QUALITY METRICS TECHNICAL CONFORMANCE GUIDE


QUALITY METRICS TECHNICAL CONFORMANCE GUIDE








Technical Specifications Document




This Document is incorporated by reference into the following Guidance Document(s):

Draft Guidance for Industry Request for Quality Metrics, published July 28, 2015




For questions regarding this technical specifications 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)




TABLE OF CONTENTS


1. INTRODUCTION
Background
Purpose
Document Revision and Control
Relationship to Other Documents
2. EXCHANGE FORMAT – ELECTRONIC SUBMISSIONS
File Transport Formats
Extensible Mark-up Language
3. FILE FORMAT – ELECTRONIC SUBMISSIONS
Variable and Dataset Descriptor Length
Special Characters:  Variables and Datasets
Variable and Dataset Names
Variable and Dataset Labels
Data Definition File
4. GENERAL CONTENT AND FORMAT OF A SUBMISSION
Data Element Specifications
Data Elements - Descriptions
Drug Product Name
Drug Designation
Applicable Monograph
Drug Product Type
Applicant Name
Final Labeler Name
Final Labeler Codes
Application Type
Application Number
NDC Product Code
Time Period Start
Lots Attempted
Lots Rejected
Out of Specification (OOS) Results – Finished Drug Product or API
Number of Lot Release and Stability Tests – Commercial Use
Out of Specification (OOS) Results Invalidated
Product Quality Complaints
Lots Attempted and Released
Annual Product Review (APR) / Product Quality Review (PQR) Completed
Annual Product Review (APR) / Product Quality Review (PQR) Required
DUNS Number
Dosage Form
Facility Establishment Inventory Number (FEI)
Establishment Activity Classification
Mandatory Data Elements – Formats
4.4.1 APR Approval
Percentage of Corrective Actions and Preventive Actions (CAPA) Involving Re-training
Process Capability (PC) or Process Performance (PP) Index Calculation
CAPA Trigger Policy
Triggers for CAPA
Optional Data Elements – Formats
5.0 DATA VALIDATION RULES
6.0 GLOSSARY



QUALITY METRICS TECHNICAL CONFORMANCE GUIDE

This technical specifications document, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfied the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, send an email to mailto:CDER- OPQ-Inquiries@fda.hhs.gov.

1.     INTRODUCTION


     Background


This Quality Metrics Technical Conformance Guide (Guide) serves as the technical reference for implementation of the draft FDA guidance for industry on Request for Quality Metrics.1 Since publication of the Pharmaceutical CGMPs for the 21st Century in 2004,2 CDER has continued to promote its vision of “a maximally efficient, agile, flexible manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight.” The draft guidance for industry on Request for Quality Metrics and this technical reference document continue FDA’s policy efforts to ensure successful implementation of CDER’s objectives outlined in the 21st Century publication. FDA expects that quality metrics calculated from data that it collects will provide objective measures that, when used with additional internal data, will provide the Agency with indicators of the effectiveness of pharmaceutical manufacturing quality systems.
The goal of these measures is to assure quality drug products are available to patients. The objectives of CDER’s quality metrics program can best be achieved through collaboration and a shared understanding of standards for metric indicators and data exchange/reporting.

This Guide supplements the draft FDA guidance for industry on Request for Quality Metrics and provides recommendations about submission of information that will support the FDA’s calculation of quality metrics.

     Purpose


This Guide provides technical recommendations for the submission of quality metric data. It is intended to ensure clear expectations for industry on the submission of quality metric data as described in the Request for Quality Metrics draft guidance.


1 See http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm455957.pdf. 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/ucm310704.htm.
2 See Pharmaceutical cGMP’s for the 21st Century: A Risk- Based Approach at



     Document Revision and Control


This document is incorporated by reference into the draft FDA guidance for industry on Request for Quality Metrics. Please refer to the draft guidance at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM455957.pdf for ongoing changes to the guidance or submission processes before final adoption.

     Relationship to Other Documents


For resources on data standards, please also refer to the Study Data Technical Conformance Guide located on the FDA Study Standards Resources Web page at http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm.

