United States: Update: FDA's Drug And Biologic Manufacturing Quality Metrics Program

The US Food & Drug Administration (FDA or the Agency) recently unveiled the next phase in the Agency's quest to implement a quality metrics program.¹ On June 29, 2018, FDA announced the availability of the Quality Metrics Feedback Program, which includes a pilot program, and the Quality Metrics Site Visit Program. These programs will allow the Agency to obtain additional stakeholder feedback on the use of quality metrics and to further develop the Quality Metrics Voluntary Reporting Program beyond what the Agency proposed in its 2016 revised draft guidance for industry, Submission of Quality Metrics Data.² FDA views quality metrics as a tool for helping to predict drug quality problems, mitigate the risk of drug shortages and inform risk-based inspection scheduling of drug manufacturing facilities.³ Below, we summarize the history of quality metrics at the Agency, FDA's quality metrics guidance for industry, the newly announced programs, and possible next steps.

Quality Metrics—What Are They and How Did We Get Here?

Definition

Quality metrics are widely used by industry "to monitor quality control systems and processes. . . . [and] robust quality metrics programs [are] a foundation for continual improvement of product and process quality."⁴ An awareness of and commitment to quality is also essential to maintaining compliance with current good manufacturing practice (CGMP) standards. In fact, the Agency expects that establishments already collect data for calculating many of the quality metrics identified in the 2016 Submission of Quality Metrics Data Guidance through their CGMP activities, specifically the review of data reflecting process trends, quality of incoming materials or components, in-process materials, and finished products. Overall, quality metrics reflect a company's commitment to a quality culture.⁵

History and Guidance

Attaining high levels of quality throughout the pharmaceutical product lifecycle is a key focal point for the Agency.⁶ The Center for Drug Evaluation and Research's (CDER) push for a quality metrics program is a product of CDER's Quality Initiative that originated with the Agency's 21st Century Initiative, a plan to modernize regulation of and improve pharmaceutical quality.^{7 8} An overarching goal of the 21st Century Initiative is to realize "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight."⁹ With the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, FDA obtained additional tools and authority that augmented its ability to fulfill its quality mission, namely the authority to obtain certain records and other information in advance or in lieu of an inspection, and the directive to implement a risk-based inspection schedule for foreign and domestic drug facilities.¹⁰

Despite significant progress toward achieving this vision and the goals articulated in the 21st Century Initiative, FDA recognized that further action was needed to address persistent and significant quality issues that contributed to drug shortages. Thus, in July 2015, FDA, led by staff in the newly formed Office of Pharmaceutical Quality (OPQ) issued the draft guidance for industry: Request for Quality Metrics.¹¹ As outlined in the draft guidance, FDA intended to request the submission of quantitative quality data from owners and operators of certain establishments involved in pharmaceutical manufacturing for the purpose of calculating four required and three optional quality metrics (e.g., Lot Acceptance Rate and Product Quality Complaint Rate, among others).¹² FDA's stated purpose for utilizing quality metrics was to develop and inform risk-based inspection scheduling, identify situations that could pose a risk of drug supply interruption, improve establishment inspections, improve evaluation of drug manufacturing and control operations, and assist FDA in identifying establishments that may "pose significant risks to consumers, such as risks from unsafe products and drug shortages."¹³

In response to numerous comments submitted to the draft guidance docket, many of which expressed concern about a mandatory reporting program and "regulation by guidance," FDA issued a revised, pared-down version of the draft guidance in November 2016: Submission of Quality Metrics Data. The revised draft guidance essentially retained the reporting program, but specified that participation would be voluntary (the Quality Metrics Voluntary Reporting Program). FDA would also focus on the following more limited set of quality metrics (three) based on data reported to the Agency: Lot Acceptance Rate (as an indicator of manufacturing process performance),¹⁴ Product Quality Complaint Rate (as an indicator of patient or customer feedback)¹⁵ and Invalidated Out-of-Specification (OOS) rate (IOOSR) (as an indicator of the operation of a laboratory).¹⁶ The revised draft guidance also proposed publishing a "Reporters List"—a list of the names of establishments that voluntarily report the quality data requested in the guidance. However, FDA has indicated that it does not intend to pursue this initiative at this time.¹⁷

