Quality by Design: A Perspective From the Office of Biotechnology Products

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Quality by Design A Perspective From the Office
of Biotechnology Products

• ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE
  October 26, 2005
• Barry Cherney, Ph.D.
• Deputy Director
• DTP/OBP/CDER

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Overview

• Introduction of Biotech Products defining the
  issues
• OBP Practice
• Designing a Quality Product
• Designing a Quality Process
• Implementation

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Office of Biotechnology Products

• Therapeutic Proteins
• Growth Factors
• Enzymes
• Cytokines
• Chemokines
• Angiogenic factors
• Toxins
• Soluble Receptors/Receptor antagonists
• mAbs (related products)
• These proteins are produced from recombinant or
  non recombinant cell culture expression systems
  and from transgenic and non transgenic systems
• Products transferred from CBER to CDER in October
  2003
• Excludes ONDCQA regulated protein products

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Biotechnology Products

• Biotechnology products tend to be
• Large, complex molecules
• Mixtures of many active ingredients
• Subject to extensive heterogeneity in quality
  attributes of the API
• Dependent on higher ordered structures and many
  times, flexibility (e.g. changes in conformation)
• Are sensitive to small changes in manufacturing
  and impurity profiles, conformation stability
  limited

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Product Variability

• Carbamylation
• Carboxylation
• Formylation
• Gamma Carboxyglutamic acid
• O-linked Glycosylation
• N-linked Glycosylation
• Methylation
• Oxidation
• Phosphorylation
• Sulphation

• Amino Acid Substitution
• Truncation
• Mismatched S-S bonds
• N- and C-terminal difference
• Aggregation
• Multimer Dissociation
• Denaturation
• Acetylation
• Acylation
• Addition of lipid
• Amidation/Deamidation

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Biotechnology Products

• Generally, have poorly understood
  structure/function relationships
• These properties of the API are hard to fully
  characterize resulting in uncertainty
• Formulations majority liquid presentations,
• less complexity then other formulations
  (stability a main issue, sampling size needs
  improvement )
• Control of the API is a major source of concern
  for Biotech products.

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Current OBP Practice
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Paradigms

• Quality is ensured by testing and rejecting lots
  that fail to meet its stated quality
  (insufficient)
• A guiding principle for the Biotech industry has
  been that the process is the product (can be too
  restrictive)
• Quality by design concept
• Quality cannot be tested into a product it has
  to be built by design. This design incorporates
  knowledge of the product and the process to
  ensure all critical quality parameters are
  adequately controlled

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Quality Control Strategy

• Product Testing
• Method Validation
• Release Testing
• Characterization
• Stability Testing

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How Much of the Iceberg (desired product) Can We
See?

• Characterization

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Comprehensive Quality Control Strategy

• Process
• Facilities and Equipment
• Control of Raw Materials
• In-Process Testing (PAT)
• In-Process Controls
• Process Validation (FED)
• cGMPs (QC/QA)

• Product
• Method Validation
• Release Testing
• Characterization
• Stability Testing

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Designing a Quality Product

• Design a high quality product that maximizes
  efficacy while minimizing adverse affects
• Design a robust quality process to efficiently
  deliver a consistant product with the expected Q,
  S, and E profile

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Q by D General Requirements for Biotech Products

• Full Characterization of the products attributes
  (establish product variability the earlier the
  better)
• Understanding the relationship between the
  products quality attributes and safety and
  efficacy
• Understanding the mechanism of action both in
  terms of efficacy and safety (Biological
  characterization)
• Understand how process affects critical quality
  attributes
• This knowledge is limited for many Biotech
  products

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The Desired Product

• Dosage form is usually a given, liquid (some
  vialed as lyophilized power)
• Excipients vary from product to product but
  mostly affect product stability
• Desired attributes of the API (Focus for
  Biotech)
• Opportunity for protein engineering -
  understanding protein structure/function
  relationship
• Limit variability for attributes that negatively
  impact on product quality (via process or
  product)

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Protein Engineering (rational design)

• Increase manufacturability
• Improving function/new properties
• Increase specificity/affinity
• Increasing Bioavailability
• Pegylation
• Glycoslation
• Adding protein domains with increased half life
  (Fc)
• Adding domains that bind to endogenous long lived
  proteins

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Protein Engineering

• Reduce tendency for aggregation
• Increase conformational stability
• Reducing immunogenicity
• Eliminate sequences that promote aggregation
• Humanizing foreign proteins (mAb)
• Pegylation
• Incorporate structures that are less immunogenic
  (disulfide bond scaffolds)
• T cell epitope engineering

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Protein Engineering

• OBP has encouraged development of innovative
  products (not a regulatory requirement)
• Less enthusiastic concerning the use of products
  whose design increases uncertainly and has no
  expected value clinically (premise limit product
  variability)
• Histidine tag proteins (Quality versus
  Manufacturability)
• Protein domains that potentially adversely impact
  safety

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Designing A Quality Process
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Examples of Problematic Process Designs

• Manufacturing capacity to clear viruses is
  limited
• Following elimination of aggregates by SEC, the
  manufacturer performs a heat treatment step for
  viral inactivation thus reintroduces aggregates
  back into the process
• Process performed at room temperature with
  negative impact on quality
• Roller bottle processes (open, multiple
  fermentations difficult to control)
• Recloning is used to establish new cell banks
  introducing variability
• Manufacturer recognized the limitations but
  regulatory hurdles are difficult to overcome
  particularly after approval

