Part I: Chemical Development in the Pharmaceutical Industry

1. Part I: Chemical Development in the Pharmaceutical Industry

2. Part I Topics • Overview of Pharmaceutical R&D • Drug Discovery and Drug Development • What is Chemical Development? • General Aspects of Chemical Development

3. Synthesis of Compounds Long Road to a New Medicine Registration Clinical Data Analysis New Medicine Full Development Candidate Medicine Tested in 3,000-10,000 Patients (Phase III) Studies in 100-300 Patients (Phase II) Large Amounts of Candidate Medicine Synthesized ExtensiveSafety Studies Studies in Healthy Volunteers Phase I Exploratory Development Formulations Developed Screening Project Team and Plans Early Safety Studies Discovery Idea

4. Pharmaceutical R&D Process 7,000,000 Compounds Screened High risk: $800 million+ Preclinical Pharmacology Clinical Pharmacology & Safety Preclinical Safety Products Exploratory Development Full Development Discovery Phase I Phase II Phase III 0 15 5 10 Drug Idea 12 - 15 Years

5. The Pharmaceutical R&D Process • Discovery Stage • Exploratory Development Stage • Full Development Stage • Registration

6. The Discovery Stage It all starts with an Idea to address a disease through an associated Therapeutic Target. Example – perhaps we can find a treatment for HIV-infected individuals if we could inhibit an enzyme which is crucial for replication of the virus. This leads to some questions…….. • Can we design and chemically synthesize a small organic molecule (i.e., a drug) which can fit into the active site of the enzyme and inhibit its function? • Can we find a way to administer this drug to humans? • Is the drug safe for humans to take? • Does the drug have the desired effect on a person’s health condition?

7. The Discovery Stage The Discovery Phase • The main goal of the Discovery Stage is to identify a single discrete organic molecule as a good candidate to become an effective, marketable drug. • The Discovery Stage can take up to 7 years, but rarely takes less than 3 years. • The candidate compound then passes into the Exploratory Development Stage where the potential of that drug candidate to become a drug is evaluated.

8. The Exploratory Development Stage • Consists of Three Phases • Preclinical Phase - animal testing • Toxicity • Phase I - initial testing in healthy humans • Toxicity • Phase II - testing in humans with the disease • Toxicity • Establish dosing parameters • Initial indications of efficacy

9. The Exploratory Development Stage The drug candidate will be given to a variety of animals and to a large number of human subjects Therefore, the need for much larger quantities of the drug becomes acute. The drug must be chemically synthesized, usually in multi-kilogram amounts and the drug purity must be very high -- generally > 95%. • Such large scale synthesis activities requires expertise in: • synthetic organic chemistry • chemical engineering • analytical chemistry

10. Exploratory Development Stage Once prepared, the drug substance must be formulated, i.e., prepared in such a way that it can easily enter living tissue and make its way to the site(s) of drug action. • This generally requires that the drug substance be combined with other organic and • inorganic compounds (called excipients) which are used to: • Control the release of the drug substance in the human body • Improve the assimilation process and bioavailability • Enhance drug dissolution • Extend the stability and shelf life of the drug substance • Aid in the manufacturing process (e.g., production of tablets and capsules) • Mask an unpleasant taste Once formulated the drug substance is called the drug product.

11. Exploratory Development Stage Common Excipients Magnesium stearate Lactose Starch Talc Sucrose Silicon dioxide Titanium dioxide Calcium phosphate Ethylcellulose Gelatin Example: Prozac (an antidepressant drug) is formulated with starch, gelatin, silicone, titanium dioxide and iron oxide, among other excipients. Once it has been formulated, the drug product is ready for administration to animals and humans.

12. Exploratory Development - Summary Large scale organic synthesis is used to produce the drug substance The drug substance is combined with excipients to produce the formulated drug product. In Phase I clinical studies, the drug product is tested in humans to assess safety, and tolerability. The drug product is toxicity-tested in animals for safety. In Phase II clinical studies, the drug product is tested in humans to determine the dose range and to collect information on efficacy. Success rates in Exploratory Development are low -- around 10 - 25%.

13. The Full Development Stage A drug candidate moves into Full Development after enough information has been gathered which gives a strong indication that the candidate will be successful in treating the disease. Phase III clinical studies in humans are then conducted to confirm the efficacy of the drug in a large population of patients. Many more activities must go on at this time to prepare to “launch” the drug.

