DR ANTHONY M CRASTO (Ph.D) PRINCIPAL SCIENTIST PROCESS RESEARCH DEC 2011 “A SHORT PRESENTATION”
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
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�
New Product Development – A Risky and Expensive Proposition Compound Success Rates by Stage
Years 0 Discovery (2–10 Years)
2 4
Phase I 20–80 Healthy Volunteers Used to Determine Safety and Dosage Phase III 1,000–5,000 Patient Volunteers Used to Monitor Adverse Reactions to Long-Term Use Additional PostMarketing Testing
6 8 10
Preclinical Testing Laboratory and Animal Testing Phase II 100–300 Patient Volunteers Used to Look for Efficacy and Side Effects
12 14 16
FDA Review Approval
5,000–10,000 Screened 250 Enter Preclinical Testing 5 Enter Clinical Testing 1 Approved by the FDA
Net Cost: $802 Million Invested Over 15 Years
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
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.
1.
2.
3.
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: 1. 2.
◦ ◦
Modern synthetic organic methodology Physicochemical properties Salt selection: based on stability, suitability Solid State Properties: Solvent dependant
1.
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,
4.
heat transfer, vessel configuration Practical Process Aspects:
5.
◦
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
Analytical
Med Chem
Safety Process Pharm R&D
Clinical Chem E R&D
Analytical
Med Chem
responsible for developing In-process assay and critical evaluation of drug substance and intermediates
Safety Process Pharm R&D
Clinical Chem E R&D
Analytical
Med Chem
Safety responsible for toxicity studies: (carcinogen, teratogen, gene toxicity)
Process Pharm R&D
Clinical Chem E R&D
Analytical
Med Chem
Safety Process Pharm R&D
Clinical Chem E R&D
responsible for formulating drug substance (API) into drug product
Analytical
Med Chem
Safety Process Pharm R&D
Clinical Chem E R&D
Oversee process transfer into Pilot plants
Analytical
Med Chem
Safety Process Pharm R&D
Clinical
Conducts clinical trials (Ph I-III) and evaluates data
Chem E R&D
Analytical
Discovers new chemical entities (NCE’s) and prepares intitial quantities
Med Chem
Safety Process Pharm R&D
Clinical Chem E R&D
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
1.
2.
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:
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 ď ˝
Use of innocuous solvents should be considered (e.g. water, supercritical CO2)
ď ˝
Avoid use of unnecessary substances
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 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
OMe
O
OMe
H N H
H
N
OH H2N
OMe Br
O
OMe Br
Remoxipride Selective Dopamine-2 Antagonist Indication: Anti-psychotic (Depression/Schizophrenia) Clinical Trials: halted in 1993 due to anemia side-effects
N
OMe
OMe
O OH
O
OMe OH
Br2 dioxane Br
84% yield 93% purity Use of toxic oxidant (bromine) Use of suspect carcinogen (dioxane) Product requires additional purification
O OH
OH
OMe
OMe
Drawbacks:
Br
OMe
O
OH
OMe Br
Br
5%
2%
Br O OMe
N O
O
N OH
OMe
OMe
O
Br (0.55 equiv)
OH OMe
water/NaOH Br
94% yield 98% purity
Green Chemistry Principles: Safer Solvents Less Hazardous Chemical Synthesis
OMe
O
Br
O
OH
O OH
OMe
OMe
Br
O
OH
O
Br
OMe
90% yield
90 % yield
86% yield
Literature: 4 steps-17% yield
O MeO
O OH
MeO
Br
OH
Br
OH
OMe
OMe
91 % yield
O
98 % yield
NR
Auerbach, Weissman Tet Letters 1993, 931
O O N
MeO
Harayama et al Synthesis 2001, 444
OMe Alkaloid Chelerythrine Br OMe
O OH
MeO
OMe O
OMe N J. Fuchs, R. Funk Org. Letters 2001, 3923 O O Alkaloid Lennoxamine
Original Route
N N
(COCl)2 CO2H
N N
t-BuNH2 C(O)Cl
N N
CONHt-Bu
95% yield
Drawbacks: 1. Use of costly Oxalyl Chloride 2. CO and CO2 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
Ritter Reaction N t-BuOH, H2SO4 N
CN
Aq AcOH
N N
CONHt-Bu
5 oC/2 h 91 %
Green Chemistry Principles: - Prevention - Safer Solvents - Less Hazardous Chemical Synthesis - Energy Efficiency
N
(COCl)2 [127]
A N
CO2H
2 t-butylNH2 [ 73]
N
C5H4N2O2 Mol. Wt.: 124.10
O C9H13N3O Mol. Wt.: 179.22
H2SO4 [98]
N
B
t-BuOH [74] N
NH
N
CN
C5 H3 N3 Mol. Wt.: 105.10
A: 179/[124+127+73+73] = 45 % B: 179/[105 + 98 +74 +18] = 61%
H2O [18]
95% aq NaOH H2
N
Pd (OH)2 N
CONHt-Bu
95%
H N
N H
L-PGA CONHt-Bu
47%
H N
N H
2 L-PGA
CONHt-Bu
98 % ee-crystalline salt
+ Boc N
N H
Boc2O CONHt-Bu
99% ee 80% yield
KOH
H N
N H
2 L-PGA
CONHt-Bu
86% ee- in ML's
Green Chemistry Principles: Prevention (Recycle R-isomer) Prevention (Recovery of PGA) Atom Economy Renewable Feedstock (PGA) Catalysis
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
-THANKS AND REGARD'S DR ANTHONY MELVIN CRASTO Ph.D amcrasto@gmail.com MOBILE-+91 9323115463 GLENMARK SCIENTIST , NAVIMUMBAI, INDIA web link http://about.me/amcrasto http://anthonymelvincrasto.brandyourself.com/ http://amcrasto.bravesites.com/ http://amcrasto.theeurekamoments.com/ http://anthonycrasto.jimdo.com/ http://www.anthonymelvincrasto.yolasite.com/ http://www.slidestaxx.com/anthony-melvin-crasto-phd https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net http://amcrasto.biz.ly/ http://anthonycrasto.wordpress.com/ http://organicchemistrysite.blogspot.com/ http://www.mendeley.com/profiles/anthony-melvin-crasto/ http://amcrasto.wix.com/anthony-melvin-crasto/apps/blog Congratulations! Your presentation titled "Anthony Crasto Glenmark scientist, helping millions with websites" has just crossed MILLION views. アンソニー 安东尼 Энтони 안토니 أنتوني join my process development group on google organic-process-development group you can post articles and will be administered by me on the google group which is very popular across the world https://sites.google.com/site/anthonycrastomycv/cv http://www.epernicus.com/amc10 http://scipeople.com/users/87574341/ https://sites.google.com/site/amcrasto/ http://www.skillpages.com/organic-chemist/thane-india/anthony-melvin.crasto http://amcrasto.mixxt.com http://join.apnacircle.com/?sponsor=anthony-melvin.crasto-ph.d&lang=en LinkedIn group SYNTHETIC ORGANIC CHEMISTRY
43