The Chemistry of Process Development in Pharmaceutical Industry

Venugopal Rao VEERAMANENI, Ph.D. Indus BioSciences (P) Ltd.

Highlights of Presentation

Introduction & Steps in Drug Discovery Introduction & Role PR&D Role in Drug Discovery

Challenges, Significance and Criteria of P R&D

Steps in Practical Process Research & Development

Steps in Drug Discovery

Target Informati Lead Medicinal Cellular Preclinic Discover cs & Discover Chemistr & al y Genomics y y Molecula Develop r Level ment Target Bioinfor Assay Library Invitro Pharmac Identifica matics Develop Develop Drug o tion ment ment Activity Kinetics Target Genomics Validatio n HTS Structure Cellular In Vivo Based Disease Pharmac DD Models ology

Drug Candidates

Assay Proteomi Biochemi Medicinal Drug Toxicolog Develop cs stry/Enzy Chemistr Mechanis y/Safety ment mology y m Pharmac olgy

Steps in Drug Discovery

Discovery & Early Development Pre Clin Study

3-4 Years

Clinical Development

6-8 Years

Submissi on Filling & Approval

1 Year

Launch & Marketi ng Phase IV Lunch

Phase 1

Phase 2

Phase 3

Target Identifi cation; LG & LO

Safety; PK/PD. Determi ne dose for Phase 2

Efficacy ; Proof of concept

Extensi ve Studies ; Efficacy & Safety

Regulat ory Review ; Efficacy & Safety. Plannin g for Manufa

Post Marketi ng Studies. Post approva l change s in Manufa

 Patent Infringement Inconsistent Raw Material Quality and Supply Hazardous or Non-Regulated Raw Materials Costly Raw Materials Unsafe or Environmentally Hazardous Reactions Low Yields Difficult-To-Achieve Levels of Purity (e.g., for enantiomers) Scale-up Difficult-To-Handle Processes

P R&D Challenges to Overcome

P R&D Commercial Challenges

Current cost of bringing new drug to market: >$800 million Success rate: 1 in 10 Time to Market: 10 to 15 years Highly competitive Highly regulated

P R&D Significance
Safety & Speed Quality & Quantit y

Cost & Time Bulk Operati on

Environ mental Impact

P R&D Philosophy
Subject Atom Economy Solvent reduction Environmentally Thinking Economically Thinking Minimal by Product Formation More from Less - Incorporate Total Value of Materials Less Solvent Waste Higher throughput, Less Energy

Reagent Catalytic, Low Stoichometry, Higher Efficiency - Higher Optimization Recyclable Reagents, Selectivity Minimize Us age Convergency Due to Increased Processed Efficiency Energy Reduction Safety From Power Generation, Transport and Use Non-Hazardous Materials Reduce Risk of Exposure, Release, Explosions & Fire Higher Efficiency . Reduced Energy , Increased Efficiency, Shorter Process and Mild Conditions Worker Safety and Reduced Down Time. Reduced Time on Special Control Measures

Meet the Challenges by executing fundamental changes to the development and manufacturing approach

P R&D Work Smarter, Not Harder

Integration Scienc e Manufacturi ng

Integrated scientific, manufacturing, & commercial objectives Development of the best route with full intrinsic process knowledge Apply new technologies for effective utilization of

PR&D - The Work Flow

Target from Discover y
RD

Best Synthetic Route

Optimize d Route

Technolo gy Transfer

IDEA

PR

PD

Routine Manufaturing

Mg to Gram Drug Disc over y

Kilogram

1 to 100Kg

> 100Kg

Pha se 1

Pha se 2

Pha se 3

P R&D Road Map Quality by Design

Designing for the API Manufacturing

Chemistry Selection

Process Devel.

