[Federal Register Volume 83, Number 50 (Wednesday, March 14, 2018)]
[Rules and Regulations]
[Pages 11139-11143]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-05143]


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DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Parts 101 and 114

[Docket No. APHIS-2009-0028]
RIN 0579-AD06


Viruses, Serums, Toxins, and Analogous Products; Expiration Date 
Required for Serial and Subserials and Determination of Expiration Date 
of Product

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Final rule.

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SUMMARY: We are amending the regulations to clarify that the expiration 
date of a serial or subserial of a veterinary biologic should be 
computed from the date of the initiation of the first potency test. We 
are also requiring the expiration dating period (stability) of a 
product to be confirmed by conducting a real-time stability study with 
a stability-indicating assay, stability monitoring of products after 
licensing, and specifying a single standard for determining the 
expiration date for veterinary biologics

DATES: Effective April 13, 2018.

FOR FURTHER INFORMATION CONTACT: Dr. Donna L. Malloy, Section Leader, 
Operational Support, Center for Veterinary Biologics Policy, 
Evaluation, and Licensing, VS, APHIS, 4700 River Road, Unit 148, 
Riverdale, MD 20737-1231; (301) 851-3426.

SUPPLEMENTARY INFORMATION:

Background

    The Virus-Serum-Toxin Act regulations in 9 CFR part 114 (referred 
to below as the regulations), contain requirements for computing 
expiration dates and determining expiration dating periods (stability) 
for veterinary biologics. Currently, Sec.  114.12 of the regulations 
requires each serial or subserial of veterinary biological products 
prepared in a licensed establishment to be given an expiration date, 
and Sec.  114.13 provides that the expiration date for each product 
shall be computed from the date of the initiation of the potency test.
    Prior to licensure, licensees and permittees must submit 
preliminary information to support the dating period shown on its 
labeling. Products are licensed with the provision that the dating 
period must be confirmed by real-time stability testing at the end of 
the predicted shelf life. Currently, the requirement in Sec.  114.13 of 
the regulations for confirming stability is contingent upon whether a 
product consists of viable or non-viable organisms. For products 
consisting of viable organisms, each serial must be tested for potency 
at release and at the approximate expiration date until a statistically 
valid stability record has been established. For products consisting of 
non-viable organisms, each serial presented in support of licensure 
(prelicensing serials) must be tested for potency at release and at or 
after the dating requested. Products with satisfactory potency tests at 
the beginning and end of dating are considered to be efficacious 
throughout the requested dating period. Current science, however, 
considers stability estimates based on potency tests conducted at the 
beginning and end of the dating (a two-point profile) to be inaccurate 
and imprecise.\1\
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    \1\ Capen, R., et al. (2012). On the shelf life of 
pharmaceutical products. AAPS PharmSciTech. DOI: 10.1208/s12249-012-
9815-2.
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    To address this situation, on September 17, 2010, we published in 
the Federal Register (75 FR 56916-56919, Docket No. APHIS-2009-0028) a 
proposal \2\ to amend the regulations by clarifying that the expiration 
date of a serial or subserial of a veterinary biologic should be 
computed from the date of the initiation of the first potency test. We 
also proposed to require the expiration dating period (stability) of a 
product to be confirmed by a real-time stability study with a 
stability-indicating assay; require stability

[[Page 11140]]

monitoring of products after licensing; and specify a single standard 
for determining the expiration date for veterinary biologics.
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    \2\ To view the proposed rule and the comments we received, go 
to http://www.regulations.gov/#!docketDetail;D=APHIS-2009-0028.
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    We solicited comments concerning our proposal for 60 days ending 
November 16, 2010. We received eight comments by that date. They were 
from licensed manufacturers, national trade associations representing 
manufacturers of animal health products, a professional organization, 
and a private citizen. The comments are discussed below by topic.
    In our review of the comments, it was evident that many commenters 
found the organization and wording of proposed Sec.  114.13 to be 
confusing. For this reason, in addition to adopting some changes 
requested by commenters to the provisions, we have reorganized and 
reworded parts of this section to more clearly describe these 
requirements.

