[Federal Register Volume 83, Number 126 (Friday, June 29, 2018)]
[Notices]
[Pages 30748-30751]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-14005]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-1903]


Modernizing Pharmaceutical Quality Systems; Studying Quality 
Metrics and Quality Culture; Quality Metrics Feedback Program

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) Center 
for Drug Evaluation and Research (CDER) is announcing two new efforts 
to gather feedback on the use of quality metrics to modernize 
pharmaceutical quality systems and advance innovation based on 
stakeholder feedback. These efforts include Type C formal meeting 
requests and pre-abbreviated new drug application (pre-ANDA) meeting 
requests, and a pilot study to gain feedback from those establishments 
for which Type C formal meetings or pre-ANDA meetings do not apply 
(e.g., active pharmaceutical ingredients (API) establishments, contract 
manufacturing organizations, over-the-counter (OTC) monograph products 
establishments, or marketed unapproved finished drug products 
establishments). Participation in either of these efforts is voluntary 
and the programs are intended to foster the joint efforts of FDA and 
stakeholders to further develop an FDA Quality Metrics Program. The FDA 
Quality Metrics Program aims to evaluate a new approach for regulatory 
oversight of pharmaceutical products through the collection of certain 
quality information developed and maintained in the course of 
manufacturing drugs under current good manufacturing practices. FDA 
intends to use quality metrics data to further develop the Agency's 
risk-based inspection scheduling (e.g., decreased surveillance 
inspection frequency for certain establishments) to improve the 
efficiency and effectiveness of establishment inspections, improve 
FDA's evaluation of drug manufacturing and control operations, and 
identify situations in which there may be a risk for drug supply 
disruption.

DATES: Submit a written request to participate in the program by July 
29, 2019. See sections II and III.B of this notice for information to 
include in such requests. FDA will start accepting requests beginning 
July 30, 2018.

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, 301-796-
3257, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    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 quality with 
input from academia and industry. The desired state was described as 
follows: ``A maximally efficient, agile, flexible pharmaceutical 
manufacturing sector that reliably produces high-quality drug products 
without extensive regulatory oversight.'' \1\
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    \1\ See ``FDA Pharmaceutical Quality Oversight: One Quality 
Voice'' at https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf.
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    There has been significant progress toward this vision 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 other 
initiatives. These programs and guidances are intended to promote 
effective use of the most current pharmaceutical science and 
engineering principles and knowledge throughout the life cycle of a 
product.
    While much progress has been made, we have not fully realized our 
21st century vision for manufacturing and quality. Rather than focusing 
on use of science- and risk-based principles as described in current 
good manufacturing practices, many establishments continue to focus on 
minimum requirements (e.g., check-box approach). Recalls and drug 
shortages, which are often indications of serious product quality 
defects caused by drug

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manufacturing issues, continue to occur.2 3 The Agency has 
found that most drug shortages stem from quality issues (e.g., 
substandard manufacturing facilities or processes, or significant 
quality defects are identified in the finished product). These 
situations necessitate remediation efforts to fix the issue, which in 
turn may interrupt production and cause a shortage of drugs. Taking 
action to reduce drug shortages remains a top priority for FDA.
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    \2\ Refer to https://www.fda.gov/Drugs/DrugSafety/DrugRecalls/default.htm for more information on drug recalls.
    \3\ In 2012, for example, based on information collected from 
manufacturers, FDA determined that 66 percent of disruptions in drug 
manufacturing were the result of either efforts to address product-
specific quality failures or broader efforts to remediate or improve 
an unsafe manufacturing facility. FDA's ``Strategic Plan for 
Preventing and Mitigating Drug Shortages,'' see figure 2, at https://www.fda.gov/downloads/drugs/drugsafety/drugshortages/ucm372566.pdf.
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    FDA sought input from industry on the establishment of an FDA 
Quality Metrics Program as another mechanism to promote continual 
improvement in manufacturing quality. FDA has also consulted with other 
stakeholders to identify mutually useful and objective quality metrics. 
The Agency learned that it should perform further studies of the FDA 
Quality Metrics Program through a pilot program and additional 
discussions with stakeholders. Based on this input, FDA is initiating 
this Quality Metrics Feedback Program to assist the Agency in the 
development of a Quality Metrics Program. Stakeholders are encouraged 
to participate in these efforts by using the two feedback procedures 
described below. Additional references may be found at the FDA web 
page, Quality Metrics for Drug Manufacturing, https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm526869.htm.
    Based on stakeholder feedback, FDA is presenting two new methods 
for engaging industry. The approaches announced in this notice provide 
industry stakeholders with an opportunity to provide information to 
further the development of the Quality Metrics Program. CDER will also 
continue to engage with trade associations to gather feedback for 
industry subsectors.
    FDA does not intend to publicly disclose information submitted to 
the Agency as part of this Quality Metrics Feedback Program that is 
exempt from disclosure under disclosure laws and regulations. The 
following types of information may be exempt from public disclosure if 
not made public by the owner: (1) Commercial relationships; (2) 
production and sales volume; (3) business plans; and (4) unapproved 
applications.

