Document ID: FDA-2014-D-1525-0357
Agency: fda
Document Type: Notice
Title: Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application; Revised Draft Guidance For Industry; Availability
Posted Date: 2017-01-13T05:00Z

[Federal Register Volume 82, Number 9 (Friday, January 13, 2017)]
[Notices]
[Pages 4358-4361]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-00722]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-D-1525]

Mixing, Diluting, or Repackaging Biological Products Outside the 
Scope of an Approved Biologics License Application; Revised Draft 
Guidance For Industry; Availability

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
announcing the availability of a revised draft guidance for industry 
entitled ``Mixing, Diluting, or Repackaging Biological Products Outside 
the Scope of an Approved Biologics License Application.'' This revised 
draft guidance describes the conditions under which FDA does not intend 
to take action against a State-licensed pharmacy, a Federal facility, 
or an outsourcing facility that mixes, dilutes, or repackages certain 
biological products outside the scope of an approved biologics license 
application (BLA). It also describes the conditions under which FDA 
does not intend to take action when a State-licensed pharmacy, a 
Federal facility, an outsourcing facility, or a physician prepares 
prescription sets of allergenic extracts for subcutaneous 
immunotherapy. This revised draft guidance for industry replaces the 
draft guidance for industry of the same title issued in February 2015.

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draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by March 14, 2017.

ADDRESSES: You may submit comments 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): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, 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-1525 for ``Mixing, Diluting, or Repackaging Biological 
Products Outside the Scope of an Approved Biologics License 
Application.'' 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 Division of Dockets 
Management 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 Division of Dockets Management. 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: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    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 Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.
    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 (CBER), Food and Drug Administration, 10903 New 
Hampshire Avenue, 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.

[[Page 4359]]

FOR FURTHER INFORMATION CONTACT: Sara Rothman, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5197, Silver Spring, MD 20903, 301-796-
3110; or 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.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a revised draft guidance for 
industry entitled ``Mixing, Diluting, or Repackaging Biological 
Products Outside the Scope of an Approved Biologics License 
Application.'' Certain licensed biological products may sometimes be 
mixed, diluted, or repackaged in a way not described in the approved 
labeling for the product to meet the needs of a specific patient. For 
example, for some biological products there is no licensed pediatric 
strength and/or dosage form. In addition, there may be certain 
circumstances when a person would remove a licensed biological product 
from its original container and place it into a different container(s) 
(repackage it), in a manner that is not within the scope of the 
approved labeling for the product. As described in the draft guidance, 
mixed, diluted, or repackaged biological products are not eligible for 
the statutory exemptions available to certain compounded drugs under 
sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) (21 U.S.C. 353a and 353b). In addition, a biological product 
that is mixed, diluted, or repackaged outside the scope of an approved 
BLA is considered an unlicensed biological product under section 351 of 
the Public Health Service (PHS) Act (42 U.S.C. 262).
    This draft guidance describes the conditions under which FDA does 
not intend to take action for violations of section 351 of the PHS Act 
and section 502(f)(1) (21 U.S.C. 352(f)(1)), section 582 (21 U.S.C. 
360eee-1), and where specified, section 501(a)(2)(B) (21 U.S.C. 
351(a)(2)(B)) of the FD&C Act, when a state-licensed pharmacy, a 
Federal facility, or an outsourcing facility dilutes, mixes, or 
repackages certain biological products outside the scope of an approved 
BLA.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). This guidance, when 
finalized, will represent FDA's current thinking on mixing, diluting, 
and repackaging of biological products not within the scope of the 
product's approved BLA as described in the approved labeling for the 
product. 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.

