pharmaceutical quality by design travel options keynote @ patheon qbd 2016
TRANSCRIPT
Pharmaceutical Quality by Design:Travel Itineraries
Ajaz S. Hussain, Ph.D.
9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1
Quality by DesignMoving to Next Generations
September 7th - 8th 2016 Patheon-Greenville
Keynote Address
Travel ItinerariesEmergency• “No-pain No-gain”
Standard• “Plan Do Check & Act”
Pathfinders• B1: “Don’t Use & Don’t
Tell”; no more!• B2: Every vertex can be
a Tipping Point• G1: Same and Similar• G2: Synthesis & Analysis
9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 2
Culture of Pharmaceutical Quality
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QbD Travel itineraries: 2015 –
20
06
-20
15…
?
History: FDA Packages: 2002-2005
Ajaz S. Hussain. FDA ACPS Meeting, 8 May 2002
Pharmaceutical Quality by Design: Review of Progress and Challenges (2012)
QbR to QbD to CPV 16 February 2015
Reorganization at FDA; Office of Pharmaceutical Quality
CDER/FDA; Emphasis on One Quality Voice . CGMP Alarm bells
– ringing again!
FDA Draft Guidance: Advancement of Emerging Technology
Applications to Modernize the Pharmaceutical Manufacturing
Base Guidance for Industry (December 2015)
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QbD Travel Itineraries
Emergency Travel Itinerary
Continued Process Verification for all
commercial products with statistical confidence,
effective QMS and CAPA
Prevent a Warning Letter
Standard Travel Itinerary
Confident adoption of PAT, ICH Q8-11 and PV 2011.
Emphasis on patient-related failure modes and justification for scale-up
and manufacturability (in submissions). Optional comparably protocol for anticipated PAS changes.
Pathfinder Option
Rapid and/or more confident development with continuous and/or real-time
release & (optional) comparability protocol for
anticipated changes.
First Traditional and Complex Generic with new
technology1
2
3
G1
G2
B1
B2
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Pathfinders
“Don’t Use & Don’t Tell” no more!
B1
Ray Scherzer ‘s challenge to Pharma: Quality By Design!
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Pathfinders
Every vertex can be a Tipping Point!
B1
Remembering Einstein’s challenge that we will never solve the problems tomorrow with the same order of consciousness we are using to create the problems of today!
G2: A Destination Reached in 2016
Synthesis
&
Analysis
Disputing a 8 year ANDA review!Totality of Evidence
The clinical endpoint BE unacceptable - API particle size/shape and manufacturing process control the root cause!
FDA accepted the in vitro particle size data from MDRS in lieu of the clinical endpoint BE study
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“.. a first in OGD history”
To create a Win-Win-Win!
“.. a first in OGD history”
Alarm Bells are Ringing, Again!
Generic Drug Scandal
Office of Pharmaceutical Science
20th Century to 21st
Century Desired State
SUPAC to Design Space
Rapid Globalization and FDASIA
Breaches in Data Integrity
Office Pharmaceutical Quality
One Quality Voice
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..a lot going on underneath..
“we can be blind to the obvious, and we are also blind to our blindness.” ― Daniel Kahneman, Thinking, Fast and Slow
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Unaccounted Cognitive Biases & Many reasons to rationalize away dissonance
What is Culture of Pharmaceutical Quality?
We make two products –medicinal product and linked evidence of its quality, safety and efficacy
Both, required by law, to be better than Placebo!
FD&C Act & CGMP regulations – quality cannot be tested into products; it has to be built-in by design! (1987 PV Guidance)
Intention determines the punishment under the law
By Design is by intention to established a Plan-Do-Check-Act Practice
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Integrating Big Ideas
Fisher, Shewhart, Deming, Kegan, Kahneman,..
Practicing: Looking Good, Being Good, Doing Good?
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Epistemology essential in human development (Orders of Consciousness) and for overcoming Immunity to Change (Professor Kegan)
Our procrustean behavior driven by our cognitive biases and blind spots! [Behavioral Economics, Kahneman & others]
Testing to Document Quality Vs QbD
Order of Consciousness and approach to SOP’s, education, training experience, supervisory oversight, etc.
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Need to reduce variance & skewness in the distributed understanding of pharmaceutical quality & risk to patients
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Elephant in the dark or men with blindfolds on?
Ex
pre
ssP
ha
rma
16
Ma
y 2
016
A 21st Century Fable about Pharmaceutical Quality and Preventing a Clash of Cultures
CPQ: Founded on Quality by Design
We do our best to develop medicines and the evidence needed to satisfy the needs of patients – we develop these products consciously, recognizing that quality cannot be tested into our products .
We know that nothing is perfect and there will be some errors in our design, systems and procedures, or we may make mistakes in following set procedures.