2.     EXCHANGE FORMAT – ELECTRONIC SUBMISSIONS


     File Transport Format


Currently, FDA receives, processes, and archives electronic dataset files in several formats. The FDA is committed to open dialog about best practices which includes a review of various formats. Extensible Markup Language (XML) shall be the recommended format for Drug Quality Metrics submission.

     Extensible Mark-up Language


Extensible Mark-up Language (XML), as defined by the World Wide Web Consortium (W3C), specifies a set of rules for encoding documents in a format that is both human-readable and machine-readable.3 XML’s primary purpose is to facilitate the sharing of structured data across different information systems.

3.     FILE FORMAT – ELECTRONIC SUBMISSIONS


     Variable and Dataset Descriptor Length


The length of variable names, descriptive labels, and dataset labels should not exceed the maximum permissible number of characters described in Table 1:

Table 1: Maximum Length of Variables and Dataset Elements


Element
Maximum Length in Characters
Variable Name
8
Variable Descriptive Label
40
Dataset Label
40




     Special Characters: Variables and Datasets


Variable names, as well as variable and dataset labels, should include only American Standard Code for Information Interchange (ASCII) text codes.

     Variable and Dataset Names


Variable and dataset names should not contain punctuation, dashes, spaces, or other non- alphanumeric symbols. In addition, the variable and dataset names should not contain special characters, including:


\ / * ,? < > | “ ‘ : % # + ( ) { } [ ]

     Variable and Dataset Labels


Variable and dataset labels can include punctuation characters. However, special characters should not be used, such as:

1.        Unbalanced apostrophe, e.g., Parkinson's.
2.        Unbalanced single and double quotation marks.
3.        Unbalanced parentheses, braces, or brackets, e.g., ‘(‘, ‘{‘and ‘[‘.
4.        ‘<’ less than sign and ‘>’ greater than sign.

     Data Definition File


The data definition file is a human and machine-readable dataset that contains a list of the datasets included in the submission along with a detailed description (i.e., metadata) of the contents of each data set.

2.    GENERAL CONTENT AND FORMAT OF A SUBMISSION


     Data Element Specifications


Below are product data elements which correlate to column product names described in Appendix-A of the draft FDA guidance for industry on Request for Quality Metrics.

     Data Elements - Descriptions

     Drug Product Name


For drugs that are subject to approved applications under section 505 of the FD&C Act or under section 351 of the PHS Act, and for drugs that are described in a drug master file (DMF) that is intended to support an application, the API/drug substance or FDF/drug product name provided in the application should be used.


For drugs that are not subject to an approved application under section 505 of the FD&C Act or under section 351 of the PHS Act, the API or FDF drug product name should be used. If the drug product name is included as part of registration, the same name included in registration should be used.

     Drug Designation


Indicate if the drug referenced in the completed data table is prescription (Rx) or over-the- counter (OTC). This element is not required to be reported for an API intended for use in the manufacture of a drug product.

     Applicable Monograph


The applicable monograph, if any, for the drug referenced. This element is not required to be reported for products that are subject to an application under either section 505 of the FD&C Act or under section 351 of the PHS Act, or covered by a submission to a DMF that is intended to support such an application.

     Drug Product Type


The drug product type – Active Pharmaceutical Ingredient (API) or Finished Dosage Form (FDF). This field is restricted to two options; only one option can be selected.

     Applicant Name


The name of the application holder.

     Final Labeler Name


The name of the labeler listed in the NDC code.

     Final Labeler Codes


The name of the labeler listed in the NDC code (for validation of text entered as “final labeler name”).

     Application Type


The application type is New Drug Application (NDA), Abbreviated NDA (ANDA), Biologics License Application (BLA), Drug Master File (DMF), or Non-application product (NA).

     Application Number


The NDA, ANDA, BLA number for an approved product or the applicable DMF number. Leave blank for non-application products.



     NDC Product Code


The final labeled NDC product code.

     Time Period Start


The beginning of the time period within which the data being reported were collected.

     Time Period End


The end of the time period within which the data being reported were collected.

     Lots Attempted


The number of lots attempted for the drug referenced above in 4.2.1 for each establishment.4

     Lots Rejected


The number of specification-related lots rejected for the drug referenced above in 4.2.1 for each establishment.

