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Submission of Quality Metrics Data

Submission of Quality

Metrics Data Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER) Tara Gooen Bizjak at 301-796-3257 or (CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 240- 402-8010.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016

Pharmaceutical Quality/CMC
Current Good Manufacturing Practices (CGMPs)

Revision 1

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1063761 RevDft

Submission of Quality

Metrics Data Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research

Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993
Phone: 800-835-4709 or 240-402-8010
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016

Pharmaceutical Quality/CMC
Current Good Manufacturing Practices (CGMPs)

Revision 1

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I. II.

A.

B. III.

A. B. C. D.

E. IV.

A. B.

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

BACKGROUND ............................................................................................................... 2

Modernization of Regulatory Oversight of Drug Quality and Promotion of
Post-Approval Improvements....................................................................................................... 2 Quality Metrics Data – Regulatory Foundation.......................................................................... 3

REPORTING OF QUALITY DATA AND CALCULATION OF QUALITY METRICS.......................................................................................................................... 5

Who Reports and Who May Contribute to a Report ................................................................. 5 Quality Metrics that FDA Intends to Calculate .......................................................................... 7 Quality Metrics Data that May Be Reported .............................................................................. 7 How to Submit Comments Within a Quality Metric Data Report and How to

Pose Questions to FDA ................................................................................................................ 11 How to Report Quality Metrics Data to FDA............................................................................ 11

THE USE OF QUALITY METRICS AND PUBLIC REPORTING ........................ 12

How FDA Intends to Use Quality Metrics ................................................................................. 12 Quality Metric Reporters List .................................................................................................... 13

GLOSSARY................................................................................................................................. 16

APPENDIX A: APPLICABLE IDENTIFYING INFORMATION AND QUALITY METRIC DATA ELEMENTS FOR PRODUCT REPORTS AND SITE REPORTS......... 17

APPENDIX B: EXAMPLES..................................................................................................... 26

Draft – Not for Implementation Contains Nonbinding Recommendations

1 Submission of Quality Metrics Data 23 Guidance for Industry1

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not create 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. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

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I. INTRODUCTION 15

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  1. 16  Quality metrics are used throughout the drugs and biologics

  2. 17  systems and processes and drive continuous improvement efforts in drug manufacturing. These

  3. 18  metrics can also be useful to FDA: to help develop compliance and inspection policies and

  4. 19  practices, such as risk-based inspection scheduling of drug manufacturers; to improve the

  5. 20  Agency’s ability to predict, and therefore, possibly mitigate, future drug shortages; and to

  6. 21  encourage the pharmaceutical industry to implement state-of-the-art, innovative quality

  7. 22  management systems for pharmaceutical manufacturing. This revised draft guidance includes an

  8. 23  explanation of how the Center for Drug Evaluation and Research (CDER) and the Center for

  9. 24  Biologics Evaluation and Research (CBER) intend to utilize submitted data and quality metrics

  10. 25  to help ensure that their policies and practices continue to support continuous improvement and

  11. 26  innovation in the pharmaceutical manufacturing industry.

27

  1. 28  In order to achieve these goals, FDA is initiating a quality metrics reporting program.

  2. 29  described in this guidance, FDA is initiating a voluntary reporting phase of the FDA quality

  3. 30  metrics reporting program.4 In the voluntary reporting phase of the program, FDA expects to

  4. 31  learn more about a limited set of quality metrics, associated analytics, and improve the FDA

  5. 32  quality metrics reporting program.

33

  1. 34  During the voluntary phase of the reporting program, FDA will accept voluntarily submissions of

  2. 35  data from owners and operators of human drug establishments. FDA expects that the large

industry to monitor quality control

3

As

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1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 This guidance uses the terms “drugs” to refer to both drugs and biologics.
3 FDA issued a draft guidance regarding the collection of quality metrics on July 28, 2015. In response to comments received in the public docket (FDA-2015-D-2537), FDA is replacing the draft guidance published in 2015 with this revised draft.

4 More details about the timing of the program are in the notice announcing the availability of this draft guidance in the Federal Register.

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  1. 36  majority of voluntary reports will be submitted by establishments engaged in the manufacture,

  2. 37  preparation, propagation, compounding, or processing of finished dosage forms (FDF) of

  3. 38  “covered drug products” or active pharmaceutical ingredients (API) used in the manufacture of

  4. 39  “covered drug products.”5

40

  1. 41  The voluntary reporting phase of the program described in this guidance is not focused on

  2. 42  reporting from certain CDER regulated manufacturers (i.e., compounders operating under

  3. 43  section 503A or registered as outsourcing facilities under section 503B of the Federal Food,

  4. 44  Drug, and Cosmetic Act (FD&C Act) or CBER regulated manufacturers of blood and blood

  5. 45  components for transfusion, vaccines, in vitro diagnostics,6 cell therapy products, gene therapy

  6. 46  products, allergenic extracts, human cells, tissues, and cellular and tissue based products).7

47

  1. 48  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 49  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 50  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 51  the word should in Agency guidances means that something is suggested or recommended, but

  5. 52  not required. Also, in this guidance, the use of the word should is used to indicate an FDA

  6. 53  preference to promote consistent reporting and counting of quality metrics data.8

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II. BACKGROUND
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A. Modernization of Regulatory Oversight of Drug Quality and Promotion of

Post-Approval Improvements

59 60

  1. 61  FDA’s approach to quality oversight has evolved in recent years. CDER and CBER are

  2. 62  committed to supporting the modernization of pharmaceutical manufacturing as part of the

  3. 63  Agency’s mission to protect and promote public health. This effort is also part of a long-term

  4. 64  strategy to mitigate drug shortages by addressing the underlying causes of shortages, as noted in

  5. 65 FDA’s Strategic Plan for Preventing and Mitigating Drug Shortages.9 In 2002, FDA launched

  6. 66  an initiative entitled “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach,” to

  7. 67  encourage the implementation of a modern, risk-based pharmaceutical quality assessment

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5 The terms “covered drug product” and “covered establishment” are defined in section III.A.
6 This guidance is not applicable to biological products that meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)).
7 The guidance does apply to licensed biological products that are plasma derived products, including recombinant and transgenic versions of plasma derivatives.
8 FDA intends to accept voluntary reports with quality metrics data that are inconsistent with the metrics and definitions in this guidance, as well as reports about establishments and products that are not the focus of the voluntary reporting phase of the quality metrics program as described in this guidance. However, as the data submitted in a manner inconsistent with the definitions and recommendations in this guidance may not be comparable with submissions from other reporters, we: (1) do not intend to include these reporters on the quality metrics reporters list, and (2) may not be able to integrate the submission of the report into FDA’s risk-based inspection model. Submissions will be evaluated on a case-by-case basis.
9 See FDA’s Strategic Plan for Preventing and Mitigating Drug Shortages at: http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf.

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  1. 68  system.10 The initiative was published with several goals, including ensuring that regulatory

  2. 69  review, compliance, and inspection policies support continuous improvement and innovation in

  3. 70  the pharmaceutical manufacturing industry. Since publication of the Pharmaceutical cGMPs for

  4. 71  the 21st Century, CDER has promoted a vision of “a maximally efficient, agile, flexible

  5. 72  manufacturing sector that reliably produces high-quality drug products without extensive

  6. 73  regulatory oversight.”11

74

  1. 75  FDA encourages manufacturers to routinely use additional quality metrics beyond the metrics

  2. 76  described in this guidance in performing product and establishment specific evaluations.12 The

  3. 77  selected metrics are not intended to be an all-inclusive set of the quality metrics that

  4. 78  manufacturers may find useful to assess a product and manufacturer’s state of quality.

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B. Quality Metrics Data – Regulatory Foundation 81

  1. 82  FDA understands that establishments involved in the manufacture, preparation, propagation, or

  2. 83  processing of human drugs, including oversight to ensure quality,13 currently use quality metrics

  3. 84  as part of the process validation lifecycle and pharmaceutical quality system (PQS) assessment.14

  4. 85  The metrics described in this guidance could be a part of such oversight.

86

  1. 87  As described in FDA’s process validation guidance, manufacturers depend on information and

  2. 88  knowledge from product and process development as the basis for establishing an approach to

  3. 89  control of the manufacturing process (i.e., a control strategy) that results in products with the

    10 See Pharmaceutical cGMP’s for the 21st Century: A Risk-Based Approach at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan ufacturingPracticescGMPforDrugs/ucm137175.htm.
    11 See FDA Pharmaceutical Quality Oversight: One Quality Voice at http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM4426 66.pdf.

