018-19666 |
[Federal Register Volume 83, Number 176 (Tuesday, September 11, 2018)] [Notices] [Pages 45944-45945] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2018-19666] ----------------------------------------------------------------------- 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AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2018-D-3151] Postapproval Changes to Drug Substances; Draft Guidance for Industry; Availability AGENCY: Food and Drug Administration, HHS.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. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled ``Postapproval Changes to Drug Substances.'' This draft guidance provides recommendations to holders of approved new drug applications, abbreviated new drug applications, new animal drug applications, abbreviated new animal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 The draft guidance applies to synthetic drug substances and the synthetic steps involved in the preparation of semisynthetic drug substances. The draft guidance covers facility, scale, and equipment changes associated with all steps of drug substance manufacturing; specification changes to starting materials, raw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 DATES: Submit either electronic or written comments on the draft guidance by November 13, 2018 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.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: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. 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: 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. 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. 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.thefederalregister.org/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
![45944 Federal Register / Vol. 83, No. 176 / Tuesday, September 11, 2018 / Notices
TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1—Continued
Number of Total Average
GFI: Formal meetings between FDA and biosimilar Number of responses per annual burden per Total hours
biological product sponsors or applicants respondents respondent responses response
CBER Information Packages ............................................... 2 2 4 30 120
Total .............................................................................. ........................ ........................ ........................ ........................ 3,405
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
Since last OMB approval, there has synthetic manufacturing process information submitted, marked and
been an increase in meeting requests changes; changes in the source of drug identified, as confidential, if submitted
with CDER and a corresponding substance; and change to container as detailed in ‘‘Instructions.’’
increase in the number of information closure system of the drug substance. Instructions: All submissions received
packages. Accordingly, we have DATES: Submit either electronic or must include the Docket No. FDA–
adjusted our estimate upward by six written comments on the draft guidance 2018–D–3151 for ‘‘Postapproval
respondents to CDER meeting requests. by November 13, 2018 to ensure that the Changes to Drug Substances.’’ Received
We attribute this change to an increase Agency considers your comment on this comments will be placed in the docket
in biosimilar product development. draft guidance before it begins work on and, except for those submitted as
Dated: September 4, 2018. the final version of the guidance. ‘‘Confidential Submissions,’’ publicly
Leslie Kux, ADDRESSES: You may submit comments viewable at https://www.regulations.gov
on any guidance at any time as follows: or at the Dockets Management Staff
Associate Commissioner for Policy.
between 9 a.m. and 4 p.m., Monday
[FR Doc. 2018–19674 Filed 9–10–18; 8:45 am] Electronic Submissions through Friday.
BILLING CODE 4164–01–P
Submit electronic comments in the • Confidential Submissions—To
following way: submit a comment with confidential
DEPARTMENT OF HEALTH AND • Federal eRulemaking Portal: information that you do not wish to be
https://www.regulations.gov. Follow the made publicly available, submit your
HUMAN SERVICES comments only as a written/paper
instructions for submitting comments.
Food and Drug Administration Comments submitted electronically, submission. You should submit two
including attachments, to https:// copies total. One copy will include the
[Docket No. FDA–2018–D–3151] www.regulations.gov will be posted to information you claim to be confidential
the docket unchanged. Because your with a heading or cover note that states
Postapproval Changes to Drug ‘‘THIS DOCUMENT CONTAINS
Substances; Draft Guidance for comment will be made public, you are
solely responsible for ensuring that your CONFIDENTIAL INFORMATION.’’ The
Industry; Availability Agency will review this copy, including
comment does not include any
AGENCY: Food and Drug Administration, confidential information that you or a the claimed confidential information, in
HHS. third party may not wish to be posted, its consideration of comments. The
ACTION: Notice of availability. such as medical information, your or second copy, which will have the
anyone else’s Social Security number, or claimed confidential information
SUMMARY: The Food and Drug confidential business information, such redacted/blacked out, will be available
Administration (FDA or Agency) is as a manufacturing process. Please note for public viewing and posted on
announcing the availability of a draft that if you include your name, contact https://www.regulations.gov. Submit
guidance for industry entitled information, or other information that both copies to the Dockets Management
‘‘Postapproval Changes to Drug identifies you in the body of your Staff. If you do not wish your name and
Substances.’’ This draft guidance comments, that information will be contact information to be made publicly
provides recommendations to holders of posted on https://www.regulations.gov. available, you can provide this
approved new drug applications, • If you want to submit a comment information on the cover sheet and not
abbreviated new drug applications, new with confidential information that you in the body of your comments and you
animal drug applications, abbreviated do not wish to be made available to the must identify this information as
new animal drug applications, and public, submit the comment as a ‘‘confidential.’’ Any information marked
holders of drug master files and written/paper submission and in the as ‘‘confidential’’ will not be disclosed
veterinary master files who may want to manner detailed (see ‘‘Written/Paper except in accordance with 21 CFR 10.20
make a change to the drug substance Submissions’’ and ‘‘Instructions’’). and other applicable disclosure law. For
manufacturing process during the drug more information about FDA’s posting
product application postapproval Written/Paper Submissions of comments to public dockets, see 80
period. The draft guidance applies to Submit written/paper submissions as FR 56469, September 18, 2015, or access
synthetic drug substances and the follows: the information at: https://www.gpo.gov/
synthetic steps involved in the • Mail/Hand delivery/Courier (for fdsys/pkg/FR-2015-09-18/pdf/2015-
preparation of semisynthetic drug written/paper submissions): Dockets 23389.pdf.
