Pengembangan Produk (Product

Development)
Najma Annuria Fithri, S.Farm.,
M..Sc., Apt.

Universitas Sriwijaya
Gemap 2013/2014
What is it?
The creation of products with new or
different characteristics that offer new or
additional benefits to the customer.

Product development may involve
modification of an existing product or its
presentation, or formulation of an entirely
new product that satisfies a newly defined
customer want or market niche.

Introduction
What are we gonna learn in the next 8 weeks ahead?

1. Novel drug delivery system (DDS) and its
implementation
Iontophoresis/Transdermal
pH sensitive DDS
Liposome/dendrimer/micelles
Nanotechnology
Mucoadhesive hydrogels
Floating systems

2. Design of experiment how to start
experimenting your formula. How to create a design
for the experiment
The aim of pharmaceutical development is to
design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product

The information and knowledge gained from
pharmaceutical development studies and
manufacturing experience provide scientific
understanding to support the establishment of
the design space, specifications, and
manufacturing controls
It is important to recognize that quality
cannot be tested into products


quality should be built in by design


Drug Discovery and Development
How are drugs discovered and developed?
Why are new drugs needed?
unmet medical need; new diseases (BSE; AIDS,
Alzheimers; obesity); low efficacy (dementia, cancer);
side effects (antidepressants, antipsychotics)

downstream health costs; (Alzheimers; spinal injury)

cost of therapy; (Viagra, Interleukins)

costs to individual/country; (depression)

sustain industrial activity; pharmaceutical industry
employs thousands and makes a massive contribution to
overseas earnings); patent expiry
Choose a disease
Choose a drug target
Identify a bioassay
bioassay = A test used to determine biological
activity.


Find a lead compound
lead compound = structure that has some activity
against the chosen target, but not yet good enough
to be the drug itself.
If not known, determine the structure of the lead
compound

Synthesize analogs of the lead
Identify Structure-Activity-Relationships (SARs)

Does it all work? Of course not. Trial and error is common
in drug and product development
Ex: Roche development of GABA agonist
Benzodiazepine
RO 48-8684
RO 48-6791
Flumazenil (RO 15-
1788)
Identify the pharmacophore
pharmacophore = the structural features directly
responsible for activity
Optimize structure to improve interactions with
target


Determine pharmacodynamics and pharmacokinetics
of the drug.
Pharmacodynamics explores what a drug does to the
body, whereas pharmacokinetics explores what the
body does to the drug.

In vivo testing: important to find out onset,
duration, efficacy, potency and toxicity of active
compound in living organism (preferably
mammal)
Patent the drug
Continue to study drug metabolism
Continue to test for toxicity
Designing a dosage form usage of design
experiment (mixture design, factorial design,
etc)
Creating formula and analysis of dosage form
Builds a knowledge on in vivo in vitro
correlation
Design a manufacturing process
Carry out clinical trials
Market the drug

Choosing a Disease
Pharmaceutical companies are commercial
enterprises
Pharmaceutical companies will, therefore,
tend to avoid products with a small market
(i.e. a disease which only affects a small
subset of the population)
Choosing a Disease

Pharmaceutical companies
will also (most of the time)
avoid products that would be
consumed by individuals of
lower economic status (i.e. a
disease which only affects
third world countries)
Choosing a Disease (cont.)
Most research is
carried out on diseases
which afflict first
world countries: (e.g.
cancer, cardiovascular
diseases, depression,
diabetes, flu, migraine,
obesity).
The Orphan Drug Act
The Orphan Drug Act of 1983 was passed to
encourage pharmaceutical companies to develop
drugs to treat diseases which affect fewer than
200,000 people in the US
Under this law, companies who develop such a
drug are entitled to market it without competition
for seven years.
This is considered a significant benefit, since the
standards for patent protection are much more
stringent.

Identifying a Drug Target
Drug Target = specific macromolecule, or
biological system, which the drug will interact
with
Sometimes this can happen through
incidental observation
Identifying a Drug Target (cont.)
Example: In addition to their being able to inhibit the uptake
of noradrenaline, the older tricyclic antidepressants were
observed to incidentally inhibit serotonin uptake. Thus, it was
decided to prepare molecules which could specifically inhibit
serotonin uptake. It wasnt clear that this would work, but it
eventually resulted in the production of fluoxetine (Prozac).