    12 One type of evaluation is an internal, independent audit and review of processes and procedures to determine whether established protocols and procedures have been followed. FDA’s Compliance Policy Guide Sec. 130.300, FDA Access to Results of Quality Assurance Program Audits and Inspections (June 2, 2007) describes our policy that during routine inspections and investigations, FDA will not review or copy these specific reports and records to encourage firms to conduct candid and meaningful audits and inspections. The voluntary submission of quality metrics data described in this guidance will be for specific data that are maintained on-site, routinely reviewed during inspections, and not subject to a request for the results of an internal audit. http://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm073841.htm.

    13 Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) section 711 added text to section 501 of the FD&C Act clarifying that, for the purposes of paragraph 501(a)(2)(B), the term “current good manufacturing practice” includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.

    14 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1). We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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Draft – Not for Implementation Contains Nonbinding Recommendations

  1. 90  desired quality attributes.15 Once a control strategy has been successfully implemented,

  2. 91  manufacturers are expected to maintain the process in a state of control over the life of the

  3. 92  process, even as materials, equipment, production environment, personnel, and manufacturing

  4. 93  procedures change.16 Current good manufacturing practice (CGMP) for human drugs require

  5. 94  manufacturers to have an ongoing program to maintain and evaluate product and process data

  6. 95  that relate to product quality.17 Best practice for this ongoing assessment is continued process

  7. 96  verification,18 which should include a Periodic Product Review (PPR), conducted at least

  8. 97  annually, in which data collected includes relevant process trends and quality of incoming

  9. 98  materials or components, in-process materials, and finished products. Some establishments may

  10. 99  call this evaluation an Annual Product Review (if conducted annually) or a Product Quality

  11. 100  Review,19 for finished drug products or APIs, respectively. We expect that most of the quality

  12. 101  metrics data described in this guidance will be collected by establishments already as part of

  13. 102  conducting the PPR.

103

  1. 104  Under Title VII section 706 of the Food and Drug Administration Safety and Innovation Act

  2. 105  (FDASIA) Public Law No. 112-144, FDA may require the submission of any records or other

  3. 106  information that FDA may inspect under section 704 of the FD&C Act, in advance or in lieu of

  4. 107  an inspection by requesting the records or information from a person that owns or operates an

  5. 108  establishment that is engaged in the manufacture, preparation, propagation, compounding, or

  6. 109  processing of a drug. The quality metrics data described in this guidance is information of the

  7. 110  type that FDA may inspect under section 704 of the FD&C Act. However, FDA does not intend

  8. 111  to require the submission of information pursuant to section 704(a)(4) of the FD&C Act in

  9. 112  implementing the voluntary phase of the quality metrics reporting program. FDA does not

  10. 113  intend to take enforcement action based on errors in a quality metrics data submission made as a

  11. 114  part of this voluntary phase of the reporting program, provided the submission is made in good

  12. 115  faith.

116

  1. 117  Section 510(h)(3) of the FD&C Act requires a risk-based inspection schedule for drug

  2. 118  establishments according to the known safety risks posed by establishments that are required to

  3. 119  register. These risks are based on certain factors described in section 510(h)(4)(A-F), including

  4. 120  the inherent risk of the drug manufactured, prepared, propagated, compounded, or processed at

  5. 121  the establishment and other factors. FDA intends to analyze the calculated quality metrics to

  6. 122  support its understanding of the safety risks of manufacturing establishments and products, and

  7. 123  as the basis for criteria it deems necessary and appropriate for allocating inspection resources.

    15 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1) for a description of other sections of 21 CFR part 211 that set forth requirements related to aspects of process validation. 16 FDASIA section 711 added text to section 501 of the FD&C Act clarifying that, for the purposes of paragraph 501(a)(2)(B), the term “current good manufacturing practice” includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.
    17 See 21 CFR 211.180(e) and section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).
    18 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1).
    19 The Product Quality Review of APIs is comparable to the Annual Product Review conducted for finished drug products under 21 CFR 211.180(e). Refer to FDA guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.

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Draft – Not for Implementation Contains Nonbinding Recommendations

REPORTING OF QUALITY DATA AND CALCULATION OF QUALITY METRICS

A. Who Reports and Who May Contribute to a Report

1. Covered Establishments and Covered Drug Products

Except as noted below, owners and operators of each 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, may submit quality metrics data. For purposes of this guidance, we will refer to the types of establishments whose owners or operators directly or indirectly submit reports as “covered establishments.”

For purposes of reporting a covered drug product or an API used in the manufacture of a covered drug product, a covered drug product is:

o subject to an approved application under section 505 of the FD&C Act or under section 351 of the Public Health Service Act (PHS) Act,

o marketed pursuant to an OTC monograph, or

o a marketed unapproved finished drug product.

Covered establishments also include (but are not limited to) contract laboratories, contract sterilizers, contract packagers,20 and other establishments, as appropriate, engaged in the manufacture, preparation, propagation, compounding, or processing of a covered drug product or API used in a covered drug product.

2. Who Reports for Covered Establishments

This guidance describes two types of quality metric data reports: (1) product reports submitted by product reporting establishments,21 and (2) site reports submitted by site reporting establishments. We encourage reports from product reporting establishments and site reporting establishments. FDA prefers for all covered establishments to work with a product reporting establishment and report data for the covered drug product so that the product reporting establishment submits a single product report that includes data from all covered establishments.

20 Contract re-packagers that purchase product and repackage it into a different primary packaging configuration are included (e.g., large bottles of tablets repackaged into unit dose blister packs). Contract re-packagers that purchase product and repackage into secondary or tertiary packaging are not included.
21 A “product reporting establishment” is one establishment who will already possess or have access to all of the quality metrics data needed to submit such reports. It is further defined in section III.A.2.a.

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  1. 162  Compilation of data into a single product report will facilitate data analysis and identification of

  2. 163  product specific issues (e.g., potential loss in drug supply).

164
165 a. Submission of a product report by a product reporting establishment

166

  1. 167  The subject of a product report will generally be a covered drug product or an API used in the

  2. 168  manufacture of a covered drug product. The report may include quality metrics data from each

  3. 169  covered establishment within the manufacturing supply chain that has the data described in this

  4. 170  guidance. FDA believes that, as part of its responsibility for oversight and controls over the

  5. 171  manufacture of drugs to ensure quality, one establishment will already possess or have access to

  6. 172  all of the quality metrics data needed to submit such reports — for example, through contract or

  7. 173  because all of the covered establishments with quality metrics data related to a covered drug

  8. 174  product or API used in the manufacture of a covered drug product will be under common

  9. 175  ownership or control.22 This establishment should combine the data so that a single report is

  10. 176  submitted. For example, a single API may be the subject of a stand-alone product report, as

  11. 177  APIs are often supplied to multiple customers and finished drug product manufacturers often use

  12. 178  multiple API suppliers.

179

  1. 180  In this guidance, we refer to the covered establishments that submit product reports to FDA as

  2. 181  “product reporting establishments.” If a product reporting establishment is gathering data from

  3. 182  covered establishments in the manufacturing supply chain for a particular product for the

  4. 183  purpose of submitting a product report, but data is not available for a covered establishment,

  5. 184  FDA prefers that the product report clearly identifies the covered establishment and that specific

  6. 185  data was not received.23

186

  1. 187  FDA believes that the quality control unit (QCU)

  2. 188  drug product or API used in a covered drug product will generally be best positioned to compile

  3. 189  reports for submission to FDA, considering the QCU responsibilities and authorities for the

  4. 190  oversight of drugs as described in 21 CFR 211.22.25

191
192 b. Submission of a site report by a site reporting establishment 193

  1. 194  If the covered establishment prefers to report directly or is unsure if all products and data will be

  2. 195  reported via a product report, the covered establishment may elect to submit a site report. In this

  3. 196  guidance, we refer to the covered establishments that submit site reports to FDA as “site

  4. 197  reporting establishments.”

198

22 See, e.g., FDASIA section 711; 21 CFR 200.10(b).
23 Refer to Appendix A.1, A.2, A.3, and A.4.
24 For the purpose of this guidance, the term “quality control unit” is synonymous with “quality unit.”
25 For APIs, these responsibilities are described in FDA guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (section 2.2).