II. Paperwork Reduction Act of 1995

    This draft guidance contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(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 reporting and recordkeeping 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.
    The draft guidance includes the following collection of information 
under the PRA.
    One condition described in the draft guidance is that if the 
labeling for the licensed biological product includes storage and/or 
handling instructions (e.g., protect from light, do not freeze, keep at 
specified storage temperature), the labeling for the biological product 
that is mixed, diluted, or repackaged specifies the same storage 
conditions.
    Another condition described in the draft guidance is that, if the 
biological product is mixed, diluted, or repackaged by an outsourcing 
facility, the label on the immediate container (primary packaging, 
e.g., the syringe) of the mixed, diluted, or repackaged product 
includes the following information:
     The statement ``This biological product was mixed/diluted 
by [name of outsourcing facility],'' or ``This product was repackaged 
by [name of outsourcing facility],'' whichever statement is 
appropriate;
     The address and phone number of the outsourcing facility 
that mixed, diluted, or repackaged the biological product;
     The proper name of the original biological product that 
was mixed, diluted, or repackaged;
     The lot or batch number of the mixed, diluted, or 
repackaged biological product;
     The dosage form and strength;
     A statement of either the quantity or the volume of the 
mixed, diluted, or repackaged biological product, whichever is 
appropriate;
     The date the biological product was mixed, diluted, or 
repackaged;
     The beyond-use-date (BUD) of the mixed, diluted, or 
repackaged biological product;
     Storage and handling instructions for the mixed, diluted, 
or repackaged biological product;
     The National Drug Code (NDC) number of the mixed, diluted, 
or repackaged biological product, if available; \1\
---------------------------------------------------------------------------

    \1\ The NDC number of the original licensed biological product 
should not be placed on the mixed, diluted, or repackaged biological 
product.
---------------------------------------------------------------------------

     The statement ``Not for resale,'' and, if the biological 
product is distributed by an outsourcing facility other than pursuant 
to a prescription for an individual identified patient, the statement 
``Office Use Only''; and
     If included on the label of the FDA-licensed product from 
which the biological product is being mixed, diluted, or repackaged, a 
list of the active and inactive ingredients; and if the biological 
product is mixed or diluted, a list of any ingredients that appear in 
the mixed or diluted product in addition to those ingredients that are 
on the label of the original FDA-licensed biological product.
    In addition, the draft guidance includes as a condition for 
biological products mixed, diluted, or repackaged by an outsourcing 
facility that, if the immediate product label is too small to bear the 
active and inactive ingredients, such information should be included on 
the label of the container from which the individual units are removed 
for administration (secondary packaging, e.g., the bag, box, or other 
package in which the mixed, diluted, or repackaged biological products 
are distributed).
    The draft guidance also describes the condition for biological 
products mixed, diluted, or repackaged by an outsourcing facility that 
the label on the container from which the individual units are removed 
for administration

[[Page 4360]]