FDA originally planned to start accepting submissions from participants in the voluntary reporting program starting in early 2018.¹⁸ However, in response to comments on the 2016 Submission of Quality Metrics Data Guidance and discussions with industry since the revised guidance was published, FDA has decided to seek more input from key stakeholders before moving forward with the Quality Metrics Voluntary Reporting Program. Hence, the introduction of the Agency's Quality Metrics Feedback and Quality Metrics Site Visit Programs, described below.

Quality Metrics Feedback and Quality Metrics Site Visit Programs

Based on industry feedback and recommendations that the Agency conduct further studies of the Quality Metrics Voluntary Reporting Program, FDA is implementing the Quality Metrics Feedback and Quality Metrics Site Visit programs announced in the Federal Register on June 29, 2018.¹⁹ The goal of these programs is for FDA to obtain additional industry and other key stakeholder input that will inform further development of the Quality Metrics Voluntary Reporting Program.

The Quality Metrics Feedback Program provides two options for interacting with the Agency: through Type C or pre-ANDA meetings, or through a Quality Metrics Pilot Program (as discussed below). With respect to the first option, new drug application (NDA) applicants or sponsors and pre-abbreviated new drug application (ANDA) applicants or sponsors may submit a Type C formal meeting request or pre-ANDA meeting request, as appropriate, to discuss with FDA their experiences with implementing quality metrics programs.²⁰ Applicants and sponsors interested in participating should be willing to provide access to current and historical product-specific metrics and supporting data (particularly the metrics that FDA specified in the 2016 Submission of Quality Metrics Data Guidance), discuss details of their quality metrics programs, and share information supporting the product-specific metrics. Applicants or sponsors may submit requests to participate in the Quality Metrics Feedback Program through a Type C or pre-ANDA meeting until July 29, 2019.

With respect to the second option of interacting with the Agency for purposes of the Quality Metrics Feedback Program, the Quality Metrics Pilot Program is geared toward establishments that may not request Type C or pre-ANDA meetings but have implemented quality metrics programs. All "covered establishments" that meet the selection criteria may apply.²¹ FDA is aiming for a diverse set of participants that covers a broad swath of the pharmaceutical industry, including manufacturers of brand, generic, biotechnology, active pharmaceutical ingredients (API), and non-application products marketed under an over-the-counter monograph; contract development and manufacturing organizations; and establishments with past or current product availability issues.

To be eligible for participation in the pilot program, establishments must have developed and implemented a quality metrics program that supports product and process quality improvement and includes product-specific measurements (minimally those specified in the 2016 Submission of Quality Metrics Data Guidance). We note that although this program is identified as a "pilot" program, it is not intended to serve as a test run of the Quality Metrics Voluntary Reporting Program outlined in the 2016 Submission of Quality Metrics Data Guidance. Rather, the goal of the Quality Metrics Pilot Program is for establishments that do not qualify for Type C or pre-ANDA meetings to meet with FDA to discuss their quality metrics programs and provide feedback to FDA. Interested participants should apply early—FDA is accepting only the first nine applicants for the Quality Metrics Pilot Program, which began on July 30, 2018 and ends on July 29, 2019.

The Quality Metrics Site Visit Program is intended to provide CDER and CBER staff with the opportunity to observe industry quality metrics programs and give industry the opportunity to convey to FDA the advantages and challenges associated with maintaining a quality metrics program. A site visit will consist of five to ten FDA staff observing how quality metrics data are gathered, collected and reported to management over a one- to two-day period. Host establishments are also invited to present overviews of their quality management programs to the visiting FDA staff. Covered establishments, including those that develop and manufacture APIs and drug products, those that do not perform physical manipulation of drugs, and the types of entities targeted by the Quality Metrics Pilot Program, are encouraged to participate.²² Companies interested in participating in the Quality Metrics Site Visit Program must submit a written or electronic site visit proposal to FDA by December 17, 2018.²³