24

in each reporting establishment for a covered

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  1. 199  The subject of a site report is a single covered establishment. A complete report would list all

  2. 200  covered products with associated quality metric data specific to each product manufactured at the

  3. 201  subject establishment as described in this guidance.26

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B. Quality Metrics that FDA Intends to Calculate 204

  1. 205  The following set of quality metrics that FDA intends to calculate based on industry reporting

  2. 206  was developed with stakeholder input. FDA used the following selection criteria in developing

  3. 207  the set of data that it is inviting covered establishments to submit: (1) objective data to provide

  4. 208  consistency in reporting, (2) of the type contained in records subject to inspection under section

  5. 209  704 of the FD&C Act, and (3) a valuable component in assessing the overall effectiveness of a

  6. 210  PQS, within reasonable limits, and in a reasonable manner, while avoiding an undue reporting

  7. 211  burden. FDA believes that these quality metrics data, in conjunction with other data accessible

  8. 212  to FDA, provide important information about operational reliability.

213

  1. 214  Using reported data described in the following section, FDA intends to calculate quality metrics

  2. 215  for each product and covered establishment, where applicable:

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  1. 233  Section IV.B describes the types of metrics FDA intends to calculate and the associated data that

  2. 234  may be submitted to calculate and understand each metric. FDA encourages product reporting 30

  3. 235  establishments to submit product reports, segmented by covered establishment, where possible.

    26 Refer to Appendix A.5, A.6, A.7, and A.8.
    27 This term does not refer to samples and protocols under 21 CFR 610.2.
    28 Reference this guidance’s Glossary for OOS result (e.g., lot release tests and long-term stability tests only). A single result (e.g., one value on a Certificate of Analysis) may result in only one OOS test result.
    29 The metric measures invalidated lot release OOS results and long-term stability OOS results, separately.
    30 FDA anticipates that data relevant to contract laboratories will generally be limited to the number of OOS results, the number of lot release and stability tests conducted, and the number of invalidated OOS.

Lot Acceptance Rate (LAR) as an indicator of manufacturing process performance. LAR = 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.

Product Quality Complaint Rate (PQCR) as an indicator of patient or customer feedback. PQCR = the number of product quality complaints received for the product divided by the total number of dosage units distributed in the current reporting timeframe.

Invalidated Out-of-Specification (OOS) Rate (IOOSR) as an indicator of the operation of a laboratory. IOOSR = the number of OOS test results for lot release27 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.28,29

C. Quality Metrics Data that May Be Reported

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  1. 236  The quality metrics data described in this draft guidance is developed and maintained in the

  2. 237  course of manufacturing drugs in compliance with CGMP. In general, the information that FDA

  3. 238  will receive is maintained in accordance with 21 CFR 211 subpart J and evaluated under 21 CFR

  4. 239  211.180(e). For non-finished drug products (e.g., APIs), refer to section 501(a)(2)(B) of the

  5. 240  FD&C Act and FDA guidance for industry Q7 Good Manufacturing Practice Guidance for

  6. 241 Active Pharmaceutical Ingredients. Data that is summed and reported as described in this

  7. 242  section is in a readily accessible format for analysis.

243

  1. 244  Reporting of data related to lots of drugs that are imported, intended for import into the United

  2. 245  States, or manufactured in the United States is preferred. However, FDA recognizes that it may

  3. 246  not be possible for some covered establishments to identify started lots, rejected lots, and OOS

  4. 247  results that are specific to drugs that are imported, intended for import, or manufactured in the

  5. 248  United States. Further, lots manufactured outside of the United States may be split after

  6. 249  manufacturing is completed and a portion is imported, or intended for import into the United

  7. 250  States. In these instances, if the manufacturing process uses the same process and controls data

  8. 251  for lots that are not specific to those that are imported, intended for import, or manufactured in

  9. 252  the United States, the report could include both data from lots not imported or intended for

  10. 253  import to the United States with the data from lots imported or intended for import to the United

  11. 254  States for the lot acceptance and invalidated OOS metrics. The selection of drugs that are either:

  12. 255  (1) imported, intended for import, or manufactured in the United States, or (2) all drugs using the

  13. 256  same manufacturing process and controls which are not necessarily imported, intended for

  14. 257  import, or manufactured in the United States, should remain consistent within and across

  15. 258  reporting cycles, unless otherwise specified. Product quality complaint data should be related to

  16. 259  drugs that are imported, intended for import or manufactured in the United States.

260

  1. 261  Reporting of data should include all manufacturing operations, including testing, which would be

  2. 262  included in a PPR (e.g., lots intended for commercial distribution, post-approval clinical trial lots

  3. 263  when the same manufacturing process and controls are used as for commercial lots).

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The number of saleable lots started which are intended for primary packaging or distribution.

The number of saleable lots released for primary packaging or distribution.
The number of saleable lots started which are intended for primary packaging or

distribution and were rejected.
The number of lots started of in-process and packaging product lots which are intended

for distributed product.

The number of in-process and packaging product lots released which are intended for distributed product.

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281 The number of in-process and packaging product lots which were intended for distributed

product and were rejected.

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320 Specific criteria for the IOOSR data:
321

Examples of saleable lots include bulk tablets, filled vials, bulk milled in-process material if manufacturing is performed at another covered establishment, bulk API, and bulk intermediate API if further manufacturing is performed at another covered establishment.

A lot may be subdivided or grouped after the first started lot is initiated. Each subsequent subdivision or grouping is considered a separate lot.

Examples of packaging product lots include multiple packaging configurations of bulk tablets (e.g., small bottles, large bottles, blisters) and labeling filled sterile vials with multiple labels (e.g., intended for different countries). The packaging operation can be stand-alone lots or included in an existing lot.

In general, FDA anticipates that the number of lots started minus the sum of lots released and lots rejected will equal the total number of lots pending disposition (e.g., work in progress, lots evaluated for batch release, lots pending disposition due to quality-related discrepancies). We recognize that there are rare instances when this construct will not be valid (e.g., lots pending disposition for an extended period) and we encourage the use of the comment text box to explain the occurrence of such an anomaly.

The number of lot release test OOS and long-term stability OOS results for the finished drug product or API where the long-term stability test supports the labeled expiration date.

The total number of lot release and long-term stability tests conducted for the finished drug product or API where the long-term stability test supports the labeled expiration date.

The number of OOS results for lot release tests and long-term stability tests for the finished drug product or API where the source of the OOS result is identified as an aberration of the measurement process and where the stability test supports the labeled expiration date.

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Draft – Not for Implementation Contains Nonbinding Recommendations

An investigation must be conducted whenever an OOS result is obtained.31 For the purpose of the quality metrics program, the following OOS results should be counted: (1) finished drug product and API and long-term stability test results only, and (2) all finished drug product and API and long-term stability test results that initially indicate OOS, even if the source of the OOS is investigated and determined to be an aberration of the measurement process. See FDA guidance for Industry Investigating Out-of- Specification (OOS) Test Results for Pharmaceutical Production (October 2006), section III, and FDA guidance for industry Sterile Drugs Products Produced by Aseptic Processing – Current Good Manufacturing Practice (September 2004), section XI.

The number of total tests is a measurement tool that: (1) provides context for the invalidated OOS rate, and (2) provides a secondary metric for manufacturing performance and the ability to produce product within limits (lot release and long-term stability OOS results investigated as a manufacturing aberration divided by the total number of lot release and long-term stability tests performed in the same current reporting period).

For the purpose of this program, an OOS result should be counted on the day that the test result is completed or the day that an OOS investigation is initiated.

341
342

343
344
345
346
347
348

349
350
351

352
353
354

355
356
357

358
359
360
361 (3) Product Quality Complaint Rate (PQCR):
362
363
The number of product quality complaints received for the product.

31 See 21 CFR 211.192 and section 501(a)(2)(B) of the FD&C Act. 10

322 323
324
325

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330
331
332
333

334
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339
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A test includes a single analytical result for lot release or a stability timepoint with an established limit (e.g., analytical chemistry, release sterility test). For example: (1) for lot release, the final content uniformity result as reported on a Certificate of Analysis is considered one test; (2) for a stability timepoint, each test performed in the timepoint would count as an individual test.

A covered establishment that manufactures API used in a covered drug product is not expected to report stability OOS results.

For stability testing, only tests that support real-time stability of the product should be counted (i.e., accelerated stability testing is excluded).

If a lot release or long-term stability test is conducted multiple times for a lot (e.g., a retest), each test should be counted.