Process Modeling

Process Scale Up

Process Control

Quality By = Design

Science of Design Evaluate Design

Manufacturing Science Predict Verify Control

Deliverables
Best Intrinsic Optimized Demonstrated Time Real Production Process Unit Production Continuous Chemistry KnowledgeOperations Process Improvements

Scale-Up Criteria Viewpoint of Out-Sourcing Firms Criteria Considerations

Reagents Cost, Purity, Availability. Specialized equipment needed Toxicity: restricting exposure requires additional PPE and monitoring. Chemical hazard: liability worse with scale-up Safety; Ease of work-up; Ease of removing solvent from final product Solvent

Work-up & Minimal reliance on chromatography; No concentrations to Isolations dryness Minimal number of repeated steps (extractions; solvent displacements); Controlled crystallization preferred over precipitation. Reaction Exotherms and gas evolution: liability worse with scale-up. RuggednesCryogenic or very high temp. require specialized equipment. s Control of reaction conditions (temp. or pH). Excluding moisture or oxygen may require additional considerations. Rapid additions and short reaction times require nonstandard equipment Yield Low yields require that more intermediates be prepared for

P R&D Steps in Practical Process Research

Approaches to Process Development. Route Selection. Reagent Selection. Solvent Selection. Running the Reaction. Effects of Water. In-Process Controls. Optimizing the Reaction by

Optimizing Catalytic Reactions Work-Up Tools for Purifying the Product Column Chromatography & Crystallization Final Product Form and Impurity Considerations. Vessels and Mixing. Preparing for and Implementing the Scale-up Run.

P R&D Steps in Practical Process Research

PR&D - Approaches
Introduction Importance of scale-up operations Importance of team work Determining operations Safety Considerations Take Advantage of Good

PR&D Approaches - Importance of Team Work

Process Engineeri ng Operatio ns Process Chemistr y

A R&D

Manufact uring Pharmac eutical Chem

Quality Analysis Quality Control Regulator y

PR&D Approaches - Importance of Team Work

S.No. 1 2 3 4 5 6 7 8 9 Department Discovery Chemistry Process Chemistry Process Development Process engineering Operations/Opera tors Manufacturing Key Responsibilities To discovering the new molecule Initially develop chemical process Optimizing process for pilot plant & manufacturing To Identify practical considerations needed for effective scale up To carry out scale up operations and prepare large quantities of materials To Manufacture drug substance in multi Kg level

Pharmaceutical To formulate drug substance from drug product Chem. Regulatory Quality To Interface with FDA and other regulatory authorities Documentation & Interface with DR&D and

PR&D Approaches Comparison of Lab Scale & Plant Scale Operation Lab Scale On Scale
Common Rotary evaporation; Concentration to dryness Use of Highly Flammable solvents Column Chromatography & Drying over agents Azeotropic drying Addition of dangerous reagents & Maintaining Cryogenic temperature & Rapid quenching Fine controlling Heating & Cooling X X X X X Easy to effect X X X X X X X X X X X X Common Easy to effect

PR&D Approaches Focus of Efforts for Preparing Batches

Reference Compound Kilo lab batches Use of most expeditious route, minimal optimization & purification by chromatography Cost of raw materials may be fairly high, invest time to decrease risk of poor yields & meeting deadline is primary concern Expensive to occupy equipment, so optimize for reasonably smooth processing. Cost of raw material may be significant, so optimize to obtain significant yields. Preferably to solve any processing problems in lab High cost and value of raw materials and intermediates. Small change in yield or quality has major financial impact.. Expensive efforts to fine tune process are

Pilot plant batches

Manufacturing

PR&D - Route Selection

Introduction Characteristics of Appropriate Route Characteristics of Cost-Effective Route Planning for Ultimate Route

PR&D - Route Selection Summary of Route Characteristics

Criteria Time Eff. Route X X X X X X X X X X X X X CostEff. Route Comments Appropriate Familiarity Fits Equipment Exp. Reagents Optimized Work up Protecting group Min. No. of Steps High Overall Yield Technically Feasibly Minimize reagents Appropriate early in drug development Familiarity developed during scale up Practicality is key Availability ? Optimize the productivity Minimize number & size Optimize productivity May include statistical optimization Reliability on scale

