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Process research overview

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DR ANTHONY CRASTO, PROCESS RESEARCH OVERVIEW, Glenmark scientist helping millions, Million hits on Google

DR ANTHONY CRASTO, PROCESS RESEARCH OVERVIEW, Glenmark scientist helping millions, Million hits on Google
amcrasto@gmail.com

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Process research  overview Process research overview Presentation Transcript

  • DR ANTHONY M CRASTO (Ph.D) PRINCIPAL SCIENTIST PROCESS RESEARCH DEC 2011 “ A SHORT PRESENTATION”
    • What is Process Research ?
    • Its 12 Principles
    • Definition
    • Objectives
    • Personnel requirements
    • GMP Considerations
    • Process economics
    • Industry challenges
    • Case Studies- Remoxipride and chiral piperazine
    • Lesson Learned: “Unlocking the Potential of Process Innovation”
  • Net Cost: $802 Million Invested Over 15 Years 5,000–10,000 Screened 250 Enter Preclinical Testing 5 Enter Clinical Testing 1 Compound Success Rates by Stage 16 14 12 10 8 6 4 2 0 Phase II 100–300 Patient Volunteers Used to Look for Efficacy and Side Effects Phase III 1,000–5,000 Patient Volunteers Used to Monitor Adverse Reactions to Long-Term Use FDA Review Approval Additional Post-Marketing Testing Phase I 20–80 Healthy Volunteers Used to Determine Safety and Dosage Preclinical Testing Laboratory and Animal Testing Discovery (2–10 Years) Years New Product Development – A Risky and Expensive Proposition Approved by the FDA
    • Objective :
    • To design elegant, practical, efficient, environmentally benign and economically viable chemical syntheses for active drug substances (“active pharmaceutical ingredient” (API))
    • Pre-Clinical: 50 g - 5 kg: Safety Assessment, formulation, metabolism
    • Clinical : 50-500 kg: Ph I-III human trials, long-term safety
    • Post Clinical : transfer process technology to Manufacturing (1000 kg - metric ton quantities/yr; depending on dose)
    • Plant :- It is a place were the 5 M’s like money, material, man, method and machine are brought together for the manufacturing of the products.
    • Pilot Plant :- It is the part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by development of liable and practical procedure of manufacture.
    • Scale-up :- The art for designing of prototype using the data obtained from the pilot plant model.
    • Lab scientist---next page
    • To carry out research and development activity in the field of Organic Chemistry, to make profit for the organization, motivate, guide & lead a team of bench scientists,
    • Conduct literature search, identify and execute new/novel routes for the synthesis, scale up from grams to kilo levels in lab., conduct pilot trials and assist in production upto ton levels.
    • Carry out impurity profiles and assist in dossier writing.
    • All the above being done keeping in mind the regulatory, safety, environmental issues.
    • To keep in mind IPR issues and draft patents , Commercial aspects taken care are the time schedules, quality parameters and cost factors.
    • All this with a view of non infringement and confidentiality. Simultaneously develop business acumen and convert to profits. file DMFS in US and EU, file patents and contribute to intellectual property
    • Keep in mind polymorphism issues
    • To try the process on a model of proposed plant before committing large sum of money on a production unit.
    • Examination of the formula to determine it’s ability to withstand Batch-scale and process modification.
    • Evaluation and Validation for process and equipments
    • To identify the critical features of the process. Guidelines for production and process controls.
    • To provide master manufacturing formula with instructions for manufacturing procedure.
    • To avoid the scale-up problems.
    • Scientists with experience in lab, 20 litre scale, pilot plant operations as well as in actual production area are the most preferable
    • As they have to understand the intent of the ICH, Pharmacopoel, Final API, Regulatory, IPM, GMP, formulator as well as understand the perspective of the production personnel.
    • The group should have some personnel with engineering knowledge as well as scale up also involves engineering principles
    • “ The ideal chemical process is that which a one-armed operator can perform by pouring the reactants into a bath tub and collecting pure product from the drain hole”
    • Sir John Conforth
    • (1975 Nobel Prize: Chemistry)
    • An amalgam of:
    • Modern synthetic organic methodology
    • Physicochemical properties
      • Salt selection: based on stability, suitability
      • Solid State Properties: Solvent dependant
        • Crystal Morphology: internal shape-affects solubility, stability
        • Crystal Habit: external shape-affects flowability, mixability
        • Particle Size: can affect bioavailability
    • Purification/Isolation technologies
    • Chemical Engineering principles: mixing, heat transfer, vessel configuration
    • Practical Process Aspects:
      • Safety
      • Quality
      • Cost
      • Reproducibility
      • Ruggedness
    • Equipment qualification
    • Process validation
    • Regularly schedule preventative maintenance
    • Regularly process review & revalidation