FDA recognizes the importance of other types of testing not discussed in this guidance (e.g., in-process testing, environmental testing, raw material and packaging component testing). However, results of these tests should not be counted in this report.

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364
365
The total number of dosage units distributed for the product. 366
367 Specific criteria for the PQCR data:
368
369

370
371
372
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374
375

376
377
378
379

  1. 380  Reporting establishments may submit a 300-word text comment to provide an explanation of

  2. 381  submitted data or report plans for improvement. FDA may refer to the comments if unusual data

  3. 382  or trends are identified, or in preparation for an on-site inspection. The submission of comments

  4. 383  is optional. In the future, FDA may consider establishing a set of codes to standardize the

  5. 384  comments.

385

  1. 386  Comments may describe special situations, such as natural disasters, the use of emerging

  2. 387  technology, or describe the manufacturing supply chain or a plan for improvement. For

  3. 388  example, an unexpected decrease in lot acceptance rate may be due to a situation outside the

  4. 389  control of the facility (e.g., an act of nature such as a storm or fire). For emerging technology,

  5. 390  the use of new, in-line analytical technology used for real time release testing with increased

  6. 391  sensitivity might result in better detection of in-process OOS results used for Real Time Release

  7. 392  Testing and thus, a temporary increase in total OOS results. However, improved detection that

  8. 393  allows for the diversion and rejection of poor quality product will provide improved assurance of

  9. 394  quality. In this instance, it may be appropriate to provide an explanation that new, improved

  10. 395  technology was implemented and that there is data demonstrating that more robust product was

  11. 396  released to the market as a result of this change (e.g., increased lot uniformity would be

  12. 397  appropriate).

398

  1. 399  Upon gathering this data, any questions that a covered establishment may have about their

  2. 400  specific situation can be sent to This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

401
402
E. How to Report Quality Metrics Data to FDA 403

  1. 404  To facilitate the quality metrics reporters list as described in section IV.B, a defined reporting

  2. 405  period (e.g., a single calendar year) is needed to reduce discrepancies between site and product

  3. 406  reporting. Therefore, reporting establishments may submit quality metrics data reports where the

The total number of all product quality complaints is based on the definition in the glossary. This number does not include multiple counting of the same product quality complaint if the complaint receiver forwards the complaint to individual manufacturers for further investigation. This number does include all potential quality issues, such as subpotency (e.g., a patient report of lack of effect).

The total number of dosage units distributed for the product is defined in the glossary.

D. How to Submit Comments Within a Quality Metric Data Report and How to Pose Questions to FDA

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  1. 407  data is segmented on a quarterly basis throughout a single calendar year.32 FDA expects to begin

  2. 408  the data analysis when the portal is closed and then publish initial findings and the quality metric

  3. 409  reporters list on the FDA Web site.

410

  1. 411  Appendix A of the draft guidance is a quality component list with the information for submission

  2. 412  into the electronic portal as well as a description of applicable quality metrics data elements

  3. 413  relevant for different business segments/types. The associated Technical Conformance Guide

  4. 414  describes additional technical details.33

415
416
417
IV. 418
419
420

  1. 421  FDA intends to use data from the quality metrics reporting program to focus the use of FDA

  2. 422  resources on the areas of highest risk to public health (e.g., risk-based inspection scheduling).

  3. 423  Specifically, we intend to:

424
425
426

  1. 427

  2. 428

  3. 429

430

  1. 431  Shortages of drugs can pose a significant public health threat; delaying, and in some cases even

  2. 432  denying, critically needed care for patients. Taking action to reduce drug shortages remains a

  3. 433  top priority for FDA. The Agency has found that the majority of drug shortages stem from

  4. 434  quality concerns—substandard manufacturing facilities or processes are discovered, or

  5. 435  significant quality defects are identified in finished drug product, necessitating remediation

  6. 436  efforts to fix the issue, which in turn, may interrupt production and cause a drug shortage. FDA

  7. 437  intends to use quality metrics, along with other measures, to identify potential shortage signals

  8. 438  and engage proactively with manufacturers to mitigate the likelihood of occurrence.

439

  1. 440  FDA may not be able to accomplish the overall goals of an FDA quality metrics reporting

  2. 441  program, as described in this draft guidance, from voluntary reporting alone. If FDA does not

  3. 442  receive a large body of data from reporting establishments, the ways in which the Agency can

  4. 443  use the information may be limited. For example, data received may not constitute a

  5. 444  representative sample of the industry. Further, a self-selection bias may increase the risk of

  6. 445  signaling an outlier where none exists. For these reasons, we expect to use the information

  7. 446  collected to specifically focus on: (1) working with establishments towards early resolution of

    32 More details about the timing of the program are in the notice announcing the availability of this draft guidance in the Federal Register.
    33 See http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM508464.pdf.

THE USE OF QUALITY METRICS AND PUBLIC REPORTING A. How FDA Intends to Use Quality Metrics

establish a signal detection program as one factor in identifying establishments and products that may pose significant risk to consumers;
identify situations in which there may be a risk for drug supply disruption; improve the effectiveness of establishment inspections; and

improve FDA’s evaluation of drug manufacturing and control operations.

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Draft – Not for Implementation Contains Nonbinding Recommendations

  1. 447  potential quality problems and to reduce the likelihood that the establishment’s operations will

  2. 448  be disrupted and impact the drug supply, (2) helping to prepare for and direct our inspections,

  3. 449  and (3) using the calculated metrics as an element of the post-approval manufacturing change

  4. 450  reporting program with an emphasis on encouraging lifecycle manufacturing improvement.

451

  1. 452  While FDA recognizes the value of quality metrics, we also recognize that the individual data

  2. 453  points and metrics described in this guidance, either individually or in combination, do not

  3. 454  definitively quantitate the quality of the establishment or its products. Further, FDA continues to

  4. 455  encourage the adoption of emerging technology. We request comments on implementing new

  5. 456  technology while maintaining robust quality metrics programs.

457

  1. 458  FDA intends to publish an analysis of the quality metrics data received on the FDA Web site to

  2. 459  share what the Agency has learned from the voluntary phase of the reporting program, and how

  3. 460  analyzing these data has affected the frequency of CGMP inspections and the ability of the

  4. 461  Agency to address potential drug shortage situations. We also intend to provide opportunities for

  5. 462  participating establishments to provide feedback and additional comments, as well as share

  6. 463  knowledge from ongoing, industry-driven quality metrics programs.

464
465
B. Quality Metric Reporters List 466

  1. 467  FDA intends to publish a list of the names of establishments that voluntarily report all or a subset

  2. 468  of quality data as described in this guidance (i.e., product reporting establishments and site

  3. 469  reporting establishments). We believe that there is a benefit to publicly sharing the names of

  4. 470  establishments that voluntarily choose to submit these quality data to FDA because, through their

  5. 471  participation, these establishments demonstrate a willingness to proactively engage with the

  6. 472  Agency in pursuit of the goals described in this guidance. Participation in this voluntary

  7. 473  reporting phase of the program also demonstrates a commitment to increasing transparency

  8. 474  between industry and FDA and a contribution to improving quality monitoring throughout the

  9. 475  industry.

476

  1. 477  This list may be useful to establishments within the pharmaceutical manufacturing industry when

  2. 478  selecting contract manufacturers and component suppliers as one element of robust outsourcer or

  3. 479  supplier selection (e.g., past inspection and regulatory authority history, audits of the facility and

  4. 480  associated systems, and analytical testing). This list may also be useful for healthcare purchasing

  5. 481  organizations, healthcare providers, patients, and consumers in sourcing drugs when used in

  6. 482  conjunction with other information (e.g., inspection history). The list will provide information

  7. 483  about whether an establishment voluntarily submitted quality metrics data to the Agency, and if

  8. 484  so how much data was submitted. It should be noted that inclusion on the list is not an indication

  9. 485  of FDA’s evaluation of the submitted data.