14. Pre-Launch Activities Drug Substance – a large scale, inexpensive and robust manufacturing process for the drug substance must be developed. Drug Product – a large scale, inexpensive and robust formulation process for the drug product must be developed. The Key Terms here are “Large Scale” and “Process.”

15. What is a “Process”? Process – a sequence of actions; in organic synthesis, those actions taken in performing a chemical reaction or series of chemical reactions; may refer to a synthesis composed of several steps Another term you may run into: API – active pharmaceutical ingredient; another term for the drug substance

16. How Large is “Large Scale”? A Typical Drug Discovery/Development Project Timeline Discovery / Preclinical Phase Phase I Phase II Phase III Phase IV Drug Candidate Named IND submitted NDA submitted Pre-Lead Synthesis (<10 g) Tox Lot Synthesis (100 g – 10 kg) Generate Ph I / II / III Batches (1 – 100’s kg) Pilot Synthesis (1 Metric Ton) Demo and Validation Lots (a few MT’s) Full Scale Manufacturing (Many MT’s) • Time from Drug Candidate to IND is 12 – 18 months - gating item is drug synthesis. • Time from Drug Candidate to NDA approval varies by therapeutic area but > 5 years. • Drug Candidate success rates vary, but 1 in 25 is typical.

17. Drug Discovery and Development - Summary Drug Discovery - the process of designing, synthesizing and demonstrating the potential of molecules as drug candidates. (Medicinal Chemistry) Drug Development - the process of making drug candidates available in large quantities by organic synthesis for purposes of further evaluation and eventual marketing. (Chemical Development)

18. What is Chemical Development? Chemistry activities required to bring a drug candidate from the discovery phase to the marketplace - Synthetic organic chemistry - Analytical Chemistry - Chemical Engineering A subset of Chemical Development is called “Process Chemistry”

19. Main Objectives ofChemical Development • THE OPTIMIZATION OF THE CHEMICAL SYNTHESIS • OF DRUG CANDIDATES IN ORDER TO INCREASE • THEIR SUPPLY AND TO MINIMIZE THEIR • COST OF PRODUCTION • 2. ENSURING THAT THE DRUG SUBSTANCE CAN BE • MADE REPRODUCIBLY AND IN HIGH PURITY DESIRED RESULT : PRODUCE THE DRUG SUBSTANCE IN THE MOST COST EFFECTIVE MANNER POSSIBLE INCREASED PROFITS

20. Process Chemistry - the discovery, optimization and scaleup of the most efficient synthetic pathway (i.e., a process) to a drug substance pathway discovery - How to synthesize the drug substance from inexpensive starting materials pathway optimization - How to get the best chemical yields along the pathway and minimize costs and waste efficiency - defined in terms of all cost parameters, including cost of materials, equipment and labor

21. Key Criteria in Chemistry Pathway Discovery and Optimization • Safety • Robustness • Cost

22. 1. Safety Process Safety – thermochemical hazards Compound Safety – biological hazards

23. 2. Robustness Reproducibility – chemistry/process must work the same way EVERY TIME • Purity (or impurity) profiles must fall within a very narrow range • or the drug is not usable – strictly defined by a compound’s • specifications as developed under FDA guidelines • Promoted by consistently following a set of procedures known • in the industry as Good Manufacturing Practices (GMP)

24. 3. Cost • Essentially, the fully-burdened cost of the • manufacture of the compound. • Elements include prices of: • all chemicals and solvent • all labor utilized • all energy costs • all disposal services • tax issues? A Process Chemist seeks the Optimum Synthetic Pathway

25. Optimum Synthesis - The best or most efficient synthesis in terms of all cost parameters Note : an optimum is defined by a point in time Corollary A - ANYTHING can be made / performed better Corollary B - It is not our job to be satisfied

26. Key Parameters in Process Work Not Well-Appreciated in Laboratory Scale Research • Heat Transport • Mass Transport • Mixing • Polymorphism

27. Heat Transport In a brisk wind, does a gnat cool off faster than an elephant? • Heating and cooling a chemical reaction is primarily a surface phenomenon. • As a reaction vessel becomes larger the surface area : volume • ratio decreases. • Therefore, heating and cooling rates must be carefully • studied reaction parameters.

28. Mass Transport Can you move a gnat from point A to point B faster than you can move an elephant? • In most chemical reactions you are physically combining (adding, mixing) one discrete chemical to another to cause a chemical reaction to occur. • It takes longer to combine (add) 100 liters of one chemical to a reaction mixture than it does to add 1 mL to a smaller reaction mixture • Therefore, addition rates must also be carefully studied reaction parameters.