Definition of and Requirement To Use a Stability-Indicating Assay

    We proposed to add a definition of the term stability-indicating 
assay to the regulations in part 101. One commenter stated that we did 
not identify the need for the addition of this definition to the 
regulations. Another commenter noted that we stated that product 
potency can degrade in a non-linear fashion and asked for clarification 
of why the profile of the degradation curve of a product is important 
in an assessment of product stability.
    In the proposed rule, we noted that current science does not 
consider stability estimates based on potency tests conducted at the 
beginning and end of dating (that is, a two-point profile) to be either 
accurate or precise. A two point profile will determine a fixed line, 
but if a stability profile is non-linear, two points are inadequate to 
estimate the profile. Further, to estimate the precision even of a 
straight line would require at least three points. For this reason we 
proposed to amend Sec.  114.13 to require testing of serials or 
subserials using a stability-indicating assay on multiple occasions 
throughout the predicted dating period, and to add a definition of the 
term stability-indicating assay to clarify what types of assays would 
be considered acceptable.
    Two commenters stated that the Animal and Plant Health Inspection 
Service (APHIS) incorrectly cited the International Cooperation on 
Harmonization of Technical Requirements for the Registration of 
Veterinary Medicinal Products (VICH) guidelines in support of the 
proposed rule. The commenters stated that of the five VICH guidelines 
that address stability, only one, VICH GL 17, Stability Testing of 
Biotechnological/Biological Veterinary Medicinal Products, addresses 
biological products, and it only applies to well-characterized proteins 
and polypeptides, and their derivatives. The commenters also noted that 
VICH GL 17 specifically excludes conventional vaccines.
    VICH is a project conducted under the World Organization for Animal 
Health that brings together the regulatory authorities of the European 
Union, Japan, and the United States and representatives from the animal 
health industry in the three regions. Regulatory authorities and 
industry experts from Australia, Canada, and New Zealand participate as 
observers. The purpose of VICH is to harmonize technical requirements 
for veterinary medicinal products (both pharmaceuticals and biologics).
    The commenters' characterization of VICH GL 17 is correct; the 
scope of those guidelines is limited to biotechnological/biological 
products and therefore they exclude conventional vaccines and numerous 
other products. However, the suggestion that APHIS proposed to apply 
the guidelines for biotechnological/biological products inappropriately 
to conventional vaccines is mistaken. We did not cite any VICH 
guidelines as a basis for the proposed rule. Rather, in the economic 
analysis that accompanied the proposed rule, we stated that the 
proposed changes were consistent with VICH recommendations, and we 
continue to believe that this statement is correct. We note that 
neither the VICH guidelines nor our regulations give specific, step-by-
step directions for determining stability, nor is this rule intended to 
provide such directions. Instead, we state that expiration dating 
period (stability) of a product should be confirmed by conducting a 
real-time stability study with a stability-indicating assay.
    Some commenters expressed concern that the proposed definition and 
its use in Sec.  114.13 would require potency tests to be quantitative. 
The commenters noted that the potency tests for many licensed products, 
some of which are codified in the regulations, are not quantitative. 
The commenters stated that this change would force licensees to develop 
and validate additional assays for many products and would create 
conflicts with the existing regulations. One commenter stated that 
developing these additional assays would be expensive, would not 
improve the quality of the products, would divert resources from new 
product development, and could lead to some products being 
discontinued. Another commenter stated that it was unclear why non-
quantitative assays are being excluded, because in many cases these 
assays are sufficient to determine whether or not a product has 
remained potent throughout the dating period.
    The rule calls for a stability-indicating assay, which is one that 
can detect changes over time. Non-quantitative assays are not 
stability-indicating because they cannot detect changes over time. 
However, in response to these comments, we have amended Sec.  114.13 to 
allow the use of codified potency tests that are not quantitative but 
that are included in the filed Outline of Production.
    APHIS does not agree that manufacturers will need to divert 
resources from developing new products to develop additional assays 
because this final rule will not require changes to biological products 
that are currently licensed. In other words, the new requirement is not 
retroactive for prior approved products, and we believe that 
manufacturers will incorporate new assay development into their new 
product development process. We have addressed this concern in detail 
in the economic analysis that accompanies this final rule.
    One commenter stated that in the definition of stability-indicating 
assay, the phrase ``in the pertinent properties of the product'' was 
too vague. The commenter suggested that the definition be revised to 
refer only to potency, and not to other properties of the product.
    APHIS agrees with the commenter. We have amended Sec.  114.13 to 
limit the requirement to potency. We have also amended the definition 
of stability-indicating assay to read ``in a pertinent property'' 
rather than ``the pertinent properties.'' This change clarifies that 
the definition is descriptive but not prescriptive, and does not impose 
any requirements.
    Two commenters expressed concern about how the rule would apply to 
unlicensed products that have already completed extensive development, 
and stated that products in development should be treated the same as 
licensed products.
    APHIS agrees with the commenters that products that have already 
completed a certain amount of development should receive some 
consideration. In response to this comment, we have amended Sec.  
114.13 to allow a product in development with an approved potency assay 
to use that assay to complete its initial confirmation of dating study.

