Document ID: FDA-2014-D-1525-0002
Agency: fda
Document Type: Notice
Title: Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application; Draft Guidance for Industry; Availability
Posted Date: 2015-02-19T05:00Z

[Federal Register Volume 80, Number 33 (Thursday, February 19, 2015)]
[Notices]
[Pages 8881-8884]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2015-03418]

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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Scope of an Approved Biologics License Application; Draft Guidance for 
Industry; Availability

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
announcing the availability of a draft guidance for industry entitled 
``Mixing, Diluting, or Repackaging Biological Products Outside the 
Scope of an Approved Biologics License Application.'' This draft 
guidance describes the conditions under which FDA does not intend to 
take action against a state-licensed pharmacy, a Federal facility, or 
outsourcing facility that mixes, dilutes, or repackages certain 
biological products without obtaining an approved biologics license 
application (BLA).

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draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by May 20, 2015.

ADDRESSES: Submit written requests for single copies of this 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; 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 guidance document.
    Submit electronic comments on the 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: Leah Christl, Center for Drugs 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 6426, Silver Spring, MD 20903, 301-796-
0869; or Stephen Ripley, Center for Biologics Evaluation and Research, 
Food and Drug Administration, 10903

[[Page 8882]]

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 draft guidance for industry 
entitled ``Mixing, Diluting, or Repackaging of Biological Products 
Outside the Scope of an Approved Biologics License Application.'' 
Certain licensed biological products may need to 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 (21 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) 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 without 
obtaining an approved BLA.
    Elsewhere in this issue of the Federal Register, the Agency is 
making available for comment a draft guidance entitled ``Repackaging of 
Certain Human Drug Products by Pharmacies and Outsourcing Facilities.'' 
When these two guidances become final, they will address and clarify 
the Agency's policy regarding hospital pharmacies repackaging and 
safely transferring repackaged drug, including biological products, to 
other hospitals within the same health system during a drug shortage. 
Therefore, under section 506F(d) of the FD&C Act (21 U.S.C. 356f(d), 
when FDA issues these as final guidances, section 506F will no longer 
apply.
    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. Comments

    Interested persons may submit either 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.

III. 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.
    Title: Draft Guidance for Industry: Mixing, Diluting, or 
Repackaging of Biological Products Outside the Scope of an Approved 
Biologics License Application.
    Description: The draft guidance describes FDA's policy with respect 
to the mixing, diluting, and repackaging of certain types of biological 
products that have been licensed under section 351 of the PHS Act when 
such activities are not within the scope of the product's approved BLA 
as described in the approved labeling for the product. The 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) and where specified, section 501(a)(2)(B) of the FD&C Act, 
when a state-licensed pharmacy, a Federal facility, or an outsourcing 
facility mixes, dilutes, or repackages certain biological products 
without obtaining an approved BLA.
    The draft guidance includes the following collection of information 
under the PRA.
    One 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 product was mixed or 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

[[Page 8883]]

repackaged biological product, if available; \1\
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    \1\ The NDC number of the original licensed biological product 
should not be placed on the mixed, diluted, or repackaged biological 
product.
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     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 ingredients are 
listed because they were listed on the original product, the label of 
the mixed, diluted, or repackaged product should include any additional 
ingredients that appear in the mixed, diluted, or repackaged product.
    Another condition in the draft guidance is that, if the immediate 
product label is too small or the mixed, diluted, or repackaged product 
is otherwise unable to accommodate a label with sufficient space 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).
    In addition, the draft guidance describes the conditions that the 
container label 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. Another condition in the draft guidance is that each mixed, 
diluted, or repackaged biological product is also accompanied by a copy 
of the prescribing information that accompanied the original licensed 
biological product that was mixed, diluted, or repackaged.
    We estimate that annually a total of approximately five registered 
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 25 
labels that include the information set forth in section III.B of the 
draft guidance (including directions for use) (``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 combined 
to provide subcutaneous immunotherapy to an individual patient) by a 
physician, state-licensed pharmacy, a Federal facility, or outsourcing 
facility. Under the draft guidance, 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;
     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 of the prescription set;
     storage and handling instructions for the prescription 
set; and
     the statement ``Not for resale''.
    In addition, under the draft guidance, 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 is also accompanied by 
instructions for use and the FDA approved package insert for each 
allergenic extract.
    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 the statement 
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 also estimate that a total of approximately five outsourcing 
facilities (``Number of Respondents'' in table 2, row 2) will each 
design, test, and produce the instructions for use and a copy of 
prescribing information, as set forth in section III.C of the draft 
guidance, for approximately 300 prescription sets (``Frequency per 
Disclosure'' in table 2, row 2) for a total of 1500 disclosures (total 
disclosures'' in table 2, row 2), which we estimate will take 
approximately 1 hour for each prescription set (``Hours per 
Disclosure'' in table 2, row 2). The provision to include http://www.fda.gov/medwatch and 1-800-FDA-1088 is not included in this burden 
estimate because they are 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)).
    The total estimated third-party disclosure burden resulting from 
the draft guidance is as follows:

[[Page 8884]]

                           Table 1--Estimated Annual Third-Party Disclosure Burden \1\
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   Biological product mixing,       Number of     Frequency per       Total         Hours per
   diluting, and repackaging       respondents     disclosure      disclosures     disclosure      Total hours
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Designing, testing, and                       5               5              25             0.5             12.5
 producing the label,
 container, packages, and/or
 outer containers for each
 mixed, diluted, or repackaged
 biological product............
Prescribing information                       5               5              25               1             25
 labeling accompanying each
 mixed, diluted, or repackaged
 drug product..................
                                --------------------------------------------------------------------------------
    Total......................  ..............  ..............  ..............  ..............             37.5
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
*(30 minutes)

                           Table 2--Estimated Annual Third-Party Disclosure Burden \1\
----------------------------------------------------------------------------------------------------------------
  Preparation of prescription       Number of     Frequency per       Total         Hours per
              sets                 respondents     disclosure      disclosures     disclosure      Total hours
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Designing, testing, and                       5             300            1500             0.5            750
 producing each label on
 immediate containers,
 packages, and/or outer
 containers....................
Including instructions for use                5             300            1500               1           1500
 labeling and the original
 package insert(s) for each
 prescription set..............
                                --------------------------------------------------------------------------------
    Total......................  ..............  ..............  ..............  ..............           2250
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
*(30 minutes)

    The draft guidance also references registration, product reporting, 
current good manufacturing practice (CGMP) requirements, and the 
payment of certain fees by human drug compounding outsourcing 
facilities. In the Federal Register of December 4, 2013 (78 FR 72899), 
FDA estimated the burden resulting from outsourcing facility 
registration. In the Federal Register of December 4, 2013 (78 FR 
72897), FDA estimated the burden resulting from outsourcing facility 
interim product reporting. In the Federal Register of April 1, 2014 (79 
FR 18297), FDA estimated the burden resulting from the payment of 
certain fees by outsourcing facilities. 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 http://www.regulations.gov.

    Dated: February 11, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-03418 Filed 2-18-15; 8:45 am]
BILLING CODE 4164-01-P