Starting a Pharmaceutical Company

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					     Technologies for the
Pharmaceutical Manufacturing
      Plant of the Future
 (In Search of the Science of
       Berkeley W. Cue
  BWC Pharma Consulting, LLC
          July 2009
Whether you agree with what you hear
today or not, the contents of this
presentation are my views and not those
of the ACS GCI Pharmaceutical
Roundtable, or any pharmaceutical or
technology company (except where
Pharmaceutical Product Life Cycle
Basic chemical raw materials ->
Regulatory starting materials (RSM’s) ->
Active Pharmaceutical Ingredient
(API)/Drug Substance -> Dosage
form/formulation/drug product -> packaged
product -> delivery/distribution -> patient
use -> drug enters the environment ->
environmental fate and effects
From David Constable (ex GSK
  Green Chemistry Advocate)
The Pharmaceutical Manufacturing
         Plant of Today
Active Pharmaceutical         Dosage Form (DF) or Drug
  Ingredient (API) or Drug      Product Plant
  Substance Plant             • Everything made in batch
• Everything made in batch      mode
  mode (2000 – 16000 liter)   • Plant operates to 3-
• Plant operates to a 3-        Sigma standard
  Sigma standard              • High speed tablet and
• Some evidence of              encapsulation machines
  process analytical            run at high speed less
  technology                    than 20% of the time
• The last API plant in the   • PAT more evident than
  US was constructed in         with API but not extensive
  1993 (and decomissioned     • Most DF plants are ex US
  in 2006)
    Sources of API Raw Materials
                  Now                              Future

          Lignin: A Source of Simple
Since Many Pharmaceuticals Are
    Aniline Derivatives……..


The known ways of carrying out this transformation are
costly, dangerous, inefficient, ugly and definitely not
green. An opportunity for innovation.
          Six Sigma Process
SIGMA      DPMO         COPQ              CAPABILITY
6 sigma    3.4       <10% of sales        World Class
5 sigma    230       10 to 15% of sales
4 sigma    6200      15 to 20% of sales   Industry average
3 sigma    67,000    20 to 30% of sales
2 sigma    310,000   30 to 40% of sales   Noncompetitive
1 sigma    700,000
         A Waste Prevention Opportunity:
                 Sigma Based

• Worldwide Rx expenditures projected to be $750
  Billion/yr (IMS 2009)
• Assume $1.50/day cost, then 500 billion
• With pharma sigma values typically 3 => 6.7%
  defect => >30 billion doses per year are
  defective and rejected to become waste or
• At an average selling price of $1.50/day this
  represents $$ billions in lost product opportunity
• A sigma value of 5 (possibly achievable using
  green chemistry principles in process design
  and technology selection) => 0.02% defect =>
  100 million doses per year defective
        Process Intensification
                                  •   In the figure to the left,
                                      examples are given for three
                                      unit operations that are often
                                      used in the chemical industry.
                                      Examples of combinations are:
                                      – Reaction-separation:
                                        Membrane reactor, reactive
                                      – Reaction-heat exchange:
                                      – Separation-heat exchange:
                                        Dephlegmators or heat
                                        integrated distillation
                                      – Reaction-separation-heat
Source:                                 exchange: Isothermal         membrane reactor

PAT should enable use of continuous processing in API synthesis
                             What is PAT?
Process Analytical Technology is:
• 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
• It is important to note that the term analytical in PAT is viewed broadly to include
   chemical, physical, microbiological, mathematical, and risk analysis conducted in an
   integrated manner.
Process Analytical Technology tools:
• There are many current and new tools available that enable scientific, risk-managed
   pharmaceutical development, manufacture, and quality assurance. These tools, when
   used within a system can provide effective and efficient means for acquiring
   information to facilitate process understanding, develop risk-mitigation strategies,
   achieve continuous improvement, and share information and knowledge. In the PAT
   framework, these tools can be categorized as:
     – Multivariate data acquisition and analysis tools
     – Modern process analyzers or process analytical chemistry tools
     – Process and endpoint monitoring and control tools
     – Continuous improvement and knowledge management tools
     An appropriate combination of some, or all, of these tools may be applicable to a single-unit
        operation, or to an entire manufacturing process and its quality assurance

               PAT Goals
Quality By Design-The goal of PAT is to
understand and control the manufacturing
process, which is consistent with our current
drug quality system: quality cannot be tested into
products; it should be built-in or should be by
Benign By Design- The goal of PAT is to analyze in
real time to prevent pollution: Include in-process
real-time monitoring and control during
syntheses to minimize or eliminate the formation
of byproducts
          Green Chemistry Tie-In to PAT

• Gains in quality, safety and/or efficiency will vary
  depending on the product and are likely to come from:
   – Reducing production cycle times by using on-, in-, and/or at-line
     measurements and controls. Energy reduction
   – Preventing rejects, scrap, and re-processing. Waste reduction
   – Considering the possibility of real time release. Waste reduction
   – Increasing automation to improve operator safety and reduce
     human error. Safety
   – Facilitating continuous processing to improve efficiency and
     manage variability
       • Using small-scale equipment (to eliminate certain scale-up issues)
         and dedicated manufacturing facilities. Process Intensification
       • Improving energy and material use and increasing capacity. Energy
Uniting QbD and BbD through PAT
       and Green Chemistry
•   Quality by Design (QbD)
    – "QbD is a systematic
      approach to product and
      process design and
        • Chi-wan Chen, deputy
          director of the Office of New
          Drug Quality Assessment
          (ONDQA) at FDA's Center for
          Drug Evaluation and
•   Benign by Design (BbD)
    – Synonymous with green
      chemistry: Green chemistry is
      the utilization of a set of
      principles that reduces or
      eliminates the use of
      hazardous substances in the
      design, manufacture and
      application of chemical
        • Paul Anastas and John
         Current State of Pharmaceutical
               API Manufacturing

