[Federal Register Volume 83, Number 237 (Tuesday, December 11, 2018)]
[Notices]
[Pages 63651-63656]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-26724]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-D-0779]


Current Good Manufacturing Practice--Guidance for Human Drug 
Compounding Outsourcing Facilities Under Section 503B of the FD&C Act; 
Draft Guidance for Industry; Availability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 the Agency) is 
announcing the availability of a revised draft guidance entitled 
``Current Good Manufacturing Practice--Guidance for Human Drug 
Compounding Outsourcing Facilities Under Section 503B of the FD&C 
Act.'' This revised draft guidance describes FDA's policies regarding 
compounders registered under section 503B of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) as outsourcing facilities and the current 
good manufacturing practice (CGMP) requirements in FDA regulations. 
Based on feedback from stakeholders and comments received on the 
initial draft guidance, the guidance is being revised, in part, to 
reflect further consideration of how CGMP requirements should be 
applied in light of the size and scope of an outsourcing facility's 
operations.

DATES: Submit either electronic or written comments on the revised 
draft guidance by February 11, 2019 to ensure that the Agency considers 
your comment on this draft guidance before it begins work on the final 
version of the guidance. Submit either electronic or written comments 
concerning the collection of information under the Paperwork Reduction 
Act of 1995 (PRA) proposed in the revised draft guidance by February 
11, 2019.

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-2014-D-0779 for ``Current Good Manufacturing Practice--Guidance for 
Human Drug Compounding Outsourcing Facilities Under Section 503B of the 
FD&C Act.'' 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

[[Page 63652]]

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 ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
    Submit comments on information collection issues under the PRA to 
the Office of Management and Budget (OMB) in the following ways:
     Fax to the Office of Information and Regulatory Affairs, 
OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or email to 
[email protected]. All comments should be identified with the 
title ``Current Good Manufacturing Practice--Guidance for Human Drug 
Compounding Outsourcing Facilities Under Section 503B of the FD&C 
Act.''
    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. 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: Marci Kiester, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 2258, Silver Spring, MD 20993-0002, 301-
796-0600.

SUPPLEMENTARY INFORMATION: 

I. Background

    FDA is announcing the availability of a revised draft guidance for 
industry entitled ``Current Good Manufacturing Practice--Guidance for 
Human Drug Compounding Outsourcing Facilities Under Section 503B of the 
FD&C Act.'' Under section 503B(b) of the FD&C Act (21 U.S.C. 353b(b)), 
a compounder can register as an outsourcing facility with FDA. Drug 
products compounded in an outsourcing facility can qualify for 
exemptions from FDA approval requirements in section 505 of the FD&C 
Act (21 U.S.C. 355), the requirement to label products with adequate 
directions for use under section 502(f)(1) of the FD&C Act (21 U.S.C. 
352(f)(1)), and the drug supply chain security requirements in section 
582 of the FD&C Act (21 U.S.C. 360eee-1), if the requirements in 
section 503B are met. Outsourcing facilities are inspected by FDA 
according to a risk-based schedule and must comply with other 
provisions of the FD&C Act, including CGMP requirements under section 
501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)). FDA intends to issue CGMP 
regulations specific to outsourcing facilities. Until final regulations 
are issued, this draft guidance describes FDA's policies regarding 
outsourcing facilities and the CGMP requirements in 21 CFR parts 210 
and 211.
    This draft guidance revises the draft guidance for industry 
entitled ``Current Good Manufacturing Practice--Interim Guidance for 
Human Drug Compounding Outsourcing Facilities Under Section 503B of the 
FD&C Act,'' which published in July 2014 (79 FR 37743). This revised 
draft guidance applies to drugs compounded in accordance with section 
503B. In addition, this guidance generally applies to drugs that 
outsourcing facilities repackage and biological products that 
outsourcing facilities mix, dilute, or repackage in accordance with 
relevant guidance for outsourcing facilities. This revised draft 
guidance reflects FDA's intent to recognize the differences between 
outsourcing facilities and conventional drug manufacturers and to 
tailor CGMP requirements to the nature of the specific compounding 
operations conducted by outsourcing facilities while maintaining the 
minimum standards necessary to protect patients from the risks of 
contaminated or otherwise substandard drug products.
    The comment period on the initial draft guidance ended on September 
2, 2014. FDA received 26 comments on the draft guidance. In response to 
received comments or on its own initiative, FDA made changes and 
updates in the revised draft guidance as follows.
    FDA received a number of comments regarding the requirements in FDA 
regulations applicable to nonsterile drug products because the draft 
guidance focused primarily on sterile compounding. To address these 
comments, the revised draft guidance differentiates between 
requirements applicable to sterile drug products and nonsterile drug 
products where appropriate. The revised draft guidance also 
distinguishes the risks presented by using sterile and nonsterile 
components in producing sterile drug products and offers 
recommendations and policies on quality control commensurate with the 
risk. Further, the revised draft guidance addresses concerns raised 
regarding FDA's policies in several other areas. FDA made significant 
revisions to address comments on (1) stability testing, including the 
assignment of a beyond use date (BUD) as an expiration date; (2) 
release testing; (3) the potential use of a drug master file to address 
contract laboratory testing arrangements and testing of component 
quality before use in compounding; (4) the use of accredited third-
party laboratories to perform testing; (5) a clear definition of ``in-
use time,'' distinguishing it from ``BUD'' and ``expiration date''; and 
(6) reserve samples.
    We note that the default BUDs and storage conditions associated 
with nonsterile drug products described in this revised draft guidance 
differ from those described for nonsterile repackaged drug products in 
FDA's guidance for industry entitled ``Repackaging of Certain Human 
Drug Products by Pharmacies and Outsourcing Facilities'' (Repackaging 
guidance). FDA believes that the BUDs described in this revised draft 
CGMP guidance are also relevant to nonsterile drug products repackaged 
by outsourcing facilities. When this guidance is finalized, we intend 
to make conforming revisions to the BUDs for repackaged nonsterile drug 
products in the Repackaging guidance, as appropriate.
    Finally, this revised draft contains revisions to the conditions 
under which the Agency generally would not intend to take regulatory 
action regarding the requirement to test the finished product before 
release (see Sec.  211.165 (21 CFR 211.165)). These revisions make a 
broader range of production volumes eligible for the relevant 
enforcement policy, which we believe would encourage additional 
compounders to register as outsourcing facilities. Compared to 
compounders that are not registered under section 503B of the

