Application of QbD Principles for Biotech

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Application of QbD Principles for Biotech
Biological Products
AAPS ISPE Present USFDA Pharmaceutical Quality
Initiatives Implementation of a Modern Risk Based
Approach

• Steven Kozlowski, M.D., Director
• Office of Biotechnology Products OPS/CDER

3/1/07
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Overview

• Definitions
• Relevant Product Attributes
• Hypotheticals Cases
• Implementation Plans

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What is Quality by Design?

• Quality
• Good pharmaceutical quality represents an
  acceptably low risk of failing to achieve the
  desired clinical attributes.
• Quality by Design (QbD)
• Means that product and process performance
  characteristics are scientifically designed to
  meet specific objectives, not merely empirically
  derived from performance of test batches.

Janet Woodcock (2004)
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ICH Q8 Design Space
Product Understanding
Quality by Design
Process Understanding
Moheb Nasr
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ICH Q8 Design Space
Product Understanding
Quality by Design
Process Understanding
Moheb Nasr
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ICH Q8 Process Analytical Technology (PAT)

• A system for designing, analyzing, and
  controlling manufacturing through
• timely measurements (i.e., during processing)
• of critical quality and performance attributes of
  raw and in-process materials and processes
• with the goal of ensuring final product quality.

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Process Importance

• Quality cannot be tested into a product but it
  must be built into the product process
• End product testing vs real time release
• For biotech
• lower heterogeneity
• greater risk of later steps changing product
• process control specs low hanging fruit
• The product is the processa biologics mantra

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Traditional Paradigm
Variability
Raw Material
Product
Jon Clark
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Dynamic System
Manufacturing Process
Raw Material
Endpoint Response
Input Response
Measurement Dependant Process Variables
Jon Clark
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Target Critical Quality Attributes
CQA
Range
Process Designed to Limit Product Variability
Range of Raw Material and Facility Attributes
Jon Clark
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Overview

• Definitions
• Relevant Product Attributes
• Hypotheticals Cases
• Implementation Plans

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Structure of complex molecules

• 1? structure
• higher order structure
• post-translational modifications
• heterogeneity

Monoclonal Ab MW 150,000 Da
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Attributes Combinatorics

• 2 x 6 x 4 x 4 x 5 x 5 x 2 9600

• (9600)2 108

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Laurence J. Peter, American business humorist

• Some problems are so complex
• that you have to be highly intelligent
• and well informed
•  

just to be undecided about them.
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• Nothing is more difficult, and therefore more
  precious, than to be able to decide.
• Napoleon Bonaparte
• Even a correct decision is wrong when it was
  taken too late.
• Lee Iacocca

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Functional Event Sequence Diagram
Oxidation Site 1
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Event Tree (Quantification)
End State
Oxidation Site 1
Low Level
No Impact
Scenario
Detectable
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Assigning Probabilities

• Actual Data
• Similarity Method
• Same Product
• Models (animals, bioassays)
• NASA Ground tests
• Related Product or Component
• Direct Data (clinical)
• Models (animals, bioassays)
• Probabilistic Structure Analysis
• e.g. probability of docking to all known
  receptors
• Far off

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Biological Activity Matrix
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Evolution of Monoclonal Antibodies
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Overview

• Definitions
• Relevant Product Attributes
• Hypotheticals Cases
• Implementation Plans

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Biotechnology Process Control
Many steps controlled by volume or time
Turbidity Conductivity
Chromatography Columns
Harvest
D02 pH
Fermentor
280nm ABS Conductivity
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Upstream Scenarios

• Clementschitsch Bayer Microbial Cell Factories
  May 2006
• Paramagnetism (oxygen/mass balance)
• Dielectric Spectroscopy (biovolume)
• 2D Fluor NIR Spectroscopy
• Mass Spectroscopy (volatile organics)

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Hypothetical Downstream

• Early product characterization
• Sub-potent charge variant
• Impurities A B

• Risk Ranking
• Buffer pH
• Column Load
• Buffer salt conc.

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Designing Spaces
Comparability between clinical to-be marketed
process/material
Ranges used in clinical studies
Ranges to achieve small-scale column
performance
Linkage between small-scale experiments and
to-be-marketed process

• charge distribution
• impurity A removal
• impurity B removal

QbD
Linkage between column performance measures
product performance
Multivariate studies at small-scale
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String Theory
Linear flow rate
Buffer ions
?
Column washes
Equilibration
Lifetime
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Challenges
Operating parameters may no longer be relevant
Relevant Material Attributes
PAT
Input parameters may not detect
Real time measurement used for control
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Platonic PAT
All clinically relevant material attributes are
measured and controlled in real time at the
correct process step on all the material
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Scotty, Beam me down!

• Rathore et al. BioPharm Int Aug 2006
• Refolding by HPLC
• Diafiltration to surrogate
• 280 nm collection vs purity input
• Science not Nomenclature Relief
• Backward, Narrow, Inward PAT
• Maes Liedekerke JPI Sept/Oct 2006

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Implementation

• Benefit from other OPS knowledge
• e.g. ONDQA pilot
• Participation in agency CRADAs for QbD
• Structure
• Mixture of research/reviewers and full time
  reviewers
• Experience with new technologies,
  fermentation/purification
• Expertise in biological characterization
• Engineer proteins for quality as well as S E
• desired product

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Small Steps

• Product Testing
• If no likely impact on S and E dont include as a
  specification (no rejection limit)
• Process Changes
• Strategy to assess risk
• Platform Strategies
• monoclonal antibodies may share a great deal of
  structure
• efficient use of prior knowledge
• long history of a regulatory path for
  modular/generic validation (Mab PTC)
• Possible complex API pilot
• Need to consider discuss further

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Credits

• Barry Cherney
• Patrick Swann
• Moheb Nasr
• Keith Webber
• Ajaz Hussain

• Jon Clark
• Chris Watts
• Ali Afnan
• Chris Joneckis