Keynote address at the 2013 Scientific Conference of the Nigerian Association of Pharmacists and Pharmaceutical Scientists in the Americas (NAPPSA). The lecture attempts to 'connect the dots' between PAT and QbD to Pharmacogenomics in the context of the authors experience at the US FDA and in industry.

1. Process Analytical Technology and
Quality by Design: Implications for Advances
in Pharmacogenomics
AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS LLC
AJAZ@AJAZHUSSAIN.COM
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

2. Framing this talk
Trial-n-error Predictive
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3. Population to individual patient
Safe and
efficacious
Not safe
Not
efficacious
Neither
safe nor
efficacious
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1. Exposure – response
-
Pharmacogenomics
2. Mechanistic
3. Diagnostic
1. Herceptin (trastuzumab)
2. Targets HER2
3. Immunohistochemistry
tests, HER2 gene-
amplification tests

4. The race to predictability
Biology and
drug discovery
Chemistry,
Manufacturing
& Controls
Clinical drug &
diagnostic
development
Health care
practices
Patient
behavior
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5. Common challenges
• Clinical endpoints relevant to patient
• Relevant quality attributes
Measurements
• Biomarkers
• New quality analytics
Validation
• Mode of actions
• Mechanisms relevant to product quality
Mechanistic
understanding
• Regulatory
• Disciplinary
Culture/mind-set
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Satisfaction
Real-time
Predictability
Efficiency

6. 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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7. Important concepts in the PAT Guidance
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8. 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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9. 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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10. 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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11. Rate of progress differs
Biology and
drug
discovery
Chemistry,
Manufacturin
g & Controls
Clinical drug
& diagnostic
development
Health care
practices
Patient
behavior
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12. Struggling with quality
Compounding challenges today
Drug shortages
cGMP issues
Data integrity issues
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13. 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 Unlimited
http://www.darpa.mil/dso/thrusts/bwd/act/amp/index.htm

15. “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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16. Flu vaccine in tobacco plant
Why?
How?
What?
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17. What? Speed, volume and affordability
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Hypothesis (target) in 2008
GSK
Facility
(Qubec, Canada)

18. 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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19. Initial disappointment to anticipation..
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Phase I Study of an Autologous Recombinant
Idiotypic 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

20. Personalized manufacturing……
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http://www.mymms.com/

21. Summary
We 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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