[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Notices]
[Pages 37743-37747]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-15370]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2014-D-0779]
Draft Guidance for Industry on Current Good Manufacturing
Practice--Interim Guidance for Human Drug Compounding Outsourcing
Facilities Under the Federal Food, Drug and Cosmetic Act; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Current Good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.'' This draft
guidance describes FDA's current expectations regarding compliance with
current good manufacturing practice (CGMP) requirements for facilities
that compound human drugs and register with FDA as outsourcing
facilities under the Federal Food, Drug, and Cosmetic Act (the FD&C
Act), in accordance with provisions added by the Drug Quality and
Security Act (DQSA). FDA is also soliciting public input on specific
potential alternative approaches regarding certain CGMP requirements.
These potential approaches are explained in detail in the draft
guidance.
DATES: Although you can comment on any guidance at any time (see 21 CFR
10.115(g)(5)), 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draft guidance before it begins work on the final version of the
guidance, submit either electronic or written comments on the draft
guidance by September 2, 2014.
ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information, Center for Drug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, 10903 New
Hampshire Ave., Bldg. 51, Rm. 2201, 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access to the draft guidance document.
Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Brian Hasselbalch, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 4364, Silver Spring, MD 20993-0002, 301-
796-3279.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a 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.'' On November 27, 2013, President Obama signed the DQSA
(Public Law 113-54), which added section 503B to the FD&C Act (21
U.S.C. 353b). Under section 503B(b) of the FD&C Act, a compounder can
register as an outsourcing facility with FDA. Drug products compounded
in a registered outsourcing facility can qualify for exemptions from
the FDA approval requirements in section 505 of the FD&C Act (21 U.S.C.
355) and 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)) if
the requirements in section 503B are met. Outsourcing facilities will
be inspected by FDA 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)).
Under section 501(a)(2)(B) of the FD&C Act, a drug is deemed to be
adulterated if it is not produced in accordance with CGMP. FDA's
regulations regarding CGMP requirements for the preparation of drug
products have been established in 21 CFR parts 210 and 211. FDA intends
to issue more specific CGMP regulations for outsourcing facilities.
Until final regulations are issued, this draft guidance describes FDA's
expectations regarding outsourcing facilities and the CGMP requirements
in parts 210 and 211 during this interim period. This draft guidance
reflects FDA's intent to recognize the differences between compounding
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 compounded drug products. This
draft guidance is only applicable to drugs compounded in accordance
with section 503B of the FD&C Act.
FDA intends to focus its inspectional and enforcement efforts on
those aspects of compounding operations that pose the highest risk to
patient safety. In particular, the primary focus of this draft guidance
is on those aspects of part 211 that relate to sterility assurance of
sterile drug products and the safety of compounded drug products more
generally, with respect to strength (e.g., subpotency, superpotency),
and labeling or drug product mix-ups.
II. Specific Request for Comments and Information
In addition to comments on the draft guidance generally, FDA is
requesting comments and related supporting information on the following
specific issues: (1) alternative approaches that would enable an
outsourcing facility to have confidence in the quality of incoming
components from sources used by multiple outsourcing facilities without
each individual outsourcing facility having to conduct periodic
laboratory testing to confirm the information in the third-party
supplier's certificate of analysis and (2) alternative approaches that
would minimize the need for outsourcing facilities to establish an in-
house laboratory while providing confidence about the accuracy of
testing performed by a third party used by more than one outsourcing
facility. FDA has described these potential alternative approaches in
the draft guidance and is seeking public comment on these and any other
alternative approaches.
This draft guidance is being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). The draft guidance, when
finalized, will
[[Page 37744]]
represent the Agency's current thinking on ``Current Good Manufacturing
Practice-Interim Guidance for Human Drug Compounding Outsourcing
Facilities under Section 503B of the FD&C Act.'' It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes and regulations.
III. Comments
Interested persons may submit electronic comments regarding this
document to http://www.regulations.gov, or written comments to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.
IV. Paperwork Reduction Act of 1995
This draft guidance contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the
information collection are given under this section with an estimate of
the annual recordkeeping, third-party disclosure, and reporting
burdens. Included in the estimate is the time for reviewing
instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
We invite comments on these topics: (1) Whether the proposed
collection of information 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 to be 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.
Title: Guidance for Industry, Current Good Manufacturing Practice--
Interim Guidance for Human Drug Compounding Outsourcing Facilities
under Section 503B of the FD&C Act.
