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 …is based on the idea that…
“whatever's wrong with you, there's a patented chemical
pill that can make it better”

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Pharmaceutical industry…

DEVELOPS

PRODUCES LICENSED

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TRENDS AND
Pipeline Risks
FORCES
Generic Drugs: stiff competition

Political pressures: pricing/licensing

Dependence on health insurance

Litigation risk

Future Growth Strategies

TERMS
Clinical Trials ●
Human studies designed to distinguish a drug’s effect from other influences.

Dose ●
The amount of drug administered to a patient or test subject at a single time.

Drug Products The finished dosage form that contains a drug substance – generally but not necessarily in
●

association with other active or inactive ingredients.

Drug Substance The active ingredient to diagnose, treat, cure, or prevent disease or affect the structure or
●

function of the body.

IND Investigational New Drug, An application that a drug sponsor must submit to the FDA before
●

beginning tests of a new drug on humans.

New Drug A drug first investigated or proposed for marketing after 1938 – that is, a drug that was not
●

generally recognized as safe and effective.

Pharmacology ●
The science that deals with the effect of drugs on living organisms.

Priority Drugs ●
A drug that appears to represent an advance over available therapy.

Side Effect Any effect other than the primary intended effect resulting from drug or non-drug treatment or
●

intervention.

Stability ●
The drug products resistance to change of its physical and chemical properties
Industry Operating
Procedures
Drug companies rely on the strength of their patents whether on the
chemical or process involved in bringing the product to the market. 
Clinical trial information that is generated on the safety and effectiveness
of a product is also submitted to approving authorities in foreign countries
to ensure statistically valid results are observed.

Marketing is another area of strength for many companies.  Detail

men, as they are called in the business, visit doctors to detail the benefits
of the company’s products and encourage the medical staff to prescribe
them to their patients.  Companies tend to specialize in specific
therapeutic areas such as central nervous system (cns), gastrointestinal,
etc. making it easier to level their sales force often striking deals to co-
market products for other companies. 
Government Regulatory
Requirements
The Food and Drug Administration makes or breaks this industry’s
potential for sales.  The FDA must give approval to market the product in
the U.S.

A drug company, in order to get marketing approval for a drug, must

show it is safe for human consumption through animal and human
testing. 

A drug company must also prove it is effective for the illness it intends to
alleviate.  The FDA does not mandate a particular methodology.  The
scientific community has established a four Phase method for
establishing the effectiveness.
 Investigational New Drug
Animal and Toxicity Studies Application

Phase I Phase II

Phase III

Phase IV

Post approval marketing Large scale trials

testing
PROCESSES INVOLVED IN
PHARMACEUTICAL
INDUSTRY
Separation Processes
Comminution

Decantation

Colation

Centrifugation

Precipitation

Filtration
Chemical Conversion Processes
Alkylation
Carboxylation and Acetylation
Condensation and Cyclization
Dehydration
• Phenobarbital USP
• Barbital
• Procaine Hydrochloride
USP
• Codeine NF and
Codeine Phosphate
USP
• Cimetidine
• Salicylic Acid and
Derivatives USP
• Acetaminophen
• Diazepam USP
• Hexylresorcinol USP
• Phenolphthalein NE
• Piperazine Citrate USP
• Thiamine and
Hydrochloride USP
• Riboflavin USP
• Ether USP
PHARMACEUTICAL
PRODUCTS
ANTIBIOTICS
“a substance produced by microorganisms, which has the
capacity of inhibiting the growth and even destroying other
microorganisms by the action of very small amounts of
antibiotics

- by Walksman

PENICILLIN

ERYTHROMYCIN

STREPTOMYCIN

CEPHALOSPORINS
PENICILLIN

- derived from Penicillium fungi

- first drugs that were effective against many previously

serious diseases such as syphilis and Staphylococcus
infections

- "penicillin" refers to the mixture of substances that are

naturally, and organically, produced
ERYTHROMYCIN

…like penicillin, also isolated by solvent-extraction methods.

It is organic base, and extractable with amyl acetate or other

organic solvents under basic conditions rather than the acidic
ones.
STREPTOMYCIN

The commercial method for producing this compound is

aerobic submerged fermentation.

The structure of streptomycin indicates its highly hydrophilic

nature, and it cannot be extracted by normal solvent procedures.
CEPHALOSPORINS

Cephalosporins were marketed when penicillin-fast organism

became prevalent.

Later, chemically modified cephalosporins were developed to

broaden the scope of their use and to be used where the originals
were losing their effectiveness.
 PRODUCTION AND
ISOLATION OF PENICILLIN,
ERYTHOMYCIN, AND
STREPTOMYCIN
BIOLOGICALS
“Biologic product means any virus, therapeutic serum, toxin,
antitoxin, or analogous product applicable to the prevention,
treatment, or cure of diseases or injuries to man.”

