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Draft Guidance for Industry Request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.
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
|