Download Process Chem Talk - San Diego Mesa College

Part I:
Chemical Development in
the Pharmaceutical Industry
Part I Topics
 Overview of Pharmaceutical R&D
Drug Discovery and Drug Development
 What is Chemical Development?
 General Aspects of Chemical Development
Long Road to a New Medicine
Registration
Clinical Data
Analysis
New
Medicine
Full Development
Studies in 100-300
Patients (Phase II)
Candidate Medicine Tested in
3,000-10,000 Patients (Phase III)
Large Amounts of
Candidate Medicine
Synthesized
Extensive
Safety Studies
Studies in Healthy
Volunteers Phase I
Formulations Developed
Exploratory
Development
Project Team and Plans
Idea
Screening
Synthesis of
Compounds
Early Safety Studies
Discovery
Pharmaceutical R&D Process
7,000,000 Compounds
Screened
High risk: $800 million+
N
HO
OH
HO
OH
N
OH OH O
O
O
O
O
O
O
N
O
OH
OH
N N
N N
N
F
O-
N
H
F
O
NH2
O
H2N
Products
CO2H
N
N
N
NHCH3
N
O HN
O
S
O
O2S
N
N
N N
CF3
F
Cl
Cl
Cl
O
Discovery
O
CH3O
O
N
H
Exploratory Development
Full Development
O
NH2
0
Idea
Phase I
Phase II
5
Phase III
10
12 - 15 Years
15
Drug
The Pharmaceutical R&D Process
 Discovery Stage
 Exploratory Development Stage
 Full Development Stage
 Registration
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?
The
Discovery
Phase
The Discovery Stage
 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.
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
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
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.
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.
Exploratory Development - Summary
Large scale organic synthesis
is used to produce the
drug substance
In Phase I clinical studies, the
drug product is tested in humans
to assess safety, and tolerability.
The drug substance is combined with
excipients to produce the formulated
drug product.
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%.
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.
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.”
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
How Large is “Large Scale”?
A Typical Drug Discovery/Development Project Timeline
Discovery / Preclinical Phase
Drug
Candidate
Named
Pre-Lead
Synthesis
(<10 g)
Phase I
IND
submitted
Tox Lot
Synthesis
(100 g – 10 kg)
Phase II
Phase III
Phase IV
NDA
submitted
Generate
Pilot
Demo and
Ph I / II / III
Synthesis Validation Lots
Batches
(1 Metric Ton) (a few MT’s)
(1 – 100’s kg)
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.
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)
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”
Main Objectives of
Chemical Development
1. 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
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
Key Criteria in Chemistry Pathway
Discovery and Optimization
1. Safety
2. Robustness
3. Cost
1. Safety
Process Safety – thermochemical hazards
Compound Safety – biological hazards
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)
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
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
Key Parameters in Process Work Not
Well-Appreciated in Laboratory Scale Research
1. Heat Transport
2. Mass Transport
3. Mixing
4. Polymorphism
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.
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.
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.
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
Sublimation point
Heat capacity
Conductivity
Volume
Density
Color
Morphology
Hygroscopicity
Solubility
Dissolution rate
Chemical stability
An organic compound may exist as many polymorphs!
Allotropism vs. Polymorphism
Allotropism
Polymorphism
Particles involved
Particles combine to form:
Atoms
Molecules or crystals
Molecules
Crystals
Examples of Allotropy:
Carbon – diamond, graphite and buckminsterfullerene
Tin – grey and white forms (Napolean’s Buttons)
Allotropes of Tin and
Napolean’s Buttons
White Tin
(metallic and malleable)
“tetragonal”
56 oF
Gray Tin
(Powdery and brittle)
“cubic”
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/
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.
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
HIV Protease Inhibitors
S
Ph
N
H
O
S
OH
O
N
H
N
N
N
N
O
CH3
H
O
Ph
Ritonavir (Abbott Labs) – the “Disappearing Polymorph”
Ph
S
O
NHtBu
O
HO
N
N
H
H
OH
H
Nelfinavir (Agouron Pharmaceuticals)
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
Returning to our main topic……
What is the bottom-line purpose
of Chemical Development
in the pharmaceutical and related industries?
In the end, it all comes down to money……
- Process chemical yields
- Process Safety
- Time required for synthesis
- Atom economy
- Effort required
- Environmental factors
- Equipment required
- Process reliability
These factors have a direct effect on the cost of drugs.
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.
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
Questions?????
Kim Albizati
Chief Scientific Officer
Strategic Enzyme Applications, Inc.
10420 Wateridge Circle
San Diego, CA 92121
858 518-9831
[email protected]
Chemical Development vs. Medicinal Chemistry
Chemical Development
Medicinal Chemistry
- primary interest is obtaining information
- primary interest is obtaining compounds
- main synthetic goal is to design the most
efficient pathway to a single compound
- main synthetic goal is to design a flexible
pathway to a large number of
structurally similar compounds
- optimize strategy, tactics and execution
of a synthesis
- optimize # of similar compounds accessible
from a synthesis route
- knowledge of mechanistic principles and
chemical reactivity are important
- knowledge of organic structure and
biochemistry are important
- generally engaged in problem solving in
organic synthetic chemistry
- generally engaged in problem solving in
“drug design”