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

Years
0 Discovery (210 Years) 2 4 Phase I 2080 Healthy Volunteers Used to Determine Safety and Dosage Phase III 1,0005,000 Patient Volunteers Used to Monitor Adverse Reactions to Long-Term Use Additional PostMarketing Testing 6 8 10 12 14 16 FDA Review Approval Preclinical Testing Laboratory and Animal Testing Phase II 100300 Patient Volunteers Used to Look for Efficacy and Side Effects 5,00010,000 Screened 250 Enter Preclinical Testing 5 Enter Clinical Testing 1 Approved by the FDA

Compound Success Rates by Stage

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 Ms 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 its 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.

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

2.

3.

The ideal chemical process is that which a onearmed 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
x x x Crystal Morphology: internal shape-affects solubility, stability Crystal Habit: external shape-affects flowability, mixability Particle Size: can affect bioavailability

3.

Purification/Isolation technologies

4.

5.

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

Analytical

Med Chem Process

Safety

Clinical Chem E R&D

Pharm R&D

Analytical

responsible for developing In-process assay and critical evaluation of drug substance and intermediates

Med Chem Process

Safety

Clinical Chem E R&D

Pharm R&D

Analytical

Med Chem Process

Safety
responsible for toxicity studies: (carcinogen, teratogen, gene toxicity)

Clinical Chem E R&D

Pharm R&D

Analytical

Med Chem Process

Safety

Clinical Chem E R&D

Pharm R&D responsible for formulating drug substance (API) into drug product

Analytical

Med Chem Process Clinical Chem E R&D

Safety

Pharm R&D

Oversee process transfer into Pilot plants

Analytical

Med Chem Process

Safety

Clinical Chem E R&D

Pharm R&D

Conducts clinical trials (Ph I-III) and evaluates data

Analytical

Discovers new chemical entities (NCEs) and prepares intitial quantities

Med Chem Process

Safety

Clinical Chem E R&D

Pharm 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: 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 CO2) ` 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 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 N H OMe

H N

OMe

O H OH H2N OMe N

Br

Br

Remoxipride
Selective Dopamine-2 Antagonist Indication: Anti-psychotic (Depression/Schizophrenia) Clinical Trials: halted in 1993 due to anemia side-effects

OMe

O OH OMe

OMe

O Br OH OMe

OMe

O OH OMe

OMe

O OH OH

Br2 dioxane
Br

Br

Br

84% yield 93% purity Drawbacks: Use of toxic oxidant (bromine) Use of suspect carcinogen (dioxane) Product requires additional purification

5%

2%

Br O OMe O OH OMe N O N Br (0.55 equiv) water/NaOH Br OMe O OH OMe

94% yield 98% purity

Green Chemistry Principles: Safer Solvents Less Hazardous Chemical Synthesis

OMe

O OH OMe

Br

O OH OMe O O

O OH Br

Br

OMe

90% yield

90 % yield Literature: 4 steps-17% yield

86% yield

O MeO OH MeO OMe Br Br

O OH OMe

O OH

91 % yield

98 % yield

NR

Auerbach, Weissman Tet Letters 1993, 931

O O MeO OMe Alkaloid Chelerythrine Br OMe MeO O N OMe O OH OMe N Harayama et al Synthesis 2001, 444

J. Fuchs, R. Funk Org. Letters 2001, 3923 O O Alkaloid Lennoxamine

Original Route

N N CO2H

(COCl)2

N N C(O)Cl

t-BuNH2

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 5 oC/2 h 91 %

N N CONHt-Bu

Green Chemistry Principles: - Prevention - Safer Solvents - Less Hazardous Chemical Synthesis - Energy Efficiency

A
N CO2H
C5H4N2O2 Mol. Wt.: 124.10

(COCl)2 [127]
2 t-butylNH2 [ 73]
N O
C9H13N3O Mol. Wt.: 179.22

NH

H2SO4 [98] t-BuOH [74]

B
N CN
C5H3N3 Mol. Wt.: 105.10

H2O [18]

A: 179/[124+127+73+73] = 45 % B: 179/[105 + 98 +74 +18] = 61%

95% aq NaOH
N

H2 Pd (OH)2

H N

H N

2 L-PGA

L-PGA
CONHt-Bu

CONHt-Bu

95%

N H

47%

N H

CONHt-Bu

98 % ee-crystalline salt

+
Boc N

Boc2O
CONHt-Bu

H N

2 L-PGA

N H

KOH

N H

CONHt-Bu

99% ee 80% yield

86% ee- in ML's

Green Chemistry Principles: Prevention (Recycle R-isomer) Prevention (Recovery of PGA) Atom Economy Renewable 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

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