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

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

Framing this talk

Trial-n-error Predictive

Population to individual patient

Safe and efficacious

Not safe

Not efficacious

Neither safe nor

efficacious

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

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

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

Important concepts in the PAT Guidance

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.

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.

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

Rate of progress differs

Biology and drug

discovery

Chemistry, Manufacturing & Controls

Clinical drug & diagnostic development

Health care practices

Patient behavior

Struggling with quality

Compounding challenges today

Drug shortages

cGMP issues

Data integrity issues

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

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

Flu vaccine in tobacco plant

What? Speed, volume and affordability

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

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

Initial disappointment to anticipation..

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……

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

Process Analytical Technology, Quality by Design & Pharmacogenomics

Health & Medicine