     Attempted Lots Pending Disposition


The number of lots attempted pending disposition for more than 30 days on the last day of the time period within which the data being reported was collected.

     Out of Specification (OOS) Results – Finished Drug Product or API


The number of test results that fall outside the specifications or acceptance criteria for the drug referenced above in 4.2.1 for each establishment.

     Number of Lot Release and Stability Tests – Commercial Use


The number of lot release and stability tests conducted for the drug referenced above in 4.2.1 for each establishment.

     Out of Specification (OOS) Results Invalidated


The number of invalidated OOS results for finished drug product or API and stability tests due to laboratory error for the drug referenced above in 4.2.1 for each establishment.



4 In this section of the guidance, “establishment” means “covered establishment” as defined in the FDA guidance for industry on Request for Quality Metrics.


     Product Quality Complaints


The sum of product quality complaints received for product distributed in the United States for the drug product referenced above in 4.2.1 across all establishments.

     Lots Attempted and Released


The number of lots attempted which are released for distribution or for the next stage of manufacturing for the finished drug product or API referenced above in 4.2.1 for each establishment.

     Annual Product Review (APR) / Product Quality Review (PQR) Completed


Indication (yes/no) of whether the APR or PQR was performed within 30 days of the annual due date.

     Annual Product Review (APR) / Product Quality Review (PQR) Required


Number of APRs or PQRs required.

   DUNS Number


The DUNS number for each establishment listed in the quality metrics data submission.

     Dosage Form


The dosage form for the drug product referenced above in 4.2.1.

     Facility Establishment Inventory Number (FEI)


The FEI for each establishment listed in the quality metrics data submission.

     Establishment Activity Classification


List the activity classification (e.g., Direct Product Manufacturing) for all establishments listed in the quality metrics data submission.

     Mandatory Data Elements – Formats


Table 2: Mandatory Data Element Formats

Data Element Name
Data Element Label
Data Element Type
Data Element Description
PRODNAME
Drug Product Name
Text

RXSTATUS
RX OTC Status
Text
RXSTATUS = RX or OTC



Data Element Name
Data Element Label
Data Element Type
Data Element Description
MONOGRPH
Applicable
Monograph
Text

PRODTYPE
Drug Product Type
Text
PRODTYPE = API, FDF
APPLICNT
Applicant Name
Text

FINLBLER
Final Labeler Name
Text

LABELER
Final Labeler Codes
Num

APPLTYPE
Application Type
Text
APPTYPE = NDA, ANDA, BLA
DMF, or NA
APPNUM
Application Number
Text

NDCCODE
NDC Product Code
Num

TIMEPRD
Time Period Start
Date

TIMEPRD
Time Period End
Date

LTSATT
Lots Attempted
Num
Number of lots attempted of the
product
LTSREJ
Lots Rejected
Num
Number of specification-related
rejected lots of the product
APRWIDD
Attempted Lots
Num
Number of attempted lots pending
disposition (more than 30 days)
OOSRES
Out-of-Specification
Results
Num
Number of OOS results - Finished
product (including stability testing)
LTRELTST
Lot Release Tests
Num
Number of lot release tests conducted for commercial use

OOSRESIN

Out-of-Specification Results Invalidated

Num
Number of OOS results for finished product and stability tests for the
product that are invalidated due to lab error

PRODQCMP
Product Quality Complaints

Num
Number of product quality complaints received for the product
distributed in the United States

LTSREL

Lots Attempted and Released

Num
Number of lots attempted that are released for distribution or for the next stage of manufacturing the
product

APRWIDD

APR/PQR
Completed

Text
Have associated APRs or PQRs been completed within 30 days of annual due date for the product?
APRWIDD = Y or N
APRPQRS
APR or PQR
Required
Num
Number of APRs or PQRs required
for the product
DUNSNUM
DUNS Number
Num
A unique nine-digit identification
number for each physical facility



Data Element Name
Data Element Label
Data Element Type
Data Element Description



location
DOSAGE
FORMS
Dosage Form
Text
Associated finished dosage form

FEINUM
Facility Establishment
Inventory Number

Num
Facility Establishment Inventory Number

ACTIVITY
Establishment Activity

Text
Subset of Business Operations: Analytical testing, Pack,
Manufacture, Other
QUARTER
Reporting Quarter
Text
QUARTER= 1, 2, 3, or 4

Optional Data Elements - Descriptions

     APR Approval


Indicate Yes/No to indicate whether each associated APR/PQR was reviewed and approved.

