• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Process research  overview

Process research overview



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



Total Views
Views on SlideShare
Embed Views



16 Embeds 462

http://www.anthonymelvincrasto.yolasite.com 154
http://newdrugapprovals.wordpress.com 101
http://newdrugapprovals.org 81
http://drug-scaleup-and-manufacturing.webnode.com 68
http://www.linkedin.com 20
http://anthonycrasto.jimdo.com 9
http://www50.jimdo.com 6
http://m.drug-scaleup-and-manufacturing.webnode.com 5
http://sitebuilder.yola.com 4
http://nepalimedchem.wordpress.com 3
http://www.newsblur.com 3
https://www.linkedin.com 3
http://medchemhot.wordpress.com 2
http://luciavazine.wordpress.com 1
http://cms.drug-scaleup-and-manufacturing.webnode.com 1
https://nepalimedchem.wordpress.com 1


Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.


14 of 4 previous next Post a comment

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
Post Comment
Edit your comment
  • Regulatory- talk of CMC (“chemistry and manufacturing controls”) section

Process research  overview Process research overview Presentation Transcript

    • 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