Question Based Development to Quality by Design to Continued Process
Verification
Ajaz S. Hussain, Ph.D.
Insight Advice & Solutions LLCNational Institute for Pharmaceutical
Technology & Education
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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?
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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)
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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.
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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”
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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”
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21 CFR 211.110a & 21 CFR 211.180
Expected trend in (2015?): 2016-18?
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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
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GADUFA Challenges @ OGD OPQ Maturing
Culture of Quality
QbD QbR CPV Quality Metrics
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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
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Are we asking the right question and at the right time?
Effective Date: 11/18/2014
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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.
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http://www.raps.org/Regulatory-Focus/News/2015/01/13/21061/FDA-Launches-New-Drug-Quality-Office-With-Goal-of-Improving-the-Pharmaceutical-Industry/
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Using Process Capability To Ensure Pharmaceutical Product Qualityby Lawrence X. Yu, Daniel Y. Peng, Robert Lionberger, Alex Viehmann and Karthik IyerThis 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.
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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
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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
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“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)
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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
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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’?
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Practice, Control, Process: Maturity
Initial
• Unpredictable
Managed
• Characterized, but reactive
Defined
• Characterized; proactive
Measured & Controlled
• In control
Optimizing
• Focus on improvement
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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 controlQuality by
DesignQuality Assured
Improvement Opportunities
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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!
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“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
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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
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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…
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