PR&D - Route Selection Criteria

Linear Synthetic Route:

A +B

Step 1

A-B

Step 1 C

A-B-C

Step 1 D Step 1 H

A-B-C-D

Step 1 E

A-B-C-D-E
Step 1 I

Step 1 F

A-B-C-D-E-F

Step 1 G

A-B-C-D-E-F-G

A-B-C-D-E-F-G-H

A-B-C-D-E-F-G-H-I

Convergent Synthetic Route:

A +B C +D E +F G +H

Step 1 Step 1 Step 1 Step 1

A-B C-D E-F G-H

Step 1

A-B-C-D
Step 1 A-B-C-D-E-F-G-H Step 1

Step 1 I

A-B-C-D-E-F-G-H-I

E-F-G-H

PR&D - Reagent Selection

Introduction The Ideal Reagent for Scale-Up Types of Reagents Reagents for deprotanation Alkoxides Amine Bases Oxidations Reductants Catalytic Reagents Polymeric reagents Biocatalysts

PR&D - Reagent Selection Characteristics of Ideal Reagents

Characteristics Comments
Specific for desired synthetic transformation Nontoxic to operators and analysts Poses no chemical reactions hazard to personal Inexpensive Readily available With increased reactivity, shortened reaction times, reaction selectivity More time required for handling more toxic reagents Consider the safety of operators, equipment and the community Minimize over all cost of product Consider outsourcing specialized compounds

Consistent quality from batch to May eliminates the needs for use-tests batch Stable with good self life Good stability at room temperature preferred

Readily generated and used if not Reproducible generation minimizes stable Readily transferred into reactors Liquids and solutions are preferred

PR&D - Solvent Selection

Introduction Selecting Solvents Based on Physical Characteristics Selected Solvent Impurities Choosing Solvents Alternatives to Classical Solvents

PR&D - Solvent Selection Primary Physical Characteristics of solvents for Scale-up Solvents Alternative Solvents
Polarity Freezing Point Boiling Point Must be compatible with and encourage the desired chemistry May limit range of low-temperature reactions A higher bp extends the temperature range of reaction without using pressurized reactor. A lower boiling solvents is easier to remove by distillation. Temperature at which a liquid produces ignitable vapors . Lower boiling solvents/compounds typically have lower flash point. Occurs primarily in etheric solvents. Slower in ketones & amides. Solvents with tendency for peroxide formation should be monitered Solvents with increased viscosity display slower filtration rates Solvents with low water-miscibility allow for easier extractive work-ups

Flash Point

Peroxide Formation Viscosity WaterMiscibility

PR&D - Solvent Selection Process Design Reasons

Goal
Provide homogeneous reaction conditions Increasing strirrability of reactions Remove impurities by distillation Remove impurities by the addition of immiscible solvents (Water) Purify product by crystalization

Impact on Processing
Increase reaction rate and decrease byproducts Minimize localized heating minimize by-product formation, increase ability to transfer slurries to filters Increase productivity, yield & quality Increase productivity, yield & quality

Increase the desired reactionIncreased productivity often through rate homogeneous reaction conditions

Increase productivity, yield & quality

Increase of safety operations Protect operators, analysts and plant facilities

PR&D - Solvent Selection Avoided/Minized on Scale

Solvents Undesirable Characteristic
MTBE MTBE NMP Heptane Heptane MDC, ACN, Toluene, DMF, nBuOH MDC Toluene THF IPA

Alternative Solvents

Diethylether Flammable Isopropyleth Flammable/Peroxide er formation HMPA Pentane Hexane Toxicity Flammable Electrostatic discharge

Chloroform Mutagenicity, Toxicity CCl4 & EDC Benzene Dioxane Mutagenicity Carcinogen Carcinogen

Acetonitrile Animal tertogen

PR&D - Solvent Selection Commonly used in Large Scale

Water Methanol Propane diol Ethanol Acetic acid nButanol iPropanol Acetonitrile MTBE Xylenes Pyridine DMSO DMF tButanol NMP Acetone Amylalcohol Dichlorometha ne Pyridine Toluene Heptane 1,4-Dioxane MIBK DME Ethyl acetate THF iPropylacetate Chlorobenzene 2-Me-THF iButylacetate Triethyl amine Cyclohexane Cyclohexane