II. Type C Formal Meetings and Pre-ANDA Meetings

    Applicants who have an interest in participating in this method of 
the FDA Quality Metrics Feedback Program should submit a written 
request. New drug application (NDA) applicants or sponsors should 
follow the procedures for submitting Type C meeting requests as 
described in the draft guidance for industry entitled ``Formal Meetings 
Between the FDA and Sponsors or Applicants of PDUFA Products (December 
2017).'' \4\ The requests should be labeled as ``Type C Meeting--
Request to Participate in the Quality Metrics Feedback Program.'' Pre-
ANDA applicants or sponsors planning to submit an original or 
supplemental pre-ANDA should submit a pre-ANDA meeting request to OPQ-
OS-Quality [email protected] and label it as ``Pre-ANDA Meeting--
Request to Participate in the Quality Metrics Feedback Program.''
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    \4\ We update guidances periodically. To make sure you have the 
most recent version of a guidance, check the FDA Drugs guidance web 
page at https://www.fda.gov/Drugs/GuidancecomplianceRegulatoryInformation/Guidances/default.htm.
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    In addition to the procedures and items outlined in the referenced 
guidances, a request for a meeting should include the following items:
    1. A description of the quality metrics currently used for the 
product and process in the facility(ies) that are specific to the risks 
of the facility(ies), products, manufacturing processes, supply chain, 
and current business decisions (e.g., amount of product held in 
inventory or days on hand). That is, the metrics which have been 
determined by the applicant to be most meaningful to product quality 
and for patient impact.
    2. A statement on whether the following quality metrics are 
measured using consistent definitions: Lot acceptance rate per product 
or rejection rate, invalidated out-of-specification rate per product, 
product quality complaint rate, process performance and process 
capability per product, corrective action and preventive action 
effectiveness, quality system timeliness, and on-time-in-full 
fulfillment of orders.
    3. A statement that suitably detailed technical definitions for the 
quality metrics data elements in the previously mentioned items (1) and 
(2) are established to enable consistent measurement and comparison.
    4. A description of the routine assessment and management oversight 
of quality culture. This assessment should include all levels of staff, 
from senior management to base level employees, to gauge and shape the 
behaviors, beliefs, values, morals, conventions, goals, and practices 
that characterize or are associated with manufacturing at the 
facility(ies).
    5. A description of the ongoing site management and senior 
management review of the quality metrics program, including 
identification of areas for continual improvement.
    To maximize the benefits of an in-person meeting, FDA prefers that 
the applicant or sponsor provide a statement of willingness for one or 
more of the following: (1) To provide access to certain current and 
historical product-specific measures and the data supporting the 
measures, including lot acceptance rate or rejection rate, product 
quality complaint rate, and invalidated out-of-specification rate; (2) 
to share available information supporting the categories (product 
specific measurements), where applicable, of process performance and 
process capability (product specific), corrective and preventive 
actions (CAPA) effectiveness, quality culture, quality system metrics 
(e.g., periodic product report on-time rate), and on-time-in-full 
fulfillment of orders (product specific); and (3) to discuss details of 
their quality metrics program, including quality metrics data 
definitions and methods of analyzing available data.
    We intend to accept as many meeting requests as Agency resources 
allow and to focus on establishments that show an interest in engaging 
in robust discussions regarding their quality metrics programs. FDA 
expects to notify companies in writing of its decision regarding 
meeting acceptance within 60 days of receipt of their requests. 
Although incomplete and/or unclear requests will generally be denied, 
FDA may contact the applicant to request additional information. Once a 
meeting is granted, the participant can engage with the Quality Metrics 
Program team in accordance with existing meeting procedures and 
guidance(s). FDA anticipates that discussions with stakeholders will 
help to further develop the Quality Metrics Program and will provide 
the Agency with information on existing industry practices using modern 
pharmaceutical quality systems.

