CONFIDENTIAL © 2017 PAREXEL INTERNATIONAL CORP.
DEVELOP A RISK-
BASED, DATA
INTEGRITY AND
METRICS-DRIVEN
QUALITY MANAGEMENT
PROGRAM
ENTERPRISE-WIDE
February 2017
Siegfried Schmitt
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL2
AGENDA
• Let’s talk about quality -
seriously!
• Risks, what risks?
• We all love to measure -
measure what?
• Interactive Exercise
• FDA Quality Metric
Initiative - Latest News!
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL3
DEFINING QUALITY - QUALITY + CULTURE = ???
Definitions abound! The editors of Quality Digest say that defining the
word "quality" is "no simple endeavour."
Juran said quality meant “fitness for use”
Deming said only the “customer” can define quality (begs a new
question, “who is the customer”?)
ISO Definition: “Quality is the totality of features and characteristics of a
product or service that bear on its ability to satisfy stated or implied
needs.”
The FDCA Sections 501(b) and (c) define adulteration of compendial
and non-compendial drugs, respectively, in part, as
[501(b)] “…(its) strength differs from, or its quality or purity falls below,
the standard set forth in (the applicable) compendium…” or
501(c)] “…If it is not subject to the provisions of paragraph (b) of this
section and its strength differs from, or its purity or quality falls below,
that which it purports or is represented to possess”
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL4
THE TERM “QUALITY” IS USED IN VARYING WAYS IN
THE BIOPHARMA AND MEDICAL DEVICE INDUSTRY
Sometimes it means “floor level” GMP compliance
21 CFR 210.1(a) states in part “The regulations set forth in this part
…contain the minimum current good manufacturing practice for
methods to be used in, and the facilities or controls to be used for, the
manufacture, processing, packing, or holding of a drug …” (emphasis
added)
Sometimes it means elevating the standard to the maximum
feasible level
Sometimes it refers to attributes of a product
Sometimes it refers to the Quality Unit , as in “Let’s ask Quality
what they think…”
Sometimes it refers to a mindset or approach to the job one is
doing
“Big Q” – the attributes of quality of the product
“Little q” – Quality Operations; the job of the Quality Unit
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL5
QUALITY IS NOT EASY
TO DEFINE! For the purpose of this
discussion, let’s use:
A “Quality” drug product
always meets specifications
that are designed to ensure
proper clinical performance,
and is manufactured under
conditions that are controlled
to assure consistently correct
results.
We can argue about the
details later.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL6
“QUALITY” IS NOT EASY TO SELL TO COMPANY
LEADERSHIP - WHY?
Because, for the most part, it does not drive sales in the drug
industry. (Maybe in devices, to an extent.)
The case usually made for a strong quality system involves
primarily avoidance of adverse consequences:
We’ll reduce deviations
We’ll have fewer defects and rejections
We’ll have fewer recalls, complaints and adverse publicity
We’ll have less of a regulatory problem and associated costs
You never hear anyone say “If we have a better quality system we will
sell more products!”
In other industries that works: Cars, consumer electronics,
barbeque grills, furniture, etc. Pharmaceuticals? Not so much.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL7
FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY
CULTURE PROBLEM” - #1
Benign Ignorance - Symptoms include:
Focus on clinical trial progress, particularly when successful, and ignoring
need to assure sound manufacturing processes and process
understanding
Leadership that has no experience running manufacturing operations
and simply has no idea of what it takes. Often seen in companies that
mature from a development focused environment to one where
someone decides to commercialize something themselves rather than
sell it off and start over.
“Virtual” organizations that think if you outsource everything you have no
responsibility for anything other than to sit back and reap the rewards
A
B
C
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL8
FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY
CULTURE PROBLEM” - #2
Pipeline panic. Symptoms include two mirror images:
The blockbuster product that has sustained us for years is
going off patent and we have nothing coming down the
pipeline to replace it. We have to push product out the door
while we still can.
Or alternatively:
Our new product is a blockbuster, we need to shove as much
of it out there as fast as possible to satisfy impatient investors,
recoup our development costs and drive up the stock price.
Don’t slow that process down for “bureaucratic reasons”!
© 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL9
FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY CULTURE PROBLEM” - #3
Our product is high medical need (or A and B together).
Our product is the only modality for use in this disease condition.
FDA has inspected us several times over many years and never found
anything seriously wrong (abdication of quality responsibility to the regulator).
We have small numbers of complaints and adverse events reported.
Our product has been sold in “Whoknowswhereistan” for years with no issues.