Description: The draft guidance describes FDA's expectations
regarding compliance with CGMP requirements for facilities that
register with FDA as outsourcing facilities under section 503B of the
FD&C Act. The primary focus of the draft guidance is on sterility
assurance of sterile products and the safety of compounded drug
products with respect to strength (e.g., subpotency, superpotency), and
labeling or drug product mix-ups. OMB has already approved the
information collection (recordkeeping) contained in FDA's CGMP
regulations in part 211 (OMB control number 0910-0139). FDA believes
that much of the recordkeeping burden that would result from the draft
guidance is already incurred by outsourcing facilities in the normal
course of their business activities. Thus, the burden estimates for
these ``usual and customary'' business practices are not included in
the calculation of burden that follows (see 5 CFR 1320.3(b)(2).
The draft guidance contains the following collections of
information under the PRA:
1. Facility Design
The draft guidance describes those elements of facility design of
outsourcing facilities that are considered critical to assuring the
quality of compounded sterile drug products at those facilities. For
example, the draft guidance states that sterile drugs should be
produced only in ISO 5 or better air quality, and that the ISO 5 zone
or critical area must be qualified (i.e., shown to meet the
specifications). In section III.A, the draft guidance lists certain
studies and tests which should be successfully performed for
outsourcing facilities, and states that the results of these studies
and tests should be documented.
We estimate that annually a total of approximately 50 outsourcing
facilities \1\ (``No. of Recordkeepers'' in table 1, row 1) will
individually document approximately 20 studies and tests (``Total
Annual Records'' in table 1, row 1) that are critical to assuring the
quality of compounded sterile drug products. We also estimate that
preparing and maintaining each record as described in the draft
guidance will take on average approximately 1.5 hours for each record
(``Average Burden per Recordkeeping'' in table 1, row 1).
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\1\ This is an estimate of the number of facilities that will
register as outsourcing facilities in fiscal year 2014 (which runs
from October 1, 2013 to September 30, 2014). As of April 30, 2014,
40 facilities had registered as outsourcing facilities, and on
average, 2 facilities have registered each month for the past 3
months, but these estimates are highly uncertain. Annual
establishment fees will be assessed for each outsourcing facility
registered on or after October 1, 2014. It is unknown how many
facilities will remain as registered outsourcing facilities once
these fees take effect.
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2. Control Systems and Procedures for Maintaining Suitable Facilities
The draft guidance describes certain controls, procedures, and
documentation that should be established and followed for maintaining
suitable facilities and to prevent contamination and mix-ups during the
course of aseptic operations at outsourcing facilities. Procedures must
be established that assign responsibility for and describe cleaning
schedules, methods, equipment, and materials. In addition, the guidance
describes that procedures should ensure recording of instances when
there is a loss of positive pressure in the clean room during
production.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 2) will
individually establish and maintain approximately 3 records (procedures
and documentation) for maintaining suitable outsourcing facilities
(``Total Annual Records'' in table 1, row 2). We also estimate that
preparing and maintaining each record as described in section III.B of
the draft guidance will take on average approximately 5 hours for each
record (``Average Burden per Recordkeeping'' in table 1, row 2).
3. Environmental and Personnel Monitoring
Under the draft guidance, procedures for environmental and
personnel monitoring in the aseptic processing area for viable,
nonviable, and total particulate matter should be established and
followed in outsourcing facilities. The procedures should include
establishing the validity of the microbiological media, including the
preparation, sterilization, and growth potential of the media used in
performing tests.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 3) will
individually establish approximately 1,200 environmental and personnel
monitoring procedures and records to document test results (``Total
Annual Records'' in table 1, row 3) for the aseptic processing areas.
We also estimate that preparing and maintaining the environmental and
personnel monitoring procedures as described in section III.C of the
draft guidance will take on average approximately 0.25
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hours for each record (``Average Burden per Recordkeeping'' in table 1,
row 3).
4. Equipment, Containers, and Closures
Procedures and documentation should be established and maintained
for testing compounding equipment and containers and closures to ensure
the quality of compounded drug products at outsourcing facilities.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 4) will
individually establish and maintain approximately 1,000 procedures and
documentation for testing equipment, containers, and closures (``Total
Annual Records'' in table 1, row 4) in the aseptic processing areas. We
also estimate that preparing and maintaining these procedures and
documentation as described in section III.D of the draft guidance will
take on average approximately 0.25 hours for each record (``Average
Burden per Recordkeeping'' in table 1, row 4).