486

  1. 487  The Agency will identify participating establishments on FDA’s Web Site according to the

  2. 488  following recognition categories:

489
490
For Product Reporting Establishments (finished drug product reporter or API reporter): 491

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Draft – Not for Implementation Contains Nonbinding Recommendations

Product Reporter Top Tier: If complete data supporting all metrics were included for each covered establishment in the manufacturing supply chain for all covered drug products (or APIs used in the manufacture of a covered drug product) for the full year reporting period

Product Reporter Mid Tier: If all covered establishments in the manufacturing supply chain for all covered products were identified in the report, and complete quality metric data was provided from at least one of the establishments for each covered drug products (or APIs used in the manufacture of a covered drug product) for the full year reporting period

34

Product Supply Chain Reporter:
manufacturing supply chain for all covered drug products (or APIs used in the manufacture of a covered drug product) were identified in the report

35

If all covered establishments in the
For Site Reporting Establishments (finished drug product reporter or API reporter):

o o

509
510
511
512
513
514
515
516
517
  1. 518  For example, if product reporting establishment Company ABC submitted a report identifying all

  2. 519  covered establishments in the manufacturing supply chain for all covered drug products (or APIs

  3. 520  used in the manufacture of a covered drug product), but did not provide quality metrics data,

Site Reporter Top Tier: If complete data supporting all metrics were included for all covered drug products (or APIs used in the manufacture of a covered drug product) for the full year reporting period

Site Reporter Mid Tier: If complete data supporting all metrics were included for at least one covered drug product (or API used in the manufacture of a covered drug product) manufactured at an establishment for the full year reporting period

  1. 521  Company ABC would have a “Product Supply Chain Reporter” designation. If product reporting

  2. 522  establishment Company ABC submitted a report identifying all establishments in the

  3. 523  manufacturing supply chain for all covered drug products (or APIs used in the manufacture of a

  4. 524  covered drug product), and metrics data was provided from the primary manufacturing

  5. 525  establishment for each product or API, but incomplete data was submitted from the other

  6. 526  establishments in the manufacturing supply chain, Company ABC would have a “Product

  7. 527  Reporter Mid Tier” designation. If product reporting establishment Company ABC submitted a

  8. 528  complete report for the data listed above for all covered drug products (or APIs used in the

  9. 529  manufacture of a covered drug product), Company ABC would have a “Product Reporter Top

  10. 530  Tier” designation.

    34 “Product Supply Chain Reporter” is defined for the purpose of FDA’s quality metric reporting program and is not associated with Title II of the Drug Quality and Security Act, the Drug Supply Chain Security Act (DSCSA).
    35 An establishment may be considered a site reporting establishment by either: (1) directly submitting data to FDA (not applicable for product reporting establishments), or (2) indirectly submitting data to FDA via a product report, submitted by a product reporting establishment.

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531

  1. 532  For site reporters, if contract manufacturer Company XYZ manufactures 30 covered drug

  2. 533  products and submitted a report with at least one covered drug product produced at the

  3. 534  establishment and data supporting all metrics, Company XYZ would have a “Site Reporter Mid

  4. 535  Tier” designation. If the report contains data for all 30 products and all metrics for each covered

  5. 536  drug product, Company XYZ would have a “Site Reporter Top Tier” designation. Alternatively,

  6. 537  if Company XYZ submitted data to reporting establishments and the data covers each product

  7. 538  manufactured at the site, and the submitted product reports reference this establishment,

  8. 539  Company XYZ would also have a “Site Reporter Top Tier” designation.

540

  1. 541  FDA does not intend to publicly disclose information submitted to the Agency as part of the

  2. 542  voluntary phase of the quality metrics program that is exempt from disclosure under the Freedom

  3. 543  of Information Act as confidential commercial information, e.g., information that would reveal

  4. 544  nonpublic commercial relationships and production volumes.

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Draft – Not for Implementation Contains Nonbinding Recommendations

545 GLOSSARY 546

  1. 547 Active Pharmaceutical Ingredient (API)

  2. 548  into a finished drug product and is intended to furnish pharmacological activity or other direct

  3. 549  effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the

  4. 550  structure or any function of the body. Active pharmaceutical ingredient does not include

  5. 551  intermediates used in the synthesis of the substance. The term includes those components that

  6. 552  may undergo chemical change in the manufacture of the drug product and be present in the drug

  7. 553  product in a modified form intended to furnish the specified activity or effect.

554

  1. 555 Batch – a specific quantity of a drug or other material that is intended to have uniform character

  2. 556  and quality, within specified limits, and is produced according to a single manufacturing order

  3. 557  during the same cycle of manufacture.37 A batch may be comprised of one lot or multiple lots.

558

  1. 559 Continued Process Verification – A process validation activity where ongoing assurance is

  2. 560  gained during routine production that the process remains in a state of control.38

561

  1. 562 Critical Quality Attribute (CQA) – A physical, chemical, biological, or microbiological

  2. 563  property or characteristic that should be within an appropriate limit, range, or distribution to

  3. 564  ensure the desired product quality.39

565

  1. 566 Dosage Units – the total number of individual dosage units (e.g., 100,000 tablets, 50,000 vials,

  2. 567  50 kg), distributed or shipped under the approved application or product family (for non-

  3. 568  application products) to customers, including distributors.40

569

  1. 570 Establishment – a place of business under one management at one general physical location.

  2. 571  The term includes, among others, independent laboratories that engage in control activities for a

  3. 572  registered drug establishment (e.g., consulting laboratories).41

573

  1. 574 Finished Dosage Form (FDF) – the physical manifestation of a drug product that contains the

  2. 575  active ingredient(s) and/or inactive ingredients that are intended to be delivered to the patient.

  3. 576  Examples include tablets, capsules, vials, solutions, creams, or ointments.42

577

  1. 578 Finished Drug Product – a finished dosage form (FDF) (e.g., tablet, capsule, or solution) that

  2. 579  contains at least one active pharmaceutical ingredient, generally, but not necessarily, in

  3. 580  association with other ingredients in finished package form suitable for distribution to

    36 Refer to 21 CFR 207.1 (effective November 29, 2016) and 21 CFR 210.3(b)(7).
    37 See 21 CFR 210.3(b)(2).
    38 Refer to FDA guidance for industry Process Validation: General Principles and Practices (Rev 1).
    39 Refer to FDA guidance for industry Q8(R2) Pharmaceutical Development.
    40 See 21 CFR 314.81(b)(2)(ii)(a), 211.196.
    41 See 21 CFR 207.1 (effective November 29, 2016).
    42 Refer to “dose form” as defined in ISO 11616:2012(en), Health informatics – Identification of medicinal products – Data elements and structures for the unique identification and exchange of regulated pharmaceutical product information.

36

– any substance that is intended for incorporation

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  1. 581  pharmacies, hospitals, or other sellers or dispensers of the drug product to patients or

  2. 582  consumers.43

583

  1. 584 Long-term testing – Stability studies under the recommended storage condition for the retest

  2. 585  period or shelf life proposed (or approved) for labeling.44

586

  1. 587 Lot – a batch, or a specific identified portion of a batch, having uniform character and quality

  2. 588  within specified limits; or, in the case of a drug product produced by continuous process, it is a

  3. 589  specific identified amount produced in a unit of time or quantity in a manner that assures its

  4. 590  having uniform character and quality within specified limits.45

591

  1. 592 Accepted Lot – a started lot which has been released for distribution or for the next stage

  2. 593  of processing. If the lot is released with an unexpectedly low yield due to an assignable

  3. 594  root cause and the associated investigation supports the release of the lot, it should be

  4. 595  considered an accepted lot.46 Investigations into low yield results should be thorough and

  5. 596  managed by the quality unit. If a lot number is closed, the lot is transferred to a new lot

  6. 597  number, and subsequently released, only the original lot should be counted. An accepted

  7. 598  lot should be counted on the day of the final disposition decision. It may be possible that

  8. 599  an accepted lot is no longer considered accepted (e.g., a stability failure, a quality

  9. 600  problem identified by a contract packager, or in the marketplace). In this case, the lot

  10. 601  should no longer be counted as an accepted lot. If the change in disposition decision is

  11. 602  after submission of quality data, the reporter may submit an amendment and it would be

  12. 603  helpful if the amendment is available for discussion during a future on-site inspection.

604

  1. 605 Started Lot – a lot intended for commercial use for which the manufacturer has issued a

  2. 606  lot number, physically charged API (for finished drug manufacturers) or primary starting

  3. 607  materials (for API manufacturers), and there will be a disposition decision.47 If the

  4. 608  manufacturing spans multiple time segments (quarters), the started lot should be counted

  5. 609  when the lot number is issued or the API or primary starting material is physically

  6. 610  charged. If unique lot numbers are issued for different packaging configurations, each lot

  7. 611  number should be counted.

