[Federal Register Volume 81, Number 227 (Friday, November 25, 2016)]
[Notices]
[Pages 85226-85229]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-28332]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-D-2537]


Submission of Quality Metrics Data; Draft Guidance for Industry; 
Availability; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability; request for comments.

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

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a revised draft guidance for industry entitled 
``Submission of Quality Metrics Data.'' In order to help develop 
compliance and inspection policies and practices, improve the Agency's 
ability to predict, and therefore possibly mitigate, future drug 
shortages, and to encourage the pharmaceutical industry to implement 
state-of-the-art, innovative quality management systems for 
pharmaceutical manufacturing, FDA intends to initiate a quality metrics 
reporting program. The revised draft guidance describes FDA's plans for 
an initial, voluntary phase of this program. FDA expects that this 
voluntary phase will allow the Agency to learn more about a limited set 
of quality metrics and associated analytics, and to help inform future 
FDA decisionmaking about its quality metrics program. This revised 
draft also provides an opportunity to gain additional perspectives from 
industry participants on the future use of quality metrics data.

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draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by January 24, 2017.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-2015-D-2537 for ``Submission of Quality Metrics Data.'' 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

[[Page 85227]]

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 (CDER), Food and Drug Administration, 10001 New Hampshire 
Ave., Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002 or 
to the Office of Communication, Outreach and Development, Center for 
Biologics Evaluation and Research (CBER), Food and Drug Administration, 
10903 New Hampshire Ave., 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.

FOR FURTHER INFORMATION CONTACT: Tara Gooen Bizjak, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 2109, Silver Spring, MD 20993-0002, 301-
796-3257; 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 ``Submission of Quality Metrics Data.'' More than a 
decade ago, FDA launched an initiative to encourage the implementation 
of a modern, risk-based pharmaceutical quality assessment system. As 
part of this initiative, and in recognition of the increasing 
complexity of pharmaceutical manufacturing, FDA developed a 21st 
century vision for manufacturing and product quality with input from 
academia and industry. FDA articulated its vision as ``a maximally 
efficient, agile, flexible pharmaceutical manufacturing sector that 
reliably produces high-quality drug products without extensive 
regulatory oversight.''
    Significant progress toward achieving this vision has occurred in 
the intervening years, as evidenced by programs and guidance from FDA 
around major initiatives such as pharmaceutical development and quality 
by design, quality risk management and pharmaceutical quality systems, 
process validation, and process analytical technology, among others. 
These programs and guidances are intended to promote effective use of 
the most current pharmaceutical science and engineering principles, and 
knowledge throughout a product's life cycle.
    Despite these achievements, however, we have not fully realized our 
21st century vision for manufacturing and quality, and indicators of 
serious product quality defects persist. The Agency has found that the 
majority of drug shortages stem from quality issues--the discovery of 
substandard manufacturing facilities or processes, or identification of 
significant quality defects in finished products, necessitating 
remediation efforts, which in turn, may interrupt production, and cause 
a shortage of drugs. Taking action to reduce drug shortages remains a 
top priority for FDA.
    The continued existence of product quality issues may point to 
increased complexities in the supply chain, limited innovation in 
manufacturing, inadequate adoption of modern manufacturing technologies 
and robust quality management systems, or other factors. As described 
in the revised draft guidance, FDA is proposing a voluntary phase of a 
quality metrics reporting program to learn more about a limited set of 
quality metrics and associated analytics. Under this program, beginning 
in early 2018, FDA anticipates accepting the voluntary submission of 
data from owners and operators of certain human drugs establishments, 
especially manufacturers of covered drug products and active 
pharmaceutical ingredients (API) used in covered drug products. A 
covered drug product is: (1) Subject to an approved application under 
section 505 of the Federal Food, Drug, and Cosmetic (the FD&C Act) (21 
U.S.C. 355) or under section 351 of the Public Health Service Act (the 
PHS Act) (42 U.S.C. 262); (2) marketed pursuant to an over-the-counter 
(OTC) monograph, or (3) a marketed unapproved finished drug product. 
Other types of establishments may also choose to submit quality metrics 
data as explained in the revised draft guidance. FDA expects to use 
information about participating establishments in our risk-based 
decisionmaking, and to evaluate our planned analytics as we further 
develop the quality metrics program as a subject of future rulemaking.
    Under Title VII section 706 of the Food and Drug Administration 
Safety and Innovation Act (FDASIA) (Pub. L. 112-144), FDA may require 
the submission of any records or other information that FDA may inspect 
under section 704 of the FD&C Act (21 U.S.C. 374), in advance or in 
lieu of an inspection by requesting the records or information from a 
person that owns or operates an establishment that is engaged in the 
manufacture, preparation, propagation, compounding, or processing of a 
drug. The quality metrics data described in the revised draft guidance 
is information of the type that FDA may inspect under section 704 of 
the FD&C Act. However, FDA does not intend to require the submission of 
information pursuant to section 704(a)(4) of the FD&C Act in 
implementing the voluntary phase of the quality metrics reporting 
program. FDA does not intend to take enforcement action based on errors 
in a quality metrics data submission made to this voluntary phase of 
the reporting program, provided the submission is made in good faith.
    Current good manufacturing practice (CGMP) for human drugs requires 
manufacturers to have an ongoing program to maintain and evaluate 
product and process data that relate to product quality (21 CFR 
211.180(e) and 21 U.S.C. 351(a)(2)(B)). Manufacturers are expected to 
use a quality program to support process validation, and manufacturers 
may include the metrics described in this guidance in their quality 
program. As discussed in the revised draft guidance, FDA encourages