 Introduction Determining Reaction Safety Assessing Safe Operating Conditions in the Lab Selecting the Reaction Scale Choosing Equivalents of Reagents, Starting Materials & etc Plan for Inert Condition if needed Charge Starting Materials and Solvents Select Reaction Temperature Select Duration & Sequence of Additions Select Reaction Pressure Adjust Stirring

PR&D - Running the Reaction

PR&D - Effects of Water

Introduction Detecting and Quantitating Water Removing Water from Routine Organic Processing Entry of Water through Processing Air Entry Water through Solvents Entry Water through Reagents Formation of Water as a By-Product & Its Removal

PR&D - In-Process Controls

Introduction The Importance of IPC for Process Filed with the
FDA

Choosing the Appropriate IPC Generating Reproducible IPC

Obtaining a Representative Sample of Process Stream Reproducible Sample Preparation Generating Reproducible Assay Data

PR&D - In-Process Controls Useful.

Analytical Method HPLC GC GC-MS TLC IR UV H NMR C NMR P NMR MC Titrations Density To Quantit IPC Monitor ative Suitabilit y R&W R&S R&S R R R R R R S & Rg Re Sol X X X X X X X X Rapid Assays X X X X X X X X X X X X X X Inexpensive Good for Assay Rapid Assays Comments Very Useful Rapid Assays

 Introduction Steps to Optimize the Reactions

PR&D - Optimizing the Reaction by Minimizing Impurities

Optimizing Reaction Temperature Optimizing Reagent Equivalents Optimizing Addition of Reagents Optimizing Use of Solvents and Cosolvents Optimizing Reaction Concentration Changing Reagents and Intermediates Optimizing Catalysts and Ligands Optimizing Stirring Importance of Extending Reaction Times

Minimizing Impurity Formation by Indentifying Impurities First

R&D - Optimizing Catalytic Reactions

Introduction Catalyst & Ligand Selection Optimizing Catalyst Concentration Generating Active Catalysts Importance of Extended Additions Influence of Co-Catalysts & Impurities Catalyst Decomposition Non-Linear Catalyst Effect

PR&D - Work-Up
Introduction Aspects of Work-up
Quench Extraction Activated Carbon Treatment Filtration Concentrating Solution/Solvent Displacement Deionization and Removing Metals Destruction of Process Streems

PR&D - Tools for Purifying the Product

Introduction Purification by column chromatography Crystallization Theory & Process Classification of solids Salt Selection Washing & Drying Solid Products

 Introduction

PR&D - Final Product Form and Impurity Considerations

Stability Testing The importance of Controlling Particle Size of a Drug Substance

The Importance of Solid State Characteristics

Preparing and Selecting the Polymorph

Varying Crystallization Condition in order to Prepare Polymorph

Purity and Impurity Considerations Freezing

PR&D - Vessels and Mixing

Introduction Batch Vs Continuous Process Batch Processing
Continuous Operations Semi continuous Operations

Use of Continuous Flow Reactors

Static Mixtures Immobilized Catalysts Photochemical Reactors Microwave Reactors Sonochemical Reactors Plug Flow Reactors Electrochemical Reactors

PR&D - Preparing for and Implementing the Scale-up Run Introduction

Anticipating Scale-Up Problems Scale-Up Considerations
Identify the Goals of Scale-Up Safety Considerations Identify Critical Processing Steps Define Equipment Limitations Develop Contingency Plan for Incomplete & Runaway Reactions Know Effects of Extended and Interrupted Processing Identify Cleaning and Waste Disposable Procedures Guidelines for Documentation: Efficient Process Transfer