5. Components
Procedures should be established and records maintained concerning
the source and quality of components such as raw materials or
ingredients used in producing compounded sterile drug products at
outsourcing facilities.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 5) will
individually establish and maintain approximately 240 records of
testing to ensure the quality of components used in producing
compounded drugs, as recommended in section III.E of the draft guidance
(``Total Annual Records'' in table 1, row 5). We also estimate that
preparing and maintaining these records will take on average
approximately 4 hours for each record (``Average Burden per
Recordkeeping'' in table 1, row 5).
6. Production and Process Controls
Production and process documentation and procedures, such as batch
records, must be established to assure the quality of compounded
sterile drug products at outsourcing facilities. Training on aseptic
technique, cleanroom behavior, gowning, and procedures covering aseptic
manufacturing area operations must be established. Sterilization
validation of operations (e.g., holding vessels, filling equipment,
lyophilizer) and periodic verification activities and results must be
documented.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 6) will
individually establish and maintain approximately 5,000 records
pertaining to production and process controls, such as validation
procedures and training, to assure the quality of compounded sterile
drug products (``Total Annual Records'' in table 1, row 6). We also
estimate that preparing and maintaining these records, as described in
section III.F of the draft guidance, will take on average approximately
0.25 hours for each record (``Average Burden per Recordkeeping'' in
table 1, row 6).
7. Release Testing
Compounded drug products produced at outsourcing facilities must be
tested to determine whether they meet final product specifications
prior to release for distribution, and procedures for final release
testing must be established and followed.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 7) will
individually establish and maintain approximately 240 records
pertaining to final release testing of compounded drug products,
including release testing procedures and documentation (``Total Annual
Records'' in table 1, row 7). We also estimate that preparing and
maintaining these records, as described in section III.G of the draft
guidance, will take on average approximately 4 hours for each record
(``Average Burden per Recordkeeping'' in table 1, row 7).
If sterility testing is not completed prior to release under
certain conditions described in section III.G of the draft guidance,
procedures must be established that specify that if the product fails
to meet a criterion for sterility, all healthcare and other facilities
that received the product must be immediately notified of the test
results and provided with any appropriate information and
recommendations to aid in the treatment of patients; the notification
must be documented; and FDA must be notified in writing.
We estimate that annually a total of 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 compounded drug product and provide
them with any appropriate information and recommendations to aid in the
treatment of patients (``Total Annual Disclosures'' in table 2, row 1).
We also estimate that preparing and sending each notification will take
approximately 5 hours (``Average Burden per Disclosure'' in table 2,
row 1).
We also estimate that annually, a total of approximately 10
outsourcing facilities (``No. of Respondents'' in table 3) will
individually submit to FDA 1 notification of the test results for any
compounded drug product that fails to meet a sterility criterion
(``Total Annual Responses'' in table 3). Preparing and submitting this
information will take approximately 5 hours per notification (``Average
Burden per Response'' in table 3).
8. 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 document the
results, establish sampling and testing procedures to ensure that
components, in-process materials, and drug products conform to the
product specifications, and keep complete records of all tests
performed to ensure compliance with established specifications and
standards, including examinations and assays.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 8) will
individually establish and maintain approximately 1,000 laboratory
records as described in section III.H of the draft guidance (``Total
Annual Records'' in table 1, row 8). We also estimate 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 8).
9. Stability/Expiration Dating
Stability testing is used to ensure that a drug product will retain
its quality (in particular, strength) and remain sterile through the
labeled expiration date. The draft guidance recommends that procedures
established by outsourcing facilities for assessing the stability of
drug products should include: (1) using stability-indicating test
methods that are reliable, meaningful and specific; (2) evaluating
samples of the drug product in the same container closure system in
which the drug product will be marketed; (3) evaluating samples for
stability that are representative of the lot or batch from which they
were obtained and are stored under suitable conditions; and (4) testing
to evaluate antimicrobial effectiveness (resistance to antimicrobial
contamination) for drug products labeled or intended to be multiple
dose.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row
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9) will individually establish and maintain approximately 90 procedures
for stability studies to determine an expiration date (``Total Annual
Records'' in table 1, row 9) for compounded drug products. We also
estimate that preparing and maintaining these procedures as described
in section III.I of the draft guidance will take approximately 5 hours
for each record (``Average Burden per Recordkeeping'' in table 1, row
9).
