2016-28332. Submission of Quality Metrics Data; Draft Guidance for Industry; Availability; Request for Comments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The Food and Drug Administration (FDA or Agency) is announcing the availability of a revised draft guidance for industry entitled “Submission of Quality Metrics Data.”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 The revised draft guidance describes FDA's plans for an initial, voluntary phase of this program.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comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance, submit either electronic or written comments on the draft guidance by January 24, 2017.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 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 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 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 [e-mail]. 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.