Quality by Design A Perspective From the Office of

							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
                    Overview
• Introduction of Biotech Products – defining the
    issues
•   OBP Practice
•   Designing a Quality Product
•   Designing a Quality Process
•   Implementation
     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
            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
                  Product Variability
• Amino Acid Substitution      • Carbamylation
• Truncation                   • Carboxylation
• Mismatched S-S bonds         • Formylation
• N- and C-terminal difference • Gamma Carboxyglutamic acid
• Aggregation                  • O-linked Glycosylation
• Multimer Dissociation        • N-linked Glycosylation
• Denaturation                 • Methylation
• Acetylation                  • Oxidation
• Acylation
• Addition of lipid            • Phosphorylation
• Amidation/Deamidation        • Sulphation
          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.
Current OBP Practice
                      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
Quality Control Strategy

   Product Testing
- Method Validation
- Release Testing
- Characterization
- Stability Testing
   How Much of the Iceberg
(desired product) Can We See?


              • Release tests

              • Characterization

?              • Process
    Comprehensive Quality Control Strategy

        Process                 Product

- Facilities and Equipment   - Method Validation
- Control of Raw Materials   - Release Testing
- In-Process Testing (PAT)   - Characterization
- In-Process Controls        - Stability Testing
- Process Validation (FED)
- cGMPs (QC/QA)
     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
       Q by D General Requirements for
              Biotech Products
• Full Characterization of the product’s attributes (establish
    product variability – the earlier the better)
•   Understanding the relationship between the product’s
    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
                 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)
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
               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
              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
Designing A Quality Process
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
                 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
    Biotechnology Process Control
            Some steps controlled by volume or time
            few measure product attributes directly

                      Turbidity
                     Conductivity


                  Harvest           Chromatography Columns

                                       Proteolytic Steps
               D02
               pH                      Renaturation
Fermentor               280nm ABS      Diafilt./Conc.
                        Conductivity   Formulation
                                       Lyophilization
        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
    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?
 Design Space (Fermentation)

                   Critical process parameters

Time


                      Media composition


       Agitation
      Expanding the Design Space
• Characterize a quality attribute with regard to
  relevant, clinically important parameters, i.e. it’s
  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
           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
                                                                           Purified/induced variants
     Biological




                                                   Clinical lot extremes




                                                                                                                       Developmental lots
   Activity Matrix




                                                                                                       Stressed lots
                                   Clinical lots
          One to some lots

           Many to all lots


Multiple binding/cellular assays

Small Animal/Complex Bioassay

Clinical/Clin Pharm

Validated bioassay
Implementation
    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
   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 don’t 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
           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.
         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/purification processes
• Expertise in biological characterization relevant to other
  CDER products
   - Consultations across CDER
            PAT Future Directions
      Many steps controlled by measuring product
      attributes (or by monitoring all DP samples)


                       Data Analysis



            In-line


                         Ion     SPR    MS
Fermentor             exchange   chip
                        chip
      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