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Process Analytical Technology and
Quality by Design: Implications for Advances
in Pharmacogenomics
AJAZ S. HUSSAIN | INSIG...
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
9/20/2013 AJAZ...
The race to predictability
Biology and
drug discovery
Chemistry,
Manufacturing
& Controls
Clinical drug &
diagnostic
devel...
Common challenges
• Clinical endpoints relevant to patient
• Relevant quality attributes
Measurements
• Biomarkers
• New q...
Passing the baton would be desirable
Need to understand and control
relevant variances
• Quality specifications – clinical...
Important concepts in the PAT Guidance
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 7
Beyond the “test-test” comparison
A focus on process understanding can reduce the burden for validating
systems by providi...
Validation
Systems that promote greater product and process understanding can
provide a high assurance of quality on every...
Systems thinking a key
The fast pace of innovation in today's information age necessitates
integrated systems thinking for...
Rate of progress differs
Biology and
drug
discovery
Chemistry,
Manufacturin
g & Controls
Clinical drug
& diagnostic
develo...
Struggling with quality
Compounding challenges today
Drug shortages
cGMP issues
Data integrity issues
9/20/2013 AJAZ S. HU...
Two examples of progress
• An MIT-Novartis collaboration could be a
boost for so-called “continuous flow”
manufacturing.
B...
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 14
Why? Speed, volume and affordability
DARPA “Accelerated Ma...
“One size fits all" to “Personalized”
Two case examples
Pandemic flu vaccine made in tobacco
plants
Personalized vaccine f...
Flu vaccine in tobacco plant
Why?
How?
What?
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 16
What? Speed, volume and affordability
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 17
Hypothesis (target) ...
Therapeutic vaccines for Non-Hodgkin’s
Lymphoma (NHL) in tobacco plant?
Vaccinate cancer patients
against their own tumor
...
Initial disappointment to anticipation..
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 19
Phase I Study of ...
Personalized manufacturing……
9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 20
http://www.mymms.com/
Summary
We are together on a journey to find more effective and efficient ways to meet the needs of
patients
Moving from ‘...
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Process Analytical Technology, Quality by Design & Pharmacogenomics

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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.

Published in: Health & Medicine
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Process Analytical Technology, Quality by Design & Pharmacogenomics

  1. 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. 2. Framing this talk Trial-n-error Predictive 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 2
  3. 3. Population to individual patient Safe and efficacious Not safe Not efficacious Neither safe nor efficacious 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 3 1. Exposure – response - Pharmacogenomics 2. Mechanistic 3. Diagnostic 1. Herceptin (trastuzumab) 2. Targets HER2 3. Immunohistochemistry tests, HER2 gene- amplification tests
  4. 4. The race to predictability Biology and drug discovery Chemistry, Manufacturing & Controls Clinical drug & diagnostic development Health care practices Patient behavior 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 4
  5. 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 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 5 Satisfaction Real-time Predictability Efficiency
  6. 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 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 6
  7. 7. Important concepts in the PAT Guidance 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 7
  8. 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. 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 8
  9. 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. 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 9
  10. 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 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 10
  11. 11. Rate of progress differs Biology and drug discovery Chemistry, Manufacturin g & Controls Clinical drug & diagnostic development Health care practices Patient behavior 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 11
  12. 12. Struggling with quality Compounding challenges today Drug shortages cGMP issues Data integrity issues 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 12
  13. 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 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 13
  14. 14. 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 14 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. 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 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 15
  16. 16. Flu vaccine in tobacco plant Why? How? What? 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 16
  17. 17. What? Speed, volume and affordability 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 17 Hypothesis (target) in 2008 GSK Facility (Qubec, Canada)
  18. 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 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 18
  19. 19. Initial disappointment to anticipation.. 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 19 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. 20. Personalized manufacturing…… 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 20 http://www.mymms.com/
  21. 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 9/20/2013 AJAZ S. HUSSAIN | INSIGHT, ADVICE & SOLUTIONS, LLC 21

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