False sense of regulatory invulnerability, which may be caused by these
or other things:
A
B
C
D
E
F
Our product is in short supply.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL10
FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY
CULTURE PROBLEM” - #4
Egotism and arrogance. Exemplified by:
We are the recognized industry leaders! We set the
standard!
We are unique!
A
B
C
The regulators do not understand our process!
With special thanks to David Chesney, formerly PAREXEL Consulting
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL11
FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY
CULTURE PROBLEM” - #5
The well worn “science versus compliance” debate:
A. We have the science to support this, who needs those stubborn
bureaucrats and their documentation rules!
B. Following GMP impedes creativity and slows the advance of
science!
C. We are the experts, don’t tell us how to do our job!
D. “Everybody knows that”!
Some thoughts on this to bear in mind:
Compliance without good science behind it is an empty exercise
and basically worthless.
No matter how good the science, you cannot test compliance into
a product, you must build it in, which requires the application of
sound quality management practices, and, yes, that involves
compliance.
You need both. There is no debate.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL12
THE FLEXIBLE, CAPABLE, APPROPRIATE QMS - FROM
SCRATCH OR FROM THE AS-IS
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL13
PROCESS VISUALIZATION VERSUS TEXT
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL14
THE QUALITY MANAGEMENT SYSTEM (QMS) -
CONCEPTUALLY
Quality System
Policy
Organization
Documents
Processes
Resources
Objectives & Planning
Support continuous
quality improvement
for processes and
product.
Demonstrate the constant
commitment of senior
management to quality.
Specify who is responsible for
each quality-related activity.
Explain how quality
commitments should be
performed (procedures)
and documented
(records).
Identify and monitor all
processes that affect
product quality.
Identify and provide the
resources and knowledge
needed in order to achieve
quality objectives.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL15
THE THREE LEVELS OF COMPLIANCE
Product and service quality – to be competitive
Product and service quality – to be competitive
Quality mindset – to strive for excellence
3
2
1
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL16
THE THREE AREAS FOR COMPLIANCE
• Strategic quarterlyRisk Management,
Auditor and inspector satisfaction
• Tactical monthlyDocumented Key Compliance processes
• Operational daily Technical support for all
compliance matters
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL17
THE QUALITY MINDSET IS ABOUT:
Being beyond compliance
Cooperation
Being open to
inspection
Taking responsibility
Innovation
Learning
Being accountable
Delivering quality in
everything we do
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL18
FROM BEING REACTIVE TO BEING PROACTIVE
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL19
COMPLIANCE AND QUALITY MANAGEMENT SYSTEM
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL20
THE COMPLIANCE PYRAMID - RISK-BASED
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL21
QUALITY RISK MANAGEMENT
Risk Management
Identify and
asses risks Develop
controls
and action
plan
Implement
controls and
evaluate
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL22
BENEFIT / RISK CONSIDERATIONS HOLISTICALLY
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL23
THE ACCEPTABILITY OF RISK
A few real examples:
• 1,000 open CAPAs, 90% between 1 and 5 years overdue
• Critical audit observation still unresolved after 1 year, with 5 minor
observations from the same audit now resolved
• No maintenance activities in the past 2 years
• Validation of large configurable Enterprise Resource Planning system
terminated 6 months before completion by senior management
• Requests by regulatory agency inspectors are never questioned,
challenged or discussed - they are always fully accepted
• The company is understaffed by around 200 quality unit personnel
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL24
THE ACCEPTABILITY OF RISK - THE BASELINE
What is your acceptance level?
How is this communicated? - Dashboards?
Is it defined by senior management?
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL25
THE RISK REGISTER
1
2
A listing of all risk assessments. How to list them, where
and who is in charge?
A risk register compliant with EU regulations.
Should sites have a formal risk register and management
process?
Yes, a risk register (or equivalent title document) should list and track all key risks
as perceived by the organisation and summarise how these have been mitigated.
There should be clear reference to risk assessments and indeed a list of risk
assessments conducted should be included or linked to the register. A
management process should be in place to review risk management - this may be
incorporated into the quality management review process.
SOURCE: http://tinyurl.com/zgv3y99
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL26
BEYOND THE FAILURE MODES AND EFFECTS ANALYSIS
(FMEA)
While FMEA is useful and versatile, some organizations
consider it a complete QRM tool in itself. This is in part
because typical FMEA worksheets include columns for risk
treatment items (i.e., risk reducing actions) and a
reassessment of the risk priority numbers (RPNs).