They arise from the action of microorganisms, and they are used
for prophylaxis, treatment, and diagnosis of infections and allergic
diseases.

Their significance greatly increased with the introduction of Salk

and Asian flu vaccines, followed by the oral vaccines for
poliomyelitis and the various types of measles vaccines.
STEROID HORMONES
“Steroids are used particularly in rheumatic diseases, in
inflammatory conditions of the skin, and in allergic conditions.”

Other uses are in menstrual irregularities, menopause, and control

of fertility and conception.

There are many other indications for the use of steroids in

medicine: in renal and cardiovascular diseases, in types of cancer,
and in various types of stress reactions.
VITAMINS
Vitamins are substances that the body needs to grow and develop
normally.

There are 13 vitamins the body needs. They are vitamins A, C, D, E,

K and the B vitamins (thiamine, riboflavin, niacin, pantothenic
acid, biotin, vitamin B-6, vitamin B-12 and folate).
Top 12 Pharmaceutical Companies
Johnson &
Johnson

Pfizer

Roche

GlaxoSmithKl
ine

Novartis

Sanofi-
Aventis

AstraZeneca

Abbott
Laboratories

Merck & Co.

Bayer
HealthCare

Eli Lilly

Bistol-Myers
Squibb
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

Modern medicine and the pharmaceutical industry both believe

there is no limit to how many prescription medications you can
simultaneously take.

If you have ten health problems, they've got ten different pills for
you.

And when those pills cause twenty different dangerous side

effects, they're ready for twenty more prescriptions for you to
dutifully swallow.
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

This idea that health is achieved by taking prescription chemicals

is ludicrous from the start.

And yet it's the foundation of the pharmaceutical industry.

Take as many pills as you "need", they insist. Don’t worry:

They’re all FDA approved!
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

This is akin to believing that if it's safe to drive 65mph

in a truck, and it's also safe to drive 65mph on a
motorcycle, then if you load your motorcycle onto the
truck, it's now safe to drive 130mph.

HOW TRUE?
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

Pharmaceuticals have NEVER been tested in

combination with other drugs.

So all the so-called "gold standard science" is

absolutely worthless at knowing what might happen
when half a dozen pharmaceutical drugs are
combined in a patient's body.
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

Despite the fact that no combination testing has ever

been done on pharmaceuticals, they are regularly
prescribed in combination.

Obviously, this creates a whole new realm of

UNKNOWN RISK based on the way multiple
drugs might chemically interact in the human body.
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

The more pharmaceuticals you take…

THE MORE DANGEROUS THEY BECOME

While one pharmaceutical chemical may at first seem
harmless (even though just one drug can actually kill you),
when you start adding a second, third, fourth and fifth
prescription on top of that, you're dealing with Acute
Pharmaceutical Toxicity (APT) that's never even been tested in
clinical trials.
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

Pharmacists are trained to help people avoid the most toxic

two-drug combinations, but they rarely have any real
knowledge about what happens when you combine three, four,
five or more drugs.

NO ONE DOES.
The science has simply never been done on that question. It's
no wonder: With all the possible combinations and
permutations of pharmaceutical toxicity, it would take literally
trillions of clinical trials to test them all.
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

So this whole idea that you can take a drug to treat one
problem, then take a second drug to treat a second problem,
and a third to treat a third problem... this entire approach to
health care, upon which modern medicine is largely based, is
flawed from the start.
In clinical trials, patients are tested for one drug at a time.

Never five

or six

or ten.
THE FATAL FLAW IN THE THEOTY
BEHIND PHARMACEUTICALS

Just because one drug in isolation seems "safe" in one trial in

NO WAY means…
it's going to be safe when combined with
half a dozen other toxic chemicals taken
by the patient at the same time.
MANUFACTURE
OF INSULIN
Getting to know… INSULIN
It is a hormone that regulates the amount of glucose (sugar) in the
blood and is required for the body to function normally.

Insulin is produced by cells in the pancreas, called the islets of

Langerhans. These cells continuously release a small amount of
insulin into the body, but they release surges of the hormone in
response to a rise in the blood glucose level.

Insulin allows the blood glucose to be transported from the blood

into the cells. Cells have an outer wall, called a membrane that
controls what enters and exits the cell.

Insulin binds to receptors on the cell's membrane. This activates a

set of transport molecules so that glucose and proteins can enter
the cell. The cells can then use the glucose as energy to carry out
its functions
WHAT IS INSULIN?
Without insulin, the blood glucose builds up in the blood and the
cells are starved of their energy source.

The cells will begin to use fat, the energy source stored for
emergencies.

When this happens for too long a time the body produces ketones,
chemicals produced by the liver.

Ketones can poison and kill cells if they build up in the body over
an extended period of time.