NH
2
N
H
HO
serotonin
O
HN
prozac
N
N
CH
3
H
3
C
Imipramine
(a classical tricyclic antidepressant)
F3C
The mapping of the human genome
should help!
In the past, many medicines (and lead compounds) were
isolated from plant sources.
Since plants did not evolve with human beings in mind,
the fact that they posses chemicals which results in
effects on humans is incidental.

Having the genetic code for the production of an
enzyme or a receptor may enable us to over-
express that protein and determine its structure
and biological function. If it is deemed important
to the disease process, inhibitors (of enzymes), or
antagonists or agonists of the receptors can be
prepared through a process called rational drug
design.

Simultaneously, Chemistry is Improving!
This is necessary, since,
ultimately, plants and natural
sources are not likely to provide
the cures to all diseases.
In a process called
combinatorial chemistry large
numbers of compounds can be
prepared at one time.
The efficiency of synthetic
chemical transformations is
improving.
Selectivity is Important!
e.g. targeting a bacterial enzyme, which is not
present in mammals, or which has significant
structural differences from the corresponding
enzyme in mammals
The Standards are Being Raised
More is known about the biological chemistry of
living systems
For example: Targeting one subtype of receptor
may enable the pharmaceutical chemist to avoid
potentially troublesome side effects.

Problems can arise
Example: The chosen target, may over time, lose
its sensitivity to the drug
Example: The penicillin-binding-protein (PBP)
known to the the primary target of penicillin in
the bacterial species Staphylococcus aureus has
evolved a mutant form that no longer recognizes
penicillin.
Choosing the Bioassay
Definitions:
In vitro: In an artificial environment, as in a test
tube or culture media
In vivo: In the living body, referring to tests
conductedin living animals
Ex vivo: Usually refers to doing the test on a tissue
taken from a living organism.
Choosing the Bioassay (cont.)
In vitro testing
Has advantages in terms of speed and requires
relatively small amounts of compound
Speed may be increased to the point where it is
possible to analyze several hundred compounds in a
single day (high throughput screening)
Results may not translate to living animals

Choosing the Bioassay (cont.)
In vivo tests
More expensive
May cause suffering to animals
Results may be clouded by interference with other
biological systems
Reducing animal usage ethic
About 50-100 million vertebrate animals/year used in
procedures around the globe
Likely to increase; more research, more targets, genetic
capability
3Rs
REPLACEMENT: use non-animal tests if possible
(cheaper, less trouble, less variable but not possible for
everything at this time)
REDUCTION: get the statistics right, dont replicate
work unnecessarily, dont overbreed
REFINEMENT: reduce suffering and severity of
procedure, pay attention to housing, stress, husbandry and
rich environments, proper analgesia and pre- and post-
operative care
Finding the Lead
Screening Natural Products
Plants, microbes, the marine world, and
animals, all provide a rich source of
structurally complex natural products.

It is necessary to have a quick assay for the
desired biological activity and to be able to
separate the bioactive compound from the
other inactive substances
Lastly, a structural determination will need to
be made

Finding the Lead (cont.)
Screening synthetic banks
Pharmaceutical companies have prepared
thousands of compounds
These are stored (in the freezer!), cataloged
and screened on new targets as these new
targets are identified

Finding the Lead (cont.)
Using Someone Elses Lead
Design structure which is similar to existing lead, but
different enough to avoid patent restrictions.
Sometimes this can lead to dramatic improvements
in biological activity and pharmacokinetic profile.
(e.g. modern penicillins are much better drugs than
original discovery).