29. Mixing • It may be hard to believe, but hand stirring and magnetic stirring • are incredibly inefficient ways to mix reactants. • Large scale chemistry uses impellers which may spin at several hundred RPM. • Mixing is even more important in heterogeneous reactions. • This is yet another factor, taken for granted at the lab scale, which must be carefully studied at large scale.

30. Polymorphs and Polymorphism “a polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state” Different polymorphs of a given compound have different physical properties: MP Color Sublimation point Morphology Heat capacity Hygroscopicity Conductivity Solubility Volume Dissolution rate Density Chemical stability An organic compound may exist as many polymorphs!

31. Allotropism vs. Polymorphism Particles involved Atoms Molecules Particles combine to form: Molecules or crystals Crystals Allotropism Polymorphism Examples of Allotropy: Carbon – diamond, graphite and buckminsterfullerene Tin – grey and white forms (Napolean’s Buttons)

32. Allotropes of Tin andNapolean’s Buttons White Tin (metallic and malleable) Gray Tin (Powdery and brittle) 56 oF “cubic” “tetragonal”

33. How are polymorphs detected and measured? Powder x-ray diffraction Single Crystal x-ray diffraction Differential scanning calorimetry (DSC) Solid state IR and NMR Raman Spectroscopy Microscopy Melting point Polymorphism in Chocolate (cocoa butter): http://hypertextbook.com/physics/matter/polymorphs/

34. Why is polymorphism important in the production of pharmaceuticals? • Interconversion among polymorphs can occur during: crystallization processes physical handling (milling, grinding and tabletting) • Solubility and dissolution rate affect a drugs’ bioavailability In general, in a series of polymorphs of a compound, the polymorph with the lowest melting point is the most thermodynamically stable.

35. What factors are important in polymorphism? • Hydrogen bonding ability • Presence of solvents • Degree of rigidity or floppiness of a molecule How widespread is polymorphism? • Estimated to be at least 50% • Some people believe that “….most organic compounds, when • studied carefully, exist in more than one crystalline form.” • - J.W. Mullin in Crystallization (4th Edition) • Oxford Univ. Press. 2001

36. HIV Protease Inhibitors Ritonavir (Abbott Labs) – the “Disappearing Polymorph” Nelfinavir (Agouron Pharmaceuticals)

37. Polymorphism - Summary • Polymorphism in organic compounds is: • Unpredictable • Easy to detect, given the right equipment • Critically important to the pharmaceutical industry • Not well appreciated by graduating chemistry students

38. Returning to our main topic…… What is the bottom-line purpose of Chemical Development in the pharmaceutical and related industries?

39. In the end, it all comes down to money…… - Process chemical yields - Time required for synthesis - Effort required - Equipment required - Process Safety - Atom economy - Environmental factors - Process reliability These factors have a direct effect on the cost of drugs.

40. The Bottom Line Process Chemistry is closer to what the average Synthesis Jock does as a graduate student than is Medicinal Chemistry. So…….. If you are more interested in the biological side of organic chemistry, you will probably enjoy Medicinal Chemistry. If you are more interested in the strategies, mechanisms and design of organic reactions, you will probably enjoy Process Chemistry.

41. Bibliography Bert Spilker “Multinational Drug Companies”, Raven Press, 1989, ISBN 0-88167-463-X Rick Ng “Drugs: From Discovery to Approval”, John Wiley and Sons, 2004, ISBN 0-471-60150-0 Bert Spilker and Pedro Cuatrecasas “Inside the Drug Industry”, Prous Science, 1990, ISBN 84-86973-22-8 “The WetFeet Insider Guide to Careers in Biotech and Pharmaceuticals”, WetFeet Inc., 2003, ISBN 1-58207-316-3

42. Questions?????

43. Kim Albizati Chief Scientific Officer Strategic Enzyme Applications, Inc. 10420 Wateridge Circle San Diego, CA 92121 858 518-9831 kalbizati@stratbiocat.com

45. Chemical Development vs. Medicinal Chemistry Chemical Development - primary interest is obtaining information - main synthetic goal is to design the most efficient pathway to a single compound - optimize strategy, tactics and execution of a synthesis - knowledge of mechanistic principles and chemical reactivity are important - generally engaged in problem solving in organic synthetic chemistry Medicinal Chemistry - primary interest is obtaining compounds - main synthetic goal is to design a flexible pathway to a large number of structurally similar compounds - optimize # of similar compounds accessible from a synthesis route - knowledge of organic structure and biochemistry are important - generally engaged in problem solving in “drug design”