FDA QMP - Practicalities of the program

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Quality Metrics Program
Practicalities of the program

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Quality Metrics Program
FDA initiative aiming to pro-actively monitor quality
in biopharmaceutical companies to:
• Move towards risk-based inspections
• Help predict possible drug shortages
• Encourage the industry to further optimise
its quality management systems for
pharmaceutical engineering

Quality metrics are already avidly used in the life sciences industry:
• To continuously monitor quality systems & processes (cGMP)
• To provide information on where improvements can be made
• As an element of the annual product review
• As a part of internal audits
• To evaluate supplier qualifications
Current use of quality metrics

The Quality Metrics Program was designed to bring the current life sciences
industry closer to the FDA’s 21st century vision on pharmaceutical engineering:
“a maximally efficient, agile, flexible pharmaceutical manufacturing sector that
reliably produces high quality drug products without extensive regulatory oversight”
Other projects driving this vision:
• Quality by Design
• Q9 Quality Risk Management
• Process Validation Guidance
• Process analytical technology (PAT)
General context

Food and Drug Administration Safety and Innovation Act (FDASIA):
• Section 704 - FDA can search databases by any field of information provided for
submission
• Section 705 - Evolution towards a risk-based inspection instead of the bi-annual
inspection
• Section 706 - Records and additional information (Quality Metrics) have to be
provided in advance or in lieu of an inspection
Legal framework

Timeline
December 2013
ISPE paper on
quality metrics
June 2015
Pilot project
report Wave 1
June 2015
Launch Wave 2
ISPE pilot
program
July 2015
FDA Draft
Guidance for
Industry
June 2016
Pilot project
report Wave 2
November 2016
Revised FDA
Draft Guidance
for Industry
Early 2018
Phased-in stage
 Voluntary submission
of quality metrics via
electronic portal
2018 - …
FDA analysis of received
data
to further improve QMP
June 2014
Launch Wave 1
ISPE pilot
program

Practicalities of the program

• Covered drug products
• Covered establishments
• Reports
• Quality metrics
• Additional elements to report
Practicalities overview

• Application products:
• Investigational New Drug (IND)
• New Drug Application (NDA)
• Abbreviated New Drug Application (ANDA)
• Biologic License Application (BLA)
• Products marketed pursuant to an Over-The-Counter (OTC) monograph
• Unapproved marketed products
(non-application products)
Covered drug products

Every establishment engaged in the manufacturing, preparation, propagation,
compounding or processing of a covered drug product or API applied in the
manufacturing of a covered drug product
 includes: contract laboratories, packages, sterilizers…
Covered establishments

• Site report
• Report on a single establishment
• Information on all products
• Product report
• Report on a single covered drug product/API
• Information from all sites
• Preferred by FDA
• Improved understanding of processes
• Facilitate identification product-specific issues
• Difficult due to complex supply chains
Reports are to be submitted annually (segmented in quarters)
Reports

Quality Metrics
Lot acceptance rate
measure the
manufacturing process
performance
Patient complaint rate
focussing on patient and
customer feedback
Invalidated out-of-
specification rate
focussed on the robustness
of the laboratory operation

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Additional reporting elements
• 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
• FEI/DUN
• Supply chain / process stage code

Quality Metrics

Lot acceptance rate
= # accepted lots
# started lots
in current reporting timeframe
in same establishment

Data to report
• Saleable lots started
• Saleable lots accepted
• Saleable lots rejected
• In-process/packaging lots started
• In-process/packaging lots accepted
• In-process/packaging lots rejected
Lot acceptance rate

Accepted lot = lot released for further processing/distribution
• Count lot on day final disposition decision
• Unexpected low yield + investigation supports release
• Count as accepted lot
• Lot n° closed, transferred to new lot n° and new lot n° is released
• Count original lot n°
• Accepted lot no longer considered accepted (f.i. stability issue)
• Do not count
Lot acceptance rate

Started lot = lot intended for commercial use for which
• Manufacturer issued lot n°
• Manufacturer physically charged API/primary starting material
• There will be a disposition decision
• When manufacturing spans multiple time segments (quarters):
• Count when lot n° is issued OR API/primary starting material is physically
charged
• Unique lot n° for ≠ packaging configurations
• Count each lot
• Count all lots that would be included in the annual product review
• Also lots for post marketing clinical trials etc.
Lot acceptance rate

Saleable lot
• Filled vials, bulk tablets, bulk API
• Bulk milled in-process material/intermediate API
when manufacturing occurs at different covered establishment
Lot acceptance rate

• Each subdivision or grouping = a separate lot
• Packaging: stand alone lot or included in existing lot
• Lots started – (lots released + lots rejected) = lots pending disposition
Lot acceptance rate

Example 1
Lot acceptance rate
In-process lots Saleable lots Packaging lot

Example 1
Lot acceptance rate
Started 12 2 1
Accepted 12 2 1
Rejected 0 0 0

Example 1
Lot acceptance rate
Started 12 2 1
Accepted 10 2 1
Rejected 2 0 0

Example 1: Data to report
• Saleable lots started 2
• Saleable lots accepted 2
• Saleable lots rejected 0
• In-process/packaging lots started 13
• In-process/packaging lots accepted 11
• In-process/packaging lots rejected 2
Lot acceptance rate

