process research overview
DESCRIPTION
PROCESS RESEARCH OVERVIEW, by DR ANTHONY CRASTOTRANSCRIPT
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DR ANTHONY M CRASTO (Ph.D)PRINCIPAL SCIENTISTPROCESS RESEARCH
DEC 2011“A SHORT PRESENTATION”
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1. What is Process Research ?2. Its 12 Principles3. Definition4. Objectives5. Personnel requirements6. GMP Considerations7. Process economics8. Industry challenges9. Case Studies- Remoxipride and chiral piperazine10. Lesson Learned: “Unlocking the Potential of
Process Innovation”
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Net Cost: $802 Million Invested Over 15 Years
5,000–10,000Screened
250Enter Preclinical
Testing
5Enter
Clinical Testing
1
Compound Success Rates by Stage
16
14
12
10
8
6
4
2
0
Phase II100–300 Patient Volunteers Used to Look for Efficacy and Side EffectsPhase 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 TestingLaboratory and Animal Testing
Discovery(2–10 Years)
Years
New Product Development – New Product Development – A Risky and Expensive PropositionA Risky and Expensive Proposition
Approved by the FDA
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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)
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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
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•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
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1. To try the process on a model of proposed plant before committing large sum of money on a production unit.
2. Examination of the formula to determine it’s ability to withstand Batch-scale and process modification.
3. Evaluation and Validation for process and equipments
4. To identify the critical features of the process. Guidelines for production and process controls.
5. To provide master manufacturing formula with instructions for manufacturing procedure.
6. To avoid the scale-up problems.
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1. Scientists with experience in lab, 20 litre scale, pilot plant operations as well as in actual production area are the most preferable
2. 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.
3. The group should have some personnel with engineering knowledge as well as scale up also involves engineering principles
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“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)
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An amalgam of:
1. Modern synthetic organic methodology2. 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
3. Purification/Isolation technologies
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4. Chemical Engineering principles: mixing, heat transfer, vessel configuration
5. Practical Process Aspects:◦ Safety◦ Quality◦ Cost◦ Reproducibility◦ Ruggedness
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Equipment qualification Process validation Regularly schedule preventative
maintenance Regularly process review & revalidation Relevant written standard operating
procedures The use of competent technically qualified
personnel
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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
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MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
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MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
responsible for developing In-processassay and critical evaluation of
drug substance and intermediates
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MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
responsible for toxicity studies: (carcinogen, teratogen, gene toxicity)
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MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
responsible for formulatingdrug substance (API) into
drug product
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MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
Oversee process transfer intoPilot plants
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MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
Conducts clinical trials (Ph I-III) and evaluates data
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MedChem
Clinical
Chem ER&D
Pharm R&D
Safety
Analytical
ProcessProcess
Discovers new chemical entities (NCE’s) and
prepares intitial quantities
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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
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1. Prevention: It is better to prevent waste than to treat/clean up after its created.
2. 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
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5 Design Safer Products: Products should be designed to effect their desired function while minimizing toxicityExample: Use of single enantiomer drug vs racemate
6. Use Safer Solvents/Auxiliaries Use of innocuous solvents should be
considered (e.g. water, supercritical CO2) Avoid use of unnecessary substances(e.g. drying agents, column chromatography)
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7. Design for Energy Efficiency: Energy requirements for a process should be
recognized for environmental and economic impact
Eg: avoid extreme cryogenics (-78 oC)Avoid prolonged reaction times8. Use of Renewable Raw Materials:
Use a renewable source rather that depleting whenever technically and economically feasible.eg: plant-derived RM; microbial reactions
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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
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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)
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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
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Remoxipride-----schizophrenia
2-Synthesis of Pyrazine Carboxamide a CHIRAL PIPERAZINE –Ingredient of antivirals , ie virs
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OMe
Br
NH
O
NH
OMe
OMe
Br
O
OMe
OHH2N
NH
Remoxipride
Selective Dopamine-2 Antagonist
Indication: Anti-psychotic (Depression/Schizophrenia)
Clinical Trials: halted in 1993 due to anemia side-effects
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OMe
Br
O
OMe
OH
OMe O
OMe
OH Br2 dioxane
OMe
Br
O
OMe
OH
OMe
Br
O
OH
OHBr
84% yield
93% purity
5% 2%
Drawbacks: Use of toxic oxidant (bromine)
Use of suspect carcinogen (dioxane)
Product requires additional purification
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OMe
Br
O
OMe
OH
OMe O
OMe
OH
94% yield
98% purity
water/NaOH
N
NO
OBr
Br(0.55 equiv)
Green Chemistry Principles: Safer Solvents
Less Hazardous Chemical Synthesis
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OMe
Br
O
OMe
OH
90% yield
Br
OMe
O
OMe
OH
90 % yield
O
Br
OHO
O
86% yield
OMe
O
OH
MeO
MeO
Br
91 % yield
O
OMe
OHBr
98 % yield
O
OH
NR
Literature: 4 steps-17% yield
Auerbach, Weissman Tet Letters 1993, 931
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Br
OMe
O
OMe
OH
N
O
O
OMe
MeO
Alkaloid Chelerythrine
Harayama et al Synthesis 2001, 444
OMe
MeO
N
O
OO
J. Fuchs, R. Funk Org. Letters 2001, 3923
Alkaloid Lennoxamine
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CONHt-Bu
N
N
Original Route
CO2H
N
N C(O)Cl
N
N
(COCl)2 t-BuNH2
95% yield
Drawbacks:1. Use of costly Oxalyl Chloride2. CO and CO2 by-products3. Lengthy time cycle due to exothermic amination reaction4. Need for 3 equiv of volatile t-butylamine5. Filtration/Disposal of voluminous amine hydrochloride salt
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N
N
CN CONHt-Bu
N
N
t-BuOH, H2SO4
91 %
Ritter Reaction
Aq AcOH
5 oC/2 h
Green Chemistry Principles: - Prevention- Safer Solvents- Less Hazardous Chemical Synthesis- Energy Efficiency
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N
N
CO2H N
N
NH
O
N
N
CN
C5H4N2O2Mol. Wt.: 124.10
C5H3N3Mol. Wt.: 105.10
C9H13N3OMol. Wt.: 179.22
(COCl)2 [127]
2 t-butylNH2 [ 73]
H2SO4 [98]
t-BuOH [74]
H2O [18]
A
B
A: 179/[124+127+73+73] = 45 %
B: 179/[105 + 98 +74 +18] = 61%
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N
N
CONHt-Bu
H2
Pd (OH)2
95% NH
HN
CONHt-Bu
L-PGA
NH
HN
CONHt-Bu
2 L-PGA
47%
86% ee- in ML's
+
NH
HN
CONHt-Bu
2 L-PGA
98 % ee-crystalline salt
95%aq NaOH
Boc2O
KOHNH
BocN
CONHt-Bu
99% ee 80% yield
Green Chemistry Principles: Prevention (Recycle R-isomer)Prevention (Recovery of PGA)Atom EconomyRenewable Feedstock (PGA)Catalysis
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Increased Regulatory controls (FDA, EPA) Downward Pricing Pressure Greater Competition in treatment options More complex molecules Corporate consolidation Dwindling # of diseases to conquer
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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”
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“A firm that can develop sophisticated process technologies more rapidly
and with fewer development resources has strategic options that
less capable competitors lack”
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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
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THANKS
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