    • Relevant written standard operating procedures
    • The use of competent technically qualified personnel
    • Adequate provision for training of personnel
    • A well-defined technology transfer system
    • Validated cleaning procedures.
    • An orderly arrangement of equipment so as to ease material flow & prevent cross- contamination
  • Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
  • responsible for developing In-process assay and critical evaluation of drug substance and intermediates Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
  • responsible for toxicity studies: (carcinogen, teratogen, gene toxicity ) Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
  • responsible for formulating drug substance (API) into drug product Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
  • Oversee process transfer into Pilot plants Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
  • Conducts clinical trials (Ph I-III) and evaluates data Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
  • Discovers new chemical entities (NCE’s) and prepares intitial quantities Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    • Patent : drafting, inventorship, litigation
    • Outsourcing : work with vendors on tech transfer; setting specs; qualifying
    • Regulatory : drafting of NDA; process range finding
    • Manufacturing: transfer of process
    • ‘ know-how’; oversee start-up
    • Prevention : It is better to prevent waste than to treat/clean up after its created.
    • 2. Atom Economy : synthetic methods should be designed to incorporate all the atoms used in the process into the final product
    • 3 . Minimize Hazardous Conditions:
    • Design process to avoid using reagents that pose safety threat
    • 4. Safer Chemistry-Accident Prevention:
    • Design processes that minimize hazards to environment and human health
    • 5 Design Safer Products:
    • Products should be designed to effect their desired function while minimizing toxicity
    • Example: Use of single enantiomer drug vs racemate
    • 6. Use Safer Solvents/Auxiliaries
    • Use of innocuous solvents should be considered (e.g. water, supercritical CO 2 )
    • Avoid use of unnecessary substances
    • (e.g. drying agents, column chromatography)
    • 7. Design for Energy Efficiency:
    • Energy requirements for a process should be recognized for environmental and economic impact
    • Eg : avoid extreme cryogenics (-78 o C)
    • Avoid prolonged reaction times
    • 8. Use of Renewable Raw Materials:
    • Use a renewable source rather that depleting whenever technically and
    • economically feasible.
    • eg: plant-derived RM; microbial reactions
    • 9. Minimize Derivatization :
    • Avoid the use of protecting groups when possible as it add steps, requires extra reagents and generates more waste.
    • 10. Catalysis:
    • Use of catalytic reagents is far superior than stoichiometric amounts
    • Example: using air as a source of oxygen for oxidation reaction
    • 11. Design for Degradation:
    • Ideally, process products and by-products should breakdown into innocuous materials and/or do not persist in the environment
    • 12. Real Time Analysis:
    • Analytical methods designed for ‘real-time’
    • In-process monitoring/control of a reaction
    • Example: Reactor-IR (in-situ probe for monitoring reactions)
    • Process Economics - Minimize inventory cost of API via:
    • Low cost RM
    • Productive/Efficient Reactions
      • High Yield
      • Highly concentrated
      • Few Steps
      • Short time cycles
      • Few Vessels
    • Remoxipride-----schizophrenia
    • 2-Synthesis of Pyrazine Carboxamide a CHIRAL PIPERAZINE –Ingredient of antivirals , ie virs
  • Selective Dopamine-2 Antagonist Indication: Anti-psychotic (Depression/Schizophrenia) Clinical Trials: halted in 1993 due to anemia side-effects
  •  
  •  
  • Auerbach, Weissman Tet Letters 1993, 931
  •  
  • Drawbacks: 1. Use of costly Oxalyl Chloride 2. CO and CO 2 by-products 3. Lengthy time cycle due to exothermic amination reaction 4. Need for 3 equiv of volatile t -butylamine 5. Filtration/Disposal of voluminous amine hydrochloride salt
  •  
  • A: 179/[124+127+73+73] = 45 % B: 179/[105 + 98 +74 +18] = 61%
  •  
    • Increased Regulatory controls (FDA, EPA)
    • Downward Pricing Pressure
    • Greater Competition in treatment options
    • More complex molecules
    • Corporate consolidation
    • Dwindling # of diseases to conquer
    • Process Development as a Competitive Weapon/Leveraging Capabilities
    • “ The power of process development lies in how it helps companies achieve accelerated time to market, rapid production ramp-up and a stronger proprietary position”
    • “ A firm that can develop sophisticated process technologies more rapidly and with fewer development resources has strategic options that less capable competitors lack ”
    • Practical Process Research & Development; Neal Anderson
    • The Merck Druggernaut: The Inside Story of a Pharmaceutical Giant ; Fran Hawthorne
    • The Development Factory: Unlocking the Potential of Process Innovation ; Gary P. Pisano
    • Principles of Process Research and Chemical Development in the Pharmaceutical Industry ; Oljan Repic
    • Process Chemistry in the Pharmaceutical Industry; Kumar Gadamasetti
    • THANKS