daltland on DSKBBV9HB2PROD with NOTICES
substances. The draft guidance covers Management Staff (HFA–305), Food and Docket: For access to the docket to
facility, scale, and equipment changes Drug Administration, 5630 Fishers read background documents or the
associated with all steps of drug Lane, Rm. 1061, Rockville, MD 20852. electronic and written/paper comments
substance manufacturing; specification • For written/paper comments received, go to https://
changes to starting materials, raw submitted to the Dockets Management www.regulations.gov and insert the
materials, intermediates, and the Staff, FDA will post your comment, as docket number, found in brackets in the
unfinished and final drug substance; well as any attachments, except for heading of this document, into the
VerDate Sep<11>2014 18:49 Sep 10, 2018 Jkt 244001 PO 00000 Frm 00070 Fmt 4703 Sfmt 4703 E:\FR\FM\11SEN1.SGM 11SEN1](https://thefederalregister.org/doc/83_FR_46120/page/1.svg)
![Federal Register / Vol. 83, No. 176 / Tuesday, September 11, 2018 / Notices 45945
‘‘Search’’ box and follow the prompts submitted by the approved application practices regulation (21 CFR 10.115).
and/or go to the Dockets Management holder is also outlined, and references The draft guidance, when finalized, will
Staff, 5630 Fishers Lane, Rm. 1061, to the appropriate pathways for such represent the current thinking of FDA
Rockville, MD 20852. submissions are provided. on Postapproval Changes to Drug
You may submit comments on any A letter of authorization must be Substances. It does not establish any
guidance at any time (see 21 CFR provided for an applicant to reference a rights for any person and is not binding
10.115(g)(5)). DMF for the proposed drug substance on FDA or the public. You can use an
Submit written requests for single § 314.420(b) (21 CFR 314.420(b)). Any alternative approach if it satisfies the
copies of the draft guidance to the addition, change, or deletion of
requirements of the applicable statutes
Division of Drug Information, Center for information in the master file must be
and regulations. This guidance is not
Drug Evaluation and Research, Food submitted to the master file in the form
of an amendment (see § 314.420(c)). subject to Executive Order 12866.
and Drug Administration, 10001 New
Hampshire Ave., Hillandale Building, Further, the master file holder must II. Paperwork Reduction Act of 1995
4th Floor, Silver Spring, MD 20993– notify each person authorized to
0002, or the Office of Communication, reference the DMF of the nature of the This draft guidance refers to
Outreach, and Development, Center for changes, and should provide as much previously approved collections of
Biologics Evaluation and Research, detail as is consistent with the information found in FDA regulations.