It is normal, easy and rewarding to work within our quality management system, without fear, to detect, correct and to learn from our mistakes.
In doing so we act consciously in the interest of patients –especially when no one else is looking, and we continually improve our quality by design and aim for right first time.
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Framework: Culture of Pharmaceutical Quality (CPQ)
Culture –Pharma Quality
Quality is Normal
Quality is Easy
Quality is Rewarding
System-
QMS
Appreciate System
Theory of Knowledge
Knowledge of Variation
Psychology of Change
Practices-GXPs
Fear Removed
Mastery
Awareness
Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment
Connect to CultureConnect to Practice Quality by Design
..a lot going on underneath..
FDASIA
New Office of Product Quality @ CDER/FDA
“One Quality Voice”
Will these changes get to the root-cause?
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Latent factors and a globalized supply chain…
Variance and skewness of latent factors
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Mental models ….
Thinking about “Not of One Mind” to “One Quality Voice” (OPQ/CDER/FDA 2016)
I believe this is a good model for Confident Quality Assurance.
While I was at FDA.After FDA Inspection
(e.g.,, Breach in Data Integrity) Current model.
Risk of
toppling?
Risk of
toppling?
6 Observations (Form 483)
Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit
Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed
Control procedures are not established which monitor the output and 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
The accuracy, specificity, and reproducibility of test methods have not been established . . .
Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures . . .
Laboratory records do not include complete data . . .
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Will the pyramid topple?What will prevent a Warning Letter? December 2013; US Facility
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How to respond to these Observation? 483 Observation # 3 relates to process which delivers products to patients.
Control procedures are not established which monitor the output and 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.
A. Process Validation Protocols for My Head Aches Capsules, 1 mg lack acceptance criteria. For example: In MyPV420 – Process Validation Protocol for My Head Aches Intermediate Delayed-Release Pellets (0.X%) lack acceptance criteria for Blend Uniformity from drums, particle size and Dissolution.
B. There is no data to support the critical process parameter ranges of the My Favorite Fluid Bed Dryer in the current/proposed commercial batch production record A1234 for My Head Aches Intermediate Delayed-Release Pellets for the following:
• Inlet Air Temperature: XX-YY C
• Inlet Air Volume: XXX- YYYY m³/h
• Microclimate Pressure: XX- YYY mbar
• Dynamic Filter Pres. Max.: X-Y bar
• Dynamic filter Pres. Min.: X -Y bar
• Dynamic filter Time: X-YY seconds
• Spray Air Pressure: X-Y bar
To be Commercialized & Commercial Products
Development or validation reports contain no data supporting identification of critical process parameters and their ranges. Key focus: Process Validation Guidance 2011.
Each observation should be addressed specifically & comprehensively
Process capability roadmap a central theme (for all products at the facility)
Plus – how are CQA’s linked to PPs; what are CPPs’ and range for controlling?
How other observation impact/interact informs the methodology and sequence of work products
Process Capability Roadmap
Measurement system capable for all QA’s & PPs?
Is the process stable for all CQA’s?
What can we do to address special causes we will observe?
Are the processes capable?
Plus +++
483 Observations
Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit
Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed
Control procedures are not established which monitor the output and 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
The accuracy, specificity, and reproducibility of test methods have not been established . . .
Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures . . .
Laboratory records do not include complete data . . .
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© Light Pharma
Process Capability: If you can’t measure it, you can’t improve it
Process Capability Roadmap:
1
Has Measurement
System capability
been verified?
STOP!
Do not compute
Proc. Cap. statistics.
Improve the Meas. System.
No
2
Is the process stable
or unstable via SPC?
Yes
STOP!
Do not compute
Proc. Cap. statistics.
Investigate special causes.
Improve process stability.
3
Is the data normal
“enough” via the
Normality Test?
STOP!
Transform data.
No4
Compute
Cpk
Yes
Unstable
Stable
0
Challenge
Specs!
p-value < 0.05
p-value > 0.05
Gage R&R
& Calibration
SPC Charts
Scott Tarpley, UK Arden House 2004
Roadmap to process capability?
Challenge specs
Measurement system capability for all CQA’s (including dissolution test)?
Is the process stable for all CQA’s?
What can we do to address special causes we will observe?
Are the processes capable?
Plus – what is the link between CQA’s & PPs; what are CPPs’ and range for controlling?
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Scott conducted a training program (2004) at FDA for the PAT Team. This slide is from my talk at a USP Annual Scientific Meeting "The Science of
Quality“. September 26–30, 2004.
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Assess impact on CQAs for all process stages and
parameters(Science, Product History,
Investigations, Complaints)
Conduct statistical analyses on all process parameters comparing PV batches and
current batches
Difference between PV and Current
Batches?