10. Packaging and Labels
Packaging of sterile drugs must ensure the sterility and integrity
of the product until it is administered to a patient, and product
labels must contain required information and labeling operations must
include controls to prevent mix-ups. Procedures should be established
by outsourcing facilities for packaging and labeling operations for
compounded sterile drug products, including the following: (1) The
container, closure, and packaging systems should provide adequate
protection against foreseeable external factors in storage, shipment,
and use that can cause contamination or deterioration; (2) packaging
records should include specimens of all labels used; procedures should
be established for issuance of labels, examination of issued labels,
reconciliation of used labels to prevent mix-ups; (3) there should be
physical/spatial separation between different labeling and packaging
operations to prevent mix-ups; and (4) controls should be established
that assure proper identification of any filled containers of sterile
products that are stored unlabeled for any period of time.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 10) will
individually establish and maintain approximately 20 procedures and
records for packaging operations and labels (``Total Annual Records''
in table 1, row 10) for compounded drug products. We also estimate that
preparing and maintaining these procedures and records as described in
section III.J of the draft guidance will take approximately 5.5 hours
for each record (``Average Burden per Recordkeeping'' in table 1, row
10).
11. Quality Assurance Activities
A quality control unit must be established by outsourcing
facilities to oversee various aspects of compounded sterile drug
production and to monitor quality assurance. The responsibilities of
the quality control unit must be established in procedures and should
include investigations and development and oversight of appropriate
corrective actions and preventive actions regarding: Rejected lots of
finished product, unexpected results or trends, validation and
stability failures, and process deviations or equipment malfunctions
that involve critical equipment. The quality control unit also is
responsible for ensuring that sampling and testing are conducted to
ensure that appropriate specifications are met, and for product
complaint handling.
We estimate that annually a total of approximately 50 outsourcing
facilities (``No. of Recordkeepers'' in table 1, row 11) will
individually establish approximately 8 procedures on the
responsibilities of the quality control unit (``Total Annual Records''
in table 1, row 10) as described in section III.K of the draft
guidance. We also estimate that preparing and maintaining these
procedures will take approximately 3 hours for each record (``Average
Burden per Recordkeeping'' in table 1, row 11).
The total estimated recordkeeping, third party disclosure, and
reporting burdens for the draft guidance are as follows:
Table 1--Estimated Annual Recordkeeping Burden \1\
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Number of Average burden
Type of recordkeeping Number of records per Total annual per Total hours
recordkeepers recordkeeper records recordkeeping
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Facility Design............... 50 20 1,000 1.5............. 1,500
Control Systems and Procedures 50 3 150 5............... 750
For Maintaining Suitable
Facilities.
Environmental and Personnel 50 1,200 60,000 0.25 (15 15,000
Monitoring. minutes).
Equipment, Containers, and 50 1,000 50,000 0.25 (15 12,500
Closures. minutes).
Components.................... 50 240 12,000 4............... 48,000
Production and Process 50 5,000 250,000 0.25 (15 62,500
Controls. minutes).
Release Testing............... 50 240 12,000 4............... 48,000
Laboratory Controls........... 50 1,000 50,000 0.5 (30 minutes) 25,000
Stability/Expiration Dating... 50 90 4,500 5............... 22,500
Packaging and Labels.......... 50 20 1,000 5.5............. 5,500
Quality Assurance Activities.. 50 8 400 3............... 1,200
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Total..................... 50 8,821 441,050 ................ 242,450
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\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\
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Type of disclosure & proposed Number of Frequency per Total annual Average burden
21 CFR section respondents disclosure disclosures per disclosure Total hours
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Notification that a compounded 10 1 10 5............... 50
drug product fails to meet a
sterility criterion.
An expiration date is added to 50 540 27,000 0.25 (15 6,750
the compounded drug product's minutes).
label.
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Total..................... 6,800
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
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Table 3--Estimated Annual Reporting Burden \1\
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Number of Average
Type of reporting & proposed 21 Number of responses per Total annual burden per Total hours
CFR section respondents respondent responses response
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Notification to FDA that a 10 1 10 5 50
compounded drug product fails
to meet a sterility criterion..
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
V. Electronic Access
Persons with access to the Internet may obtain the document at
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.
Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-15370 Filed 7-1-14; 8:45 am]
BILLING CODE 4164-01-P