This can lead to serious illness and coma.

WHAT IS INSULIN?
Without insulin, the blood glucose builds up in the blood and the
cells are starved of their energy source.

The cells will begin to use fat, the energy source stored for
emergencies.

When this happens for too long a time the body produces ketones,
chemicals produced by the liver.

Ketones can poison and kill cells if they build up in the body over
an extended period of time.

This can lead to serious illness and coma.

People who do not produce the necessary amount of insulin have

diabetes.
FROM SCRATCH
RAW MATERIALS AND EQUIPMENTS
Common bacteria:
Escherichia coli
(yeast is also used)

Amino-acid Sequencing Machine

Large Tanks
Centrifuge
Chromatography And X-ray Crystallography Instruments
 A GLIMPSE OF EVERYTHING…
• Human insulin is grown in the lab inside common bacteria. Escherichia coli
is by far the most widely used type of bacterium, but yeast is also used.
• Researchers need the human protein that produces insulin.
• Manufacturers get this through an amino-acid sequencing machine that
synthesizes the DNA. Manufacturers know the exact order of insulin's
amino acids (the nitrogen-based molecules that line up to make up
proteins). There are 20 common amino acids.
• Manufacturers input insulin's amino acids, and the sequencing machine
connects the amino acids together.
• Also necessary to synthesize insulin are large tanks to grow the bacteria,
and nutrients are needed for the bacteria to grow.
• Several instruments are necessary to separate and purify the DNA such as
a centrifuge, along with various chromatography and x-ray crystallography
instruments.
THE MANUFACTURING
PROCESS
WORKING WITH HUMAN INSULIN…
The insulin gene is a protein consisting of two separate chains of
amino acids, an A above a B chain, that are held together with
bonds. Amino acids are the basic units that build all proteins. The
insulin A chain consists of 21 amino acids and the B chain has 30.
WORKING WITH HUMAN INSULIN…
Before becoming an active insulin protein, insulin is first
produced as preproinsulin. This is one single long protein chain
with the A and B chains not yet separated, a section in the middle
linking the chains together and a signal sequence at one end telling
the protein when to start secreting outside the cell.

After preproinsulin, the chain evolves into proinsulin, still a

single chain but without the signaling sequence. Then comes the
active protein insulin, the protein without the section linking the A
and B chains. At each step, the protein needs specific enzymes
(proteins that carry out chemical reactions) to produce the next form
of insulin.
STARTING WITH A AND B
One method of manufacturing
insulin is to grow the two insulin
chains separately.

This will avoid manufacturing

each of the specific enzymes
needed.

Manufacturers need the two

mini-genes: one that produces
the A chain and one for the B
chain.

Since the exact DNA sequence

of each chain is known, they
synthesize each mini-gene's
DNA in an amino acid
sequencing machine
STARTING WITH A AND B
These two DNA
molecules are then
inserted into plasmids,
small circular pieces of
DNA that are more
readily taken up by the
host's DNA.

Manufacturers first insert the plasmids into a non-harmful type of the

bacterium E. coli. They insert it next to the lacZ gene. LacZ encodes for 8-
galactosidase, a gene widely used in recombinant DNA procedures
because it is easy to find and cut, allowing the insulin to be readily removed
so that it does not get lost in the bacterium's DNA. Next to this gene is the
amino acid methionine, which starts the protein formation.
STARTING WITH A AND B
The recombinant, newly formed, plasmids are mixed up with the bacterial
cells. Plasmids enter the bacteria in a process called transfection.

Manufacturers can add to the cells DNA ligase, an enzyme that acts like glue
to help the plasmid stick to the bacterium's DNA.
STARTING WITH A AND B

The bacteria synthesizing the insulin then undergo a fermentation

process.

They are grown at optimal temperatures in large tanks in manufacturing

plants.

The millions of bacteria replicate roughly every 20 minutes through cell

mitosis, and each expresses the insulin gene.
 STARTING WITH A AND B
After multiplying, the cells are taken out of the tanks and broken open to extract the
DNA.
One common way this is done is by first adding a mixture of lysozome that digest
the outer layer of the cell wall, then adding a detergent mixture that separates the fatty
cell wall membrane.
The bacterium's DNA is then treated with cyanogen bromide, a reagent that splits
protein chains at the methionine residues. This separates the insulin chains from the rest
of the DNA.
STARTING WITH A AND B
The two chains are then mixed
together and joined by disulfide
bonds through the reduction-
reoxidation reaction.

An oxidizing agent (a material that

causes oxidization or the transfer of
an electron) is added.

The batch is then placed in a

centrifuge, a mechanical device that
spins quickly to separate cell
components by size and density.
The DNA mixture is then purified so
that only the insulin chains remain.
PROINSULIN PROCESS
Starting in 1986, manufacturers began to use another method to
synthesize human insulin.