[[Page 11141]]

Diagnostic Test Kits

    One commenter asked about how the proposed rule would apply to 
diagnostic test kits. The commenter stated that most test kits are 
interpreted by qualitative means, such as a visual assessment of a 
reaction. The commenter stated further that a quantitative result is 
not needed because these test kits do not report a concentration or 
titer.
    The provisions of this rule do not apply to diagnostic test kits. 
We have amended the regulatory text in Sec.  114.13 to clarify this.

Expiration Date Required for a Serial

    We proposed to require that the expiration date of a serial be 
computed from the date of the initiation of the first potency test of 
the serial. One commenter asked that we change this provision to allow 
the expiration date to be calculated from a date of or prior to the 
date of the initiation of the first potency test. The commenter stated 
that this would allow assignment of expiration dates based on 
manufacturing activities (such as final formulation) that precede 
initiation of the first potency test. The commenter further stated that 
in many cases, this would be a more efficient practice for a 
manufacturer and would also ensure that serial expiration dating does 
not exceed that calculated from the date of the first potency test.
    APHIS agrees with the commenter. In response to this request, we 
have amended Sec.  114.12 to allow the expiration date to be computed 
from a date no later than the date of the initiation of the first 
potency test.

Determination of the Expiration Dating Period of a Product

    We proposed to require stability studies to begin on the day of 
filling or final formulation. Some commenters stated that the 
requirement to start on a single specific day was impractical and too 
restrictive.
    In response to this comment, we have changed the requirement for 
testing sequences in Sec.  114.13 to indicate that the first test in 
the sequence shall be as close as practical to the day of filling into 
final containers or the date of final formulation if the potency of the 
product is tested in bulk form.

Testing

    Some commenters stated that the testing intervals for in vitro 
tests in Sec.  114.13(a) and for animal tests in Sec.  114.13(b) 
require too much testing.
    The sequence of intervals for in vitro tests is designed to allow 
estimation of the potency profile. It is typical of the contemporary 
approach to product shelf life assessment and has been adopted under 
various regulatory systems throughout the world. Furthermore, in many 
cases the number of serials that would be tested under the amended 
regulations is fewer than are used under the current regulations, so 
the total number of tests would be approximately the same, but the 
resulting data would be more informative. In response to the comments, 
we have clarified the provisions in the final rule for those situations 
when animal testing would be allowed. Specifically, we have clarified 
that in those cases where animal testing would be necessary, the tests 
would be of three serials at the start and end of the proposed dating 
period. This will effectively reduce the number of animal tests 
required as compared to the original proposal.
    One commenter expressed concern that the changes would require the 
use of more animal tests, contrary to APHIS' commitment to reduce, 
refine, and replace the use of animals in testing.
    APHIS disagrees that the rule will require more animal testing. On 
the contrary, by calling for stability-indicating assays, it 
discourages the use of animal tests, since most stability-indicating 
assays are in vitro tests conducted without animals. As explained 
above, however, we have clarified the requirements for situations when 
animal testing would be allowed.