[[Page 85228]]

manufacturers to routinely use additional quality metrics beyond the 
metrics described in this guidance in performing product and 
establishment specific evaluations.
    FDA envisions information collected from a fully implemented 
quality metrics reporting program will be an important factor in 
further focusing the use of FDA resources on the areas of highest risk 
to public health, which may include: (1) Establishing a signal 
detection program as one factor in identifying establishments and 
products that may pose significant risk to consumers; (2) identifying 
situations in which there may be a risk for drug supply disruption; (3) 
improving the effectiveness of establishment inspections; and (4) 
improving FDA's evaluation of drug manufacturing and control 
operations.
    FDA has engaged with stakeholders in several ways to develop 
mutually useful and objective quality metrics. On July 28, 2015, FDA 
published a draft guidance entitled ``Request for Quality Metrics'' (80 
FR 44973). On August 24, 2015, FDA conducted a public meeting to 
discuss the draft guidance at the Agency's campus in Silver Spring, MD. 
FDA has also consulted stakeholders at various trade and professional 
association meetings, and published a prior request for comment in the 
Federal Register on February 12, 2013 (78 FR 9928), that concerned 
manufacturing quality metrics as they relate to drug shortages. These 
efforts identified several categories of quality-related information 
that CDER and CBER considered in developing the quality metrics 
discussed in the guidance. The revised draft guidance announced in this 
notice replaces the currently published draft guidance.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on the submission 
of quality metrics data. It does not establish any rights for any 
person and is not binding on FDA or the public. You can use an 
alternative approach if it satisfies the requirements of the applicable 
statutes and regulations.

