Process Chemistry Techniques In Active Pharmaceutical Ingredient Development And Commercialization : Process Chemistry Techniques In Active Pharmaceutical Ingredient Development And Commercialization DR ANTHONY M CRASTO (Ph.D)
29th DEC 2011
“A SHORT PRESENTATION” Overview : What is Process Research ?
Its 12 Principles
Case Studies- Remoxipride and chiral piperazine
Lesson Learned: “Unlocking the Potential of Process Innovation” Overview Slide 3: 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 Effects Phase III1,000–5,000 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 Testing
Laboratory and Animal Testing Discovery
(2–10 Years) Years New Product Development – A Risky and Expensive Proposition Approved by the FDA What is Process Research ? : 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) What is Process Research ? Definitions--Process Research : 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 Definitions--Process Research Laboratory Scientist-at the bench : Laboratory Scientist-at the bench 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 Elaboration on objectives : Elaboration on objectives To try the process on a model of proposed plant before committing large sum of money on a production unit.
Examination of the formula to determine it’s ability to withstand Batch-scale and process modification.
Evaluation and Validation for process and equipments
To identify the critical features of the process. Guidelines for production and process controls.
To provide master manufacturing formula with instructions for manufacturing procedure.
To avoid the scale-up problems. Personnel requirements : 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 Personnel requirements What is Process Research ? : “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) What is Process Research ? What is Process Research ? : An amalgam of:
Modern synthetic organic methodology
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
Purification/Isolation technologies What is Process Research ? What is Process Research ? : Chemical Engineering principles: mixing, heat transfer, vessel configuration
Practical Process Aspects:
Ruggedness What is Process Research ? GMP CONSIDERATIONS : Equipment qualification
Regularly schedule preventative maintenance
Regularly process review & revalidation
Relevant written standard operating procedures
The use of competent technically qualified personnel GMP CONSIDERATIONS CONTD……… : 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 CONTD……… Process Research: Customers : Process Research: Customers Process Research: Customers : Process Research: Customers responsible for developing In-process
assay and critical evaluation of
drug substance and intermediates Process Research: Customers : Process Research: Customers responsible for toxicity studies:
(carcinogen, teratogen, gene toxicity) Process Research: Customers : Process Research: Customers responsible for formulating
drug substance (API) into
drug product Process Research: Customers : Process Research: Customers Oversee process transfer into
Pilot plants Process Research: Customers : Process Research: Customers Conducts clinical trials
(Ph I-III) and evaluates data Process Research: Customers : Process Research: Customers Discovers new chemical
entities (NCE’s) and
prepares intitial quantities Other Customers : 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 Other Customers 12 Principles of Process Chemistry : 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 12 Principles of Process Chemistry 12 Principles of Process Chemistry : 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) 12 Principles of Process Chemistry 12 Principles of Process Chemistry : 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
eg: plant-derived RM; microbial reactions 12 Principles of Process Chemistry 12 Principles of Process Chemistry : 9. Minimize Derivatization:
Avoid the use of protecting groups when possible as it add steps, requires extra reagents and generates more waste.
Use of catalytic reagents is far superior than stoichiometric amounts
Example: using air as a source of oxygen for oxidation reaction 12 Principles of Process Chemistry 12 Principles of Green Chemistry : 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) 12 Principles of Green Chemistry Process Economics : Process Economics- Minimize inventory cost of API via:
Low cost RM
Short time cycles
Few Vessels Process Economics Case Studies from Literature : Remoxipride-----schizophrenia
2-Synthesis of Pyrazine Carboxamide a CHIRAL PIPERAZINE –Ingredient of antivirals , ie virs Case Studies from Literature Case Study 1: Remoxipride : Case Study 1: Remoxipride Selective Dopamine-2 Antagonist
Indication: Anti-psychotic (Depression/Schizophrenia)
Clinical Trials: halted in 1993 due to anemia side-effects Original Bromination : Original Bromination Improved Bromination : Improved Bromination Other Examples : Other Examples Auerbach, Weissman Tet Letters 1993, 931 Useful Methodology : Useful Methodology CASE STUDY 2-Synthesis of Pyrazine Carboxamide : CASE STUDY 2-Synthesis of Pyrazine Carboxamide 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 Improved Route to Pyrazine Carboxamide : Improved Route to Pyrazine Carboxamide Atom Economy Comparison : Atom Economy Comparison A: 179/[124+127+73+73] = 45 %
B: 179/[105 + 98 +74 +18] = 61% Chiral Piperazine via Resolution/Racemization : Chiral Piperazine via Resolution/Racemization Industry Challenges : Increased Regulatory controls (FDA, EPA)
Downward Pricing Pressure
Greater Competition in treatment options
More complex molecules
Dwindling # of diseases to conquer Industry Challenges Lessons Learned : 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” Lessons Learned Lessons Learned : “A firm that can develop sophisticated process technologies more rapidly and with fewer development resources has strategic options that less capable competitors lack” Lessons Learned Further Reading : 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 Further Reading END : THANKS END