Statistical Methodology and Uniform Standards

    Some commenters noted that the rule does not include the 
statistical criteria that the agency might use to evaluate stability 
studies. One of the commenters stated that the proposal did not provide 
guidance on statistical methodology. Another commenter expressed 
concern that the testing requirements could be unreasonably burdensome 
and that if a licensee is required to have an extremely high 
statistical certainty, they might have to increase the potency of the 
product, which could lead to safety problems.
    The current regulations require that licensees and permittees 
conduct stability studies. We proposed to amend the regulations to 
provide information that is lacking in the current regulations on how 
to conduct stability studies. We did not recommend that the potency of 
a product ever be increased. In fact, a more precise understanding of a 
vaccine's potency could allow a manufacturer to reduce the formulated 
potency of a vaccine while verifying that it would maintain adequate 
potency throughout its shelf life.
    When providing guidance on methodology for implementing a codified 
rule, APHIS follows its usual practice of including such information in 
published guidance documents. Draft guidance documents are posted on 
the Center for Veterinary Biologics (CVB) website for comment. The 
policy on posting draft documents and instructions for commenting on 
them are described in CVB Notice No. 05-16, available online at http://www.aphis.usda.gov/animal_health/vet_biologics/publications/notice_05_16.pdf. We will consider all comments when formulating 
further guidance related to the draft document.
    A commenter stated that, as proposed, the rule does not establish a 
uniform standard and that a number of items, including threshold values 
of confidence intervals or prediction intervals, interpretation of 
continuous or categorical data sets, and testing intervals for post-
licensure monitoring vs. licensing studies should be addressed in the 
regulations.
    APHIS disagrees with the commenter. The rule establishes a uniform 
standard for the design of stability studies. It does not include 
detailed methodological procedures for technical statistical methods 
which must be tailored to the data at hand. The information the 
commenter cited is typically covered in guidance documents. As we 
discussed above, these guidance documents are made available on the 
APHIS website for review by stakeholders before they are finalized.
    One commenter stated that the requirement that manufacturers submit 
a plan to monitor the stability of their products and the suitability 
of the dating periods for those products and that the plan includes 
regularly testing serials for potency with stability-indicating assays 
is too vague.
    APHIS disagrees. The expectation that product stability should be 
monitored by a routine ongoing program is not unusual in the modern 
manufacturing environment. That expectation is clearly stated in the 
rule; however, the rule also allows the manufacturer the flexibility to 
design a program that meets the needs of the particular product.
    Some commenters expressed concern that the rule would prevent 
manufacturers from developing new products because the new requirements 
would require them to test every serial of a vaccine for stability.
    The rule does not require that every serial of a vaccine be tested 
for stability. We proposed in Sec.  114.13(a) that at least three 
production serials be tested. That requirement now appears in Sec.  
114.13(e) but is otherwise unchanged.

[[Page 11142]]

    A commenter expressed concern that the rule could be applied 
retroactively to any licensed product at any time.
    The rule does not apply retroactively. As we explained in the 
proposed rule, the new requirements apply to licensed products with a 
completed stability study only if the manufacturer makes a change to 
one of the stability criteria, such as the dating period, or a major 
change to the product or its potency test.
    Therefore, for the reasons given in the proposed rule and in this 
document, we are adopting the proposed rule as a final rule, with the 
changes discussed in this document.