II. Revisions to the 2015 Draft Guidance

    On July 28, 2015, FDA announced the availability of the draft 
guidance entitled ``Request for Quality Metrics'' (80 FR 44973). The 
revised draft guidance includes the following changes from the earlier 
draft guidance: Adoption of a phased-in (voluntary) approach, reduction 
in the number of data elements requested (i.e., reduction in reporting 
burden), support for both product reports and site reports, 
modifications to the quality metrics data definitions, addition of 
clarifying examples for the definitions, addition of comment fields, 
and clarification of special considerations for non-application and OTC 
product reporting. FDA recognizes that a voluntary phase of the program 
would give participants an opportunity to demonstrate transparency and 
a willingness to proactively engage with the Agency in pursuit of the 
goals described in the revised draft guidance. FDA also expects that it 
will be able to use information submitted during a voluntary phase of 
the program to inform risk-based decisionmaking, and to help evaluate 
our planned analytics as we further develop the quality metrics 
reporting program as a subject of future rulemaking.
    A voluntary program would also allow all types of drug 
manufacturing establishments to report information. For example, active 
ingredient manufacturers, including those manufacturing atypical active 
ingredients, and excipient manufacturers, may participate in the 
voluntary phase of the reporting program. While the program is geared 
towards finished drug products and API manufacturing, all manufacturers 
may report quality metrics data. FDA may not be able to accomplish the 
overall goals of an FDA quality metrics reporting program, as described 
in the draft guidance, from voluntary reporting alone. If FDA does not 
receive a large body of data from reporting establishments, the ways in 
which the Agency can use the information may be limited. For example, 
the data received may not constitute a representative sample of the 
industry. Further, a self-selection bias may increase the risk of 
signaling an outlier where none exists. For these reasons, we expect to 
use the information collected during this voluntary phase of the 
program to specifically focus on: (1) Working with establishments 
towards early resolution of potential quality problems and to reduce 
the likelihood that the establishment's operations will be disrupted 
and impact the drug supply, (2) helping to prepare for and direct our 
inspections, and (3) use of the calculated metrics as an element of the 
post-approval manufacturing change reporting program with an emphasis 
on encouraging lifecycle manufacturing improvement.
    We intend to include the reporting of quality metrics as a factor 
in our surveillance inspection risk-based model, publish a list of 
reporters who provide a certain amount of information, share publicly 
the measured impact on inspection frequency reduction, and provide an 
opportunity for participants to submit feedback.
    In the revised draft guidance, FDA has reduced the proposed 
footprint of the program from four primary metrics and three optional 
metrics to three primary metric areas (i.e., lot acceptance rate, 
invalidated out-of-specification rate, and product quality complaint 
rate). FDA continues to recognize the importance of measuring an 
establishment's pharmaceutical quality system robustness and quality 
culture (e.g., senior management engagement, Corrective Action and 
Preventive Action effectiveness and continual improvement, and process 
capability/performance). Furthermore, these areas continue to be 
covered on FDA drug establishment manufacturing inspections, and 
concomitant metrics may be added as the program matures.
    FDA revised the guidance to clarify the technical definitions and 
provide illustrative examples for specific scenarios (see Appendix B of 
the revised draft guidance). FDA revised the draft guidance to 
contemplate submission of either product reports segmented by site, or 
site reports segmented by product. FDA intends to publicly recognize 
both product reporting and site reporting establishments on a quality 
metrics reporters list. The Agency intends to encourage product 
reporting because it demonstrates a certain level of oversight and 
controls over the manufacturing of drug products across the supply 
chain. In addition, we believe that a product report is better suited 
to identify potential drug supply disruptions. As described in the 
revised draft guidance, FDA intends to publish a quality metrics 
reporters list that includes product reporters that provide a list of 
the establishments in their product supply chain and some or all of the 
quality metrics data identifying them as ``Product Reporter Top Tier'' 
or ``Product Reporter Mid Tier'', respectively. The proposed quality 
metrics reporter list would also identify reporters who provide only 
the list of the establishments in their product supply chain.
    In the approach described in the revised draft guidance, site 
reporting establishments would also be included on the quality metrics 
reporters list, as there may be scenarios where product reporting 
establishments do not have access to this information or may choose not 
to report for covered establishments. FDA intends to provide an 
opportunity

[[Page 85229]]