612

43 See 21 CFR 207.1 (effective November 29, 2016).
44 See FDA guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products.
45 See 21 CFR 210.3(b)(10).
46 For example: (1) if the power fails halfway through a tableting operation and a portion of the manufactured tablets are acceptable to release for distribution, this is considered an accepted lot, (2) if an API lot is reworked and released under the original lot number, the lot is considered an accepted lot, (3) for continuous manufacturing, if there was an unplanned shut down of the line due to quality reasons, this would be not be considered an accepted lot, (4) if the entire lot is rejected due to an OOS, the lot would not be considered an accepted lot, and (5) if the entire lot is rejected due to a potential contamination, the lot would not be an accepted lot.
47 See 21 CFR 211.101.

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  1. 613 Lot Release Test – includes all tests of conformance to final specifications, including all real

  2. 614  time release tests, and all in-process tests that act as a surrogate for final lot release (e.g., real

  3. 615  time release testing is approved in the application).48,49

616

  1. 617 Out-of-Specification (OOS) Result – all test results that fall outside the specifications or

  2. 618  acceptance criteria established in drug applications, drug master file, official compendia, or by

  3. 619  the manufacturer.50 An investigation must be conducted whenever an OOS result is obtained.51

  4. 620  For the purpose of the quality metrics program, the following test events should be counted: (1)

  5. 621  lot release, including in-process tests that act as a surrogate for a lot release test,52 and long-term

  6. 622  stability test results only and, (2) all lot release and long-term stability test results, even if the

  7. 623  source of the OOS is later determined to be due to a measurement aberration.53

624

  1. 625 Invalidated OOS – any out-of-specification result where the investigation identifies the

  2. 626  source of the OOS result as an aberration of the measurement process. Invalidation of a

  3. 627  discrete test result may be done only upon the observation and documentation of a test

  4. 628  event that can reasonably be determined to have caused the OOS result.54 For the

  5. 629  purpose of the quality metrics program, the following test events should be included: (1)

  6. 630  lot release55 and stability test results only and, (2) all lot release and stability test results

  7. 631  that initially appear as OOS, even if invalidated by a subsequent laboratory investigation.

632

  1. 633 Periodic Product Review – an evaluation, conducted at least annually, of the quality standards

  2. 634  of a drug product to determine the need for changes in drug product specifications or

  3. 635  manufacturing or control procedures.56

636

  1. 637 Product Family – for finished drug products, any combination of National Drug Code (NDC)

  2. 638  product code segments where the API and FDF is the same (i.e., a product family could be

  3. 639  multiple strengths or only a single strength).57 For APIs, the product family is defined by the

  4. 640  NDC product code segment. A product family is defined for the purpose of grouping non-

  5. 641  application drugs for the submission of quality metric data. Grouping is likely consistent with

  6. 642  how products are grouped for the Periodic Product Review (e.g., Annual Product Review).58

    48 See 21 CFR 211.165.
    49 This term does not refer to samples and protocols under 21 CFR 610.2.
    50 See FDA guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.
    51 See 21 CFR 211.192 and section 501(a)(2)(B) of the FD&C Act.
    52 For example, if a near infrared (NIR) spectroscopy-based method is approved for testing active content of core tablets for release as an alternative to testing active content on finished tablets by traditional high-performance liquid chromatography (HPLC) method, and the NIR result is reported on the Certificate of Analysis, this test should be counted as a single analytical result and OOS result, as appropriate, for the purpose of this guidance.
    53 Each test may also be defined as a single analytical result listed on the Certificate of Analysis.
    54 See 21 CFR 211.160(a) and FDA guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.
    55 This term does not refer to samples and protocols under 21 CFR 610.2.
    56 See 21 CFR 211.180(e).
    57 See 21 CFR 207.35.
    58 See 21 CFR 211.180(e).

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643

  1. 644 Product Quality Complaint – a complaint involving any possible, including actual, failure of a

  2. 645  drug to meet any of its specifications designed to ensure that any drug conforms to appropriate

  3. 646  standards of identity strength, quality, and purity.59

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59 See, e.g., 21 CFR 211.160(b); 211.198.

19

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APPENDIX A: APPLICABLE IDENTIFYING INFORMATION AND QUALITY METRIC DATA ELEMENTS FOR PRODUCT REPORTS AND SITE REPORTS

This appendix provides clarity on which identifying information and quality metric data elements are applicable for submission in the voluntary phase of the quality metrics reporting program. Technical details of quality metric data submissions are provided in the Technical Conformance Guide.60 Data standards are available for certain identifying information elements (e.g., dose forms, business operations).61

Appendix A is separated into eight (8) subparts. Each subpart corresponds to a different combination of report type, establishment type, and product type, as described in this draft guidance. Specifically:

Product Report, segmented by all sites o Application Product

62

Finished Drug Product: Appendix A.1

API: Appendix A.2 o Non-Application Product

Finished Drug Product: Appendix A.3 API: Appendix A.4

Site Report, segmented by products
o Manufacturing with product quality oversight responsibilities only: Appendix A.5 o Manufacturer with testing responsibilities: Appendix A.6
o Manufacturer without testing responsibilities: Appendix A.7
o Manufacturer with testing responsibilities only: Appendix A.8

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60 See http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM508464.pdf.
61 See http://www.fda.gov/forindustry/datastandards/structuredproductlabeling/ucm162038.htm.
62 For a product report, when information was not provided by a contract facility, the corresponding data elements should be marked as “not provided.”

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Appendix A.1: Applicable Inputs for a Product Report Submission, Application Product, Finished Drug Product

page24image6920 page24image7808 page24image14664 page24image16000 page24image17312 page24image18624 page24image20256 page24image21128

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

X

N/A

X

X

page24image29920

X

X

page24image31552

N/A

page24image32632 page24image32952

X

page24image34176

X

X

page24image35800

N/A

page24image36976 page24image37136

X

page24image38624

X

N/A

N/A

page24image41320

N/A

page24image42816

N/A

N/A

page24image45040

N/A

X

page24image47264

X

page24image48488

N/A

N/A

N/A

page24image55184 page24image55984 page24image56736 page24image57640 page24image67408 page24image67888 page24image69584 page24image70488 page24image71664 page24image72568 page24image73744 page24image74648 page24image76304 page24image76888 page24image77616 page24image78096

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page24image100360 page24image101712 page24image102192 page24image103264 page24image104592 page24image113936 page24image116112 page24image118192 page24image120272 page24image122832 page24image124144

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page24image148752 page24image149552 page24image150304 page24image151208 page24image160976 page24image161456 page24image163152 page24image164056 page24image165232 page24image166136 page24image167312 page24image168216 page24image169872 page24image170456 page24image171184 page24image171664

Contract Laboratory performing release or stability testing only

N/A

N/A

page24image176832

N/A

N/A

page24image178720

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

page24image190752

N/A

N/A

N/A

page24image193800

N/A

N/A

page24image196120

N/A

N/A

page24image198440

N/A

X

page24image201184

X

page24image202352

X

675

X = Input is applicable to report; N/A = Input is not applicable to report

18

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN

Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

676 677

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.2: Applicable Inputs for a Product Report Submission, Application Product, API

page25image6504 page25image9528 page25image14072 page25image15408 page25image19640 page25image20856

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

N/A

N/A

X

X

page25image29488

X

X

N/A

page25image32352 page25image32776

X

page25image33832

X

X

page25image35720

N/A

page25image36904 page25image37224

X

X

page25image39512

N/A

N/A

page25image41576

N/A

page25image42800

N/A

N/A

page25image44448 page25image44768

N/A

X

page25image46576 page25image46896

X

N/A

page25image49184

N/A

N/A

page25image54368 page25image55280 page25image59008 page25image59488 page25image66192 page25image66672 page25image68368 page25image69272 page25image74880 page25image75360 page25image76768 page25image77248

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page25image99776 page25image100512 page25image101424 page25image102800 page25image104368 page25image105152 page25image112336 page25image114512 page25image121024 page25image122912

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page25image147168 page25image148080 page25image151808 page25image152288 page25image158992 page25image159472 page25image161168 page25image162072 page25image167680 page25image168160 page25image169568 page25image170048

Contract Laboratory performing release or stability testing only

N/A

N/A

page25image174776

N/A

N/A

N/A

N/A

page25image179760

N/A

N/A

X

X

N/A

N/A

X

page25image187880

X

N/A

N/A

page25image190928

N/A

N/A

N/A

N/A

N/A

N/A

page25image198320

X

X

page25image200640

X

678

X = Input is applicable to report; N/A = Input is not applicable to report

19

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

679 680

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.3: Applicable Inputs for a Product Report Submission, Non-application Product, Finished Drug Product

page26image6584 page26image9608 page26image14152 page26image15488 page26image19720 page26image20936

