DR ANTHONY M CRASTO (Ph.D)PRINCIPAL SCIENTISTPROCESS RESEARCH

DEC 2011“A SHORT PRESENTATION”

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”

Net Cost: $802 Million Invested Over 15 Years Net Cost: $802 Million

Invested Over 15 Years

5,000–10,000Screened

250Enter Preclinical

Testing

5Enter

Clinical Testing

1

Compound Success Rates by Stage

Compound Success Rates by Stage

1616

1414

1212

1010

88

66

44

22

00

Phase II100–300 Patient Volunteers Used to Look for Efficacy and Side Effects

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

Phase III1,000–5,000 Patient

Volunteers Used to Monitor Adverse Reactions to

Long-Term Use FDA Review ApprovalFDA Review Approval

Additional Post-Marketing Testing

Additional Post-Marketing Testing

Phase I 20–80 Healthy Volunteers Used to Determine Safety

and Dosage

Phase I 20–80 Healthy Volunteers Used to Determine Safety

and Dosage

Preclinical TestingLaboratory and Animal Testing

Preclinical TestingLaboratory and Animal Testing

Discovery(2–10 Years)

Discovery(2–10 Years)

YearsYears

New Product Development – New Product Development – A Risky and Expensive PropositionA Risky and Expensive Proposition

New Product Development – New Product Development – A Risky and Expensive PropositionA Risky and Expensive Proposition

Approved by the FDA

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

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. 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

“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. 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

4. Chemical Engineering principles: mixing, heat transfer, vessel configuration

5. 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

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for developing In-processassay and critical evaluation of

drug substance and intermediates

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

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

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

responsible for formulatingdrug substance (API) into

drug product

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

Oversee process transfer intoPilot plants

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

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

MedChem

Clinical

Chem ER&D

Pharm R&D

Safety

Analytical

ProcessProcess

Discovers new chemical entities (NCE’s) and

prepares intitial quantities

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. 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

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)

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

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

Br

NH

O

N

H

OMe

OMe

Br

O

OMe

OHH2N

N

H

Remoxipride

Selective Dopamine-2 Antagonist

Indication: Anti-psychotic (Depression/Schizophrenia)

Clinical Trials: halted in 1993 due to anemia side-effects

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

OMe

Br

O

OMe

OH

OMe O

OMe

OH

94% yield

98% purity

water/NaOH

N

N

O

OBr

Br(0.55 equiv)

Green Chemistry Principles: Safer Solvents

Less Hazardous Chemical Synthesis

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

Br

OMe

O

OMe

OH

N

O

O

OMe

MeO

Alkaloid Chelerythrine

Harayama et al Synthesis 2001, 444

OMe

MeO

N

O

O

O

J. Fuchs, R. Funk Org. Letters 2001, 3923

Alkaloid Lennoxamine

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

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

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%

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

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