Executive Orders 12866 and 13771 and Regulatory Flexibility Act

    This rule has been determined to be not significant for the 
purposes of Executive Order 12866 and, therefore, has not been reviewed 
by the Office of Management and Budget. This rule is not an Executive 
Order 13771 regulatory action because this rule is not significant 
under Executive Order 12866.
    In accordance with 5 U.S.C. 604, we have performed a final 
regulatory flexibility analysis, which is summarized below, regarding 
the economic effects of this rule on small entities. Copies of the full 
analysis are available on the Regulations.gov website (see footnote 2 
in this document for a link to Regulations.gov) or by contacting the 
person listed under FOR FURTHER INFORMATION CONTACT.
    We are amending the Virus-Serum-Toxin Act regulations concerning 
expiration dates for serials and subserials and the determination of 
the dating period (stability) of veterinary biological products. This 
rule will establish a uniform standard in stability testing for 
confirming the dating period and expiration date requirements. The 
changes will clarify and streamline the current regulations to ensure 
supplies of pure, safe, potent, and effective veterinary biological 
products.
    This rule will affect all veterinary biologics licensees 
(manufacturers of veterinary biologics) and permittees (importers of 
veterinary biologics). Currently, there are approximately 100 
veterinary biological establishments, including permittees. Among these 
veterinary biological establishments, 53 veterinary vaccine 
manufacturers and permittees hold 1,378 vaccine licenses.
    The annual value of veterinary biological product shipments 
averaged between $4.3 billion and $4.4 billion, 2010-2013, having grown 
from $2.3 billion in 2006. U.S. exports of veterinary vaccines showed a 
substantial increase between 2006 and 2013, from $291 million in 2006 
to $861 million in 2013. U.S. imports of veterinary vaccines are small; 
on average, $5.5 million of veterinary vaccines were imported annually 
from 2006 to 2013, resulting in a large trade surplus (exports minus 
imports) in the veterinary vaccine trade. In 2013, the United States 
was the largest exporter of veterinary vaccines in the world, followed 
by the Netherlands and Belgium.
    This rule will help veterinary biologics manufacturers establish 
the best method for confirming stability. The rule aims to enable these 
manufacturers to take advantage of scientific advances and readily 
respond to changing international technical standards in the global 
market.
    Over a 3-year period from 2012 through 2014, we received 76 reports 
from manufacturers that contained 192 vaccine stability studies. Based 
on the specific tests conducted in these stability studies, we estimate 
the costs associated with the current requirements, costs associated 
with the new requirements, and costs manufacturers actually incurred in 
conducting these 192 studies. We estimate that the annual total cost to 
the industry of stability studies under the current requirements is 
about $847,000 and the annual total cost to the industry under the new 
requirements will be about $858,000, that is, an annual cost increase 
of about $11,000 to the industry.
    We note that the 3-year data show that manufacturers actually 
conducted more testing than is required under either the current or new 
requirements; we estimate that the manufacturers incurred costs 
totaling about $1,689,000 annually, which is $831,000 more than what 
the new requirements are estimated to cost. To provide context on 
industry effects, if establishments were to limit themselves to the new 
requirements, which are aligned with contemporary science and 
international standards, the industry may save about $831,000 annually 
in testing, an average of about $15,700 per establishment (based on 53 
manufacturers). We anticipate that industry will follow the new 
requirements, although some firms may elect to perform more testing 
than required by APHIS in order to satisfy the regulatory requirements 
of other countries. In addition to the aforementioned annual costs, we 
expect that the industry will incur one-time costs that are necessary 
to understand the new requirements, train employees, and update 
policies and procedures accordingly.
    According to the Small Business Administration size standards, most 
veterinary biologics manufacturers are small entities with no more than 
500 employees. We expect that the estimated annual costs for the 
industry will not cause significant economic impacts for most 
veterinary biologics licensees and permittees, based on the estimated 
$11,000 annual cost increase to the industry (about $200 annual cost 
increase per manufacturer or permittee).

Executive Order 12372

    This program/activity is listed in the Catalog of Federal Domestic 
Assistance under No. 10.025 and is subject to Executive Order 12372, 
which requires intergovernmental consultation with States and local 
officials. (See 2 CFR chapter IV.)

Executive Order 12988

    This final rule has been reviewed under Executive Order 12988, 
Civil Justice Reform. It is not intended to have retroactive effect. 
This rule will not preempt any State or local laws, regulations, or 
policies where they are necessary to address local disease conditions 
or eradication programs. However, where safety, efficacy, purity, and 
potency of biological products are concerned, it is the Agency's intent 
to occupy the field. This includes, but is not limited to, the 
regulation of labeling. Under the Act, Congress clearly intended that 
there be national uniformity in the regulation of these products. There 
are no administrative proceedings which must be exhausted prior to a 
judicial challenge to the regulations under this rule.

Paperwork Reduction Act

    This final rule contains no new information collection or 
recordkeeping requirements under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501 et seq.).

List of Subjects

9 CFR Part 101

    Animal biologics.