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

X

X

X

N/A

page26image29568

N/A

N/A

X

page26image32432 page26image32856

X

page26image33912

X

X

page26image35800

X

page26image36984 page26image37304

X

X

page26image39592

N/A

N/A

page26image41656

N/A

page26image42880

N/A

N/A

page26image44528 page26image44848

N/A

X

page26image46656 page26image46976

X

N/A

page26image49264

N/A

N/A

page26image54448 page26image55360 page26image59088 page26image59568 page26image66272 page26image66752 page26image68448 page26image69352 page26image74960 page26image75440 page26image76848 page26image77328

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page26image99856 page26image100592 page26image101504 page26image102880 page26image104448 page26image105232 page26image112416 page26image114592 page26image121104 page26image122992

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page26image147248 page26image148160 page26image151888 page26image152368 page26image159072 page26image159552 page26image161248 page26image162152 page26image167760 page26image168240 page26image169648 page26image170128

Contract Laboratory performing release or stability testing only

N/A

N/A

page26image174856

N/A

N/A

N/A

N/A

page26image179840

N/A

N/A

X

X

N/A

N/A

X

page26image187960

X

N/A

N/A

page26image191008

N/A

N/A

N/A

N/A

N/A

N/A

page26image198400

X

X

page26image200720

X

681

X = Input is applicable to report; N/A = Input is not applicable to report

20

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

682 683

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.4: Applicable Inputs for a Product Report Submission, Non-application Product, API

page27image6504 page27image9528 page27image14072 page27image15408 page27image19640 page27image20856

Product Reporting Establishment [Manufacturing with oversight responsibilities only]

X

X

X

X

N/A

page27image29488

N/A

N/A

X

page27image32352 page27image32776

X

page27image33832

X

X

page27image35720

X

page27image36904 page27image37224

X

X

page27image39512

N/A

N/A

page27image41576

N/A

page27image42800

N/A

N/A

page27image44448 page27image44768

N/A

X

page27image46576 page27image46896

X

N/A

page27image49184

N/A

N/A

page27image54368 page27image55280 page27image59008 page27image59488 page27image66192 page27image66672 page27image68368 page27image69272 page27image74880 page27image75360 page27image76768 page27image77248

Contract Manufacturer performing release or stability testing

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page27image99776 page27image100512 page27image101424 page27image102800 page27image104368 page27image105152 page27image112336 page27image114512 page27image121024 page27image122912

Contract Manufacturer not performing release or stability testing (FDF, packaging, sterilizing, etc.)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page27image147168 page27image148080 page27image151808 page27image152288 page27image158992 page27image159472 page27image161168 page27image162072 page27image167680 page27image168160 page27image169568 page27image170048

Contract Laboratory performing release or stability testing only

N/A

N/A

page27image174776

N/A

N/A

N/A

N/A

page27image179760

N/A

N/A

X

X

N/A

N/A

X

page27image187880

X

N/A

N/A

page27image190928

N/A

N/A

N/A

N/A

N/A

N/A

page27image198320

X

X

page27image200640

X

684

X = Input is applicable to report; N/A = Input is not applicable to report

21

Product Name

Rx/OTC

OTC Monograph

Product Type

Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter

Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

685 686 687

Contains Nonbinding Recommendations

Draft — Not for Implementation

Appendix A.5: Applicable Inputs for a Site Report Submission, Manufacturer with oversight responsibilities only (e.g., application holder)

page28image10968 page28image11392 page28image11992 page28image12864 page28image14016 page28image14616 page28image15600 page28image16640 page28image18128 page28image19448 page28image19608 page28image20752

Finished Drug Product – Application

X

X

N/A

X

X

X

X

N/A

page28image33112 page28image33536

X

page28image34592

X

page28image35920

X

N/A

page28image37984

X

page28image39040

X

N/A

page28image40936

N/A

page28image42432

N/A

N/A

N/A

page28image45288

N/A

X

page28image47520 page28image47680

X

N/A

page28image49736

N/A

N/A

page28image53544 page28image53968 page28image54448 page28image54872 page28image58456 page28image59360 page28image60512 page28image61096 page28image65832 page28image66736 page28image69992 page28image70896 page28image71784 page28image72264 page28image73936 page28image74520 page28image77160 page28image78072 page28image78792 page28image79376

Finished Drug Product – Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

X

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

N/A

page28image108928 page28image109352 page28image109832 page28image110256 page28image110544 page28image111128 page28image111856 page28image112336 page28image113512 page28image114416 page28image114704 page28image115288 page28image116296 page28image116776 page28image117672 page28image118576 page28image120264 page28image120744 page28image122352 page28image122512 page28image123256 page28image123416 page28image124416 page28image125328

API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

X

N/A

N/A

N/A

N/A

N/A

X

X

N/A

N/A

N/A

page28image149416 page28image149896 page28image150664 page28image150984 page28image151464 page28image151784 page28image152960 page28image153864
688
689
690
691
692
693
694
695
696

X N/A X X N/A N/A N/A X X X X N/A X X N/A N/A N/A N/A N/A N/A X X X = Input is applicable to report; N/A = Input is not applicable to report

API – Non Application

N/A N/A N/A

page28image182800 page28image191456 page28image191616 page28image191776 page28image191936

22

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type

Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form
Active Ingredient Supply Chain/Process Stage

Code FEI/DUN

Started: In- process/Packaging

Started: Saleable

Rejected: In-process/ Packaging

Rejected: Saleable

Released: In- process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

697 698

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.6: Applicable Inputs for a Site Report Submission, Manufacturer that perform testing

page29image5240 page29image5664 page29image8256 page29image9576 page29image18056 page29image20088 page29image21280

Finished Drug Product – Application

X

X

N/A

X

X

X

X

N/A

page29image32328

X

page29image33504 page29image33664

X

page29image34984

X

N/A

page29image36896 page29image37216

X

page29image38440

X

X

page29image40072

X

page29image41144 page29image41568

X

page29image42792

X

X

page29image44416

X

X

page29image46752 page29image46912

X

X

page29image49400

X

X

page29image52680 page29image53104 page29image53584 page29image54008 page29image57304 page29image57784 page29image59456 page29image60040 page29image72880 page29image73464 page29image76120 page29image77024 page29image77912 page29image78392

Finished Drug Product– Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

page29image99512 page29image99936 page29image101784 page29image103352 page29image103672 page29image104136 page29image105840 page29image106288 page29image119712 page29image122952 page29image124744

API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

page29image147744 page29image148224 page29image148992 page29image149312 page29image149792 page29image150112 page29image151800 page29image152280

API – Non Application

page29image173504 page29image174096

X

N/A

X

X

page29image178576

N/A

N/A

N/A

page29image181616

X

X

X

X

N/A

X

X

X

X

X

X

X

X

page29image196696

X

X

X

page29image200184

X

page29image201776

X

699
700
701
702
703
704

X = Input is applicable to report; N/A = Input is not applicable to report

23

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN

Started: In-process/Packaging

Started: Saleable Rejected: In-process/Packaging Rejected: Saleable

Released: In-process/Packaging Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

705 706

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.7: Applicable Inputs for a Site Report Submission, Manufacturer that does not perform testing

page30image5320 page30image5744 page30image8456 page30image13000 page30image13424 page30image14192 page30image14904 page30image16048 page30image17872 page30image18760 page30image19184 page30image20400 page30image21168

Finished Drug Product– Application

X

X

N/A

X

X

X

page30image30552

X

N/A

page30image32192 page30image32616

X

page30image33672

X

page30image35000

X

N/A

X

X

X

X

page30image41088

X

page30image42736

X

X

page30image44384

X

X

X

N/A

page30image48736

N/A

N/A

page30image52336 page30image52760 page30image53240 page30image53664 page30image57248 page30image58152 page30image64432 page30image64856 page30image65336 page30image65760 page30image66224 page30image66704 page30image67432 page30image68016 page30image69016 page30image69920 page30image71952 page30image72752 page30image73504 page30image73928 page30image74408 page30image74832 page30image75920 page30image76720 page30image77184 page30image77664