They started with the direct precursor to the insulin gene, proinsulin.

Many of the steps are the same as when producing insulin with the A and B
chains, except in this method the amino acid machine synthesizes the
proinsulin gene.

The sequence that codes for proinsulin is inserted into the non-pathogenic
E. coli bacteria.

The bacteria go through the fermentation process where it reproduces and

produces proinsulin.

Then the connecting sequence between the A and B chains is spliced away
with an enzyme and the resulting insulin is purified.
PROINSULIN PROCESS
At the end of the manufacturing process ingredients are added to insulin to
prevent bacteria and help maintain a neutral balance between acids and
bases.

Ingredients are also added to intermediate and long-acting insulin to

produce the desired duration type of insulin. This is the traditional method
of producing longer-acting insulin.

Manufacturers add ingredients to the purified insulin that prolong their

actions, such as zinc oxide.

These additives delay absorption in the body. Additives vary among

different brands of the same type of insulin.
TRADITIONAL
PROCESS
Insulin is isolated from the
pancreas of beef and hogs
and was one of the first
proteins to be obtained in
crystalline form.
 Refrigerated at -20°C

treat w/ ethyl alcohol

Extracted with acidulated alcohol

 neutralized with
ammonia

removes alcohol
concentrated
extract
ANALOG INSULIN
In the mid 1990s, researchers began to improve the way human insulin
works in the body by changing its amino acid sequence and creating an
analog, a chemical substance that mimics another substance well enough
that it fools the cell.

Analog insulin clumps less and disperses more readily into the blood,
allowing the insulin to start working in the body minutes after an injection.
There are several different analog insulin.

Humulin insulin does not have strong bonds with other insulin and thus, is
absorbed quickly.

Another insulin analog, called Glargine, changes the chemical structure of

the protein to make it have a relatively constant release over 24 hours with
no pronounced peaks.
ANALOG INSULIN
Instead of synthesizing the exact DNA sequence for insulin, manufacturers
synthesize an insulin gene where the sequence is slightly altered.

The change causes the resulting proteins to repel each other, which
causes less clumping.

Using this changed DNA sequence, the manufacturing process is similar to

the recombinant DNA process described.
QUALITY CONTROL
 After synthesizing the human insulin, the structure and purity of the
insulin batches are tested through several different methods.

High performance liquid chromatography is used to determine if there

are any impurities in the insulin.

Other separation techniques, such as X-ray crystallography, gel

filtration, and amino acid sequencing, are also performed.

Manufacturers also test the vial's packaging to ensure it is sealed

properly.

Manufacturing for human insulin must comply with National Institutes

of Health procedures for large-scale operations. The United States
Food and Drug Administration must approve all manufactured insulin.
THE FUTURE
 Since insulin was first synthesized, diabetics needed to regularly
inject the liquid insulin with a syringe directly into their bloodstream.
This allows the insulin to enter the blood immediately.

For many years it was the only way known to move the intact
insulin protein into the body.
 The insulin
insulin
pump pumpallows a controlled release in the body. This is
a computerized pump, about the size of a beeper, that diabetics can wear
on their belt or in their pocket. The pump has a small flexible tube that is
inserted just under the surface of the diabetic's skin. The diabetic sets the
pump to deliver a steady, measured dose of insulin throughout the day,
increasing the amount right before eating. Researchers are exploring the
possibility of implantable insulin pumps. Diabetics would control these
devices through an external remote control.

Researchers are exploring other drug-delivery options. Ingesting insulin

through pills ispills
one possibility. The challenge with edible insulin is that the
stomach's high acidic environment destroys the protein before it can move
into the blood. Researchers are working on coating insulin with plastic the
width of a few human hairs. The coverings would protect the drugs from the
stomach's acid.
 Last 2001 promising tests are occurring on inhaled
inhaled insulin
devices and manufacturers could begin producing the products within
the next few years. Since insulin is a relatively large protein, it does not
permeate into the lungs. Researchers of inhaled insulin are working to
create insulin particles that are small enough to reach the deep lung. The
particles can then pass into the bloodstream. Researchers are testing
several inhalation devices much like that of an asthma inhaler.

Another form of aerosol device undergoing tests will administer insulin

to the inner cheek. Known as buccal (cheek) buccal insulin
(cheek), diabetics
insulin will
spray the insulin onto the inside of their cheek. It is then absorbed through
the inner cheek wall.

Insulin
Insulin patchesare
patches another drug delivery system in
development. Patches would release insulin continuously into the
bloodstream. Users would pull a tab on the patch to release more insulin
before meals. The challenge is finding a way to have insulin pass through
the skin. Ultrasound is one method researchers are investigating. These low
frequency sound waves could change the skin's permeability and allow
insulin to pass.
68 Colour scheme

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