     APR Approval by Quality Unit and/or Operations Unit


If response to 4.4.1 is Y, indicate whether the approving entity was: 1. Head of the quality unit;
2. Head of the operations unit; 3. Both; or 4. Other.

     Percentage of Corrective Actions and Preventive Actions (CAPA) Involving Re- training


Indicate the estimated percentage of your corrective actions plans that involved re-training of personnel (i.e., a root cause of the deviation is lack of adequate training).

     Process Capability (PC) or Process Performance (PP) Index Calculation


Indicate Yes/No if PC or PP Index was calculated for each critical quality attribute as part of that product’s APR or PQR.

     CAPA Trigger Policy


Indicate Yes/No if establishment management has a policy requiring CAPA at some lower process capability or performance index.

     Triggers for CAPA


Related to 4.4.5, indicate what PC or PP index value triggers a CAPA.


4.5 Optional Data Elements – Formats


Table 3: Optional Data Element Formats

Data Element Name
Data Element Label
Data Element Type
Data Element Description

APRAPPVD

APR/PQR Approved

Text
Was each APR/PQR reviewed and approved?
APRAPPVD = Y or N

APRAPPVDY
APR/PQR Approved by Quality and/or
Operations Unit
Text
1. Head of the quality unit; 2. Head of the operations unit; 3. Both; or 4.
Other.
CAIRTP
CAPAs Requiring
Re-Training
NUM
What percentage of CAPA required
re-training of personnel?

PCPPCALC
PC/PP Index Calculation

Text
Is a PC or PP Index calculated for all CQA?
PCPICALC = Y or N

REQCAPA
CAPA Trigger Policy

Text
Are CAPAs triggered at some lower PC or PP Index?
REQCAPA = Y or N
PCPPCAPA
Triggers for CAPA
Num
What PC or PP index value triggers
a CAPA?

5.0 DATA VALIDATION RULES

For purposes of this Guide, data validation is a process that attempts to ensure that submitted data are both compliant and useful. Compliant means the data conform to the applicable and required data standards. Useful means that the data support the intended use (i.e., regulatory review and analysis). Data validation is one method used to assess submission data quality. Standardized data do not ensure quality data, but they do make it easier to assess some aspects of data quality by facilitating the automation of various data checks. Data validation relies on a set of validation rules that are used to verify that the data conform to a minimum set of quality standards. The data validation process can identify data issues early in the review that may adversely affect the use of the data. FDA recognizes that it is impossible or impractical to define a priori all the relevant validation rules for any given submission. Sometimes serious issues in the submitted data are only evident through manual inspection of the data and may only become evident once the review is well under way. Often these issues are due to problems in data content (i.e., what was or was not submitted, or issues with the collection of original source data), and not necessarily how the data were standardized.

When the FDA guidance for industry on Request for Quality Metrics is published in final, the validation rules will be posted to the external FDA Web page. Establishments should validate their metric data before submission using the posted validation rules and correct any validation errors.


6.0 Glossary


The following is a list of acronyms and terms used in this technical specifications document:

API:
Active Pharmaceutical Ingredient
APR:
Annual Product Review
ASCII:
American Standard Code for Information Interchange
BLA:
Biologics License Application
CAPA:
Corrective Action and Preventive Action
CBER:
Center for Biologics Evaluation and Research
CDER:
Center for Drug Evaluation and Research
DMF:
Drug Master File
DUNS:
Data Universal Numbering System
ESG:
Electronic Submissions Gateway
FD&C Act:
Federal Food, Drug, and Cosmetic Act
FDF:
Finished Dosage Form
FEI:
Facility Establishment Identifier Number
NDA:
New Drug Application
NDC:
National Drug Code
OOS:
Out-of-Specification
OPQ:
Office of Pharmaceutical Quality
OTC:
Over the Counter
PQR:
Product Quality Review
PQS:
Pharmaceutical Quality System
Rx:
Prescription
W3C:
World Wide Web Consortium
XML:
Extensible Markup Language


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