Implementing the Scale-Up Run

PR&D - Troubleshooting
Introduction Physical and Chemical Causes of Processing Problem Steps for Troubleshooting A Process
Confirm that there is Problem Determine Whether the problem is Serious Enough Spend Time Compare Processing Steps to those used in Successful Batches Identify as assay to monitor key Processing Confirm that the cause of the problem has been identified Propose alternative treatments to eliminate the problem

Manufacturing of Intermediate for Anti Ulcer Agents

O N
O O S N

Case Study

S N H N O
N

N H

Omeprazole

Esomeprazole

R R1
F F O O S N H N O F N F F

O Cl

N
O O O S N H N O F N F

Lansoprazole
O

Pentoprazole

O S

N H N

Rabeprazole

Manufacturing of Intermediate for Anti Ulcer Agents

NO1 R1 R1 R1 R1 Cl R1 R R1 R

Case Study

II
N O N O

III
N O

IV
N O N O

Cl

Step IV Modified by Changing chlorination reagent Acetyl chloride in ethanol used instead of HCl, Thionyl Chloride, and etc 30Kg scale performed without any issues

Improved Process for Pioglitazone Anti Diabetic

S
O

Case Study

Pioglitazone

NH

I
N OH N

II
OR N O Step II
NaOH/MDC or K2CO3 1eq K2CO3 PhMe 7.4 Vol

S
O

III

N Step III

NH IV Step IV

Pioglitazone

Step I
Med Chem Tosyl group Route Improved 1 eq MsCl Route 1eq TEA, (Feasibilit PhCH3 7 Vol y)

Piperidine/ Ethanol

Pd/H2 , Dioxane

0.72 eq of 1.2 eq of NaBH4 Piperidine, MeOH 0.4eq of DMG 13 times H2O:MeOH:DMF 0.83 eq of 1.2 eq of NaBH4 Piperidine, MeOH 0.4eq of DMG

Improved 1.12 eq MsCl 1.07 eq Route 1.25eq TEA, K2CO3

Synthesis of Efavirenz Analogue (NNRTI)

Original Method:
Cl N O N H O O O N O MgBr Cl

Case Study

Cl N

NH 1

Cl NH

Cl NH O

Cl NH

N H

N H

Synthesis of Efavirenz Analogue (NNRTI)

Optimized Method:
Cl O

Case Study

BCl1 /AlCl1
N NH 1

Cl

Cl

Cl O

Cl N

Cl NH 1

KOCN
NH 1 N H O

Cl N

Cl NH O

Deprotection Resolution
O

Cl NH

N H

Case Study - Process Development of Hexahydrofuro[2,3-b]furan-3-ol moiety

O O

O O O O S H1 N O OHO N Darunavir (TMC-1 1 1) NH

Hexahydrofuro[1 -b]furan-1 ,1 -ol (Bisfuran Alcohol)

O O OO O O S HO O N Brecanavir (GW1 1 1 ) 11 1 NH O N S

OH

H1 N

HO HN O O O O

O N P HN O O O O O

GS-1 1 11

Case Study - Process Development of Hexahydrofuro[2,3-b]furan-3-ol moiety

Reported synthetic route
OH EtO 1 C Br OH OH

LAH LDA
CO1 Et HO CO1 Et

OH

Acetone PTSA
HO

O O

CO1 Et

Oxidation

O O

CSA MeOH
MeO

O OH

O1

O OH MeO O

CSA MeOH

O O

CHO

Enantioselective Synthesis

HO

Problems with enantiomeric purity Scalability

Case Study - Process Development of Hexahydrofuro[2,3-b]furan-3-ol moiety

New Route Development and Process Optimization
O O OH O O O O O O

Process Development
1 Cobaloxime )
O OH O O NaBH 1 O O O O O O

NaBH1 /NaOH
O

Enzymatic Resolution Acetylation (1 )

HO

(1 )

NIS

CH1 1/ 1 Cl C

(1 )