include directions for use, including, as appropriate, dosage and 
administration, and the following information to facilitate adverse 
event reporting: http://www.fda.gov/medwatch and 1-800-FDA-1088.
    Finally, the draft guidance described a condition for biological 
products repackaged by an outsourcing facility for which the BUD is 
established based on a stability program conducted in accordance with 
Appendix A of the draft guidance, that the outsourcing facility 
maintains records of the testing performed in accordance with Appendix 
A.
    We estimate that annually a total of approximately 15 outsourcing 
facilities that mix, dilute, or repackage biological products (``Number 
of Respondents'' in table 1, row 1) will each design, test, and produce 
approximately five different labels (``Frequency per Disclosure'' in 
table 1, row 1), for a total of 75 labels that include the information 
set forth in section III.B of the draft guidance (including directions 
for use) as well as inclusion of storage and/or handling instructions 
(``Total Disclosures'' in table 1, row 1). We also estimate that 
designing, testing, and producing each label will take approximately 
0.5 hours (``Hours per Disclosure'' in table 1, row 1). The provision 
to add http://www.fda.gov/medwatch and 1-800-FDA-1088 is not included 
in this burden estimate because it is not considered a collection of 
information under the PRA because the information is ``originally 
supplied by the Federal Government to the recipient for the purpose of 
disclosure to the public'' (5 CFR 1320.3(c)(2)).
    Section III.C of the draft guidance discusses the preparation of 
prescription sets (i.e., licensed allergenic extracts that are mixed 
and diluted to provide subcutaneous immunotherapy to an individual 
patient) by a physician, State-licensed pharmacy, a Federal facility, 
or outsourcing facility. One of the conditions described in the draft 
guidance is if the prescription set is mixed or diluted by an 
outsourcing facility, the label on the immediate container of the 
prescription set (primary packaging) includes:
     The patient's name as identified on the prescription or 
order;
     The statement ``This prescription set was prepared by 
[name of outsourcing facility]'';
     The address and phone number of the outsourcing facility 
that prepared the prescription set;
     The identity of each allergenic extract in the 
prescription set and the quantity of each;
     The dilution of each dilution vial;
     The lot or batch number of the prescription set;
     The date the prescription set was prepared;
     The BUD as the expiry date for the prescription set;
     Storage and handling instructions for the prescription 
set; and
     The statement ``Not for resale.''
    Another condition under the draft guidance is that if the 
prescription set is prepared by an outsourcing facility, the label of 
the container from which the individual units of the prescription set 
are removed for administration (secondary packaging) includes the 
following information to facilitate adverse event reporting: http://www.fda.gov/medwatch and 1-800-FDA-1088. Each prescription set prepared 
by an outsourcing facility is also accompanied by instructions for use.
    We estimate that annually a total of approximately five outsourcing 
facilities that prepare prescription sets (``Number of Respondents'' in 
table 2, row 1) will each include the information set forth in section 
III.C of the draft guidance (including directions for use) on the 
labels, packages, and/or containers of approximately 300 prescription 
sets (``Frequency per Disclosure'' in table 2, row 1) for a total of 
1500 disclosures (``Total Disclosures'' in table 2, row 1). We also 
estimate that the initial process of designing, testing, and producing, 
and attaching each label, package, and/or container to each 
prescription set will take approximately 0.5 hours (``Hours per 
Disclosure'' in table 2, row 1). The provision to add ``http://www.fda.gov/medwatch'' and ``1-800-FDA-1088'' is not included in this 
burden estimate because it is not considered a collection of 
information under the PRA because the information is ``originally 
supplied by the Federal Government to the recipient for the purpose of 
disclosure to the public'' (5 CFR 1320.3(c)(2)).
    We estimate that annually a total of approximately 5 outsourcing 
facilities that repackage biological products and establish a BUD in 
accordance with Appendix A (``No. of Recordkeepers'' in table 3) will 
maintain approximately 150 records of the testing, as described in 
Appendix A (``total annual records'' in table 3). We estimate that 
maintaining the records will take approximately 5 minutes per record.
    The total estimated third-party disclosure burden resulting from 
the draft guidance is as follows:

                                               Table 1--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                Number of
 Biological product mixing, diluting, and     Number of      disclosures per     Total annual        Average burden per disclosure         Total hours
               repackaging                   respondents        respondent       disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Designing, testing, and producing the                  15                  5               75   0.5 (30 minutes).......................            37.5
 label, container, packages, and/or outer
 containers for each mixed, diluted, or
 repackaged biological product.
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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
     Preparation of prescription sets         Number of      disclosures per     Total annual        Average burden per disclosure         Total hours
                                             respondents        respondent       disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Designing, testing, and producing each                  5                300            1,500   0.5 (30 minutes).......................             750
 label on immediate containers, packages,
 and/or outer containers.
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

[[Page 4361]]

                                                   Table 3--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                              Number of     Number of records    Total annual
          Type of recordkeeping             recordkeepers    per recordkeeper      records          Average burden per recordkeeping       Total hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Records that the outsourcing facility                   5                 30              150   0.083 (5 minutes)......................            12.5
 maintains of the testing performed in
 accordance with Appendix A of the
 guidance.
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    The draft guidance also references registration, adverse event 
reporting, product reporting, and current good manufacturing practice 
(CGMP) requirements for outsourcing facilities. The collections of 
information for outsourcing facility registration have been approved by 
the Office of Management and Budget (OMB) under OMB control number 
0910-0777 (79 FR 69859). The collections of information for adverse 
event reporting by outsourcing facilities have been approved by OMB 
under OMB control number 0910-0800 (80 FR 60917). In the Federal 
Register of December 4, 2013 (78 FR 72897), FDA estimated the burden 
resulting from outsourcing facility electronic drug product reporting. 
In the Federal Register of July 2, 2014 (79 FR 37743), FDA estimated 
the burden resulting from outsourcing facility compliance with CGMP 
requirements.

IV. Electronic Access

    Persons with access to the Internet can obtain the document at 
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm or https://www.regulations.gov.

    Dated: January 10, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-00722 Filed 1-12-17; 8:45 am]
BILLING CODE 4164-01-P