Process research overview


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

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  • Regulatory- talk of CMC (“chemistry and manufacturing controls”) section
  • Process research overview

    2. 2. <ul><li>What is Process Research ? </li></ul><ul><li>Its 12 Principles </li></ul><ul><li>Definition </li></ul><ul><li>Objectives </li></ul><ul><li>Personnel requirements </li></ul><ul><li>GMP Considerations </li></ul><ul><li>Process economics </li></ul><ul><li>Industry challenges </li></ul><ul><li>Case Studies- Remoxipride and chiral piperazine </li></ul><ul><li>Lesson Learned: “Unlocking the Potential of Process Innovation” </li></ul>
    3. 3. 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
    4. 4. <ul><li>Objective : </li></ul><ul><li>To design elegant, practical, efficient, environmentally benign and economically viable chemical syntheses for active drug substances (“active pharmaceutical ingredient” (API)) </li></ul><ul><li>Pre-Clinical: 50 g - 5 kg: Safety Assessment, formulation, metabolism </li></ul><ul><li>Clinical : 50-500 kg: Ph I-III human trials, long-term safety </li></ul><ul><li>Post Clinical : transfer process technology to Manufacturing (1000 kg - metric ton quantities/yr; depending on dose) </li></ul>
    5. 5. <ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>Scale-up :- The art for designing of prototype using the data obtained from the pilot plant model. </li></ul><ul><li>Lab scientist---next page </li></ul>
    6. 6. <ul><li>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, </li></ul><ul><li>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. </li></ul><ul><li>Carry out impurity profiles and assist in dossier writing. </li></ul><ul><li>All the above being done keeping in mind the regulatory, safety, environmental issues. </li></ul><ul><li>To keep in mind IPR issues and draft patents , Commercial aspects taken care are the time schedules, quality parameters and cost factors. </li></ul><ul><li>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 </li></ul><ul><li>Keep in mind polymorphism issues </li></ul>
    7. 7. <ul><li>To try the process on a model of proposed plant before committing large sum of money on a production unit. </li></ul><ul><li>Examination of the formula to determine it’s ability to withstand Batch-scale and process modification. </li></ul><ul><li>Evaluation and Validation for process and equipments </li></ul><ul><li>To identify the critical features of the process. Guidelines for production and process controls. </li></ul><ul><li>To provide master manufacturing formula with instructions for manufacturing procedure. </li></ul><ul><li>To avoid the scale-up problems. </li></ul>
    8. 8. <ul><li>Scientists with experience in lab, 20 litre scale, pilot plant operations as well as in actual production area are the most preferable </li></ul><ul><li>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. </li></ul><ul><li>The group should have some personnel with engineering knowledge as well as scale up also involves engineering principles </li></ul>
    9. 9. <ul><li>“ 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” </li></ul><ul><li>Sir John Conforth </li></ul><ul><li>(1975 Nobel Prize: Chemistry) </li></ul>
    10. 10. <ul><li>An amalgam of: </li></ul><ul><li>Modern synthetic organic methodology </li></ul><ul><li>Physicochemical properties </li></ul><ul><ul><li>Salt selection: based on stability, suitability </li></ul></ul><ul><ul><li>Solid State Properties: Solvent dependant </li></ul></ul><ul><ul><ul><li>Crystal Morphology: internal shape-affects solubility, stability </li></ul></ul></ul><ul><ul><ul><li>Crystal Habit: external shape-affects flowability, mixability </li></ul></ul></ul><ul><ul><ul><li>Particle Size: can affect bioavailability </li></ul></ul></ul><ul><li>Purification/Isolation technologies </li></ul>
    11. 11. <ul><li>Chemical Engineering principles: mixing, heat transfer, vessel configuration </li></ul><ul><li>Practical Process Aspects: </li></ul><ul><ul><li>Safety </li></ul></ul><ul><ul><li>Quality </li></ul></ul><ul><ul><li>Cost </li></ul></ul><ul><ul><li>Reproducibility </li></ul></ul><ul><ul><li>Ruggedness </li></ul></ul>
    12. 12. <ul><li>Equipment qualification </li></ul><ul><li>Process validation </li></ul><ul><li>Regularly schedule preventative maintenance </li></ul><ul><li>Regularly process review & revalidation </li></ul><ul><li>Relevant written standard operating procedures </li></ul><ul><li>The use of competent technically qualified personnel </li></ul>
    13. 13. <ul><li>Adequate provision for training of personnel </li></ul><ul><li>A well-defined technology transfer system </li></ul><ul><li>Validated cleaning procedures. </li></ul><ul><li>An orderly arrangement of equipment so as to ease material flow & prevent cross- contamination </li></ul>
    14. 14. Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    15. 15. 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