Next Steps

Implementing a Quality Metrics Voluntary Reporting Program and mitigating drug shortages remain top priorities for the Agency. To ensure industry participation, we expect that FDA will incorporate lessons learned from the Quality Metrics Feedback and Site Visit programs into a revised draft or final guidance as it proceeds to implement the next iteration of the Quality Metrics Voluntary Reporting Program. It is also possible that FDA will eventually pursue notice and comment rulemaking to fully implement its quality metrics initiatives, at least for a mandatory reporting program. Although the quality metrics initiative has had a rocky history to date, a reasonably implemented program could yield benefits for industry, patients and FDA. Companies that may have contemplated participation in the past should evaluate FDA's latest actions in this area.

Footnote

1 Quality Metrics Site Visit Program for Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research Staff; Information Available to Industry Quality Metrics Site Visit Program), 83 Fed. Reg. 30751 (June 29, 2018); Modernizing Pharmaceutical Quality Systems; Studying Quality Metrics and Quality Culture; Quality Metrics Feedback Program (Quality Metrics Feedback Program), 83 Fed. Reg. 30748 (June 29, 2018).

2 FDA Draft Guidance for Industry, Submission of Quality Metrics Data, Rev. 1 (2016 Submission of Quality Metrics Data Guidance) (Nov. 2016).

3 Mitigating drug shortages by addressing the underlying causes of shortages is a long-term Agency priority. See generally, Strategic Plan for Preventing and Mitigating Drug Shortages (Oct. 2013).

4 Quality Metrics for Drug Manufacturing (updated July 16, 2018).

5 Id.

6 See also the Center for Devices and Radiological Health's Premarket Approval Critical-to-Quality and Manufacturing and Product Quality Pilot Programs (updated Aug. 23, 2018).

7 The Center for Biologics Evaluation and Research (CBER) is also a partner in the Quality Metrics guidance, and the guidance applies to products approved under section 351 of the Public Health Service Act.

8 CDER's Quality Initiative (updated Aug. 28, 2017); Final Report, Pharmaceutical CGMPs for the 21st Century―A Risk-Based Approach (Sept. 2004).

9 FDA Pharmaceutical Quality Oversight, at 1.

10 See FDASIA, Pub. L. No. 112-144; FDASIA Title VII Overview (updated Mar. 28, 2018).

11 Request for Quality Metrics; Notice of Draft Guidance Availability and Public Meeting; Request for Comments, 80 Fed. Reg. 44973 (July 28, 2015); FDA Draft Guidance for Industry, Request for Quality Metrics (2015 Quality Metrics Guidance) (July 2015).

12 2015 Quality Metrics Guidance at 11.

13 Id. at 7-8.

14 The number of accepted lots in a timeframe divided by the number of lots started by the same covered establishment in the current reporting timeframe.

15 The number of product quality complaints received for the product divided by the total number of dosage units distributed in the current reporting timeframe.

16 The number of OOS test results for a lost release and long-term stability testing invalidated by the covered establishment due to an aberration of the measurement process divided by the total number of lot release and long-term stability OOS test results in the current reporting timeframe.

17 Quality Metrics for Drug Manufacturing (updated July 16, 2018).

18 See Submission of Quality Metrics Data; Draft Guidance for Industry; Availability; Request for Comments, 81 Fed. Reg. 85226 (Nov. 25, 2016).

19 See supra, n.1.

20 "A Type C meeting is any meeting other than a Type A, Type B or Type B (EOP) meeting regarding the development and review of a product, including meetings to facilitate early consultations on the use of a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval in the proposed context of use." Draft Guidance for Industry, Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products, at 4 (Dec. 2017).

21 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 product subject to an approved NDA or marketed pursuant to an OTC monograph, or a marketed unapproved finished drug product). SeeQuality Metrics Feedback Program.

22 See Quality Metrics Site Visit Program.

23 Quality Metrics Site Visit Program for Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research Staff; Information Available to Industry; Extension of the Proposal Period, 83 Fed. Reg. 41080 (Aug. 17, 2018).

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