This approach essentially leaves out the third and fourth
elements: risk communication and risk review. Despite this
limitation, many companies still rely on FMEA as their overall
approach to QRM.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL27
COMMUNICATION - THE WEAK LINK WHEN IT COMES
TO RISK
Communication is a key issue in all of science and
engineering. The best scientific argument may fail to convince
if it cannot be communicated cogently to the stakeholders.
This is especially true of Risk Acceptability Criteria.
Make sure you have internal communications and external
communication policies and procedures
SOURCE: https://store.pda.org/ProductCatalog/Product.aspx?ID=3447
© 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL28
FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY CULTURE PROBLEM” - #3
An organization’s culture can limit how QRM is applied proactively
Misapplying a specific risk-assessment tool as a QRM process
Using rating scales that are neither specific nor appropriate to a given
situation
Not acknowledging when uncertainty (or the lack of important information) is
present
0Neglecting to keep risk assessments current with changes that could affect
underlying assumptions and key decisions
.
2
3
4
5
6
7
Using QRM to justify an action instead of as a tool for truly assessing and
exploring risks
Issues with using Quality Risk Management incorrectly:
1 Using formal QRM tools in situations where they are not actually needed
SOURCE: James Vesper and Keven O’Donnell in Pharmaceutical Engineering Nov - Dec 2016
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL29
THE VALUE OF DATA FOR QUALITY METRICS
“In the inspection realm, we find too many, disturbing
examples of firms providing us with false information, and
doing so deliberately.
In order for those of us at FDA to do our jobs, we must
receive accurate information from firms. Quality metrics based
on false data are meaningless. An NDA or ANDA based on
false information can be a danger to the public.
Fundamentally, data integrity is a corporate responsibility.
There are other examples of corporate responsibility that our
Office of Criminal Investigations has emphasized.”
SOURCE: Howard Sklamberg, Deputy Commissioner, Global Regulatory Operations and Policy, U.S.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL30
A FEW DEFINITIONS TO START WITH
Metric:
A measure against a standard (standards of measurement by
which efficiency, performance, progress, or quality of a plan,
process, or product can be assessed)
Indicator:
Provides indication of performance (qualitative or quantitative),
e.g., to evaluate success of an organisation or activity
Key Performance Indicator (KPI):
Target critical areas of performance (not all indicators are key)
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL31
MEASURABLE COMPLIANCE - METRICS
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL32
QUALITY METRICS - MEASURE WHAT?
FDA Submission of Quality Metrics Data Guidance for Industry,
Revision 1, November 2016
FDA Quality Metrics Technical Conformance Guide Technical
Specifications Document, Version 1.0, June 2016
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL33
WHY THIS PROGRAM?
The proposed guidance is designed to drive manufacturing modernization
and also reduce the compliance burden.
Companies that have standardized processes and are able to maintain the
required quality standards would be subject to less frequent inspections,
giving them a strong incentive to focus on process improvement.
It is part of FDA’s Pharmaceutical cGMPs for the 21st Century - A Risk-
Based Approach initiative
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL34
HOW TO PREPARE?
People:
Senior management buy-in
Allocation of resources and organizational adjustments to
implement and run the processes required
Awareness creation and training
Technology:
Automation of data collection and reporting
Interfaces for multiple systems
Data calculation and trending algorithms
Data dashboards
© 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL35
Verification that all required data are collated
HOW TO PREPARE CONT.
Standardization of data and of the processes for reporting
the data
Validation of the processing systems
Identification of the quality metrics2
3
4
5
Processes:
Identification of the processes that manage the quality
metrics data 1
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL36
HOW TO PREPARE - SUMMARY
Courtesy of Steve Mendivil PDA Quality Metrics Task Force lead
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL37
QUALITY INDICATORS - FDA VIEW 1
Accepted lots/Total number of lots started.Metric
RationaleThis rate is an indicator of manufacturing process
performance, and is proposing it in terms of accepted
lots.
Measurement“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.”
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL38
QUALITY INDICATORS - FDA VIEW 2
Product quality complaints received / Total dosage units
distributed.Metric
Rationale
This rate is an indicator of patient or customer feedback and
is proposing it in terms of complaints per distributed dosage
units, which will remove lot size as a variable in the complaint
equation
Measurement“The number of product quality complaints received for the
product divided by the total number of dosage units
distributed in the current reporting timeframe.”
