QbR to QbD to CPV 16 February 2015

Question Based Development to Quality
by Design to Continued Process
Verification
Ajaz S. Hussain, Ph.D.
Insight Advice & Solutions LLC
National Institute for Pharmaceutical
Technology & Education
4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 1

Does your QbD program delivery confidence in CQA’s?
Does it reduce the risk of development failure?
Does it provide a process which is stable and ‘in control’?
Does it reduce risk of GMP noncompliance?

Continuous Process Verification: An alternative approach to process
validation in which manufacturing process performance is continuously
monitored and evaluated. (ICH Q8)
Continuous Quality Verification (CQV) is described as an approach to
process validation where manufacturing process (or supporting utility
system) performance is continuously monitored, evaluated and adjusted
as necessary”. (ASTM E2537-08)
Continued Process Verification - a stage (Stage 3) of the Process
Lifecycle, after Performance Qualification (FDA Process Validation 2011)

Stage 3 ― Continued Process Verification (FDA)
..continual assurance that the process remains
in a state of control (the validated state) during
commercial manufacture…PV Guidance 2011
An ongoing program to collect and analyze product and process data
that relate to product quality must be established (§ 211.180(e)). The
data collected should include relevant process trends and quality of
incoming materials or components, in-process material, and finished
products. The data should be statistically trended and reviewed by
trained personnel. The information collected should verify that the
quality attributes are being appropriately controlled throughout the
process.

21 CFR 211.180
“Firm must review, at least annually,
the quality standards of each drug
product to determine the need for
changes in drug product
specifications or manufacturing or
control procedures”

21 CFR 211.110a
“Control procedures shall be
established to monitor the output and
to validate the performance of those
manufacturing processes that may be
responsible for causing variability in
the characteristics of in-process
material and the drug product”

21 CFR 211.110a & 21 CFR 211.180
Expected trend in (2015?): 2016-18?

High risk at foreign facilities;
Quality Unit ineffective
 Breaches in assurance of data
integrity; “Data too good to be
true“
Effectiveness of CAPA and
Complaint Resolution
Sporadic & heterogeneous
enforcement of CPV & Statistical
Confidence
[Pharmaceutical Equivalence
challenges and high profile
generic recalls ]
Current Concerns 2015  CPV & Statistical Confidence – the
“C“ in GMP
 Ppk & Cpk linked to CAPA; Facility risk
classification
 Question based Review improved and
integrated with Process Validation &
CPV
 “In Control“ the Engineering
Perspective
 Starting to realize the ‘Vision
2020’- “I can see clearly now”
Continual Improvement a reality;
CAPA is not continual
improvement
 “And so gradually over the next
couple of years or so I think
purchasers will become aware
that they need to pay for reliability
– just like we would do with a car."
Dr. Janet Woodcock, Director
Center for Drug Evaluation and
Research, FDA (June 2013)
2016-18
2018-2020
OPQ
Successful
Pressureof
Shortages
Metrics&Risk
Based
GADUFA Challenges @ OGD OPQ Maturing
Culture of
Quality
QbD QbR CPV Quality
Metrics

Culture of
Quality
QbD QbR CPV Quality
Metrics
Are we asking the right question and at the right time?

Culture of
Quality
QbD QbR CPV Quality
Metrics
Are we asking the right question and at the right time?
Effective Date: 11/18/2014

CDER OPS MAPP 5015.10 (Selected Questions 14-17)
• 14. What is the rationale for selecting this manufacturing process for the drug product?
• 15. What is the potential risk of each process step to impact the drug product CQAs and how
is the risk level justified?
• 16. For each of the potentially high risk manufacturing unit operations:
• a) What input material attributes and process parameters were selected for study and
what are the justifications for the selection?
• b) What process development studies were conducted? Provide a summary table listing
batch size, process parameter ranges, equipment type and estimated use of capacity.
• c) What process parameters and material attributes were identified as critical and how do
they impact the drug product CQAs?
• d) How were the process parameters adjusted across lab, pilot/registration and commercial
scale? What are the justifications for any changes?
• 17. If applicable, what online/at-line/in-line monitoring technologies are proposed for routine
commercial production that allows for real-time process monitoring and control? Provide a
summary of how each technology was developed.

http://www.raps.org/Regulatory-Focus/News/2015/01/13/21061/FDA-Launches-New-Drug-Quality-Office-With-Goal-of-Improving-the-Pharmaceutical-Industry/

Using Process Capability To Ensure
Pharmaceutical Product Quality
by Lawrence X. Yu, Daniel Y. Peng, Robert
Lionberger, Alex Viehmann and Karthik Iyer
This article introduces the definition and
calculation of process capability, illustrates their
use in the pharmaceutical industry, and
describes the relationship of process capability
with production batch failure rate. The use of
process capability in product development,
process scale up and qualification, and
commercial production is also described.