Finished Drug Product– Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page30image98784 page30image99208 page30image103696 page30image105968 page30image107624 page30image108048 page30image108920 page30image110128 page30image110880 page30image111304 page30image112672 page30image113880 page30image115464 page30image115944 page30image117312 page30image118400 page30image118880 page30image119952 page30image120376 page30image122368 page30image122848 page30image123632

API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

X

X

X

X

X

X

X

X

N/A

N/A

N/A

page30image146632 page30image147112 page30image147880 page30image148200 page30image148680 page30image149000 page30image150176 page30image151080

API – Non Application

page30image172008 page30image172600

X

N/A

X

X

N/A

page30image177808

N/A

N/A

X

X

X

X

N/A

page30image185928 page30image186520

X

page30image187520

X

X

page30image189400

X

page30image191160

X

X

X

page30image194480

X

X

page30image196368 page30image196960

X

N/A

page30image199120

N/A

page30image200280

N/A

707
708
709
710
711
712
713
714

X = Input is applicable to report; N/A = Input is not applicable to report

24

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form

Active Ingredient
Supply Chain/Process Stage Code FEI/DUN

Started: In-process/Packaging

Started: Saleable Rejected: In-process/Packaging Rejected: Saleable

Released: In-process/Packaging Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

715 716

Contains Nonbinding Recommendations

Draft — Not for Implementation
Appendix A.8: Applicable Inputs for a Site Report Submission, Manufacturer with Testing Only

`

page31image5696 page31image6120 page31image8832 page31image10128 page31image13472 page31image13896 page31image15272 page31image16424 page31image17192 page31image18512 page31image20544 page31image20968 page31image21736

Finished Drug Products– Application

X

X

N/A

X

X

X

X

N/A

page31image32856 page31image33280

X

page31image34336

X

page31image35664

X

N/A

X

page31image38952

X

N/A

N/A

page31image41656

N/A

N/A

N/A

page31image44936

N/A

N/A

page31image47168 page31image47592

N/A

X

X

X

page31image61224 page31image61648 page31image62128 page31image62552 page31image62840 page31image63424 page31image64152 page31image64632 page31image67176 page31image67656 page31image69352 page31image70256 page31image72368 page31image72848 page31image74456 page31image74880 page31image75360 page31image75784

Finished Drug Product – Non- application

X

X

X

X

N/A

N/A

N/A

X

X

X

X

X

X

X

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

X

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API – Application

X

N/A

N/A

X

X

X

X

N/A

X

X

X

N/A

X

X

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

X

X

X

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API – Non Application

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X

N/A

X

X

N/A

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N/A

N/A

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X

X

X

X

N/A

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X

X

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N/A

N/A

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N/A

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N/A

N/A

N/A

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N/A

N/A

X

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X

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X

717

X = Input is applicable to report; N/A = Input is not applicable to report

25

Product Name Rx/OTC

OTC Monograph Product Type Applicant Name

Application Type Application Number

NDC Product Code Number(s)

Reporting Time Period Quarter
Dose Form Active Ingredient

Supply Chain/Process Stage Code FEI/DUN
Started: In-process/Packaging

Started: Saleable

Rejected: In-process/Packaging

Rejected: Saleable

Released: In-process/Packaging

Released: Saleable

Number of quality complaints

Number of Dosage Units Distributed

Sum of Release test and Stability test OOS results where the source of the OOS result is identified as an aberration of the measurement process

Sum of Release test and Stability test OOS results

Sum of all Release and Stability Tests

718 APPENDIX B: EXAMPLES

719
720 (1)

721 722 723

724

725 726 727

728

729 730

731

732

733

734
735
736
737
738
739
740
741
742
743
744
745
746
747
748

749 750 751

Lot Acceptance Rate

a.

An establishment manufactures a product where six small in-process lots are combined into a single unit operation to make one saleable lot (e.g., tablet, liquid, filled vial). Two saleable lots are then combined into one packaging lot.

Assuming all lots that are started are released:

In-process and packaging lots started and released: 13 [six lots from the first saleable lot, six lots from the second saleable lot, and the single packaging lot]

Saleable lots started and released: 2
An establishment manufactures one saleable lot that is separated into five

packaged lots.
Assuming all lots that are started are released:

In-process and packaging lots started and released: 5

Saleable lots started and released: 1

For an OTC monograph product, one batch of saleable product is packaged into an unlabeled primary pack and the primary pack is subsequently labeled and placed into secondary packaging at three different packagers. In this scenario, all four of these facilities are considered covered establishments (one for the bulk manufacturing and three for primary labeling). For the manufacturer of the unlabeled primary pack OTC product, the unlabeled primary pack lots are saleable lots. The lots which are distributed by each packaging establishment are also saleable lots.

Facility A manufactures the product and Facility B packages the product. Facility B discovers a defect that leads to the rejection of the lot; the defect was due to the manufacturing at Facility A. In this situation, Facility A should not count this product lot as a released lot, despite the initial release. For Facility B, if the defect was discovered upon incoming acceptance testing and the packaging lot was not yet started, the lot should not be counted. If a packaging lot was started, it should be counted as a lot started, not as a released lot.

For a non-functional or functional film-coated tablet where the coating process consists of multiple separate coating pan loads, the count of lots depends on whether the separate pan loads are considered unique lots or if the loads are part

b.

c.

d.

e.

Contains Nonbinding Recommendations

Draft — Not for Implementation

26

752 753 754

755
756
757
758

759 (2)

760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778 (3)

779
780
781
782
783
784
785
786
787
788

789 790

f.

Contains Nonbinding Recommendations

Draft — Not for Implementation

of a single started lot. For either functional or non-functional coatings, samples collected and testing for finished drug product release should be representative of the lot.

Facility A initiates manufacturing of Product Z in the last quarter of the reporting cycle or ceases manufacturing of Product Y in the first quarter of the reporting cycle An explanation of the partial year can be described in the comment field. The product report or site report would be considered complete for that product.

Product Quality Complaint Rate

a. b.

c.

If a lot is distributed to five customers and all customers report the same complaint, this should be counted as five complaints.

If a lot is distributed and a single customer submits the same complaint from different departments, only a single complaint should be counted. If submitting a site report, the covered establishment may choose to include this complaint in their data if it is the least burdensome option.

A lot is distributed to three regions and a complaint is received on that lot from a region outside of the United States. In this instance, the complaint does not need to be reported as part of the quality metrics program. The covered establishment may choose to include this complaint if it could be applicable to product imported or intended for import to the United States or its territories.

a.

b. c.

Regarding analytical tests with multiple sample preparations or injections involved in the test to generate the final result, one test is represented by a single analytical result with an established limit. For example, one content uniformity test proceeding to stage two may have 30 invalidated results. Only one OOS result would be counted.

If two samples from one lot are tested with two injections each and there is one result reported on the Certificate of Analysis, this is considered one release test.

If an OOS result occurs during in-process testing for a test that is considered a real time release test, this is considered a release OOS result for the purpose of this guidance.

For a site report by a packager, if a complaint is received and potentially due to the packager’s operations (e.g., discolored tablet or powder), the complaint should be counted by the site reporting establishment.

d.
Invalidated Out of Specification (OOS) Result Rate

27

 

791 d. 792
793

794 e. 795
796
797

798 799 800

801 f. 802
803
804

805
806
807
808
809

Contains Nonbinding Recommendations

Draft — Not for Implementation

If more than one OOS result is observed during finished drug product testing (e.g., the lot fails both assay and uniformity), this is considered multiple release OOS results.

50 kg of an API is packaged into five 10 kg packages and three to five of the five containers are tested; the Certificate of Analysis reports the average. If one or more of the container results is OOS for the same attribute, the establishment should initiate an OOS investigation and count these OOS results as a single OOS result. A single API container with an OOS result should result in an investigation for the lot in its entirety. After the investigation is complete, subsequent retesting should be counted as a new release test.

Company A does not declare an OOS result until the laboratory investigation proves the result is valid.63 If invalid, and the original result is not labeled as an OOS, there will be no record of invalidating an OOS result, thus resulting in a lower Invalidated OOS Rate for Company A. For the purpose of the quality metrics program, a lot release OOS result should be counted prior to the laboratory investigation, in accordance with the term “OOS result” as defined in this guidance. Furthermore, these type of results should be evaluated as part of the PPR to determine the need for changes in drug product specifications or manufacturing or control procedures.64

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63 It should be noted that this practice is inconsistent with the recommendations outlined in FDA guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.
64 Refer to 21 CFR 211.180(e).

28