Finding the Lead (cont.)
Enhance a side effect
O
NH
S
O
O
NH
tolbutamide
NH
2
S
O
O
H
2
N
sulphanilamide
(an antibacterial with the side effect of
lowering glucose levels in the blood and also
diuretic activity)
(a compound which has been optimized to only
lower blood glucose levels. Useful in the treatment
of Type II diabetes.)
S
NH
N
O
O
S
O
O
H
2
N
Cl
Chlorothiazide
(a compound which has been optimized to only display diuretic
activity.)
Use structural similarity to a natural ligand
N
NH
2
HO
H
N
N(CH
3
)
2
H
S
H
N
O
O
H
3
C
5-Hydroxytryptamine (5-HT)
Serotonin (a natural neurotransmitter
synthesized in certain neurons in the CNS)
Sumatriptan (Imitrex)
Used to treat migrain headaches
known to be a 5-HT
1
agonist
Computer-Assisted Drug Design
If one knows the precise molecular structure of the
target (enzyme or receptor), then one can use a
computer to design a perfectly-fitting ligand.
Drawbacks: Most commercially available programs
do not allow conformational movement in the target
(as the ligand is being designed and/or docked into
the active site). Thus, most programs are somewhat
inaccurate representations of reality.

Serendipity: a chance occurrence
Must be accompanied by an experimentalist who
understands the big picture (and is not solely
focused on his/her immediate research goal), who
has an open mind toward unexpected results, and
who has the ability to use deductive logic in the
explanation of such results.
Example: Penicillin discovery
Example: development of Viagra to treat erectile
dysfunction

Finding a Lead (cont.)
Sildenafil (compound UK-92,480) was synthesized by a
group of pharmaceutical chemists working at Pfizer's
Sandwich, Kent research facility in England.
It was initially studied for use in hypertension (high blood
pressure) and angina pectoris (a form of ischaemic
cardiovascular disease).
Phase I clinical trials under the direction of Ian Osterloh
suggested that the drug had little effect on angina, but that
it could induce marked penile erections.

Pfizer therefore decided to market it for erectile dysfunction,
rather than for angina.
The drug was patented in 1996, approved for use in erectile
dysfunction by the Food and Drug Administration on March 27,
1998, becoming the first pill approved to treat erectile
dysfunction in the United States, and offered for sale in the
United States later that year.
It soon became a great success: annual sales of Viagra in the
period 19992001 exceeded $1 billion.

Finding a Lead (cont.)
N
N
S
O
O
N
N
N
NH
O
O
viagra
(Sildenafil)
Structure-Activity-Relationships (SARs)
Once a lead has been discovered, it is important to
understand precisely which structural features are
responsible for its biological activity (i.e. to identify
the pharmacophore)

The pharmacophore is the precise section of the
molecule that is responsible for biological activity
This may enable one to prepare a more active
molecule
This may allow the elimination of excessive
functionality, thus reducing the toxicity and cost of
production of the active material
This can be done through synthetic modifications
Example: R-OH can be converted to R-OCH3 to see
if O-H is involved in an important interaction
Example: R-NH2 can be converted to R-NH-COR to
see if interaction with positive charge on protonated
amine is an important interaction

Next step: Improve Pharmacokinetic
Properties
Improve pharmacokinetic properties.
pharmacokinetic = The study of absorption,
distribution, metabolism and excretion of a drug
(ADME).
Metabolism of Drugs
The body regards drugs as
foreign substances, not
produced naturally.
Sometimes such substances
are referred to as
xenobiotics
Body has goal of removing such xenobiotics
from system by excretion in the urine
The kidney is set up to allow polar substances
to escape in the urine, so the body tries to
chemically transform the drugs into more polar
structures.
Metabolism of Drugs (cont.)
Phase 1 Metabolism involves the conversion
of nonpolar bonds (eg C-H bonds) to more
polar bonds (eg C-OH bonds).
A key enzyme is the cytochrome P450 system,
which catalyzes this reaction:
RH + O
2
+ 2H
+
+ 2e

ROH + H
2
O
Mechanism of Cytochrome P450
Phase I metabolism may either
detoxify or toxify.
Phase I reactions produce a more polar
molecule that is easier to eliminate.
Phase I reactions can sometimes result in a
substance more toxic than the originally
ingested substance.
An example is the Phase I metabolism of
acetonitrile
The Liver
Oral administration frequently brings the
drugs (via the portal system) to the liver
Metabolism of Drugs (cont.)
Phase II metabolism links the drug to still more
polar molecules to render them even more easy to
excrete