Identify potential impact of process parameter on CQA
Low/HighOr
Not Applicable
Calculate Process Capability for CQA(s)
that may be impacted
Ppk > 1.3 ?
Identify Set-point, Set-point range and Operating
Range using existing supporting data
Prepare and Approve Process Parameter Summary Report
Update Master Batch Record with new ranges
YES
YES
Further evaluation required
N/A
Low/High
NO
NO
2
1
3
4
Should we take this path?
Initial decision tree: Validation batches Vs Current?
To be commercialized vs. products in commerce?Current PPs, set-points, ranges – supporting data? Equipment Qualification Ranges Vs. Process set-points and ranges?Analytical method validation & capability? Data in PD Reports, Validation Reports, SOP’s, BMRs,……?Deviations, Complaints, CAPA?
What are the most important questions?What assumptions can we accept/justify?How precise do our answers need to be?
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BMRSOPsValidation
Reports
CQAs, PPs & CMA’s30-60 consecutive batches
ComplaintsCAPA
Database ready for statistical analysis
METHADOLOGY[ASTM E2709 & E2281]
Manual input
Manual input
Questions
AssumptionsPrecision
STATISTICAL METHADOLOGY2
Scientific Impact Assessment(Structured/protocol based FMEA)
3
System wide CAPA
Although the other 5 observations posed significant challenge –interconnections; it is a system!
An integrated Statistical Assessment & Scientific Impact Analysis provided a way forward
System wide implementation - an integrated adoption of PAT, ICH Q8-11 and PV 2011!
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“No Pain No Gain” the name is justified!
1
2
3
What will you choose (or have already chosen)?
“Travel with Family”
“No-pain No-gain”
FDA current thinking: Question Based Review, Ppk & CPK
Adapted from: “Using process capability to achieve product quality.” March/April 2015. Pharmaceutical Engineering.
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Process Capability Roadmap
Patient Related Failure Modes
Patient Related Failure Modes & Totality of Evidence
How is “clinically relevant evaluation of pharmaceutical equivalence” demonstrated?
How will you demonstrate that “fewer risks are managed by BE study alone”?
What additional steps are necessary to design a bioequivalence trial to complement equivalence in design and performance?
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Future is upon us!
“No-pain No-gain” : 1 to 2 and then to 3
or
“Travel with Family”: 2 & 3
What will you choose (or have already chosen)?
Vertex or Tipping Point?
Quality & Assurance
Our knowledge pyramid topples easily because it is an upside down pyramid for several reasons
Need to keep regulatory decisions close to observation or review to maintain objectivity (& thwart corruption)
Market failure and information asymmetry
Prevailing ontological and epistemological gaps
Improving the system: One Quality Voice
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US FDA is a large complex organization. How to turn a large ship? How to keep the knowledge pyramid from toppling so frequently? How to improve assurance the system delivers?
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“Tipping point”
Summary Review of Regulatory Action for
Vertex’s NDA 206038: “Quality-by-Design (QBD)
process for the development of the product,
manufacturing process, and control strategy. A
fully continuous drug product manufacturing
process was applied to the manufacture of the
product, which is a unique and a new process”
“The pharmaceutical industry has been so slow to adopt .., but I think the time is now,” FDA Commissioner Margaret Hamburg said during a tour of Vertex’s new continuous manufacturing line in South Boston. WSJ 9/2/2015
What impact can FDA Commissioners’ comments, made in New England, have in FDA District Offices based in other regions?
A unique and new process was utilized in an NDA submission! It also provided for a rapid Quality-by-Design development of
product, manufacturing process and control strategy! These two aspects justify
the label – Tipping point.
Headquarters andReview Centers.
Independence of District Offices from Review Centers is an important concept.
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Martin VanTrieste, R. Ph. SVP Quality Amgen PIA Meeting –June 21, 2012
From an FDA Presentation: “FDA’s Evolving Approach toPharmaceutical Quality” October 21, 2015
One of several ways C” in GGMP Emerges?
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The outcome from conducting a single USP test
cannot be assumed for all the untested units in the batch
Implementation of Process Validation 2011 progresses.
Summary
Additional roadmap considerations
Target Product Profile (patient related failure modes)
QTPP – RLD CQA Characterization driven (statistical confidence)
ICH Q8 outlines a QbD methodology; don’t forget QbD is also the paradigm
Culture of Pharmaceutical Quality is founded on QbD Paradigm
QbD @ Patheon
Quality assured for patients
Synthesis of knowledge by integrating analyses
Effective communication of Why with the clients and regulators
Patheon an important Integrator ; Pathfinder opportunity!
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Thank you!
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Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom. Viktor E. Frankl
Between regulatory query and response there is Design Space. In that space is our comparability protocol…
will be to arrive where we started and know the place for the first time.
T. S. Eliot
We shall not cease from exploration, and the end of all our exploring …….