•   Batch Mode, continuous or semi continuous rare
•   Early commitment to “locked” process
•   Early commitment to RSM’s
•   Industry reluctant to use new technology
•   Fundamental green chemistry and engineering principles
    generally less well developed
•   High degree of uncertainty that precludes risk based
    (regulatory) decisions or even discussions
•   Manufacturing difficulties may be due to less R&D
    experience/”biotech paradigm”
•   May be inadequate to meet future needs
•   Process waste is an accepted “cost of doing business”
Flow Reactors
Flow Reactors: Number Up
    Instead of Scale Up
Commercial Scale Flow Reactors
  Advantages of Continuous Flow
       Reactor Chemistry
• Increase
  – Efficiency of chemical processing
  – Scalability of chemical processing
  – Quality of chemical processing
• Decrease
  – Cost
  – Environmental Impact
  – Process variability
Pregabalin (slides compliments of
 Peter Dunn-Pfizer Global R&D)
Pregabalin Launch Process
Asymmetric Hydrogenation Route
Biotransformation Route
Biocatalytical Kinetic Resolution
Material Flow and Fate
Material Utilization Comparison
 Pregabalin Biotransformation
Process-Environmental Benefits
           Commercial Scale
Simulated Moving Bed
      tend to be used in pilot scale facilities
     2-20X more productive than batch, 5-50X
   less solvent
      Several drugs made commercially:Insulin,
   Lexapro, Keppra, Zoloft, Zyrtec single isomer
  Supercritical Fluid Chromatography
      Potentially the greenest of all, just starting to
   be popular in R&D
• Bioavailability refers to the extent to and rate at which
  the active moiety (drug or metabolite) enters systemic
  circulation, thereby accessing the site of action.
• Bioavailability of a drug is largely determined by the
  properties of the dosage form (which depend partly on its
  design and manufacture), rather than by the drug's
  physicochemical properties, which determine absorption
  potential. Differences in bioavailability among
  formulations of a given drug can have clinical
  significance; thus, knowing whether drug formulations
  are equivalent is essential

    Dosage Forms

Hot Melt Extrusions
               Hot Melt Extruder

Source:Chokshi and Zia, Iranian J.Pharm. Res., 3, 3-16, 2004
 Hot Melt Extrusion Technology,,20378,00.html
     Benefits of HME Processing
The benefits of using HME over traditional
  processing techniques include:
• fewer unit operations;
• better content uniformity;
• an anhydrous process;
• a dispersion mechanism for poorly soluble
• a low energy alternative to high-shear
• less processing time compared with
  conventional wet granulation.
            Dosage Forms

Spray Dry Dispersions

Spray Dry Dispersion (SDD)
SDD- A Scalable Technology
SDD Formulations Increase
Plasma Concentration (AUC)
    Batch vs. Continuous Processing
       For Pharmaceutical Drugs
•   Vast majority of API manufacture      •   Limited use of continuous flow
    uses batch processing                     processing to date
•   Batch uses fixed stirred reactors     •   Continuous uses micro channel
•   Each scale increase requires              flow reactors
    revalidating critical process         •   Number up vs. scale up
    parameters                                 – Critical process parameters do not
     – Usually the process must be re            change
       optimized at each scale increase   •   Ideal opportunity for PAT use
•   Limited use of PAT                    •   Smaller facility footprint
•   Large facility footprint              •   Smaller environmental footprint
•   Large environmental footprint              – Lower to no solvent use
     – 80-90% solvent/water               •   Cleaning challenge unknown but
•   Difficult to clean to <10 ppm prior       predicted to be easier
    resident spec
     – Note: Cleaning solvents not
       included in MI or E-factor waste
    Elements of A Greener Approach to
    Pharmaceutical Product Manufacture
•   Use raw materials produced from renewable, bio-based building blocks
     –   Cellulose, hemi cellulose and lignin
•   Manufacture API using micro channel flow reactors instead of batch stirred tank
     –   Number up vs. scale up
     –   PAT monitoring of all critical quality and environmental parameters
     –   Target E</=10, limit solvent use, recover, recycle/reuse whenever possible
•   API streams are pooled and passed through a purification chromatograph such as
     –   Target all PRS’s <0.1% and no PGI’s at LOD/LOQ
     –   PAT monitoring all critical quality and environmental parameters
•   Purified API eluent is combined with a polymeric excipient(s), selected to maximize
    bioavailability and delivery rate, and
     –   Processed with hot melt extrusion or spray dried to obtain API/polymer particles
     –   PAT monitoring all critical quality and environmental parameters
     –   Goal is high and reproducible bioavailability/”just for you” concepts
•   API/polymer particles are tabletted or encapsulated and packaged in biodegradable
     –   Target >5 sigma (now 3 sigma = 7% failure rate)
     –   PAT monitoring all critical quality and environmental parameters
•   Expiration date is set based on real shelf life and not on some arbitrary 2 year
    endpoint from a 1 year ICH stability study
     –   May require ongoing stability studies to extend expiry
                   In Closing
• How drugs are made in the pharmaceutical
  Industry will change dramatically over the next
  couple of decades
  – Science of Scale
  – Integrated API and dosage form plants
  – Extensive use of PAT
  – Substantial increase in process quality and
  – Back at the ranch, are you being taught any of the
    technologies discussed today?
  – If you want to work in the pharmaceutical industry,
    why not?

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