    16. 16. responsible for toxicity studies: (carcinogen, teratogen, gene toxicity ) Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    17. 17. responsible for formulating drug substance (API) into drug product Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    18. 18. Oversee process transfer into Pilot plants Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    19. 19. Conducts clinical trials (Ph I-III) and evaluates data Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    20. 20. Discovers new chemical entities (NCE’s) and prepares intitial quantities Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    21. 21. <ul><li>Patent : drafting, inventorship, litigation </li></ul><ul><li>Outsourcing : work with vendors on tech transfer; setting specs; qualifying </li></ul><ul><li>Regulatory : drafting of NDA; process range finding </li></ul><ul><li>Manufacturing: transfer of process </li></ul><ul><li>‘ know-how’; oversee start-up </li></ul>
    22. 22. <ul><li>Prevention : It is better to prevent waste than to treat/clean up after its created. </li></ul><ul><li>2. Atom Economy : synthetic methods should be designed to incorporate all the atoms used in the process into the final product </li></ul><ul><li>3 . Minimize Hazardous Conditions: </li></ul><ul><li>Design process to avoid using reagents that pose safety threat </li></ul><ul><li>4. Safer Chemistry-Accident Prevention: </li></ul><ul><li>Design processes that minimize hazards to environment and human health </li></ul>
    23. 23. <ul><li>5 Design Safer Products: </li></ul><ul><li>Products should be designed to effect their desired function while minimizing toxicity </li></ul><ul><li>Example: Use of single enantiomer drug vs racemate </li></ul><ul><li>6. Use Safer Solvents/Auxiliaries </li></ul><ul><li>Use of innocuous solvents should be considered (e.g. water, supercritical CO 2 ) </li></ul><ul><li>Avoid use of unnecessary substances </li></ul><ul><li>(e.g. drying agents, column chromatography) </li></ul>
    24. 24. <ul><li>7. Design for Energy Efficiency: </li></ul><ul><li>Energy requirements for a process should be recognized for environmental and economic impact </li></ul><ul><li>Eg : avoid extreme cryogenics (-78 o C) </li></ul><ul><li>Avoid prolonged reaction times </li></ul><ul><li>8. Use of Renewable Raw Materials: </li></ul><ul><li>Use a renewable source rather that depleting whenever technically and </li></ul><ul><li>economically feasible. </li></ul><ul><li>eg: plant-derived RM; microbial reactions </li></ul>
    25. 25. <ul><li>9. Minimize Derivatization : </li></ul><ul><li>Avoid the use of protecting groups when possible as it add steps, requires extra reagents and generates more waste. </li></ul><ul><li>10. Catalysis: </li></ul><ul><li>Use of catalytic reagents is far superior than stoichiometric amounts </li></ul><ul><li>Example: using air as a source of oxygen for oxidation reaction </li></ul>
    26. 26. <ul><li>11. Design for Degradation: </li></ul><ul><li>Ideally, process products and by-products should breakdown into innocuous materials and/or do not persist in the environment </li></ul><ul><li>12. Real Time Analysis: </li></ul><ul><li>Analytical methods designed for ‘real-time’ </li></ul><ul><li>In-process monitoring/control of a reaction </li></ul><ul><li>Example: Reactor-IR (in-situ probe for monitoring reactions) </li></ul>
    27. 27. <ul><li>Process Economics - Minimize inventory cost of API via: </li></ul><ul><li>Low cost RM </li></ul><ul><li>Productive/Efficient Reactions </li></ul><ul><ul><li>High Yield </li></ul></ul><ul><ul><li>Highly concentrated </li></ul></ul><ul><ul><li>Few Steps </li></ul></ul><ul><ul><li>Short time cycles </li></ul></ul><ul><ul><li>Few Vessels </li></ul></ul>
    28. 28. <ul><li>Remoxipride-----schizophrenia </li></ul><ul><li>2-Synthesis of Pyrazine Carboxamide a CHIRAL PIPERAZINE –Ingredient of antivirals , ie virs </li></ul>
    29. 29. Selective Dopamine-2 Antagonist Indication: Anti-psychotic (Depression/Schizophrenia) Clinical Trials: halted in 1993 due to anemia side-effects
    30. 32. Auerbach, Weissman Tet Letters 1993, 931
    31. 34. 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
    32. 36. A: 179/[124+127+73+73] = 45 % B: 179/[105 + 98 +74 +18] = 61%
    33. 38. <ul><li>Increased Regulatory controls (FDA, EPA) </li></ul><ul><li>Downward Pricing Pressure </li></ul><ul><li>Greater Competition in treatment options </li></ul><ul><li>More complex molecules </li></ul><ul><li>Corporate consolidation </li></ul><ul><li>Dwindling # of diseases to conquer </li></ul>
    34. 39. <ul><li>Process Development as a Competitive Weapon/Leveraging Capabilities </li></ul><ul><li>“ 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” </li></ul>
    35. 40. <ul><li>“ A firm that can develop sophisticated process technologies more rapidly and with fewer development resources has strategic options that less capable competitors lack ” </li></ul>
    36. 41. <ul><li>Practical Process Research & Development; Neal Anderson </li></ul><ul><li>The Merck Druggernaut: The Inside Story of a Pharmaceutical Giant ; Fran Hawthorne </li></ul><ul><li>The Development Factory: Unlocking the Potential of Process Innovation ; Gary P. Pisano </li></ul><ul><li>Principles of Process Research and Chemical Development in the Pharmaceutical Industry ; Oljan Repic </li></ul><ul><li>Process Chemistry in the Pharmaceutical Industry; Kumar Gadamasetti </li></ul>
    37. 42. <ul><li>THANKS </li></ul>