1 NaIO1 ) ) K1 1(OH)1 (1 OsO

(1 )
O HO

AcO

Synthesis and Optical Resolution

Case Study Manufacturing of Sertraline by Pfizer (Treatment for Depression) Sertraline-Active Ingredient in Zoloft
Pfizers Conventional 3 step process Reduced to a Single Step
NMe NHMe NHMe TiCl1 /MeNH1 Tolene/Hexane O OH Cl Cl NMe NHMe NHMe Pd/C, H1 THF Cl Cl Isolated D-Mandelic acid Cl Cl Isolated Cl Sertraline mandelate Cl

MeNH1 EtOH Cl Cl

Pd/CaCO1 EtOH Cl Cl Not Isolated Cl

D-Mandelic acid Cl

Sertraline mandelate Cl Cl

Solvent use reduced from 60,000 to 6,000 gallons per ton of sertraline Eliminated the use of 440 metric tons of titanium dioxide per year

Sertraline Process Solvent Waste/Kg

M ethanol Ethyl acetate Etha nol TH F Hx e ane Toluene M ethylene chloride

1 1L/kg 1 1 L/kg 1 1 L/kg 1 2 L/kg 2 1L/kg Discovery Route 1 Commercial 1 Commercial 1 Commercial Chiral Tetralone st nd rd

Case Study Manufacturing of Sildenafil by Pfizer

Sildenafil useful for the treatment male impotency Old synthetic route is having 10 linear steps Potentially toxic materials in the final reaction Multiple crystalizations are needed to get pure compound Difficulties in Scale up process.
Old Synthetic Route:
O O HO Pr O H1 N O N H N N Pr OEt HN N Pr SO1 Cl Pr O N N OEt HN N Pr N N HNO1 O1 N HO O N N H1 N O N N H1 N SnCl EtOH H1 N O N N O N N N Pr O S O N N O OEt Cl

SOCl1 NH1 OH O1 N Pr

Pr N N

Pr OEt HN

EtO

Commercial/Convergent Route:
O H1 N O1 N N N Pr OEt O OH NaOH/H1 O S O O N SO1 Cl N H1 N Pd-C/H1 H1 N O N N

Case Study Manufacturing of Sildenafil by Pfizer

OEt O Pr OEt O Pr N H H1 N N N O KOBut/tBuOH O S O N N O OEt HN N Pr N N

CDI
OH O S O N N

OEt OH

H O ClSO1 SOCl1

Pd/C & H2 Used for reduction of nitro to amine instead of SnCl/EtOH During Sulfonation, thionyl chloride used to convert sulfonic acid (intermedite) to Sulfonyl chloride Sulfonamide formation was performed in aq. NaOH CDI used in the formation of amide (coupling) instead of Oxalyl chloride

Case Study Manufacturing of Sildenafil by Pfizer

How the amount of waste produced in the manufacture (L of waste/kg of product) has decreased over the past 13 years.
Pyridine Toluene t-Butanol 2-Butanone Ethyl Acetate Ether Methanol Ethanol Acetone Methylene Chloride

1816 L/kg Medicinal Chemistry 1990

139 L/kg Optimized Med. Chemistry 1994

31 L/kg Commercial Route (1997)

10 L/kg Commercial Route following solvent recovery

Case Study Manufacturing of Ibuprofen by BHC in 1961 Ibuprofen (Pain Killer,) discovered
Traditional Synthesis (by Boots) involves 6 steps. And atom utilization is only 40%
O CO1 Et O CHO

AlCl1 1 /Ac O
ClCH1 1 CO Et NaOEt
CHNOH CN

H1 O

CO1 H

Excess AlCl3 is used old process and which gave 20,000 tones of solid waste.

Case Study Manufacturing of Ibuprofen by BHC expire in 1984) BHC Redesigned in 1990 (after patent
Catalytic Synthesis, completed in 3 steps 77% Atom Utilization
O OH CO1 H

HF/Ac1 O

H1 R-Ni

Pd CO

Catalytic amount of Hydrofluoric acid used instead of AlCl3. Catalyst Reused in Next Batch. Acetic acid is by product in first step, was converted to Ac2O (99% of recovered)

Low Cost API Production

"Thanks"