Example 2
Lot acceptance rate
Saleable lots Packaging lot

Example 2
Lot acceptance rate
Saleable lots Packaging lot
Started 1 5
Accepted 1 4
Rejected 0 1

Example 2: Data to report
• Saleable lots started 1
• Saleable lots accepted 1
• Saleable lots rejected 0
• In-process/packaging lots started 5
• In-process/packaging lots accepted 4
• In-process/packaging lots rejected 1
Lot acceptance rate

Example 3: primary & secondary packaging
Lot acceptance rate
In-process Primary packaging Secondary packaging

Establishment A
Establishment B
Establishment C
Establishment D
In-process Primary packaging Secondary packaging
Lot acceptance rate

Lot acceptance rate
Establishment A
Establishment B
Establishment C
Establishment D
Saleable lot

Example 4: manufacturing by A, packaging by B
B discovers defect due to manufacturing by A
• A must count lot as rejected
 B did not yet initiate packaging
• B does not count lot
 B initiated packaging
• B counts lot as rejected
Lot acceptance rate

Example 5
Start manufacturing in final quarter
Halt manufacturing in first quarter
 Use comment section to describe partial year
Lot acceptance rate

=
# product quality complaints
Total # dosage units distributed

Product quality complaint
A complaint involving any possible, including actual, failure of a drug to meet any of its
specifications (identity, strength, quality and purity)
Dosage units
Total # individual dosage units distributed or shipped under the approved application or
product family to costumers, including distributers

Data to report
• Number of product quality complaints
• Total number of dosage units distributed

1 lot
customer
customer
customer
customer
customer
complaint
complaint
complaint
complaint
complaint
 Count 5 complaints
Example 1

Example 2
1 lot
department
department
department
department
department
complaint
complaint
complaint
complaint
complaint
 Count 1 complaint
customer

Example 3
1 lot
customer Japan
customer EU
customer US
complaint
 Can choose to count complaint or not
 FDA prefers that complaint is counted
 Certainly when product is imported to US

Example 4: site report by packager
• When complaint potentially due to packager’s operation
 Complaint reported by site reporting establishment

Example 5: OTC products
• “The product is grape flavoured but I prefer cherry”
 Do not count
• “The grape flavour does not taste right”
 Count
Do not count complaints regarding preference
 Only count complaints regarding identity, strength, quality and purity

Invalidated out-of-specification (OOS)
rate
= # invalidated OOS test results
total # test results
for test on long term stability and lot release tests

Data to report
• Sum all release and stability tests
• Sum release and stability test OOS results
• Sum invalidated release and stability test OOS results
rate

OOS result
All test results outside of specifications/acceptance criteria for
• Lot release tests
• Long-term stability tests
Invalidated OOS result
OOS due to aberration of measurement procedure
 Observation & documentation of a test event that can reasonably be
determined to have caused the OOS result
rate

Lot release test
All tests evaluating conformance to final specifications
• Real-time release tests
• In-process tests that are surrogates for final release tests
Long-term stability tests
Only real-time stability tests
 No accelerated stability tests
rate

Count OOS on:
• The day the result is completed
• The day the OOS investigation is initiated
 Prior to result of investigation!
• 1 result for 1 test
• Establishment that manufactures API  No stability OOS results
• Multiple long-term stability tests  Count all
rate

Example 1
Release tests
rate
Impurities OOS
Content uniformity pass
Dissolution pass
Sum release & long-term stability tests: 3
Sum OOS results release & long-term stability tests: 1

Example 1
Long-term stability tests
rate
3m 6m
Appearance pass pass
Degradation products IOOS OOS
Sum OOS results release & long-term stability tests:
2
Sum IOOS results release & long-term stability
tests: 1

Example 2
rate
Raw material Processing FDF
2 raw material
OOS results
3 in-process
OOS results
10 lot release tests
1 OOS results

rate
2 raw material
OOS results
3 in-process
OOS results
1 OOS results
Example 2

Example 3
rate
2 raw material
OOS results
3 in-process OOS results
1 OOS for real-time release test
1 OOS results

Example 4
rate
50 kg
API
10 kg
10 kg
10 kg
10 kg
10 kg
OOS
pass
OOS
 Count as 1 OOS
pass Average on
Certificate of
Analysis

• Submission of Quality Metrics Data: Revised Draft Guidance for Industry (November
2016)
• Federal Register Notice of Availability (November 2016)
• Quality Metrics, Technical Conformance Guide (Version 1.0, June 2016)
• CDER Small Business and Industry Assistance article: FDA’s Quality Metrics reporting
program: Submission of Quality Metrics Data (November 2016)
• ISPE Quality Metrics Initiative, A Report from the Pilot Project (June 2015) (Wave 1
Report)
• ISPE Quality Metrics Initiative, Quality Metrics Pilot Program (June 2016) (Wave 2 Report)
Sources

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FDA QMP - Practicalities of the program

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