9 CFR Part 114

    Animal biologics, Reporting and recordkeeping requirements.

    Accordingly, we are amending 9 CFR parts 101 and 114 as follows:

PART 101--DEFINITIONS

0
1. The authority citation for part 101 continues to read as follows:

    Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.4.


[[Page 11143]]



0
2. Section 101.5 is amended by adding paragraph(s) to read as follows:


Sec.  101.5  Testing terminology.

* * * * *
    (s) Stability-indicating assay. A stability-indicating assay is a 
validated quantitative analytical procedure that can detect changes 
over time in a pertinent property of the product.

PART 114--PRODUCTION REQUIREMENTS FOR BIOLOGICAL PRODUCTS

0
3. The authority citation for part 114 continues to read as follows:

    Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.4.


0
4. Section 114.12 is revised to read as follows:


Sec.  114.12  Expiration date required for a serial.

    Unless otherwise provided for in a Standard Requirement or filed 
Outline of Production, each serial or subserial of a biological product 
prepared in a licensed establishment shall be given an expiration date 
according to the dating period of the product when computed from a date 
no later than the date of the initiation of the first potency test of 
the serial or subserial. A licensed biological product shall be 
considered worthless under the Virus-Serum-Toxin Act after the 
expiration date appearing on the label.

0
5. Section 114.13 is revised to read as follows:


Sec.  114.13  Determination of the dating period of a product.

    The following requirements do not apply to those biological 
products used for diagnostic purposes.
    (a) Stability criteria. Stability criteria include the 
specifications for potency at release, potency throughout the dating 
period, and the length of the dating period.
    (b) Stability study requirement. The dating period of each fraction 
of each product shall be confirmed by conducting a stability study.
    (c) Licensure prior to completion of a stability study. Prior to 
licensure, the licensee shall propose a dating period for the product 
based on preliminary information available about the stability of each 
of its fractions. If the preliminary stability information is 
acceptable, the product may be licensed with the provision that the 
proposed dating period must be confirmed by conducting a real-time 
stability study with a stability-indicating potency assay that can 
detect changes over time in the potency of the product.
    (d) Use of stability-indicating assay. Stability studies must be 
conducted with a stability-indicating assay, with the following 
exceptions:
    (1) If the potency test specified in the filed Outline of 
Production of a licensed product is the one stated in the regulations, 
that potency test may be used in place of a stability-indicating assay 
for that fraction.
    (2) If the initial confirmation of dating study of a product in 
development on April 13, 2018 has an approved potency assay, that assay 
may be used.
    (e) Number of serials. At least three production serials of the 
product shall be selected for testing in the stability study.
    (f) Testing sequences--(1) Initial test. The first test in the 
sequence shall be as close as practical to the day of filling into 
final containers or the date of final formulation if the potency of the 
product is tested in bulk form.
    (2) Subsequent testing for in vitro assays. (i) One test every 3 
months during the first year of storage;
    (ii) One test every 6 months during the second year of storage; and
    (iii) One test annually thereafter throughout the proposed dating 
period.
    (3) Subsequent testing for in vivo assays. One test at the end of 
the proposed dating period.
    (g) When to conduct a stability study. Stability studies must be 
conducted for the following:
    (1) Newly licensed products whose dating has not been confirmed;
    (2) Licensed products with confirmed dating but a major change to 
the product or to the potency test has occurred; and
    (3) Licensed products with confirmed dating in which a change in 
one or more of the stability criteria is requested.
    (h) Submitting data. At the completion of the real-time stability 
study to confirm or change the dating period, the data shall be 
submitted to Animal and Plant Health Inspection Service for approval 
for filing and the approved for filing date shall be specified in 
section VI of the filed Outline of Production at the next revision.
    (i) Monitoring stability of the product. For products licensed 
subsequent to April 13, 2018, the licensee or permittee shall submit a 
plan to monitor the stability of the product and the suitability of its 
dating period that includes regularly testing selected serials for 
potency during and at the end of dating.

    Done in Washington, DC, this 9th day of March 2018.
Kevin Shea,
Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 2018-05143 Filed 3-13-18; 8:45 am]
BILLING CODE 3410-34-P