45944 Federal Register / Vol. 83, No. 176 / Tuesday, September 11, 2018 / Notices 

TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1—Continued 

GFI: Formal meetings between FDA and biosimilar 

biological product sponsors or applicants 

Number of 

respondents 

Number of 

responses per 

respondent 

Total 

annual 

responses 

Average 

burden per 

response 

Total hours 

CBER Information Packages ............................................... 2 2 4 30 120 

Total .............................................................................. ........................ ........................ ........................ ........................ 3,405 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

Since last OMB approval, there has 

been an increase in meeting requests 

with CDER and a corresponding 

increase in the number of information 

packages. Accordingly, we have 

adjusted our estimate upward by six 

respondents to CDER meeting requests. 

We attribute this change to an increase 

in biosimilar product development. 

Dated: September 4, 2018. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2018–19674 Filed 9–10–18; 8:45 am] 

BILLING CODE 4164–01–P 

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Substances; Draft Guidance for 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 This draft guidance 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 The draft guidance applies to 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 The draft guidance covers 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.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 


daltland on DSKBBV9HB2PROD with NOTICES
Federal Register / Vol. 83, No. 176 / Tuesday, September 11, 2018 / Notices 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 

§ 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 § 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 § 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 (§§ 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 (§§ 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 § 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/Guidance

ComplianceRegulatoryInformation/ 

Guidances/default.htm, https://

www.fda.gov/BiologicsBloodVaccines/ 

GuidanceComplianceRegulatory

Information/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 


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