O O
OH HO
OH
HO
O P
HO
O
O
P
HO
O
O O
HO
OH
N
NH
O
O
R OH
O O
OH HO
OH
HO
O
R
Glucuronic Acid
UDP Glucuronic Acid
More easily excreted than ROH itself
glucuronosyltransferase
enzyme
Drug
Drug
Metabolism of Drugs (cont.)
Another Phase II reaction is sulfation (shown
below)
R OH
O
N
N
N
N
NH
2
OH O
O P
O
O
-
O S
O
O
O
-
P O O
-
O
-
3'-Phosphoadenosine-5'-phosphosulfate
Drug
R O
SO
3
-
Sulfated Drug
(more easily excreted)
Phase II Metabolism
Phase II reactions most commonly detoxify
Phase II reactions usually occur at polar sites,
like COOH, OH, etc.
Manufacture of Drugs
Pharmaceutical companies must make a profit to continue to exist
Therefore, drugs must be sold at a profit
One must have readily available, inexpensive starting materials
One must have an efficient synthetic route to the compound
As few steps as possible
Inexpensive reagents

The route must be suitable to the
scale up needed for the production of
at least tens of kilograms of final
product
This may limit the structural
complexity and/or ultimate size (i.e.
mw) of the final product
In some cases, it may be useful to
design microbial processes which
produce highly functional, advanced
intermediates. This type of process
usually is more efficient than trying to
prepare the same intermediate using
synthetic methodology.

Toxicity
Toxicity standards are continually becoming
tougher
Must use in vivo (i.e. animal) testing to screen for
toxicity
Each animal is slightly different, with different metabolic
systems, etc.
Thus a drug may be toxic to one species and not to
another

Example: Thalidomide
Thalidomide was developed by German pharmaceutical
company Grnenthal. It was sold from 1957 to 1961 in almost
50 countries under at least 40 names. Thalidomide was
chiefly sold and prescribed during the late 1950s and early
1960s to pregnant women, as an antiemetic to combat
morning sickness and as an aid to help them sleep. Before its
release, inadequate tests were performed to assess the drug's
safety, with catastrophic results for the children of women who
had taken thalidomide during their pregnancies.
Antiemetic = a medication that helps prevent
and control nausea and vomiting
Birth defects
caused by use of thalidomide
Example: Thalidomide
From 1956 to 1962, approximately 10,000 children were born with
severe malformities, including phocomelia, because their mothers had
taken thalidomide during pregnancy. In 1962, in reaction to the tragedy,
the United States Congress enacted laws requiring tests for safety during
pregnancy before a drug can receive approval for sale in the U.S.
N
O
O
NH
O
O
Thalidomide
Phocomelia presents at birth very short or absent long bones
and flipper-like appearance of hands and sometimes feet.
Example: Thalidomide
Researchers, however, continued to work with the drug. Soon
after its banishment, an Israeli doctor discovered anti-
inflammatory effects of thalidomide and began to look for uses
of the medication despite its teratogenic effects.

He found that patients with erythema nodosum leprosum, a
painful skin condition associated with leprosy, experienced
relief of their pain by taking thalidomide.

Teratogenic = Causing malformations in a fetus
Thalidomide
Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller
University in New York City showed that thalidomide worked in
leprosy by inhibiting tumor necrosis factor alpha. Kaplan
partnered with Celgene Corporation to further develop the
potential for thalidomide.
Subsequent research has shown that it is effective in multiple
myeloma, and it is now approved by the FDA for use in this
malignancy. There are studies underway to determine the drug's
effects on arachnoiditis, Crohn's disease, and several types of
cancers.

Literature
Haffner Marlene E; Whitley Janet; Moses Marie Two decades of orphan
product development. Nature reviews. Drug discovery (2002), 1(10),
821-5. Link
Franks Michael E; Macpherson Gordon R; Figg William D Thalidomide.
Lancet (2004), 363(9423), 1802-11. Link
Abou-Gharbia, Magid. Discovery of innovative small molecule
therapeutics. Journal of Medicinal Chemistry (2009), 52(1), 2-9. Link
Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical
industrys grand challenge. Nature Reviews Drug Discovery (2010), 9:
203-214.
Jorgensen, W. L. The many roles of computation in drug discovery. Science
(2004) 303: 1813-1818.
Butcher, E. C. et al. Systems biology in drug discovery. Nature
biotechnology (2004) 22(10): 1253-1259.