Product &
Process Design
Process scale-up
& Qualification
Commercial
Manufacturing
Get the CQA’s right
Ensure your process is
well understood!
Control (CMAs + CPPs) →
CQA in Control
Common & Special
Causes, Control Strategy.
Initial Ppk reasonable.
Sable process on scale-up
and in Operations. Why?
Process Qualification
Protocol with Confidence.
What?
Process Qualified with
Confidence. How?
Process “in control”;
Cpk/Ppk monitoring &
trending; reduced
(traditional) testing.
Process “not in control”;
statistically meaningful
testing; effective CAPA –
identify and eliminate
‘special causes’; improve
control strategy

This journey began decades ago…..
Useful information on http://www.slideshare.net/a2zpharmsci

“And like the
heroes of the
French Revolution,
we look to a future
that will bring us
everything or
nothing, depending
on the public
trust”
 The Nation Needs a Comprehensive
Pharmaceutical Engineering Education and
Research System
 “A recent re-examination by the US Food and Drug
Administration of the current pharmaceutical quality
decision-making system raised fundamental
questions about its efficiency and its continuing
effectiveness to address the increasing
complexity of pharmaceutical systems.”
 “….low success rate for identifying the root
cause of deviations and out-of-specification
observations as well as the predominant focus
on end-product testing—often based on an
inadequate statistical consideration of inherent
variability and static process conditions— which,
some argue, evolved to facilitate regulatory document
expectations for “process validation.”
VIEWPOINT 2005
Pharmaceutical Technology SEPTEMBER 2005

“Generics is all about file first and figure out later” State
of QbD Implementation Report to FDA June 2010, Ted Fuhr,
Mckinsey& Company
“It would also mean the FDA had no power to deny tentative
approval to an application that clearly could never win final approval -
an applicant could state in its ANDA that it planned to
manufacture a generic drug in an outhouse behind the
applicant's house using a child's chemistry set.“
U.S. District Judge Beryl Howell (March 11, 2015)
Generics need to be defended

Rationalization &
Attitude
Pressure &
Incentive
Opportunity –
‘holes in the QMS”
“The key to good
decision‐making is not
knowledge, it is
understanding. We are
swimming in the former.
We are desperately
lacking in the latter” ‐
Malcolm Gladwell

Do these questions continue to linger in
Company X?
What is pharmaceutical quality?
Compendial testing sufficient?
Process validation – representative of commercial manufacturing?
Any deviation from cGMP means the product is ‘adulterated’?

Practice, Control, Process: Maturity
Initial
• Unpredictable
Managed
• Characterized,
but reactive
Defined
• Characterized;
proactive
Measured &
Controlled
• In control
Optimizing
• Focus on
improvement
Capability Maturity Model Integration; Carnegie Mellon University
A validated process?

Maturity Level & Assurance of Quality
Managed Characterized,
but reactive
High risk of
‘Cheating by
Design’
“Trial
Injections”
“Testing in to
Compliance”
Defined Characterized;
proactive
Lower level of
assurance
Stopping &
Correcting
Batch
Rejection
Measured &
Controlled
In control
Quality by
Design
Quality
Assured
Improvement
Opportunities

Risk of unintended or intended normative
support for ‘testing into compliance’?
attitude
toward
performing
the
behavior
Process
validation is
done so
quality is
good;
test prone to
error
“Batch failure
means I made
a mistake”
subjective
norm
Documents
not critical;
Compendial
testing
sufficient
Local
regulators
collect & test
samples – no
issue there!
“Testing into compliance”

 Systems thinking: System is the product of interacting parts; improving the parts
taken separately will not improve the system
CEO &
Sr. Management
Culture
of Quality
Managers &
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy

What will it take to ensure that your QbD program delivers
(a) confidence in the CQA’s?
(b) provides a ‘stable’ and ‘in control’ process?
(c) reduces the risk of development failure?
(d) reduce risk of GMP noncompliance?

To remain true to ‘first do no harm’ we, the
legitimate pharmaceutical community, have
inherited, and accepted, a culture of quality
that demands that our intention, our
awareness and our skills deliver ‘quality by
design’ with continued vigilance to detect,
correct and to prevent errors that have caused,
or have the potential to cause, harm to the
patients we serve. We also recognize the
limitations of our pharmacovigilance.
We must more clearly recognize that CAPA is
not ‘continual improvement’ and that we
must strengthen our culture of quality to
deliver continual improvement in our ability
to assure quality, reduce costs and enhance
confidence in what we do. Ajaz S. Hussain, Ph.D., Mumbai, 24 March 2015
VIEWPOINT 2015

9. Into a blind darkness they enter who follow after the Ignorance, they as if into a greater darkness who devote
themselves to the Knowledge alone.
10. Other, verily, it is said, is that which comes by the Knowledge, other that which comes by the Ignorance; this
is the lore we have received from the wise who revealed That to our understanding.
11. He who knows That as both in one, the Knowledge and the Ignorance, by the Ignorance crosses beyond
death and by the Knowledge enjoys Immortality
Isha Upanishad: Knowledge and Ignorance, Verses 9 – 11
VIDYA AND AVIDYA
VOLUME 17 THE COMPLETE WORKS OF SRI AUROBINDO (2003)
The problem of reductionism: - it works for small, not for big steps - it misses the
whole - it misses the meaning - in the end, it undercuts itself.
Systems approach……
Note. I have take a different point
of view from that of Dharm P. S.
Bhawuk, Science of Culture and
Culture of Science: Worldview and
Choice of Conceptual Models &
Methodology. The Social Engineer.
Vol. 11, No. 2, July, 2008.
Practicing to improve
(awareness of) our
intentions is our
wisdom tradition, and
is reflected in our laws,
in US, India and
around the globe…

QbR to QbD to CPV 16 February 2015

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QbR to QbD to CPV 16 February 2015