[[Page 63653]]

FD&C Act, outsourcing facilities are subject to increased Federal 
oversight through FDA inspection on a risk-based schedule, as well as 
to additional standards that help to assure the quality of their 
compounded drug products. Outsourcing facilities produce drug products 
for hospitals, clinics, or healthcare practitioners to keep on hand as 
``office stock'' for patients who present with an immediate need for 
them. The revised draft guidance addresses standards critical to 
reducing the risk of patient harm while balancing appropriate 
flexibility. FDA is seeking public comment on whether the conditions 
outlined in the revised draft appropriately balance the risks and needs 
associated with drugs produced for office stock, including comments on 
the production volumes specified in the guidance.
    This revised 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 ``Current 
Good Manufacturing Practice--Guidance for Human Drug Compounding 
Outsourcing Facilities Under Section 503B of the FD&C Act.'' 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

    Under the PRA (44 U.S.C. 3501-3520), Federal Agencies must obtain 
approval from OMB for each collection of information that they conduct 
or sponsor. ``Collection of Information'' is defined in 44 U.S.C. 
3502(3) and 5 CFR 1320.3(c) and includes Agency requests or 
requirements that members of the public submit reports, keep records, 
or provide information to a third party. Section 3506(c)(2)(A) of the 
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal Agencies to provide a 
60-day notice in the Federal Register for each proposed collection of 
information before submitting the collection to OMB for approval. To 
comply with this requirement, FDA is publishing notice of the proposed 
collection of information set forth in this document.
    With respect to the collection of information associated with this 
document, FDA invites comments on these topics: (1) Whether the 
proposed information collected is necessary for the proper performance 
of FDA's functions, including whether the information will have 
practical utility; (2) the accuracy of FDA's estimate of the burden of 
the proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information collected; and (4) ways to 
minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

1. Quality Assurance Activities

    A quality control unit must be established by outsourcing 
facilities to oversee various aspects of drug production and to monitor 
quality assurance (see, e.g., Sec.  211.22 (21 CFR 211.22)). The 
responsibilities of the quality control unit must be established in 
procedures (Sec.  211.22(d)) and should include investigations and 
development and oversight of appropriate corrective and preventive 
actions regarding results of tests and examinations, unexpected results 
or trends, failures that occur during validation or revalidation of 
sterilization or depyrogenation processes, stability failures, 
environmental and personnel monitoring results that exceed alert or 
action limits, process deviations or equipment malfunctions that 
involve critical equipment, and complaints that indicate possible drug 
product contamination or other risks to patients. The quality control 
unit must periodically (at least annually) review records of 
compounding operations to evaluate the quality standards for each drug 
product to determine the need for changes in specifications or control 
procedures (21 CFR 211.180(e)).
    FDA estimates that annually approximately 74 outsourcing facilities 
\1\ (``No. of Recordkeepers'' in table 1, row 1) will individually 
establish approximately 13 procedures on the responsibilities of the 
quality control unit (``No. of Records per Recordkeeper'' in table 1, 
row 1) as described in section III.A of the guidance. FDA also 
estimates that preparing and maintaining these procedures will take 
approximately 3 hours for each record (``Average Burden per 
Recordkeeping'' in table 1, row 1).
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    \1\ This figure is based on the number of outsourcing facilities 
that were registered on July 27, 2018.
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2. Facility Design

    The revised draft guidance describes those elements of facility 
design of outsourcing facilities that are considered critical to 
assuring the quality of sterile drug products at those facilities. For 
example, the draft guidance states that sterile drugs should be 
produced only in ISO 5 (International Organization for Standardization) 
or better air quality and that the ISO 5 zone or critical area must be 
qualified (i.e., shown to meet the specifications) (see Sec. Sec.  
211.42 and 211.113(b) (21 CFR 211.42 and 211.113(b))). The revised 
draft guidance lists certain studies and tests that should be 
successfully performed for outsourcing facilities and states that the 
results of these studies and tests should be documented.
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 2) will individually document 
approximately 20 studies and tests (``No. of Records per Recordkeeper'' 
in table 1, row 2) that are critical to assuring the quality of sterile 
drug products. FDA also estimates that preparing and maintaining each 
record as described in the guidance will take on average approximately 
1.5 hours for each record (``Average Burden per Recordkeeping'' in 
table 1, row 2).

3. Control Systems and Procedures for Maintaining Suitable Facilities

    The revised draft guidance describes procedures that should be 
established and followed that assign responsibility for sanitation and 
describe the cleaning schedules, methods, equipment, and materials to 
be used in cleaning buildings and facilities. For multiuse facilities 
and nondedicated equipment, changeover and cleaning procedures for 
equipment and utensils must be established and followed to prevent 
contamination (see Sec. Sec.  211.42 and 211.67). Procedures for 
cleaning and disinfecting must also be established (see Sec. Sec.  
211.42, 211.56, and 211.67). If powder drugs are handled, procedures 
must be established and followed to appropriately manage cross-
contamination risk (Sec.  211.100 (21 CFR 211.100)). Processes and 
procedures should minimize contamination risks posed by the number and 
complexity of manipulations, number of simultaneous operations and 
workstations, and staging of materials used in the process. Temperature 
and humidity must be maintained in cleanrooms; such controls are 
critical to reduce microbial growth (see 21 CFR 211.46). In addition, 
the guidance describes that procedures should ensure recording of 
instances when there is a loss of positive pressure in the cleanroom 
during production.
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 3) will individually 
establish and maintain approximately 6 records (procedures and 
documentation) for

[[Page 63654]]

maintaining suitable outsourcing facilities (``No. of Records per 
Recordkeeper'' in table 1, row 3). FDA also estimates that preparing 
and maintaining each record as described in the guidance will take on 
average approximately 5 hours for each record (``Average Burden per 
Recordkeeping'' in table 1, row 3).

4. Environmental and Personnel Monitoring

    The revised draft guidance states that operations and appropriate 
written procedures designed to prevent microbial contamination include 
a well-defined and documented program for environmental monitoring that 
evaluates the potential routes of microbial contamination of the human 
drug that could arise from the air, surfaces, process, operation, and 
personnel practices (see Sec. Sec.  211.42(c)(10)(iv), 211.100, and 
211.113(b)). Personnel monitoring should include a routine program for 
daily/shift monitoring of operators' gloves and an appropriate schedule 
for monitoring other critical sites of the gown (e.g., gown sleeves for 
hood work) during or immediately after completion of aseptic 
operations; establish and justify limits that are based on the 
criticality of the operation relative to the contamination risk to the 
product; and call for an investigation of results that exceed the 
established levels or demonstrate an adverse trend, a determination of 
the impact on the sterility assurance of finished products intended to 
be sterile, and the development and execution of appropriate corrective 
actions. This monitoring should take place before planned disinfection 
so that actual operating conditions are being assessed. In addition, an 
outsourcing facility or its contract laboratory should establish 
procedures for establishing the validity of media if microbiological 
media used in performing tests, including environmental and personnel 
monitoring, are not purchased from a qualified supplier.
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 4) will individually 
establish approximately 1,200 environmental and personnel monitoring 
procedures and records to document test results (``No. of Records per 
Recordkeeper'' in table 1, row 4) for aseptic processing areas. FDA 
also estimates that preparing and maintaining the environmental and 
personnel monitoring procedures as described in the guidance will take 
on average approximately 0.25 hours for each record (``Average Burden 
per Recordkeeping'' in table 1, row 4).

5. Containers and Closures

    Scientifically sound and appropriate criteria for containers and 
closures must be established to ensure that containers and closures 
used for drug products are suitable for each drug product for which 
they will be used (see Sec.  211.160(b) (21 CFR 211.160(b))). 
Appropriate procedures must be established for testing the containers 
and closures to determine whether they meet the criteria for use, and 
the tests and results must be documented (see 21 CFR 211.84(d)(3) and 
211.184). Procedures for storage, if appropriate, of sterilized 
containers or closures must be established in a manner to prevent 
contamination and to maintain sterility (see 21 CFR 211.80(a) and (b)).
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 5) will individually 
establish and maintain approximately 300 procedures and pieces of 
documentation for testing containers and closures (``No. of Records per 
Recordkeeper'' in table 1, row 5) in the aseptic processing areas. FDA 
also estimates that preparing and maintaining these procedures and 
documentation as described in the guidance will take on average 
approximately 0.25 hours for each record (``Average Burden per 
Recordkeeping'' in table 1, row 5).

6. Equipment

    Procedures should be established and records maintained for routine 
calibration and maintenance of equipment (mechanical, electronic, or 
automated).
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 6) will individually 
establish and maintain approximately 150 procedures and pieces of 
documentation for the calibration and maintenance of equipment (``No. 
of Records per Recordkeeper'' in table 1, row 6). FDA also estimates 
that preparing and maintaining these records will take on average 
approximately 0.25 hours for each record (``Average Burden per 
Recordkeeping'' in table 1, row 6).

7. Components

    Procedures should be established and records maintained concerning 
the source and quality of components such as raw materials or 
ingredients used in producing nonsterile and sterile drug products at 
outsourcing facilities. The revised draft guidance also states that FDA 
generally does not intend to take regulatory action against an 
outsourcing facility regarding testing components if an adequate 
supplier quality agreement is in place and maintained appropriately.
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 7) will individually 
establish and maintain approximately 150 records of testing to ensure 
the quality of components used in producing drug products, as 
recommended in the guidance (``No. of Records per Recordkeeper'' in 
table 1, row 7). FDA also estimates that preparing and maintaining 
these records will take on average approximately 4 hours for each 
record (``Average Burden per Recordkeeping'' in table 1, row 7).

8. Production and Process Controls

    Production and process documentation and procedures, such as batch 
records, must be established to assure the quality of drug products at 
outsourcing facilities (see Sec.  211.100). Training on aseptic 
technique, cleanroom behavior, gowning, and procedures covering aseptic 
manufacturing area operations must be established (see 21 CFR 
211.25(a)). The validation of sterilization operations (e.g., holding 
vessels, filling equipment, lyophilizers) and periodic verification 
activities and results must be documented (see Sec.  211.113(b)).
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 8) will individually 
establish and maintain approximately 1,325 records pertaining to 
production and process controls, such as validation procedures and 
training, to ensure the quality of sterile drug products (``No. of 
Records per Recordkeeper'' in table 1, row 8). FDA also estimates that 
preparing and maintaining these records, as described in the guidance, 
will take on average approximately 0.25 hours for each record 
(``Average Burden per Recordkeeping'' in table 1, row 8).

9. Release Testing

    Drug products produced at outsourcing facilities must be tested to 
determine whether they meet final product specifications before release 
for distribution, and procedures for final release testing must be 
established and followed (Sec. Sec.  211.165 and 211.167).
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 9) will individually 
establish and maintain approximately 1,725 records pertaining to final 
release testing of drug products, including release testing

[[Page 63655]]

procedures and documentation (``No. of Records per Recordkeeper'' in 
table 1, row 9). FDA also estimates that preparing and maintaining 
these records, as described in the guidance, will take on average 
approximately 1.5 hours for each record (``Average Burden per 
Recordkeeping'' in table 1, row 9).
    If sterility testing is not completed before release under certain 
conditions described in Appendix A of the guidance, procedures should 
be established that specify that if the product fails to meet a 
criterion for sterility, all healthcare and other facilities that 
received the product should be immediately notified of the test results 
and provided with any appropriate information and recommendations to 
aid in the treatment of patients; the notification should be 
documented; and FDA should be notified in writing.
    FDA estimates that annually approximately 10 outsourcing facilities 
(``No. of Respondents'' in table 2, row 1) will individually send 
approximately 1 notification of test results to all healthcare and 
other facilities that received the drug product and provide them with 
any appropriate information and recommendations to aid in the treatment 
of patients (No. of Disclosures per Respondent'' in table 2, row 1). 
FDA also estimates that preparing and sending each notification will 
take approximately 5 hours (``Average Burden per Disclosure'' in table 
2, row 1).
    FDA also estimates that annually approximately 10 outsourcing 
facilities (``No. of Respondents'' in table 3) will individually submit 
to FDA 1 notification of the test results for any drug product that 
fails to meet a sterility criterion (``No. of Responses per 
Respondent'' in table 3). Preparing and submitting this information 
will take approximately 5 hours per notification (``Average Burden per 
Response'' in table 3).

10. Laboratory Controls

    Each laboratory used to conduct testing of components, in-process 
materials, and finished drug products for outsourcing facilities must 
follow written procedures for the conduct of each test and must 
document the results; establish sampling and testing procedures to 
ensure that components, in-process materials, and drug products conform 
to the product specifications; keep complete records of all tests 
performed to ensure compliance with established specifications and 
standards, including examinations and assays; and, if using a validated 
or an established compendial test, verify and document that the test 
procedure works under the conditions of actual use (see Sec. Sec.  
211.160 and 211.194).
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 10) will individually 
establish and maintain approximately 200 laboratory records as 
described in the guidance (``No. of Records per Recordkeeper'' in table 
1, row 10). FDA also estimates that preparing and maintaining these 
records will take on average approximately 0.5 hours for each record 
(``Average Burden per Recordkeeping'' in table 1, row 10).

11. Stability/Expiration Dating

    Stability testing is used to ensure that a drug product will retain 
its quality (e.g., strength) and remain sterile, if applicable, through 
the labeled expiration date. The draft guidance states that procedures 
established by outsourcing facilities for assessing the stability of 
drug products must include the following: Using stability-indicating 
test methods that are reliable, meaningful, and specific; evaluating 
samples of the drug product in the same container-closure system in 
which the drug product will be marketed; evaluating samples for 
stability that are representative of the lot or batch from which they 
were obtained and are stored under suitable conditions; and testing to 
evaluate antimicrobial effectiveness for drug products labeled or 
intended to be multiple dose (see Sec. Sec.  211.122, 211.160, and 
211.166). The guidance states that regardless of whether an expiration 
date or BUD to be used as an expiration date is used, container-closure 
integrity testing and antimicrobial effectiveness testing (for products 
labeled as multiple dose) are required to be completed before a batch 
is released (see Sec. Sec.  211.166 and 211.167). Each of these studies 
only needs to be conducted once for each formulation and container-
closure system, and a bracketing or matrixing approach can be 
considered to minimize the amount of testing needed. Outsourcing 
facilities are also responsible for including appropriate labeled 
directions for use for drug products, which may include in-use time if 
the product requires additional manipulation before administration. 
Appropriate studies, including stability studies, would need to support 
the stated in-use time.
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 11) will individually 
establish and maintain approximately 75 procedures for stability 
studies to determine an expiration date (``No. of Records per 
Recordkeeper'' in table 1, row 11) for drug products. FDA also 
estimates that preparing and maintaining these procedures as described 
in the guidance will take approximately 5 hours for each record 
(``Average Burden per Recordkeeping'' in table 1, row 11).
    FDA also estimates that annually approximately 74 outsourcing 
facilities (``No. of Respondents'' in table 2, row 2) will add 
approximately 540 expiration dates to the labeling of drug products 
(``No. of Disclosures per Respondent'' in table 2, row 2). FDA also 
estimates that preparing the labeling will take approximately 0.25 
hours (``Average Burden per Disclosure'' in table 2, row 2).

12. Packaging and Labels

    Packaging of drugs must ensure the sterility, if applicable, and 
integrity of the product until it is administered to a patient, product 
labels must contain required information, and labeling operations must 
include controls to prevent mixups (see Sec. Sec.  211.94, 211.122, 
211.125, 211.130, and 211.134). The following must be implemented by 
outsourcing facilities for packaging and labeling operations to ensure 
the quality of drug products: The container, closure, and packaging 
systems adequately protect against foreseeable external factors in 
storage, shipment, and use that can cause contamination or 
deterioration; packaging records include specimens or copies of all 
labels used; adequate controls are established for issuing labels, 
examining issued labels, and reconciling used labels to prevent mixups; 
different labeling and packaging operations are adequately separated to 
prevent mixups; and controls are established that ensure proper 
identification of any filled containers of products that are stored 
unlabeled for any period of time (see Sec. Sec.  211.94, 211.122, 
211.125, 211.130, 211.134, and 211.188).
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 12) will individually 
establish and maintain approximately 20 procedures for packaging and 
labeling operations (``Records per Recordkeeper'' in table 1, row 12) 
for drug products. FDA also estimates that preparing and maintaining 
these procedures as described in the guidance will take approximately 
5.5 hours for each record (``Average Burden per Recordkeeping'' in 
table 1, row 12).

13. Reserve Samples

    An appropriately identified reserve sample that is representative 
of each lot or batch of drug product must be retained and stored under 
conditions

[[Page 63656]]

consistent with product labeling (21 CFR 211.170).
    FDA estimates that annually approximately 74 outsourcing facilities 
(``No. of Recordkeepers'' in table 1, row 13) will individually 
establish and maintain approximately 12 procedures and records for 
reserve samples (``Records per Recordkeeper'' in table 1, row 13) for 
drug products. FDA also estimates that preparing and maintaining these 
procedures and records as described in the guidance will take 
approximately 0.5 hours for each record (``Average Burden per 
Recordkeeping'' in table 1, row 13).
    FDA estimates the burden of this collection of information as 
follows:

                                                   Table 1--Estimated Annual Recordkeeping Burden \1\
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                                                                 Number of
                  Activity                       Number of      records per    Total annual        Average burden per recordkeeping         Total hours
                                               recordkeepers   recordkeeper       records
--------------------------------------------------------------------------------------------------------------------------------------------------------
Quality assurance activities................              74              13             962  3.........................................           2,886
Facility design.............................              74              20           1,480  1.5.......................................           2,220
Control systems and procedures for                        74               6             444  5.........................................           2,220
 maintaining suitable facilities.
Environmental and personnel monitoring......              74           1,200          88,800  0.25 (15 minutes).........................          22,200
Containers and closures.....................              74             300          22,200  0.25 (15 minutes).........................           5,550
Equipment...................................              74             150          11,100  0.25 (15 minutes).........................           2,775
Components..................................              74             150          11,100  4.........................................          44,400
Production and process controls.............              74           1,325          98,050  0.25 (15 minutes).........................          24,513
Release testing.............................              74           1,725         127,650  1.5.......................................         191,475
Laboratory controls.........................              74             200          14,800  0.5 (30 minutes)..........................           7,400
Stability/Expiration dating.................              74              75           5,550  5.........................................          27,750
Packaging and labels........................              74              20           1,480  5.5.......................................           8,140
Reserve samples.............................              74              12             888  0.5 (30 minutes)..........................             444
                                             -----------------------------------------------------------------------------------------------------------
    Total...................................  ..............  ..............  ..............  ..........................................         341,973
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                                               Table 2--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Number of
             Type of disclosure                  Number of      disclosures    Total annual          Average burden per disclosure          Total hours
                                                respondents   per respondent    disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notification that a drug product fails to                 10               1              10  5.........................................              50
 meet a sterility criterion.
An expiration date is added to the drug                   74             540          39,960  0.25 (15 minutes).........................           9,990
 product's label.
                                             -----------------------------------------------------------------------------------------------------------
    Total...................................  ..............  ..............  ..............  ..........................................          10,040
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                                                     Table 3--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                         Type of reporting                              Number of      responses per     Total annual    Average burden    Total hours
                                                                       respondents       respondent       responses       per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notification to FDA that a drug product fails to meet a sterility                10                1               10                5               50
 criterion.........................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

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 or 
https://www.regulations.gov.

    Dated: December 4, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-26724 Filed 12-10-18; 8:45 am]
 BILLING CODE 4164-01-P