III. Pilot Program

A. Participation

    Establishments eligible to participate in this voluntary Quality 
Metrics Pilot

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Program are limited to nine or fewer firms that follow the procedures 
set forth in section III.B and meet the following selection criteria:
    1. The company must be a covered establishment. A covered 
establishment is an owner or operator of an establishment that is 
engaged in the manufacture, preparation, propagation, compounding, or 
processing of a covered drug product, or an API used in the manufacture 
of a covered drug product. A covered drug product is: (1) Subject to an 
approved application under section 505 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 355) or under section 351 of the Public Health 
Service Act (42 U.S.C. 262); (2) marketed pursuant to an OTC monograph; 
or (3) a marketed unapproved finished drug product. A covered 
establishment does not need to be involved in the physical manipulation 
of a drug.
    2. The company must have a quality metrics program that has been 
developed and implemented by the quality unit and that is used to 
support product and process quality improvement. The established 
quality metrics program must include product-specific measurements and 
include at a minimum: (1) Lot acceptance rate or rejection rate, (2) 
invalidated out-of-specification rate, and (3) product quality 
complaint rate. If a product is manufactured at more than one location, 
these product specific metrics could be limited to operations at the 
participating covered establishment. To provide feedback on recommended 
changes in the metrics definitions, send an email to OPQ-OS-
Quality[email protected].
    The ideal participant in the Quality Metrics Pilot Program will 
have the following elements in their quality metrics program:
    1. Quantitative measurement of quality metrics for the products and 
processes in the facility(ies) that are specific to the risks of the 
facility(ies), products, manufacturing processes, supply chain, and 
current business decisions (e.g., amount of product held in inventory 
or days on hand);
    2. Certain quality metrics measured, such as lot acceptance rate or 
rejection rate per product, invalidated out-of-specification rate per 
product, product quality complaint rate, process performance and 
process capability per product, CAPA effectiveness, quality system 
timeliness, and on-time-in-full fulfillment of orders;
    3. Suitably detailed technical definitions for the quality metrics 
data elements to enable consistent measurement and comparison;
    4. routine assessment and management oversight of quality culture 
at multiple levels of staff, such as senior management to base level 
employees, to assess and shape the behaviors, beliefs, values, morals, 
conventions, goals, and practices that characterize or are associated 
with manufacturing at the facility(ies); and
    5. Ongoing site management and senior management review of the 
quality metrics with identification of areas for continual improvement.
    The establishments that will likely benefit most from the Quality 
Metrics Pilot Program and discussions with FDA are those that are able 
to: (1) Provide access to certain current and historical product-
specific measures and the data supporting the measures, including lot 
acceptance rate or rejection rate, product quality complaint rate, and 
invalidated out-of-specification rate; (2) share available information 
supporting the following categories (product specific measurements), 
where applicable, of process performance and process capability 
(product specific), CAPA effectiveness, quality culture, quality system 
metrics (e.g., periodic product report on-time rate), and on-time-in-
full fulfillment of orders (product-specific); (3) discuss details of 
their quality metrics program, including quality metrics data 
definitions and methods of analyzing available data (for comparison 
purposes, we are interested in establishments that are willing to 
provide data based on definitions in the draft guidance as well as 
their preferred definitions); (4) be available for real-time 
consultations with FDA; (5) provide information about the firm's 
quality management system related to the quality metrics program; and 
(6) comment on and discuss their experiences with this Quality Metrics 
Pilot process.

B. Procedures

    To be considered for the voluntary Quality Metrics Pilot Program, a 
company should submit a statement of interest for participation to OPQ-
OS-Quality[email protected]. The statement of interest should include 
agreement to the selection qualities listed in section III.A.
    The following captures the proposed process for the Quality Metrics 
Pilot Program selection:
    1. FDA will collect statements of interest for participation in the 
pilot program beginning July 30, 2018.
    2. FDA will select the first nine participants that submit a 
statement of interest in participation meeting the selection criteria 
in the first paragraph of section III.A. While any covered 
establishment meeting the criteria may request inclusion in the pilot 
program per the first paragraph of section III.A, FDA would prefer that 
establishments for which Type C formal meetings and pre-ANDA meetings 
are not applicable use this approach. Additionally, FDA is seeking 
participants that represent different sectors of the pharmaceutical 
industry, including companies that manufacture the following types of 
products: Brand, generics, biotechnology, APIs, and non-application 
products marketed under the OTC monograph system. Furthermore, we are 
looking for representation from contract development and manufacturing 
organizations, establishments with small and large portfolios, and 
establishments with past or current product availability issues (e.g., 
history of a drug supply issue or recall).
    3. Lessons learned from the initial participants in the pilot 
program (maximum of nine participants) will help inform FDA's thinking 
as it refines the Quality Metrics Program.

IV. Beginning Date of the Quality Metrics Pilot Program and Type C 
Formal Meetings and Pre-ANDA Meetings

    FDA intends to accept requests for participation in the voluntary 
Quality Metrics Pilot Program and Type C formal meetings and Pre-ANDA 
meetings beginning July 30, 2018. The pilot program will begin July 30, 
2018 and will close July 29, 2019. The Type C formal meetings and pre-
ANDA meetings will be granted based on the schedules described in the 
associated guidance documents.

V. Paperwork Reduction Act of 1995

    This notice refers to previously approved collections of 
information found in FDA regulations. These collections of information 
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 
collections of information in 21 CFR part 505 have been approved under 
OMB control number 0910-0001 and the collections of information in 21 
CFR parts 210 and 211 have been approved under OMB control number 0910-
0139.
    The collections of information to be included in a meeting request 
for a product submitted in an NDA is approved under OMB control number 
0910-0429. The collections of information to be included in a meeting 
request for a product submitted in an ANDA is approved under OMB 
control number 0910-0797.


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    Dated: June 25, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-14005 Filed 6-28-18; 8:45 am]
 BILLING CODE 4164-01-P


