Process Analytical Technology, Quality by Design & Pharmacogenomics
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Process Analytical Technology and Quality by Design: Implications for Advances in PharmacogenomicsAJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS LLC
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 1
Scientific Conference of the Nigerian Association of Pharmacists and Pharmaceutical Scientists in the Americas NAPPSA: Annual Conference 20 September 2013
Framing this talk
Trial-n-error Predictive
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 2
Population to individual patient
Safe and efficacious
Not safe
Not efficacious
Neither safe nor
efficacious
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1. Exposure – response -Pharmacogenomics
2. Mechanistic3. Diagnostic
1. Herceptin (trastuzumab)2. Targets HER2 3. Immunohistochemistry
tests, HER2 gene-amplification tests
The race to predictabilityBiology and
drug discovery
Chemistry, Manufacturing
& Controls
Clinical drug & diagnostic
development
Health care practices
Patient behavior
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Common challenges• Clinical endpoints relevant to patient
• Relevant quality attributesMeasurements
• Biomarkers
• New quality analyticsValidation
• Mode of actions
• Mechanisms relevant to product quality
Mechanistic understanding
• Regulatory
• DisciplinaryCulture/mind-set
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Satisfaction
Real-time
Predictability
Efficiency
Passing the baton would be desirable
Need to understand and control relevant variances
• Quality specifications – clinical relevance
• Product for a population
• Product for a individual patient
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Important concepts in the PAT Guidance
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Beyond the “test-test” comparison
A focus on process understanding can reduce the burden for validating systems by providing more options for justifying and qualifying systems intended to monitor and control biological, physical, and/or chemical
attributes of materials and processes.
• In the absence of process knowledge, when proposing a new process analyzer, the test-to-test comparison between an online process analyzer and a conventional test method on collected samples may be the only available validation option. In some cases, this approach may be too burdensome and may discourage the use of some new technologies.
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Validation
Systems that promote greater product and process understanding can provide a high assurance of quality on every batch and provide
alternative, effective mechanisms to demonstrate validation (per 21 CFR 211.100(a), i.e., production and process controls are designed to ensure
quality).
• In a PAT framework, validation can be demonstrated through continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and process end points.
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Systems thinking a key
The fast pace of innovation in today's information age necessitates integrated systems thinking for evaluating and timely application of efficient tools and systems that satisfy the needs of patients and the
industry.
• Many of the advances that have occurred, and are anticipated to occur, are bringing the development, manufacturing, quality assurance, and information/knowledge management functions so closely together that these four areas should be coordinated in an integrated manner
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Rate of progress differs
Biology and drug
discovery
Chemistry, Manufacturing & Controls
Clinical drug & diagnostic development
Health care practices
Patient behavior
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Struggling with quality
Compounding challenges today
Drug shortages
cGMP issues
Data integrity issues
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Two examples of progress
• An MIT-Novartis collaboration could be a boost for so-called “continuous flow” manufacturing.
Breakthrough Offers a Better Way to Make
Drugs (MIT Technology Review Nov. 2012)
• Predicting Health and Disease
• Accelerated Manufacture of Pharmaceuticals
• Modular Immune in vitro constructs
DARPA Accelerated Manufacturing
Programs
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Why? Speed, volume and affordability
DARPA “Accelerated Manufacture of Pharmaceuticals”
Program goal of 3 million doses in 12 weeks
Three phases, each phase has milestones that require logarithmic improvements (10X between each phase) in efficiency, production speed, and cost effectiveness.
Phase I is to achieve > 1 dose/L*wk for a subunit vaccine and >0.025 dose/L*wk for a monoclonal antibody.
The final cost metric required is < $1/dose for the subunit vaccine and <$10/dose for the monoclonal antibody.
Approved for Public Release, Distribution Unlimitedhttp://www.darpa.mil/dso/thrusts/bwd/act/amp/index.htm
“One size fits all" to “Personalized”
Two case examples
Pandemic flu vaccine made in tobacco plants
Personalized vaccine for non-Hodgkin’s lymphoma made in tobacco plants
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Flu vaccine in tobacco plant
Why?
How?
What?
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What? Speed, volume and affordability
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Hypothesis (target) in 2008
GSKFacility
(Qubec, Canada)
Therapeutic vaccines for Non-Hodgkin’s Lymphoma (NHL) in tobacco plant?
Vaccinate cancer patients against their own tumor
cells?
Plant made single chain variable region (scFv) vaccines? (Dr. Ron Levy; Stanford)
Alison a. Mccormick. Human Vaccines 7:3, 305-312; March
2011
NHL: B-cell surface Immunoglobulin (Ig)
marks the malignant cell, (unique identifier)
Unique idiotype Ig - as a tumor associated
antigen?
Historical proof of concept:
Antibodies in mice against Ig for each patient; when given back this custom
anti-idiotype antibody - remissions. However ; reoccurrence- “antigenic
escape”.
Solution: (1) coupling to a strongly immunogenic carrier protein (2) with
adjuvants and (3) immune response to the vaccine
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Initial disappointment to anticipation..
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Phase I Study of an Autologous RecombinantIdiotypic Vaccine Manufactured by magnICON® Technology for the Treatment of Patients With Relapsed or Transformed Follicular Lymphoma Sponsor: Bayer
Enrollment: 28
Study Start Date: January 2010
Estimated Study Completion Date: September 2013
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
clinicaltrials.gov
Personalized manufacturing……
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http://www.mymms.com/
SummaryWe are together on a journey to find more effective and efficient ways to meet the needs of patients
Moving from ‘trial-n-error’ to predictive approaches; it the most logical approach to progress forward; an ability to reliably predict is a strong demonstration of understanding
The FDA’s initiatives – PAT, Pharmaceutical Quality for 21st Century, Critical Path Initiative laid down the foundation for moving towards predictive approaches
Integrated systems thinking and informatics are key to progress; the FDA’s PAT Guidance captured these concepts
Progress in the CMC and clinical disciplines has lagged behind the progress in systems biology; there is need for catch-up
There are pockets of significant progress; a concerted effort to reinvigorate progress in the CMC arena is on-going
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