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Process Control

• Current OBP expectations are that critical
  sources of variation should be identified and
  controlled (raw materials/ unit operations)
• Controlled through in-process testing (PAT or
  other tests), monitoring operating parameters and
  process validation
• Based on long standing paradigm that process
  consistency product consistency

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Biotechnology Process Control
Some steps controlled by volume or time few
measure product attributes directly
Turbidity Conductivity
Harvest
Chromatography Columns
D02 pH
Fermentor
280nm ABS Conductivity
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The Essence of PAT

• Process decisions (in real time) are based on
  assessments of critical material attributes
• Forward-feed of incoming material
• Feedback by in-process monitoring
• Product quality is monitored and controlled
  during the manufacturing process
• End points achievement of the desired material
  attribute
• Currently, limited use of PAT in Biotech products
  but applicability is promising

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Process Control of Unit Operations

• Identify intended functions of unit operations
  and the critical product attributes potentially
  affected
• Establish desired limits of attribute (typically
  established by estimates of process capability)
• Identify critical variables for the process step
• Establish the range of the variables that
  provides assurance that you can meet your quality
  expectations
• First principles ??
• Empirical approach using multi variant analysis
  FED, but can you extrapolate to larger scales?

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Design Space (Fermentation)
Critical process parameters
Time
Media composition
Agitation
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Expanding the Design Space

• Characterize a quality attribute with regard to
  relevant, clinically important parameters, i.e.
  its affect on
• Potency
• Bioavailability
• Biodistribution
• Immunogenicity
• This information can be used to set
  specifications to ensure product quality as it
  relates to S and E and expand the design space

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Examples from Biotech

• For a highly glycoslyated protein various
  isoforms were isolated and monitored for relevant
  bioactivity in a animal model suitable for Pk
  measurements. Outcome widen specs for isoform
  profile
• Monitored product isoforms from human serum
  samples over time, showed rates of decay were
  similar concluded isoforms did not impact
  bioavailability Outcome broaden acceptance
  criteria
• Use of multiple lots of drug product in clinical
  trials to establish a link between variability of
  product attributes and clinical performance

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Biological Activity Matrix
Purified/induced variants
Developmental lots
Clinical lot extremes
Stressed lots
Clinical lots
Multiple binding/cellular assays
Small Animal/Complex Bioassay
Clinical/Clin Pharm
Validated bioassay
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Implementation
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Regulatory Relief (based on process understanding)

• Validate the process is capable of impurity
  removal to appropriate levels (non toxic
  impurities)
• Relief Impurity is not routinely measured when
  operating under the validated state (removed from
  specifications)
• Different approaches depending on the nature of
  the impurity
• Validate capacity to remove those impurities that
  are added at fixed concentrations (fixed input)
• Validate excess capacity for removal of
  impurities that variable (alternatively control
  of input levels of impurities)
• Examples Host Cell Proteins/DNA

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Regulatory Relief (based on product understanding)

• Understanding of the relationship between the
  quality attribute and its impact on safety and
  efficacy can reduce regulatory requirements
• Relief If no likely impact on S and E dont
  include as a specification (no rejection limit)
• use as a process consistency measure, where
  exceeding a limit initiates an investigation
• if not a consistency measure, drop the test
  entirely
• Transitioning to this new paradigm of action
  versus rejection limits
• Need to discuss more extensively in-house and
  provide reviewer training

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Implementation of Q by D

• Q by D a major fear by industry is that
  reviewers will not understand or be receptive to
  the submission paraphrased from Dr. Ken Morris,
  Q by D presentation October 17, 2005
• OBP review is based on scientific merits of the
  proposal and not simply reliance on existing
  practice. Guidance helps frame the issue but
  science and knowledge dictates the outcome.
• For example, we try to stay away from
  proscriptive rules i.e. rejection limits can be
  established /- 3 SD. Instead, we evaluate the
  proposal using our best scientific judgment and
  are open to other statistical analysis but links
  between the attribute and what is known regarding
  its impact on S and E are important. Lack of
  knowledge increases uncertainty and may result in
  tighten controlled.

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Implementation of Q by D

• Structure of OBP
• Product reviewers a mixture of
  research/reviewers and full time reviewers
• Research conducted in molecular and cellular
  biology and pharmaceutical science
• Expertise in biological characterization of
  protein products is critical for meaningful risk
  assessment
• Provides hands on experience with latest
  techniques familiarity with fermentation/purificat
  ion processes
• Expertise in biological characterization relevant
  to other CDER products
• Consultations across CDER

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PAT Future Directions
Many steps controlled by measuring product
attributes (or by monitoring all DP samples)
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Continued and Future Directions

• Training of OBP product reviewers in PAT (4 OBP
  product reviewers will undergo extensive training
  for Biotech products), Q by D, and new
  analytical techniques (Biosensors SPR) for
  biotech products
• Q by D discussions within and outside Agency
• Encourage biological characterization of products
• Encourage industry to incorporate new or under
  utilized analytical methods for control of
  in-process materials and purified proteins