for both types of establishments to benefit from this incentive.
    In order to implement a phased-in approach, FDA intends to begin 
collecting quality metrics data as part of a voluntary phase of the 
program. The first phase of the quality metrics program outlined in the 
revised draft guidance would be fully voluntary. After evaluating the 
results of the voluntary phase of the quality metrics program in 2018, 
FDA intends to initiate notice and comment rulemaking under existing 
statutory authority to develop a mandatory quality metrics reporting 
program.
    FDA carefully considered supporting flexible data collection 
timeframes for the purposes of reporting. In the context of a program 
that required product-based reporting, such flexibility would be 
feasible. However, in the context of the voluntary phase of the 
reporting program, FDA is proposing a common timeframe to facilitate 
publication of the quality metrics reporters list, and given the need 
to identify duplicate data if both the product reporting establishment 
and site reporting establishment submit data.
    A Technical Specifications Document entitled ``Quality Metrics 
Technical Conformance Guide, Version 1.0'' was published on June 27, 
2016 (81 FR 41545). This guide provides technical recommendations for 
the submission of quality metrics data. It is intended to serve as the 
technical reference for implementation of the quality metrics program. 
FDA intends to publish Version 2.0 of the Technical Conformance Guide 
soon after publication of the revised draft guidance. We anticipate 
that the electronic submission platform will be available to test in 
2017.
    Reporting establishments will be able to submit 300 word text 
comments to provide an explanation of submitted data or report plans 
for improvement. FDA may refer to the comments if unusual data or 
trends are identified or as preparation for an onsite inspection. The 
submission of comments is optional. In the future, FDA may consider 
establishing a set of codes to standardize the comments.
    FDA also revised the draft guidance to address the special 
complexities for grouping non-application drug products. Defining a 
``product'' for the purpose of grouping non-application drugs for the 
submission of quality metrics data proved challenging without an 
application number. Using one segment to group products, such as active 
pharmaceutical ingredient(s), manufacturing process, minor formulation 
changes, or stock-keeping unit, is an imperfect solution. For the 
purpose of this revised draft guidance, FDA has defined a product 
family for finished drug products as any combination of National Drug 
Code (NDC) product code segments where the active pharmaceutical 
ingredient and dose form is the same (i.e., a product family could be 
multiple strengths or only a single strength). For APIs, the product 
family is defined by the NDC product code segment. Our intent is to 
define product family in a way that was likely consistent with how 
products are grouped for the Periodic Product Review per 21 CFR 
211.180(e) (e.g., Annual Product Review). We expect that this approach 
will group similar products with similar manufacturing operations 
together.
    There are also special considerations with respect to product 
quality complaints for OTC products. Manufacturers of OTC products 
typically receive much more frequent communications from customers than 
manufacturers of prescription drug products, and the nature of these 
communications are quite different. The definition of a product quality 
complaint is intended to cover any possible or actual quality issue, 
while excluding preferential complaints. We anticipate that our 
analytics will account for this imbalance in reporting type between 
prescription and OTC drug products.

III. How To Report Quality Metrics Data to FDA

    FDA expects to encourage reporting establishments to submit quality 
metrics data reports where the data is segmented on a quarterly basis 
throughout a single calendar year. At present, FDA intends to open the 
electronic portal in January 2018 to receive voluntary submissions of 
data. FDA expects to publish a Federal Register notice providing 
instructions on the submission of voluntary reports and specifying the 
dates that we intend to open the portal, published no fewer than 30 
days before the portal is opened (e.g., before December 1, 2017). FDA 
expects to begin the data analysis once the portal is closed and then 
publish initial findings and the quality metric reporters list on the 
FDA Web site.
    To reduce discrepancies between site and product reporting, FDA is 
proposing a defined, uniform reporting period.
    In the rare instance that a reporting establishment or covered 
establishment discovers an error in its submission, an amendment may be 
made with an associated explanation via email to [email protected]. The amendment process is specified in the 
Technical Conformance Guide.

IV. Paperwork Reduction Act of 1995

    This revised 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 (44 U.S.C. 3501-
3520). The collection of some of the information requested in the 
revised draft guidance is covered under FDA regulations at 21 CFR parts 
210 and 211 and approved under OMB control number 0910-0139. In 
accordance with the PRA, FDA intends to solicit public comment and 
obtain OMB approval for any information collections recommended in this 
guidance that are new or that would represent material modifications to 
those previously approved collections of information found in FDA 
regulations or guidances. Subject to OMB approval, FDA anticipates that 
it will begin collecting quality metrics data in January 2018.

V. Electronic Access

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

    Dated: November 18, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-28332 Filed 11-23-16; 8:45 am]
 BILLING CODE 4164-01-P