Food and Drug Administration, 10903 confidentiality agreement between the These collections of information are
New Hampshire Ave, Bldg. 71, Rm. master file holder and the authorized subject to review by the Office of
3128, Silver Spring, MD 20993–0002. person, so that the authorized person Management and Budget (OMB) under
Send one self-addressed adhesive label can determine how to report the the Paperwork Reduction Act of 1995
to assist that office in processing your changes in the approved application (44 U.S.C. 3501–3520). The collections
requests. See the SUPPLEMENTARY (see § 314.420(c)). In turn, application of information in § 314.70 have been
INFORMATION section for electronic holders must notify FDA of each change approved under OMB control number
access to the draft guidance document. in each condition established in an 0910–0001; the collections of
approved application, excluding the
FOR FURTHER INFORMATION CONTACT: information in 21 CFR part 211 have
variations already provided for in the
Carolyn Cohran, Center for Drug been approved under OMB control
application (§§ 314.70, 314.97, 514.8).
Evaluation and Research, Food and When drug substance information is number 0910–0139; and the collections
Drug Administration, 10903 New contained in an application, rather than of information in 21 CFR 514.8 have
Hampshire Ave., Bldg. 51, Rm 4151, in a referenced DMF, such changes must been approved under OMB control
Silver Spring, MD 20993–0002, 240– be submitted to FDA in the form of a number 0910–0032. In accordance with
402–8612; Stephen Ripley, Center for supplement to the approved application the PRA, prior to publication of any
Biologics Evaluation and Research, or in an annual report (§§ 314.70, final guidance document, FDA intends
Food and Drug Administration, 10903 314.97, 514.8). to solicit public comment and obtain
New Hampshire Ave., Bldg.71, Rm. This draft guidance addresses how the OMB approval for any information
7301, Silver Spring, MD 20993–0002, risk of one or more change(s) to the drug collections recommended in this draft
240–402–7911; or Dennis Bensley, substance should be assessed and guidance that are new or that would
Center for Veterinary Medicine, Food provides recommendations regarding represent material modifications to
and Drug Administration, 7500 Standish the documentation needed to support those previously approved collections of
Place, Rm. E334, Rockville, MD 20855, such changes for the drug substance,
240–402–0696. information found in FDA regulations or
and where applicable, for the drug guidances.
SUPPLEMENTARY INFORMATION: product made with modified drug
substance. The draft guidance covers the III. Electronic Access
I. Background
following changes: (1) facility, scale,
FDA is announcing the availability of and equipment changes associated with Persons with access to the internet
a draft guidance for industry entitled all steps of drug substance may obtain the draft guidance at either
‘‘Postapproval Changes to Drug manufacturing; (2) specification changes https://www.fda.gov/Drugs/Guidance
Substances.’’ As part of the to starting materials, raw materials, ComplianceRegulatoryInformation/
reauthorization of the Generic Drug User intermediates, and the unfinished and Guidances/default.htm, https://
Fee Amendments (GDUFA II), FDA final drug substance; (3) synthetic www.fda.gov/BiologicsBloodVaccines/
committed to issuing a guidance on manufacturing process changes; (4) GuidanceComplianceRegulatory
postapproval changes to Type II Active changes in the source of drug substance; Information/default.htm, or https://
Pharmaceutical Ingredients Drug Master and (5) change to container closure www.regulations.gov.
Files (DMFs) and submission system of the drug substance. Dated: September 4, 2018.
mechanisms for abbreviated new drug This draft guidance does not address
application holders who reference such postapproval changes to peptides, Leslie Kux,
DMFs (see GDUFA Reauthorization oligonucleotides, radiopharmaceuticals; Associate Commissioner for Policy.
Performance Goals and Program or drug substances isolated from natural [FR Doc. 2018–19666 Filed 9–10–18; 8:45 am]
Enhancements Fiscal Years 2018–2022, sources or produced by procedures BILLING CODE 4164–01–P
known as the GDUFA II Commitment involving biotechnology; or
Letter, at https://www.fda.gov/ nonsynthetic steps (such as
daltland on DSKBBV9HB2PROD with NOTICES
downloads/ForIndustry/UserFees/ fermentation) for semisynthetic drug
GenericDrugUserFees/UCM525234.pdf). substances. This draft guidance also
This draft guidance is intended to fulfill does not address complex active
that commitment by describing the ingredients as defined in the GDUFA II
documentation for master file holders or Commitment Letter.
drug substance manufacturers, as This draft guidance is being issued
appropriate. The documentation to be consistent with FDA’s good guidance
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Document Created: 2018-09-11 01:03:12
Document Modified: 2018-09-11 01:03:12
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Notices | |
| Action | Notice of availability. | |
| 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. | |
| 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. | |
| FR Citation | 83 FR 45944 |
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