Optional Additional Reading
Bartlett J Blake; Dredge Keith; Dalgleish Angus G The
evolution of thalidomide and its IMiD derivatives as anticancer
agents. Nature reviews. Cancer (2004), 4(4), 314-22. Link
Cragg, G. M.; Newman, D. J. Nature: a vital source of leads for
anticancer drug development. Phytochemistry Reviews
(2009), 8(2), 313-331. Link
Betz, U. A. K. et al. Genomics: success or failure to deliver
drug targets? Current Opinion in Chemical Biology (2005), 9:
387-391
Sams-Dodd, F. Target-based drug discovery: is something
wrong? Drug Discovery Today (2005) 10: 139-147.

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KOMPETENSI FARMASIS DALAM
PRODUCT DEVELOPMENT

1. MEMILIKI PENGETAHUAN DALAM FORMULASI
2. MENGAPLIKASIKAN FORMULA PADA FASILITAS
PRODUKSI
3. MAMPU MENGEVALUASI, MERANCANG dan
MENENTUKAN BAHAN PENGEMAS YANG COCOK
4. MAMPU MENYUSUN DATA PENUNJANG REGISTRASI
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1. MEMILIKI PENGETAHUAN DALAM
FORMULASI
Memahami dan dapat menjalankan
preformulasi
Dapat membuat formula sediaan
obat yang berkualitas

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2. MENGAPLIKASIKAN FORMULA
PADA FASILITAS PRODUKSI

Melakukan pemilihan mesin dan prosedur
pembuatan
Dapat melakukan scale-up
Dapat melakukan validasi proses
Dapat menyiapkan master formula
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3. MAMPU MENGEVALUASI,MERANCANG
dan MENENTUKAN BAHAN PENGEMAS YANG
COCOK

Dapat melakukan pemilihan , pengujian dan
penelitian bahan pengemas
Dapat melakukan trial pengemasan dan
evaluasinya
Dapat melakukan pengujian stabilitas bahan
pengemas
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4. MAMPU MENYUSUN DATA
PENUNJANG REGISTRASI
Mampu mengevaluasi data-data
penunjang proses registrasi
Dapat melakukan validasi proses
dan membuat rancangan kemasan
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KONSEP DASAR
PENGEMBANGAN PRODUK
MENGUBAH BAHAN BAKU MENJADI PRODUK SEDIAAN
FARMASI YANG BERKUALITAS MENGGUNAKAN
PROSEDUR FABRIKASI YANG TELAH DITETAPKAN







PRODUK SEDIAAN FARMASI YANG BERKUALITAS ?

+
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Pengembangan Produk Baru dapat
berupa :
Adaptasi sederhana produk asli dan
kemasannya
Adanya rancang ulang total
Penggantian produk sama sekali
baru
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KESEIMBANGAN ANTARA :





Tingginya nilai produk terkait dengan manfaat
produk total, mencakup:
Produk nyata (barang secara fisik , pengepakan)
Produk tidak nyata (citra, garansi, informasi, dll)
Nilai produk Harga produk
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Pelayanan
purna
jual
Jaminan
Produk
pelengkap
Syarat pembayaran
Instalasi
Pengiriman
Barang
konsumsi
Produk tambah
PRODUK
TOTAL
Produk Berwujud
Ciri khas
Model
Pengema-san
Mutu
Merek
Keuntungan atau
jasa bersih
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PARAMETERS OF DRUG QUALITY

1. SAFE (AMAN)
TIDAK MENIMBULKAN EFEK SAMPING YANG TIDAK
DIKEHENDAKI PADA PEMBERIAN DOSIS TERAPEUTIK

2. EFFECTIVE (BERKHASIAT)
MENIMBULKAN EFEK FARMAKOLOGIS PADA HEWAN
ATAU MANUSIA

3. ACCEPTABLE (NYAMAN)
DAPAT DITERIMA OLEH PASIEN (PENGGUNA OBAT)

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KANDUNGAN SEDIAAN OBAT

R/ Bahan obat (Zat aktif)
Bahan tambahan (Eksipien)



SAFE BAHAN AKTIF

EFFECTIVE BAHAN AKTIF

ACCEPTABLE EKSIPIEN

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Quality does not just happen


Quality has to be designed and built into
a product during the entire
manufacturing process