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL39
QUALITY INDICATORS - FDA VIEW 3
OOS test results invalidated / Total OOS test resultsMetric
RationaleThis is an indicator of the operation of a laboratory. It includes
stability testing and only focuses on cases where measurement
aberrations led to the invalidation of OOS results.
Measurement
“The number of OOS test results for lot release 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.”
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL40
IT’S STILL IN THE DESIGN PHASE
FDA is planning to open an electronic portal in January 2018
for voluntary submission of quality metrics data, which the
agency is encouraging companies to submit on a quarterly
basis.
But, the clock is ticking
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL41
QUALITY INDICATORS - WHAT YOU SHOULD MEASURE
ANYWAY
Inspection Preparation Effort - known?
Remedial Action Effort - measured?
% Right First Time - where are you?
Percentage GMP Systems validated - tracked?
Compliance level with key regulations - red, amber or
green?
Time to respond to medical queries
© 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL42
HOW TO PREPARE CONT.
Identification of the quality metrics2
3
4
5
Processes:
Identification of the processes that manage the quality
metrics data 1
6
Verification that all required data are collated
Standardization of data and of the processes for reporting
the data
Validation of the processing systems
Validation of the processing systems
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL43
THE ANNUAL QUALITY PRODUCT REVIEW (APR) OR
PRODUCT QUALITY REVIEW (PQR)
The FDA “Annual product review” is intended to confirm that
every batch of product released during the review period
complied with the registered process and specification.
The EU PQR concentrates on the quality system and process
to show that they continue to produce consistently good
quality product.
SOURCE: http://tinyurl.com/zyrzesd
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL44
THE ANNUAL QUALITY
PRODUCT REVIEW (APR)
OR PRODUCT QUALITY
REVIEW (PQR)
From the stone age to the 21st
century:
• From manual transcription to
interlinked computerized
systems.
• From manual entry into
spreadsheets to real-time
trending data, providing an
immediate snapshot of the
quality and compliance status of
the company.
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL45
QUALITY INDICATORS?
Some not so sensible ones:
Number of 483 observations in a FDA inspection
All deviations closed out in 30 days
All audit trails reviewed
Incentive systems and their influence on corporate culture:
• “What gets measured gets done” (an old maxim from the
Management by Objectives approach, attributed to several
people)
• What gets tangibly incentivised gets done first!
• Systems that incentivise “pushing product out the door” or which
have unbalanced objectives that fail to consider quality and
compliance can quickly drive behaviours in the wrong direction
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL46
INTERACTIVE EXERCISE• Please split up in groups
• Then select one of these topics
(preferably all topics should be
covered by a team):
o Defining an objective
o Managing risks
o Reporting quality metrics
• Please provide solutions and/or
strategies for how to achieve the
desired outcomes
• Prepare to share your findings
with the rest of the audience
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL47
INTERACTIVE EXERCISE - DEFINING AN OBJECTIVE
Your company is planning to launch a new product 3 years from now
Your operations, marketing, quality and other teams need a common
objective (preferably no more than one or two sentences)
Define this objective:
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL48
INTERACTIVE EXERCISE - MANAGING RISKS
Your company is planning to launch a new product 3 years from now.
Your operations, marketing, quality and other teams need to work out the
risks associated with this launch.
Define the approach:
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL49
INTERACTIVE EXERCISE - REPORTING QUALITY
METRICS
Your company is planning to launch a new product 3 years from now.
Your operations, marketing, quality and other teams need to define and
report quality metrics to senior management and the authorities.
Define the quality metrics:
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL50
FDA ON QUALITY METRICS - NEWS TICKER
+++ Latest News +++ Latest News +++
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL51
FDA ON QUALITY METRICS - TIMELINE
SOURCESteve Mendivil, from the Opening Presentation
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL52
FDA ON QUALITY METRICS - NEWS TICKER
To be completed at the conference
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL53
QUALITY METRICS - A FEW OPEN QUESTIONS
Open questions:
• Does FDA have the legal authority to
request quality metrics?
• How should FDA implement the program?
• Product segmented by site or Site
segmented by product?
• Optional Metrics?
• Should FDA share peer ranking?
• Metric reporting leading to more drug
shortages?
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL54
THE COMPLIANCE PYRAMID - VALUE GENERATION
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL55
CURRENT VERSUS DESIRED COMPLIANCE STATE
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL56
COMPLIANCE FRAMEWORK
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL57
YOUR PRESENTER
Siegfried Schmitt, Ph.D., FRSC
CChem CSci
Principal Consultant
PAREXEL International
+44 7824 592401
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL58
THANK YOU
© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL58