1

Acknowledgement

1. NOOR ERLIANA BINTI RAMLI

2. NUR ASYKIN BINTI HAMID
3. NUR SHAFINA AKMA BINTI ZAKARIA
4. NUR SYARIFAH KHAIRINA BINTI MASHOD
5. NURASHIKIN BINTI MAZLAN
6. NURUL FATIN BINTI ABDUL AZIZ

1. NURUL AFIFAH BINTI PAHARUDIN

2. NUR FARAHIN AZWA BINTI ROSLI
3. NUR HAZWANI BT LAIDIN
4. NOR AIDA BINTI MOHD SHAHARANEE

2
TABLE OF CONTENTS

CHAPTER 1 INTRODUCTION
1.1 HISTORY AND DEFINITION OF BIOTECHNOLOGY
1.2 DEFINITION OF HEALTHCARE BIOTECHNOLOGY AND
BIOPHARMACEUTICAL
1.3 LIST OF BIOTECHNOLOGY DRUGS AVAILABLE IN THE MARKET
AND THEIR SUCCESSFUL TREATMENT OF DISEASES

CHAPTER 2 HEALTHCARE BIOTECHNOLOGY

2.1 BIOPHARMACEUTICAL

2.1.1 INTRODUCTION OF BIOPHARMACEUTICAL

2.1.2 PRODUCTION PROCESSES OF BIOPHARMACEUTICAL
2.1.3 BATCH, FED-BATCH AND CONTINUOUS BATCH PRODUCTION
2.1.4 TYPES OF BIOPHARMACEUTICAL
2.1.5 QUALITY CONTROL OF BIOPHARMACEUTICAL PRODUCTION
2.1.6 GOOD MANUFACTURING PRACTICE (GMP) IN PRODUCTION PROCESS
2.1.7 INNOVATIVE DRUG DELIVERY SYSTEM

2.2 THE DIFFERENCES BETWEEN TRADITIONAL DRUGS AND

BIOPHARMACEUTICALS

2.3 AVAILABILITY OF BIOPHARMACEUTICALS

2.4 GENERIC BIOPHARMACEUTICALS PRODUCTS / BIOSIMILARS

2.5 CURRENT BIOPHARMACEUTICALS IN CLINICAL TRIALS

2.5.1 BACKGROUND
2.5.2 PROMISES & PROSPECTIVE USES
2.5.3 SUCCESS RATE

2.6 OTHER THERAPEUTIC BIOTECHNOLOGY

2.6.1 GENE THERAPY

3
CHAPTER 3 THE ROLE OF PHARMACIST IN
PHARMACEUTICAL DISPENSING
3.1 REQUIRED KNOWLEDGE

3.2 RESPONSIBILITY

3.3 OPENNESS IN RECOMMENDING GENERIC PRODUCTS

CHAPTER 4 ETHICAL ISSUES IN PHARMACEUTICAL

INDUSTRY
4.1 BUSINESS ETHICS

4.2 SOCIAL BEHAVIOR ETHICS

4.3 ETHICAL DRUG DEVELOPMENT

CHAPTER 5 CONCLUSION & FUTURE DIRECTION

5.1 PERSONALIZED MEDICINE AND HEALTHCARE

5.2 GENETIC TESTING

5.3 INCREASING DEMAND OF BIOPHARMACEUTICAL

5.4 RELEVANCE OF BIOTECHNOLOGY FOR PHARMACEUTICALS

AND HEALTHCARE SERVICES

5.4.1 CONTINUOUS PROFESSIONAL EDUCATION IN BIOPHARM

5.4.2 GENETIC COUNSELING/GENETIC TESTING SERVICES
AND AFFILIATED SERVICE
5.4.3 PATIENT EDUCATION OF BIOPHARMACEUTICALS

5.4 PROBLEM RELATED TO COST

5.5 CONCLUSION

4
CHAPTER 1. INTRODUCTION
1.1 HISTORY AND DEFINITION OF BIOTECHNOLOGY

During World War I, the food was less and the resource was fading. At that time, Max
Delbruck grew yeast on a huge scale to meet the needs. The industrial potential of fermentation
was outgrowing its traditional home in brewing. Then, the “zymotechnology” soon gave way to
“biotechnology.” At 1919 in Hungary, Kerl Ereky coined the word “biotechnology” as a
technology based on converting raw materials into a more useful product. Then, Ereky
developed a theme that will go through the 20th century that the biotechnology could provide
solutions to social crisis like food and energy shortage through his book that entitled
Biotechnologie. According to Ereky, the term “biotechnologie” indicated the process where raw
material is biologically upgraded until it can form a socially useful products.[1]

After the World War I, German dictionaries included the term “biotechnology” and after
that being use widely. Emil Siebel who is the son of John Ewald Siebal, exit from his father
company and establish a new company named “Berau of Biotechnology”. The company offered
expertise in fermented nonalcoholic drinks. In 1940s, penicillin which is an antibiotic was
produced industrially in the U.S. using a deep fermentation process. Whilst in 1950s, steroids
were synthesized using fermentation technology. [1]

Then a new field arise which is known as genetic engineering. In Asilomar Conference in
1975, Joshua Lederberg spoke on emerging the fields in biotechnology. By 1978, genetic
engineering allowed synthetic human insulin to be synthesized. In 1988, Food and Drug
Administration (FDA) only approved 5 proteins from genetically engineered cells as drugs.
However, by the end of the 1990s, the number reaches up to 125. Nowadays, genetic engineering
is a hot topic in gene therapy, stem cell research, cloning, as well as genetically-modified food.
Nowadays, it seems that the natural product that used as pharmaceutical drug is the solutions to
health and community problems. This relationship of biotechnology serving social needs began
centuries ago.[1]

Karl Ereky who is a Hungarian engineer referred the term “biotechnology” as methods
and techniques that using the aid of living organisms which allow the production of substances

5
from raw materials. In 1992, a standard definition of biotechnology officially agreed by 168
member nations and as well as by Food and Agriculture Organization of the United Nations
(FAO) and the World Health Organization (WHO). The standard definition of “biotechnology”
is any technological application that uses biological systems, living organisms or derivatives
thereof, to make or modify products and processes for specific use. [2]

Biotechnology is a collection of techniques or processes that used the living organisms or

their units to develop added-value products and services. As it being applied on industrial and
commercial scale, biotechnology will give rise to the term of bio-industries. Conventional
biotechnologies include plant and animal breeding that use micro-organisms and enzymes in
fermentations, preparation as well as preservation of products. Whereas in more advanced and
modern biotechnology where mainly related to use of recombinant deoxyribonucleic acid (DNA)
techniques. Modern pharmaceutical biotechnologies include gene cloning, recombinant DNA
technology and genetic engineering.[2]

1.2 DEFINITION OF HEALTHCARE BIOTECHNOLOGY AND

BIOPHARMACEUTICAL

If whole aspect is taken into consideration, health care is a really complex set of practices
as it is integrating a variety of goods and services. A significant source of goods or products for
health care is from the booming from the biotechnology industry. Biotechnology industry
provides resources that serve the well-being of many people.[1] Biotechnology tools and
techniques open new research avenues for discovering how healthy bodies work and what goes
wrong when problems arise. By knowing the molecular basis of health and disease, it leads to
improved and novel methods for treating and preventing diseases. In human health care,
biotechnology products include quicker and more accurate diagnostic tests and therapies with
fewer side effects. It is depend on the body's self-healing capabilities.[2]

Pharmaceutical biotechnology is the use of living things to create or modify drugs and
other substances for the purpose of control, prevention and cure. Whilst, biotech pharmaceuticals
is any medically useful drugs whose manufacturing process that involves microorganisms or
substances that living organisms produced. The term “biopharmaceutical” is widely use,
however the meaning behind the term is hardly defined by its own users. Definitions of

6
biopharmaceutical in common use vary greatly, ranging from those based on the biological
source and nature of products as well as their manufacture to those based purely on business
models, perceptions and public relations. These definitions include pharmaceuticals
manufactured using living organisms (biotechnology), only the subset of these pharmaceuticals
involving genetic engineering, or simply all pharmaceuticals (including small-molecule drugs),
with everything “pharmaceutical” now “biopharmaceutical”[3]. But, biopharmaceutical generally
defined as is a pharmaceutical product manufactured by biotechnology methods which involves
live organisms or bioprocessing.[3]

Adapted from: What is a Biopharmaceutical?

Part 1: (Bio) Technology-Based Definitions by Ronald A. Rader, Page 62 BioExecutive International
MARCH 2005

7
Four major definitions related to biotechnology:

1. Broad Biotechnology: Defined as pharmaceuticals manufactured by biotechnology

methods, with the products have obviously having biological sources, usually involves
live organisms or their active components.
2. New Biotechnology: Defined as products that based on platform technologies that
developed in recent decades, that usually only include recombinant proteins and
monoclonal antibodies as being biopharmaceuticals and excluding the non recombinant
cultured proteins, blood and plasma proteins, vaccines and other classes of products.
3. Biotechnology Business: Products, technologies and companies that not have any
involvement or use of biotechnology and thus it not called biopharmaceutical. This
company simply includes all or everything from biotech-like pharmaceutical.
4. Pharma Business: Defined as all pharmaceuticals as biopharmaceuticals. The
biopharmaceutical is used as a synonym for pharmaceuticals and the pharmaceutical
industry is now the biopharmaceutical industry.

1.3 LIST OF BIOTECHNOLOGY DRUGS AVAILABLE IN THE MARKET AND

THEIR SUCCESSFUL TREATMENT OF DISEASES

Recent days, there are many biopharmaceutical products available in the market. Each
year, increasing number of new biopharmaceutical is approved by the FDA and many are still in
the process of applying for the FDA approval. Big pharmaceutical companies compete with each
other by spending large sum of money on the research and innovation of new drug, primarily on
biotechnology drugs although economic crisis strikes almost all part of the world.

Biopharmaceutical worth to be invested upon as it gives really high profits to the

pharmaceutical company. In addition, when its patent expired, it is impossible for other
manufacturers to produce the exactly the same drug as the original drug. Generic products will
have fewer issues on biopharmaceutical as in traditional chemical drug. Below are the list of
biopharmaceuticals available in current market and also their cure for diseases.

8
The list of biotech drugs below is updated 3/01/08 and obtained from
http://www.maxcarerx.com/pdf/completebiotechlist.pdf.
Some additional drugs added marked with (*) is obtained from
http://www.phrma.org/files/attachments/2009%20Approvals%200820209_web.pdf], Titled
Medicines listed are new molecular entities and new biologics approved at 2009, Last updated on
08/20/2009
Drug Name Drug Classification
ACTIMMUNE INJ 2MU/0.5 Interferon- Respiratory
ADVATE INJ Hemophilia – Factor VIII
ALDURAZYME INJ 2.9MG/5M Enzyme Replace MPS1
ALPHANATE INJ Hemophilia – Factor VIII
ALPHANINE SD INJ 250-1500 Hemophilia -Factor IX
AMEVIVE INJ 15MG Psoriasis
ARALAST INJ A1PI/Emphysema
ARANESP INJ RBC Stim Factor
ATGAM INJ 250MG Anti Rejection
AVONEX INJ Multiple Sclerosis
BARACLUDE Hepatitis B
BEBULIN VH INJ 200-1200 Hemophilia -Factor IX
BENEFIX INJ 1000UNIT Hemophilia -Factor IX
BETASERON INJ 0.3MG Multiple Sclerosis
BRAVELLE INJ 75UNIT Ovulation Induction
CARBOPLATIN Oncology
CEREDASE INJ 80UNT/ML Gaucher Disease
CEREZYME INJ Gaucher Disease
CETROTIDE KIT LH Inhibitor
CHOR GONADOT INJ 10000UNT Ovulation Induction
COPAXONE KIT 20MG/ML Multiple Sclerosis
COPEGUS TAB 200MG Interferon/Ribavirin
CYTOGAM INJ CMV Imunoglobulin
ELAPRASE INJ 6MG/3ML Hunter Syndrome
ENBREL INJ Rheumatoid Arthritis
EPOGEN INJ RBC Stim Factor
EXJADE TAB Chronic Iron Overload
FABRAZYME INJ 35MG Enzyme - Fabry Dz.
FABRAZYME INJ 5MG Fabry Dz
FEIBA VH INJ IMMUNO Hemophilia - Inhibitor
FLOLAN INJ 0.5MG Primary Pulmonary HTN
FOLLISTIM AQ INJ Follicle Stimulation
FORTEO SOL 750/3ML Osteoporosis
FUZEON KIT HIV Antiviral
GAMMAGARD INJ Immunoglobulins

9
GAMMAGARD SD INJ Immunoglobulins
GAMUNEX INJ 10% Immunoglobulins
GANIRELIX AC INJ Ovulation Induction
GEMZAR INJ 1 GM Oncology
GENOTROPIN INJ 0.2MG Growth Hormone
GEREF DIAG INJ 50MCG Growth Hormone
GLEEVEC TAB Oncologic
HELIXATE FS SOL 1000UNIT Hemophilia -Factor VIII
HEMOFIL M INJ Hemophilia -Factor VIII
HEPSERA TAB 10MG Hepatitis B
HERCEPTIN INJ 440MG Oncologic
HUMATE-P INJ Hemophilia -Factor VIII
HUMATE-P SOL Hemophilia -Factor VIII
HUMATROPE INJ Growth Hormone
HUMIRA KIT Rheumatoid Arthritis
HYALGAN INJ 20MG/2ML Osteoarthritis
INCRELEX INJ 40MG/4ML Growth Failure
INFERGEN INJ 15MCG Interferon
INTRON A VIAL Interferon
IPLEX INJ Neuromuscular and metabolic disorders
IRESSA TAB 250MG Oncologic
IVEEGAM EN INJ 5GM HU Immunoglobulins
KINERET INJ Rheumatoid Arthritis
KOATE-DVI INJ 1000UNIT Hemophilia -Factor VIII
KOGENATE FS INJ 1000UNIT Hemophilia -Factor VIII
LETAIRIS TAB 10MG Pulmonary Arterial HTN
LETAIRIS TAB 5MG Pulmonary Arterial HTN
LEUKINE INJ WBC- Stim Factor
LEUPROLIDE INJ 1MG/0.2 Oncology
LUCENTIS SOL Macular Degeneration
LUPR DEP-PED INJ Hormone Therapy
LUPRON Hormone Therapy
LUVERIS INJ 75UNIT Follicle Stimulation
MACUGEN INJ Neovascular AMD
MENOPUR INJ 75UNIT Follicle Stimulation
MONARC-M INJ Hemophilia -Factor VIII
MONOCLATE-P INJ Hemophilia -Factor VIII
MONONINE INJ Hemophilia -Factor IX
MYOZYME SOL 50MG Pompe Disease
NAGLAZYME INJ 1MG/ML Mucopolysaccharidosis VI
NEUMEGA INJ 5MG Platelet-Stim Factor
NEUPOGEN INJ WBC- Stim Factor
NEXAVAR TAB 200MG Renal Cell Carcinoma
NORDITROPIN INJ 10/1.5ML Growth Hormone

10
NORDITROPIN INJ 15/1.5ML WBC- Stim Factor
NOVAREL INJ 10000UNT Ovulation Induction
NOVOSEVEN INJ Hemophilia - Inhibitor
NUTROPIN AQ INJ 10MG/2ML Growth Hormone
ORTHOCLONE INJ OKT3 Anti Rejection
PANGLOBULIN INJ Immunoglobulins
PEGASYS INJ Interferon
PEG-INTRON KIT Interferon
POLYGAM S/D Immunoglobulins
PREGNYL INJ 10000UNT Ovulation Induction
PROCRIT INJ RBC-Stim Factor
PROFILNINE INJ Hemophilia -Factor IX
PROPLEX T INJ FACT IX Hemophilia -Factor IX
PULMOZYME SOL 1MG/ML Respiratory - CF
RAPTIVA KIT Psoriasis
REBETOL CAP Ribavirin
Rebetron™ Interferon
REBIF Multiple Sclerosis
RECOMBINATE Hemophilia -Factor VIII
REFACTO INJ Hemophilia -Factor VIII
REMICADE INJ Rheumatoid Arthritis
REMODULIN INJ Pulmonary Arterial HTN
REPRONEX INJ Follicle Stimulation
REVATIO TAB Pulmonary Aterial HTN
REVLIMID CAP 10MG Anemia/ Multiple Myeloma
RIBAPAK PAK Chronic HCV
RIBASPHERE CAP 200MG Anti-Viral
RIBAVIRIN CAP Anti-Viral
RITUXAN INJ Oncologic
ROFERON-A KIT Interferon
SAIZEN INJ Growth Hormone
SOMAVERT INJ 20MG Acromegaly
SUPPRELIN LA KIT 50MG Central Precocious Puberty
SYNAGIS INJ RSV
THYROGEN INJ 1.1MG Thyroid Stim Hormone
TRACLEER TAB 125MG Pulmonary Arterial HTN
TYSABRI INJ Multiple Sclerosis
VENTAVIS SOL 10MCG/ML Pulmonary Aterial HTN
VIDAZA INJ 100MG Myelodysplastic syndrome
VISUDYNE INJ 15MG Subfoveal Choroidal Neovascularization
VIVAGLOBULIN Primary Immune Deficiency
WINRHO SDF INJ 5000UNIT Rh Immunoglobulin
XELODA TAB 150MG Oncologic
XOLAIR SOL 150MG Allergic Asthma

11
ZAVESCA CAP 100MG Gaucher Disease
ZENAPAX INJ 25MG/5ML Anti Rejection
ZOLADEX IMP Oncologic
ZOLINZA CAP 100MG Oncologic
ZORBTIVE INJ 8.8MG (hGH) Short Bowel Syndrome
AFLURIA Seasonal Influenza
*DYSPORT cervical dystonia
*FLUARIX Seasonal Influenza
*FLUZONE Seasonal Influenza
*FLULAVAL Seasonal Influenza
*FLUVIRIN Seasonal Influenza
*FLUMIST Seasonal Influenza
*ILARIS Cryopyrin-associated
*SIMPONI periodic syndrome
Rheumatoid (CAPS)
Arthritis
*IXIARO arthritis
Japanese Enchephalitis Vaccine
*ATRYN enitis
Antithrombin deficiency

12
CHAPTER 2.
HEALTHCARE BIOTECHNOLOGY

2.1 BIOPHARMACEUTICAL

2.1.1 INTRODUCTION OF BIOPHARMACEUTICAL

Biopharmaceuticals are medical drugs produced using biotechnology. They are proteins
(including antibodies), nucleic acids (DNA, RNA or antisense oligonucleotides) used for
therapeutic or in vivo diagnostic purposes, and are produced by means other than direct
extraction from a native (non-engineered) biological source.[1] The first such substance approved
for therapeutic use was biosynthetic human insulin made via recombinant DNA technology.[2]
Sometimes referred to as rHI, under the trade name Humulin. It was developed by Genentech,
but licensed to Eli Lilly and Company, who manufactured and marketed the product starting in
1982.[2] Biopharmaceutical classification consist of blood factors (Factor VIII and Factor IX),
thrombolytic agents (tissue plasminogen activator) , hormones (insulin, glucagon, growth
hormone, gonadotrophins) , haematopoiesis growth factors (Erythropoietin, colony stimulating
factors) , interferons (Interferons-α, -β, -γ) , interleukin-based products (Interleukin-2) , vaccines
(Hepatitis B surface antigen) , monoclonal antibodies (Various) and additional products
(tumour necrosis factor, therapeutic enzymes)[5]
Biopharmaceuticals have the advantage that they can be specifically targeted towards a
particular disease or area of the body.[6] Biopharmaceuticals constitute 11% of the current drugs
on the market and 32% of all drugs under development.[6] The drug development process,
however, is long and expensive: The average time for development is 12 years, and the average
cost is USD 1.2 billion.[6] Not surprisingly, the biopharmaceutical industry is seeking to reduce
costs and the time to market.[6]

The biopharmaceutical market witnessed 15–17% revenue growth in 2004, which is more
than double the growth rate of the global pharmaceutical market.[7] With revenues of $45 billion
in 2004, the global biopharmaceutical sector accounted for approximately 8.1% of the total
global pharmaceutical market.[ 7] Revenues are anticipated to reach $92 billion in 2011, at an
average annual growth rate (AAGR) of 10.3% for the period 2004–2011.[7] Projects in the
13
pipeline and continued research advances are likely to foster the growth of this segment
further.[4] Biopharmaceuticals account for about 25–30% of the total product pipeline .[7]

Adapted from:
Mar 1, 2006
By: Himanshu C. Parmar
Pharmaceutical Technology Europe
Biopharmaceuticals market overview
http://pharmtech.findpharma.com/pharmtech/article/articleDetail.jsp?id=310779

2.1.2 PRODUCTION PROCESSES OF BIOPHARMACEUTICAL-

UP STREAM AND DOWN STREAM PROCESSES

The manufacturing proses of human proteins by the methods of modern biotechnology is

separated into two major steps that is the upstream processing during which proteins are
produced by cells genetically engineered to contain the human gene which will express the
protein of interest.[8] Whereas, the downstream processing are the processes in which the
produced proteins are isolated and purified.[8] Following purification of the protein of interest,
the next step is the formulation of the final product (addition of excipients to the protein). It is
also filter sterilized, filled aseptically, lyophilized, sealed, inspected and labeled in this step.
Upstream processing, downstream processing, final drug production, and the general
environment of the facility are monitored by the quality control division of the manufacturing
facility.[8] A master production batch record (MPBR) governs the behaviors of the people

14
entrusted to carry out these various processes (upstream and downstream processing and quality
control) according to validated protocols and standard operating procedures (SOPs).[8]

UPSTREAM PROCESS

The state-of-the-art upstream processing areas and technologies have been designed to provide
maximum flexibility and capacity to meet the needs of clients requiring process development
from early development stages through to the provision of product for use in all phases of
clinical trials.

Today the most common type of upstream processing of proteins utilizes two tools:

BIOREACTORS SUSPENDED CELLS

1)Stainless steel are most common Suspension (or attached) cells transformed
with expression vectors genetically engineered
2)glass bioreactors such as spinner flasks and
to contain one (or more) human genes that
plastic bioreactors such as hollow fiber
produce copious amounts of their protein(s).
bioreactors are used as well

Upstream processing of proteins using bioreactors and cells usually begins with the
preparation of the inoculum which proceeds in scale-up steps until enough inoculum is made to
aseptically inoculate the final, sterile, media-filled bioreactor. Batch, fed-batch and continuous
culture refer to whether or not the cells are fed after they are inoculated. In batch culture there is
no additional feeding, while in fed-batch culture fewer medium is used at the beginning of a run
and feeding is done at intervals to a maximum volume during the run. In continuous culture feed
is constantly added and medium is constantly withdrawn. In fed-batch and especially continuous
culture the cells can be maintained in a steady state, continuously producing human protein for
up to several months at a time.

During the culture period samples are removed, aseptically, and various parameters are
measured by fermentation technicians or operators including optical density (OD) and live cell
count. Samples are also brought to quality control where other parameters may be measured such
as the levels of glucose, lactate and ammonia, as well as the identity and concentration of the

15
human protein that the cells are producing. Quality control would also collect environmental
samples during the upstream processing run to ensure that the air quality and the quality of the
water for injection (WFI) are maintained within acceptance criteria specified by the validation
protocols, SOPs and PBRs.

In addition, the parts of upstream processing are the initial purification steps which could
include centrifugation and/or filtration in order to separate cells from media. The cells or the
media would be discarded to the kill tank, depending on where the protein was located. In this
course we are using glass bioreactors and representative of three types of cells used in upstream
processing of human protein pharmaceuticals: bacterial, animal, and fungal cells. In bacteria,
such as biotechnology's workhorse, Escherichia coli , proteins remain inside the cell so the cells
are separated from the media and the media is discarded to the kill tank. In animal cells, such as
Chinese Hamster Ovary (CHO) cells, and in fungal cells, such as the yeast Pichia pastoris,
proteins are secreted into the media so the media is saved for later isolation and purification of
the protein of interest in downstream processing.

Adapted from: http://www.microfiltindia.com/images/upstream.jpg

16
DOWNSTREAM PROCESS

Downstream processing refers to the recovery and purification of biosynthetic products,

particularly pharmaceuticals, from natural sources such as animal or plant tissue or fermentation
broth, including the recycling of salvageable components and the proper treatment and disposal
of waste. It is an essential step in the manufacture of pharmaceuticals such as antibiotics,
hormones (e.g. insulin and human growth hormone), antibodies (e.g. infliximab and abciximab)
and vaccines; antibodies and enzymes used in diagnostics; industrial enzymes; and natural
fragrance and flavor compounds. Downstream processing is usually considered a specialized
field in biochemical engineering, itself a specialization within chemical engineering, though
many of the key technologies were developed by chemists and biologists for laboratory-scale
separation of biological products.[9]

Adapted from http://www.microfiltindia.com/images/downstream.jpg

17
 Stages in Downstream Processing

Removal of insolubles

First step and involves the capture of the product as a solute in a particulate-free liquid. For example the separation
of cells, cell debris or other particulate matter from fermentation broth containing an antibiotic. Typical operations
to achieve this are filtration, centrifugation, sedimentation, flocculation, electro-precipitation, and gravity
settling. Additional operations such as grinding, homogenization, or leaching, required to recover products from
solid sources such as plant and animal tissues, are usually included in this group.

Product Isolation

Removal of those com ponents whose properties vary markedly from that of the desired product. For most
products, water is the chief impurity and isolation steps are designed to remove most of it, reducing the volume of
material to be handled and concentrating the product. Solvent extraction, adsorption, ultrafiltration, and
precipitation are some of the unit operations involved.

Product Purification

Separate those contaminants that resemble the product very closely in physical and chemical properties.
Consequently steps in this stage are expensive to carry out and require sensitive and sophisticated equipment.
This stage contributes a significant fraction of the entire downstream processing expenditure. Examples of
operations include affinity, size exclusion, reversed phase chromatography, crystallization and fractional
precipitation.

Product Polishing

Final 1.http://en.wikipedia.org/wiki/Downstream_processing
processing steps which end with packaging of the product in a form that is stable, easily transportable and
convenient. Crystallization, desiccation, lyophilization and spray drying are typical unit operations. Depending on
the product and its intended use, polishing may also include operations to sterilize the product and remove or
deactivate trace contaminants which might compromise product safety. Such operations might include the
removal of viruses or depyrogenation.

18
 2.1.3 BATCH, FED-BATCH AND CONTINUOUS BATCH

Batch production is the manufacturing technique of creating a component at a

workstation before moving to the next step in production. Batch production is common in
bakeries and in the manufacture of sports shoes, pharmaceutical ingredients (APIs), inks, paints
and adhesives. In the manufacture of inks and paints, a technique called a colour-run is used. A
colour-run is where one manufactures the lightest colour first, such as light yellow followed by
the next increasingly darker colour such as orange, then red and so on until reaching black and
then starts over again. This minimizes the cleanup and reconfiguring of the machinery between
each batch. White (by which is meant opaque paint, not transparent ink) is the only colour that
cannot be used in a colour-run because a small amount of white pigment can adversely affect the
medium colours.[10]

Continuous production is a method used to manufacture, produce, or process materials

without interruption. This process is followed in most oil and gas industries and petrochemical
plant and in other industries such as the float glass industry, where glass of different thickness is
processed in a continuous manner. Once the molten glass flows out of the furnace, machines
work on the glass from either side and either compress or expand it. Controlling the speed of
rotation of those machines and varying them in numbers produces a glass ribbon of varying
width and thickness.

Continuous production is largely controlled by production controllers with feedback. The

majority of transducers and controllers employ PID (Proportional, Integral, and Derivative)
control which controls the final output element based on the variables response to the control
element.

The most important difference between batch production and continuous production is
that in Continuous the chemical transformations of the input materials are made in continuous
reactions that occur in flowing streams of the materials whereas in batch they are done in
containers.[11]

19
 A 'fed-batch' is a biotechnological batch process which is based on feeding of a growth
limiting nutrient substrate to a culture. The fed-batch strategy is typically used in bio-industrial
processes to reach a high cell density in the bioreactor. Mostly the feed solution is highly
concentrated to avoid dilution of the bioreactor. The controlled addition of the nutrient directly
affects the growth rate of the culture and allows to avoid overflow metabolism (formation of side
metabolites, such as acetate for Escherichia coli, lactic acid in cell cultures, ethanol in
Saccharomyces cerevisiae), oxygen limitation (anaerobiosis). In most cases the growth-limiting
nutrient is glucose which is fed to the culture as a highly concentrated glucose syrup (600-850
g/l). Substrate limitation in „fed-batch’ offers the possibility to control the reaction rates to avoid
technological limitations connected to the cooling of the reactor and oxygen transfer. - Substrate
limitation also allows the metabolic control, to avoid osmotic effects, catabolite repression and
overflow metabolism of side products.[12]

2.1.4 TYPE OF BIOPHARMACEUTICAL

MONOCLONAL ANTIBODIES

Monoclonal antibody is antibody produced artificially by fusing antibody-forming

lymphocytes from mouse spleen with mouse myeloma cells.[13] The resulting hybrid cells
multiply rapidly like cancer cell and produce the same antibody as their parent lymphocytes. [13]
Monoclonal antibody therapy is the use of monoclonal antibodies (mAb) to specifically bind to
target cells. This may then stimulate the patient's immune system to attack those cells. It is
possible to create a mAb specific to almost any extracellular or cell surface target, and thus there
is a large amount of research and development currently being undergone to create monoclonals
for numerous serious diseases such as rheumatoid arthritis, multiple sclerosis and different types
of cancers. There are a number of ways that mAbs can be used for therapy. For example , mAb
therapy can be used to destroy malignant tumor cells and prevent tumor growth by blocking
specific cell receptors. Variations also exist within this treatment, e.g. radioimmunotherapy,
where a radioactive dose localizes on target cell line, delivering lethal chemical doses to the
target.[12]

20
 Production of monoclonal antibodies involves in vivo or in vitro procedures.[14] Before
production of antibodies by either method, hybrid cells that will produce the antibodies are
generated.[13] The generation of mAb-producing cells requires the use of animals, usually mice .[14]
The procedure yields a cell line capable of producing one type of antibody protein for a long period.
A tumor from this “immortal” cell line is called a hybridoma .[13]

Step 1

Immunization of Mice and Selection of Mouse Donors for Generation of Hybridoma Cells

Step 2

Screening of Mice for Antibody Production

Step 3

Preparation of Myeloma Cells

Step 4

Fusion of Myeloma Cells with Immune Spleen Cells

Step 5
Cloning of Hybridoma Cell Lines by “Limiting Dilution” or Expansion and Stabilization of
Clones by Ascites Production

21
Adapted from website http:// www.antibodystation.com/img/mono...duct.gif

VACCINE

A vaccine is a biological preparation that improves immunity to a particular disease.[15] A

vaccine typically contains an agent that infect cell and cause disease in microorganism and is
often made from weakened or killed forms of the microbe.[15] The agent stimulates the body's
immune system to recognize the agent as foreign, destroy it, and remember it, so that the
immune system can more easily recognize and destroy any of these microorganisms that it later
[15]
encounters. Vaccines can be prophylactic because prevent or ameliorate the effects of a
future infection by any natural or wild pathogen. Vaccine also use in therapeutic uses , it against
cancer cell. [15] Methods of developing new vaccines are highly variable, differing for each type
of virus or bacteria. Animal experiments are usually required for selecting the initial materials in
the formula, establishing the stability and formulation of the vaccine, and determining the mode

22
and frequency of administration. Experimental vaccines are tested for safety and efficacy on
animals before clinical tests on humans begin.[14]

INTERFERONS

Interferons (IFNs) are proteins made and released by the cells of vertebrates in response
to the presence of pathogens such as viruses, bacteria, or parasites or tumor cells.[15] They allow
communication between cells to trigger the protective defenses of the immune system that
eradicate pathogens or tumors.[15] IFNs belong to the large class of glycoproteins known as
cytokines.[15] Although they are named after their ability to interfere with viral replication within
host cells . IFNs have other functions like activate immune cells such as natural killer cells and
macrophages , they increase recognition of infection or tumor cells by up-regulating antigen
presentation to T lymphocytes and they increase the ability of uninfected host cells to resist new
infection by virus.[15] Certain host symptoms, such as aching muscles and fever, are related to the
production of IFNs during infection.[15]

About ten distinct IFNs have been identified in mammals , seven of these have been
described for humans.[15] They are typically divided among three IFN classes , Type I IFN, Type
II IFN, and Type III IFN. IFNs belonging to all IFN classes are very important for fighting viral
infections.[15] Interferon was scarce and expensive until 1980 when the interferon gene was
inserted into bacteria using recombinant DNA technology, allowing mass cultivation and
purification from bacterial cultures[16] or derived from yeast . Reiferon Retard is the first yeast
derived interferon-alpha 2a.

Based on the type of receptor through which they signal, human interferons have been classified
into three major types.

 Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known
as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I
interferons present in humans are IFN-α, IFN-β and IFN-ω.[17]

 Interferon type II: Binds to IFNGR. In humans this is IFN-γ.

23
  Interferon type III: Signal through a receptor complex consisting of IL10R2 (also called
CRF2-4) and IFNLR1 (also called CRF2-12). Acceptance of this classification is less
universal than that of type I and type II, and unlike the other two, it is not currently
included in Medical Subject Headings.[18]

The manufacture of Betaferon

THROMBOLYTIC AGENTS

Thrombolysis requires the use of thrombolytic drugs, which are either derived from
Streptomyces species or more recently using recombinant biotechnology whereby tPA is
manufactured by bacteria, resulting in a recombinant tissue plasminogen activator or rtPA.[19]
Thrombolysis is the breakdown (lysis) of blood clots[19]

24
 Chart of Thrombolytic process

HORMONE

There are many type of hormone nowadays produced by biotechnology . Hormone also
use as therapy for some disease. Although steroid and easily-synthesized hormones have been
used to manipulate farm-animal growth and reproduction for several years, endocrinologists
investigating the role of polypeptide hormones in these contexts have long been frustrated by the
lack of sufficient material to thoroughly examine the possibility that such hormones might
enhance production on a commercial scale. However, the last 7 years have witnessed the rapid
development of techniques which have added new dimensions to the possibility of using
polypeptide hormones to improve animal growth, lactation and reproduction.[20]

Most important among these is the application of recombinant-DNA technology to the

biosynthetic production of purified protein hormones from prokaryotic, and possibly eukaryotic,
cells. Recent advances in the same area have shown that it is possible to control endogenous
hormone secretion by the direct transfer of the appropriate cloned genes (transgenic) to early
embryos. Furthermore, site-directed mutagenesis and the specificity of monoclonal antibodies
offer two methods for manipulating and directing hormonal activity towards a specified purpose.
Recombinant-DNA-derived human insulin and human growth hormone (hGH) are already being
marketed for controlling diabetes mellitus and the treatment of hypopituitary children
respectively. The application of biotechnology to animal production centres almost exclusively

25
on growth hormone (GH) but a certain amount of work is being carried out with the insulin-like
growth factors (somatomedins) and epidermal growth factor.[20]

TYPES OF HORMONE DESCRIPTION

1. Human Insulin 1) Use of recombinant DNA technology to

modify Escherichia coli bacteria to produce
human insulin, which was performed at
Genentech in 1978[19]

2) Genentech researchers produced artificial

genes for each of the two protein chains that
comprise the insulin molecule. The artificial
genes were then inserted into plasmids among
a group of genes that are activated by lactose.
Thus, the insulin producing genes were also
activated by lactose. The recombinant plasmids
were inserted into Escherichia coli bacteria,
which were induced to produce 100,000
molecules of either chain A or chain B human
insulin.[22] The two protein chains were then
combined to produce insulin molecules.[19]

2. Human Growth Hormone Prior to the use of recombinant DNA

technology to modify bacteria to produce
human growth hormone, the hormone was
manufactured by extraction from the pituitary
glands of cadavers, as animal growth hormones
have no therapeutic value in humans.
Production of a single year's supply of human
growth hormone required up to fifty pituitary
glands[22],

3. Human Blood Clotting Factors
The first human blood clotting factor to be
produced in significant quantities using
recombinant DNA technology was Factor IX,
which was produced using transgenic Chinese
hamster ovary cells in 1986. Lacking a map of
the human genome, researchers obtained a

26
 known sequence of the RNA for Factor IX by
examining the amino acids in Factor IX.

4. Transgenic Farm Animals Recombinant DNA techniques have also been

employed to create transgenic farm animals
that can produce pharmaceutical products for
use in humans. For instance, pigs that produce
human hemoglobin have been created. While
blood from such pigs could not be employed
directly for transfusion to humans, the
hemoglobin could be refined and employed to
manufacture a blood substitute.[23]

2.1.5 QUALITY CONTROL OF BIOPHARMACEUTICAL PRODUCTION

Quality Control (QC) is a system of routine technical activities to measure and control the
quality of the inventory as it is being developed. Quality Assurance (QA) activities include a
planned system of review procedures conducted by personnel not directly involved in the
inventory compilation/development process.[24] The QC system is designed to provide routine
and consistent checks to ensure data integrity, correctness and completeness. Second, identify
and address errors and omissions.[24] Third , document and archive inventory material and record
all QC activities.[24] Besides , the company-wide quality approach places an emphasis on three
aspects :

1. Elements such as controls, job management, defined and well managed processes.
performance and integrity criteria, and identification of records

2. Competence, such as knowledge, skills, experience, and qualifications

3. Soft elements, such as personnel integrity, confidence, organizational culture, motivation,

team spirit, and quality relationships.

Like in traditional pharmaceutical production, consumer and patient safety have become
the prerequisites for biopharmaceutical product development, production and marketing. The
ability to provide an effective, pure, safe product is the primary factor determining the product‟s
success.[25]

27
 2.1.6 GOOD MANUFACTURING PRACTICE (GMP) IN PRODUCTION PROCESS

Many reasons will cause adulteration of drugs. Of special interest in this context are all issues
connected to good manufacturing practices (GMPs) as defined by, for example, the US Food and
Drug Administration (FDA). Producer must fulfill the GMP regulation during production
biopharmaceutical ensure that a drug meets the requirements of safety, identity and strength, and
meets the quality and purity characteristics . GMP regulation are covered in processing and
packaging product , method used in preparation and facilities like machine and other thing that
used in production. There are different between biopharmaceutical and common drug,
biopharmaceutical used biological agent or known as organism like bacteria in its production.
Production of biopharmaceutical will face some difficulty . Chemically derived products tend to
be more stable than biopharmaceuticals consisting of proteins or polypeptides, such as cytokines,
erythropoietins, plasminogen activators, blood-plasma factors, growth hormones, insulin,
monoclonal antibodies and certain types of vaccine. The metabolic pathways of organisms used
in the production of biopharmaceuticals are complex and their response to changes in the
environment are often unpredictable. This means that the process parameters must be carefully
adjusted and controlled to ensure batch-to-batch reproducibility. The biocompatible chemicals
and moderate temperatures and pressures used for production enhance process safety for the
operator and the environment but can promote the growth of contaminating microorganisms.
Complex downstream-processing steps are normally needed to remove impurities without
damaging the product.[25]

QA and QC measures for biopharmaceutical development and production have been

established by national authorities to address concerns about product safety, and international
MRAs have paved the way for international harmonization. Resource management and careful
planning are the keys to successful implementation of QA–QC systems. Authorities require
careful validation and full documentation of facilities, equipment, processes and procedures.
Although a substantial effort is required initially to establish a QA–QC system and substantial
resources are needed for its maintenance, it will eventually develop into a valuable asset.[25]

28
Methods of quality control:

The widely accepted concept for the safe handling of biological agents for contained use
is based upon biological and physical containment measures, and safe working techniques.
Biological containment is based on genetic constructs that confine the proliferation of biological
agents to the defined process areas. Physical containment relies on equipment with the
appropriate seals and filters, designed to minimize the release of viable production organisms.
Safe working techniques include limited access and inactivation of waste streams. Even though
no non-pathogenic recombinant DNA production strains have shown any adverse effects in the
environment, public concern has created the demand for these low-emission production methods
to minimize residual risks.[25]

GMP function is to assuring the quality of the product by assuring the quality of the
process. GMP should also be part of process development such as development reports and
approval requirements , proceed through validation , manufacturing, controls and end-product
testing and reach into the distribution network of the product. Process development is often seen
as being incompatible with GMP compliance, as development requires flexibility. Compliance
will always involve process improvement.GMP compliance for the production of
biopharmaceuticals.[25]

1. All procedures that have an impact on product quality need to be identified. A formal
written system of documents, including Standard operating procedures ( SOPs), must be
established. The procedures should describe in detail all the tasks that are to be performed
to ensure a certain goal, such as performing analytical tests and organizational matters.
SOPs should contain specifications and must define the circumstances under which the
procedure is deemed to be successful. They are only one element in an array of necessary
procedures, such as master procedures, batch production records and analytical
procedures.
2. One of the fundamentals of all quality-assurance concepts is the need for meticulous
records of all activities. Activities that have not been recorded are worthless in respect to
regulatory compliance as inspecting authorities consider the not performed unless they

29
 have been recorded. Organizing the documentation structure and maintaining it is
therefore one of the most important tasks in setting up a QA system, and is the basis of
any validation. Documentation has to be adequate to ensure the traceability of the
production history of every batch, including all associated issues such as raw materials,
cleaning procedures, packaging, labeling and distribution.

3. Validation is the action of proving that any material, process, procedure, activity,
equipment or mechanism that is used can and does achieve the desired and intended
results.

4. Complete validation of a process can extend from planning and designing an equipment
item to its routine inspection within production, with the whole cycle incorporating
several elements.
Design qualification (DQ) User-requirement specifications and detailed
functional specifications for engineering design and
procurement.
Installation qualification (IQ) Verifying that all key aspects of hardware
installation adhere to appropriate codes and
approved design intentions.
Process-change control Ensure that product quality is maintained or
optimized after changes have been made to the
process.
Operational qualification (OQ) verifying that subsystems perform as intended with
model process materials such as water.
Performance qualification (PQ) of equipment.

5. Most biotechnological operations are run under aseptic conditions that free from viable
organisms other than the production organism. Validation has to ensure that the cleaning
procedures are adapted to the equipment and the type of contamination. The hygienic
design of fermentation equipment is crucial for cleaning procedures to be successful.

30
6. The reproducibility of cleaning procedures can be optimized by designing equipment
with automatic cleaning-in-place (CIP) systems, removing the need to dismantle it. The
design of hygienic equipment is based on some very simple criteria. Process validation
and GMP production can be achieved by checking for these criteria at a very early stage
of the project. All surfaces must be resistant to the product and to cleaning at the full
range of operating pressures and temperatures. The surfaces should also be free from
crevices, their surface roughness should be 0.5 μm or less and they should either be easily
accessible for manual cleaning and visual inspection or be validated for CIP.

7. Hygienic design also extends to the external parts of the equipment, including issues such
as adequate insulation to avoid condensation on external surfaces of the equipment, with
the insulation sealed with stainless-steel cladding, preferably fully welded, and the
equipment and supports either sealed to the building with no gaps or pockets, or with
adequate clearance to allow for inspection and cleaning.

8. Purification processes must be validated to prove that they are capable of removing
impurities to an acceptable level. In the production of biopharmaceuticals, emphasis is
put on components originating from the host cell such as protein and DNA , media
components or substances used during downstream processing like nutrients, buffer
components, stabilizers, chromatography media and potential external contamination by
adventitious agents (bacteria, virus and mycoplasmas, as well as scrapie-like agents in
cell cultures) which should not be present throughout the process but could accidentally
contaminate the culture.

9. Analytical procedures must have their statistical accuracy, precision, sensitivity,

robustness and ruggedness tested.

10. Analytical procedures used to evaluate the quality of the final product have the highest
priority for full and comprehensive validation

31
 2.1.7 INNOVATIVE DRUG DELIVERY SYSTEM

- LIPOSOMAL DRUG DELIVERY SYSTEMS

Source: http://www.medgadget.com/archives/img/534tra1.jpg

The ideal solution to overcome effectiveness of drug‟s problems is the targeting of drugs using
suitable carriers like serum proteins, immunoglobulins, synthetic polymers, liposomes, niosomes,
microspheres, erythrocytes, reverse micelles, pharmacosomes, monoclonal antibodies. Among
these carriers, liposomes show great potentials of effective delivery of drugs to the site of action
and of controlling the release of these drugs at a predetermined rate.[26]

Liposomes are lyotropic liquid crystals composed of relatively biocompatible and

biodegradable materials and consist of an aqueous core entrapped by one or more bilayers of
natural and/or synthetic lipids. Drugs with widely varying lipophilicities can be encapsulated in
liposomes either in the phospholipid bilayer, in the entrapped aqueous core or at the bilayer
interface. Reformulation of drugs in liposomes has provided an opportunity to enhance the
therapeutic indices of various agents mainly through the alteration of biodistribution. They are
versatile drug carriers, which can be used to control retention of entrapped drugs in the presence
of biological fluids, controlled vesicle residence in the systemic circulation or other
compartments in the body and enhanced vesicle uptake by target cells . [26]Liposomes composed
of natural lipids are biodegradable, biologically inert, weakly immunogenic , produce no
antigenic or pyrogenic reactions and possess limited intrinsic toxicity. Therefore, drugs

32
encapsulated in liposomes are expected to be transported without rapid degradation and
minimum side effects to the recipients. Moreover, efforts have been made to assess the
specificity of drug carriers to the target organs, cells or compartments within the cells .
Liposomes are better suited for assessing their targetable properties because of the ease of
modifying their surface when compared to other drug carriers such as nanoparticles and
microemulsions.[26]

Drug deliver by liposome

Adapted from website http://www.di.uq.edu.au/sparq/images/proj5fig6.jpg

33
2.2 THE DIFFERENCES BETWEEN TRADITIONAL DRUGS AND
BIOPHARMACEUTICALS
There are significant differences between traditional drugs and biopharmaceutical.
Public should realized their difference and should know the facts these two type of
medicinal products.
Structure mechanism
Discovery
Manufacturing analysis
Route of administration
Transport
Stability
Price
Safety, efficacy and Quality
Traditional Drugs
Small molecule
Moderate protein activity
High-throughput screening
rational drug design
Chemical method;
chromatographic and
spectrometric
Oral, rectal, pulmonary,
vaginal, topical, parenteral.
Transport across biological
barriers
Good
Cheaper
Scientific evidence from study
to evaluate the safety and
effectiveness are limited. The
safety, effectiveness and
quality of finished herbal
medicine products depend on
the quality of their source and
Biopharmaceutical
Large complex molecules or
cells
Replace or supplement
naturally occurring molecule
Mimic or modify naturally
occurring molecules or cells
Chemical or via host cells;
chromatographic,
spectrometric,
Structural, sequencing,
bioassay
Parenteral
Unable to cross biological
barriers
Poor
More expensive due to their
high development and
manufacturing costs
More safe and has higher
efficacy due their specific
action. High quality due to
production process.
34
 how elements are handled
through production
processes.[27]

Medicines are produced Manufacturing processes for

Production Process
according to the national
formulary and
Good Manufacturing Practices
(GMP) standards.
biopharmaceuticals are
highly complex and require
hundreds of specific
isolation and purification
steps. [28]

2.3 AVAILABILITY OF BIOPHARMACEUTICALS

The availability of biopharmaceuticals has been increasing over the past decade and it is
estimated that by 2010 around half of pharmaceuticals is from biopharmaceuticals. The first
generation of such products was of non-human origin, such as bovine-insulin, streptokinase or
staphylokinase. These were followed by natural products of human origin, such as growth
hormone or factor VIII. The more recent preparations include human recombinant DNA
[29]
products, such as interferon (IFN)a 2a, IFNb, erythropoietin, insulin and growth hormone. In
the study of Prices And Availability Of Biopharmaceuticals, sales of biopharmaceuticals in the
United States are six times larger than Biologics market in Japan and US has highest highest
biopharmaceutical share (12.9 percent) of total drug spending among all countries studied which
are France, Germany, Italy , United Kingdom and Japan. Recently, from 2001 to 2005 others
countries spend more rapidly on biologics grew than in the US except Japan and Mexico. The
biopharmaceuticals is spent depend on the compounds available and on the use and prices of
those compounds. The United States leads in the availability of biopharmaceutical molecules,
then Germany, France, Spain and the United Kingdom. Similarly, of the sixty nine new biologics

35
launched since 1996, the United States still the highest percentage of availability of
biopharmaceuticals.[30] Even though only 6.3 percent of all molecules available in the United
States in 2005 were biologics, 18 percent of new molecules approved in the United States since
1996 have been biologics. The resulting sample includes 152 biologic molecules, of which 22 are
available only in and 39 are not available in the United States. We followed the IMS
classification of products by therapeutic class, such as antineoplastics, blood products, vaccines,
and so on. The availability of such molecules has revolutionized the way we treat many diseases
including anaemia associated with renal dysfunction.

2.4 GENERIC BIOPHARMACEUTICALS PRODUCTS / BIOSIMILARS

Biosimilars or similar biological medicinal product is the consequent production of

follow up patent-free biotechnological drugs, which have already expired or will expire in next
few years (including Humulin®, Intron A®, Procrit®/Eprex®, andNeupogen®) and have similar
ingredient to the lead product but not necessarily change in the clinical. [25][31][32]

The issues that causes for concern of the biosimilars include testing for similarity and
comparability of the biosimilars with the originator products, as well as guidelines for long-term
pharmacovigilance programmes and assessment of potential complications arising from both
short and long-term use. A challenge for biosimilar manufacturers is to demonstrate that their
products have enough similarity to the originator product, in addition to show constancy of
quality between different production runs from their own manufacturing facilities. The
maintenance of consistent product efficacy is also important in order to avoid product
“overdosing” and the connected risks of adverse events to occur. [28]

Bioequivalence of a drug is achieved if it‟s extend and rate of absorption are not statistically
different from those of the reference product when administered at the same molar dose.
Bioequivalence study can be conducted to compare two medicinal products containing the
similar active ingredient. So, bioequivalence study can be used to test the biosimilars. Several
test can be used to assess equivalence which include comparative the bioavailability studies, in
which the active drug substance or one or more metabolites is measured in an accessible

36
biological fluid such as plasma, blood urine, comparative pharmacodynamics studies in humans,
comparative clinical trials and in- vitro dissolution tests.[33]

Biosimilars has price lower than the originator due to the lower development costs such as
recombinant human erythropoietin and human growth hormone. The development of biosimilars
is more complex than that of synthetic generic drugs, it is impossible to produce same
biosimilars from the originator protein. Slight differences in the product such as formulation and
packaging can have serious consequences for the patient. With the potential to reduce health care
costs, it is clear that biosimilars are going ahead. However, patient safety should be the first
consideration. So, much work still needs to be done in order to show that biosimilars are as safe
and effective as their originator products. [31][34]

2.5 CURRENT BIOPHARMACEUTICALS IN CLINICAL TRIALS

2.5.1 BACKGROUND

Currently, there has been estimated that around 418 medicines including vaccines have been
produced through biotechnology in different stages of development in order to cure more than
100 diseases. This includes medicines and vaccines to treat cancer, infectious disease,
autoimmune disorders, HIV Infection and related-conditions, cardiovascular diseases,
monoclonal antibodies targeting asthma, lupus and various types of cancer, antisense products as
potential treatments for cancer and heart disease and also gene therapy testing in cancer and heart
disease.[35][36]

Majority of these clinical trial are directing for life-threatening disease or disease which the
current therapies is not really effective such as HIV and certain cancer. Apparently, the most
popular disease target is cancer which show large number of previous and ongoing clinical trial.
Meanwhile, cardiovascular disease appears to be less popular as choice for current clinical trial
eventhough the fact that it is the most promising disease target. [37]

Monoclonal antibodies are one of the rapidly developed classes of biopharmaceuticals, with
more than 200 products in clinical evaluation and also in preclinical development. These

37
products are being produced in order for treating a large number of chronic diseases especially
arthritis, cancer, infection, inflammation and cardiovascular diseases.[38]

2.5.2 PROMISES & PROSPECTIVE USES

Technology that is used for producing biopharmaceuticals have evolved over a few decades and
will continue to do so even in the future. Biopharmaceutical therapies promises to be an effective
yet safe treatment in the future which will soon cure disease and replace traditional therapy.
For example, in improving of therapeutic angiogenesis, new vectors can be used in order to
reduce possible risk for immune response and also other gene regulation expression system to
enhance clinical safety and efficacy. [37]

However, in achieving the goal to cure diseases, pharmaceutical biotechnology faces a lot of
hurdles especially during the clinical trials. Among them, lack of funding is a major constraints,
especially for new biotech companies[39].These obstacles must be overcome in the future so that
success rate of these clinical trial will be of a great success.

We cannot expect a complete recovery from the initial treatment with any biopharmaceutical
therapies. It has been a phenomena that most patients, including their families that suffer from
life-threatening heredity diseases are very keen to participate in early clinical trials even with the
very minimum possibilities that the original experiments will alleviate symptoms. However,
potential benefit of these treatment must always balanced with the associated risk for each
clinical trial.

The biopharmaceutical technology is still in its infancy. In order to improve the better effect on
treatment of disease, a better understanding and information from clinical application of the
product might give a new insights into direction of future research and clinical trials. [40]

38
 2.5.3 SUCCESS RATE

Many current biopharmaceuticals are being studied in clinical trials. Although all of these studies
reported positive effects, most of the trials were small, and study methodology and reporting of
data were generally of poor quality. Most of the trials were uncontrolled. The biopharmaceutical
industries are among the most research-intensive industries and have been the main highlight of
several studies because of the cost benefit and social return on research and development. The
new drugs that are developed have given effect on increased longevity, worker productivity, and
savings in other types of medical expenditures.

Different division of biopharmaceutical and healthcare sectors such as therapeutics, diagnostics,

stem cell research, healthcare related bioinformatics and animal health care had made a great
achievement in this field. For example, India has produced a recombinant hepatitis B vaccine,
insulin, erythropoietin, granulocyte colony-stimulating factor, interferon, and streptokinase with
great success. This is proven with the development of the first locally recombinant hepatitis B
vaccine named “Sanvac” that has reduced the cost for local consumer compared to imported
price[39].

For other example, there has been a positive results in safety and efficacy of ex vivo gene
delivery of a pre-clinical studies on nerve growth factor gene therapy for Alzheimer disease.
Therefore, further phase I clinical trial is undertaken involving 8 individual with mild Alzheimer
disease. [41]

However, clinical research also encounter its own barrier like high costs, slow results, lack of
funding, burden from the regulatory body, fragmented infrastructure, incompatible databases,
and lack of qualified investigators and willing participants. These obstacles may block the further
development and success of clinical studies.[42]

39
2.6 OTHER THERAPEUTIC TECHNOLOGIES FROM BIOTECHNOLOGY

2.6.1 Gene Therapy

Introduction and overview

Gene therapy can be shortly termed as the use of genes for therapeutic effects. The therapeutic
effects may be achieves by either expressing therapeutically beneficial protein or correcting
genetic abnormalities in human body. Gene therapy is used to treat human disease and is
important especially for the replacement of a defective or missing enzyme or protein. Since
many hereditary diseases are caused by defects in single genes, the potential of this technique in
treating human disease is promising. Gene therapy can be considered similar to organ
transplantation in the sense that the tissue transplantation from normal donors will also results in
the transfer of normal genes into the patient but apparently the techniques between both of them
are very different.[43]

The gene therapy offer much promise that yet to be realized. This is because of some factors that
prevent gene therapy from becoming an effective form of treatment. These obstacles comprises
from developing reliable vectors, consistently ensuring safety, targeting the correct cells, and
preventing genetic changes from being passed on from parents to children. [44]

Although at this time no clinical trial has been seen as a breakthrough in overcoming all these
barriers, gene therapy is a very active area of research. Researchers hope that with continued
study, advances in gene therapy will eventually make it a practical approach to treating disease.

The ethics issues revolving around gene therapy in humans is not very uncommon nowadays. On
contrary, it has been widely debated for many years still talk about it in present. Most of the
people that concern about this issues believes that it would be acceptable to insert genetic
material into a human being if the purpose is to correcting a severe genetic abnormalities in that
patient which involves somatic gene therapy. Whereas, any action to correct germ cells by doing
gene manipulation in order to enhance or improve a person‟s gene do not have acceptance at this

40
time. However, it is toleratable for a patient suffering a serious genetic disorder with a condition
that it is being carried out under the same strict criteria that cover other new and experimental
medical procedures. [45]

Procedures

The disease that is to be treated must be well understood and the faulty gene involved in that
disease must be identified. The gene involved must be copied to replace faulty gene and target
cell in the body must be identified and readily accessible. Besides, a suitable gene delivery
system or vector must be available to efficiently deliver and expressing the copies of the gene to
target cells with low adverse effects. [40][46]
Among the vectors that are used as delivering system are harmless virus and also stem cells. By
using harmless virus as a vector to carry genes into target cells, the virus genes is removed from
its own structure and is replaced by the human gene. Then, the genetically modified virus can be
inserted into target cell efficiently. [47]
Another vector that is used as a delivery vector is stem cell which is any precursor cell or a cell
whose daughter cells may differentiate into other cell types with different functions. Human gene
can be inserted into them but before that the stem cell need to be altered accordingly through
appropriate procedure so that they can easily accept human genes that can change their behavior.
For instance, a patient with cancer that is undergoing chemotherapy will be of great advantages if
he is previously undergo stem cell transplantation where the gene inserted might be able to
survive chemotherapy and produce new protein that is destroyed during the procedure. [47]
The transfer of recombinant genes into target cells require appropriate techniques which can be
divide into 4 categories. First is viral RNA viruses (or retroviruses) and viral DNA. Second is
through chemical like calcium phosphate-mediated DNA uptake. Third is fusion of DNA-loaded
membranous vesicles, such as liposomes to target cells. The last one is physically through
microinjection or electroporation.[48]

41
Mechanism of Action

Gene therapy is relatively a very intricate process. Sometimes, it is not fully understood. It
involves a number of complex process ranging from transport to organ, tissue targeting, cellular
trafficking, regulation of gene expression level and duration, biological activity of therapeutic
protein, safety of the vector and gene product and much more. [40]
Following vector delivery in the circulation, the receptor on the target tissue will recognize the
vector. [40]The vector carrying the gene of interest into the target cell not just deliver the gene but
also is capable of inserting the human gene that is being carried into the genetic makeup of the
cell and integrated in the cell‟s DNA.[47]

This is done when the vector is taken up by the cell, trafficking to the nucleus and vector DNA is
delivered in to the nucleus. The previously transplanted gene can then function by delivering the
instructions and information through DNA transcription and RNA translation in order for the
target cell to synthesis the protein that is damaged, missing or altered. The resulting protein may
act as autocrine, paracrine or even enter the circulation to act on distant target cell and interact
with the receptor on target cell to elicit biological response. [47] [37]

Success Story

Gene therapy hold a great potential for success in improving human health. Gene therapy is a
promising area of research; however it is not completely perfect. Some clinical trials have
recorded successes but apart from that, some gene therapy related trial ends in tragic events. For
example, gene therapy–related death of Jessie Gelsinger and other unreported gene therapy–
related complications.[38]

But, several significant barriers stand in the way of gene therapy becoming a reliable form of
treatment. The barriers include developing reliable vectors, consistently ensuring safety,
targeting the correct cells, and preventing genetic changes from being passed on from parents to
children.[44]

42
Most successful gene therapy approaches must meet a few requirements in order to effectively
elicit therapeutic effects while at the same time minimize the adverse effects. Among the the
requirements are using therapeutically suitable genes, approve safety and efficacy in appropriate
pre-clinical model and also suitable manufacturing and analytical process for clinical
investigations. The success of gene therapy is also greatly rely on suitable gene delivery system
or vector that can selectively and efficiently deliver and expressing a gene to target cells with
[37][38][46]
low adverse effects. However, it is important to note that every gene therapy approaches
has its own barrier to overcome like

One of the clinical trials that has been seen as a success in this field is Phase I Clinical Trial of
Nerve Growth Factor Gene Therapy for Alzheimer Disease. In this clinical trial, Alzheimer
disease which is a neurogenerative disorder with loss of cholinergic neuron function is treated by
using nerve growth factor (NGF) which also delay aging, enhance memory and prevent
cholinergic injury[49].We hope that with continued study, advances in gene therapy will
eventually make it a practical approach to treating disease. It also been found that NGF gene
delivery has three potential beneficial effect. First, NGF cause „trophic‟ response with growing
of cholinergic axon into the site of NGF delivery. Second, the glucose uptake by cortical
nervous is increased. Thirdly, the progress of the Alzheimer‟s disease seemed to be delayed. [49]

The Role Of Human Genome Project In Gene Therapy

Human Genome Project is the most well-known successful project involving with gene therapy.
Human genome project involve with the access to whole genome sequences for a large number
of organisms and in the future the whole process of discovery in molecular and cellular biology
is about to make a difference. Based on this project, researchers started to develop interest in
order to understand of the precise mechanisms at molecular level that is responsible for a vast
number of human disease processes.[50]The genetic message encoded in DNA will not just help
to explain how human function as a living thing but also explain at the chemical level, the impact
of genetic factors that is responsible for a vast number of fatal disease. By understanding this
process, the genetic factors can be altered to treat those disease like Alzheimer‟s disease, cancer
and other more. [51]

43
CHAPTER 3.
ROLE OF PHARMACIST IN
PHARMACEUTICAL DISPENSING
3.1 REQUIRED KNOWLEDGE

Therapy with biotech drugs is rapidly growing, ever changing area of therapeutics.
Pharmacist need to keep informed of current information about existing agent such as new
indications, management of adverse effects, result of studies describing drug interaction or
changes in information regarding product stability and reconstitution. Pharmacists will also be
interested in the status of new agents as they move through the FDA approval process.[52]
To be a confident provider of biotech products, a pharmacist must remember the
contemporary understanding of the immune system, autoimmune disease and mechanism of
actionby which drugs modify the immune system. Pharmacist must recognize biotechnology
primarily refers to a set of tools that has allowed great strides to be mad in basic research, the
understanding of disease and development of new therapeutic agent. It is essential for
pharmacists to have a basic understanding of recombinant DNA technology and monoclonal
antibody technology. Pharmacist may need to review or learn a new thing about protein
chemistry and those characteristics that affect therapeutic activity, product storage and routes of
administration of these drugs. Apart from this textbook, several publications, videotapes and
continuing professional education programs from industry and academic institutions are
available to pharmacists for learning about the technical aspects of product storage and handling.
Pharmacist also need to become familiar with the drug delivery systems currently in use for
biotech drugs as well as those that are in development.[52]

The source of information about biotechnology is increasing especially in the internet.

Many manufacturer and specific product websites provide a variety of education material
including continuing education program for physician, pharmacist and nurses. These programs
often focus on specific disease stated as well as drug therapy. The program sometimes include
slides, videos and brochures. Since most biotechnology products are parenteral products, several
manufacturers have produced videotapes,, which show the proper procedure for product

44
administration, storage and handling. These instructional tapes are beneficial not just for patient
but also for health professional who may not be skilled in injection technique.[52]

3.2 RESPONSIBILITY

Biotechnology products may present additional challenge since they are protein and
subject to denaturation and thus requires special handling technique.

Pharmacist maybe reluctant to provide pharmaceutical care services to patient who

require therapy of biotechnology drug for a variety of reason including lack of knowledge about
the tools of biotechnology, lack of understanding of the therapeutic aspect of recombinant
protein product, lack of familiarity of the side effect and patient counseling information, lack of
familiarity of handling, storage and reconstitution of protein and also difficulty in handling
reimbursement issue.[52]

Pharmacist may review biotechnology drugs as quite different from traditional parenteral
product like familiar oral dosage form. However in most respect, the service offered by
pharmacist are the same as provided by traditional tablets or injectable products. It is important,
regardless of the product being dispensed, to ensure that the patient understands the use, dosage
regimen, potential adverse effects, proper storage and handling instructions as well as specific
training on the administration of the drug and proper disposal of unused medication. When
patients do not understand the administration and monitoring requirements of biotechnology
products, scheduling training sessions for patients or including a caregiver during the counseling
session should be considered to ensure appropriate patient care.[52]

The pharmacist is responsible for the storage, preparation and dispensing of

biotechnology drugs as well as patient education regarding the use of these products. In many
cases, pharmacists must have additional training in order to be prepared for this role. This is
especially true for pharmacist who practice in the ambulatory setting since these products are
increasingly available for administration by patient at home. Pharmacists of the future my stock
pumps, patches, time-release tablets, liposomes, implants, and vials of tailored monoclonal
antibodies. With gene therapy and gene splicing on the horizon, it is possible that the pharmacist
may eventually prepare and dispense gene therapy products tailored for specific patient.[52]

45
 Biotech products have unique storage requirements when compared to the majority of
products that pharmacist normally dispense. The shelf life of these product often considerably
shorter than for traditional compounds. For example, interferon-a2a (Roche, 2005) is only stable
in a refrigerator in the ready-to-use solution for 2 years. After the first dose, catridges may be
stored at less than 25°C for up to 28 days although refrigeration is recommended. Since most of
these products need to be kept at refrigerated temperatures, some pharmacies may need to
increase cold storage space in order to accommodate the storage needs.[52]

Since biotech product are primarily protein, they are subject to denaturation when
exposed to extreme temperature. In general, most biotech products are shipped by the
manufacturer in gel ice containers and need to be stored at 2°C to 8°C (Banga and Reddy, 1994).
Once reconstituted, they should be stored under refrigeration until just prior to use. There are few
exceptions to this rule. For example, alteplase(tissue plaminogen activator) iyophilized powder is
stable at room temperature for several year at the temperature not to exceed 30°C (86°F).
However after reconstitution, the product should be used within 8hours (Genentech, 2005). For
individual product temperature requirements, the product insert, product website or the
manufacture should be contacted.[52]

Most biotech products may adhere to either plastic or less containers such as syringes,
polyvinyl chloride (PVC) intravenous bags, infusion equipment, and glass intravenous bottles.
The effectiveness of the product may be reduced three- or four- fold due to adherence. In order to
decrease the amount of adherence, human serum albumin (HAS) is usually added to the
solutions. [52]

3.3 OPENNESS IN RECOMMENDING GENERIC PRODUCTS

Generic product has almost equal efficacy with the original drug. This is a fact as
bioequivalence studies have been done by a drug company before permitted to produce any
generic drug. They are almost the same in term of efficacy. This fact is also applies to
biopharmaceuticals. As an example, when the blockbuster drug, human insulin has its pattern
expired, other companies produced their own insulin product and be able to sell it with much
more cheaper price because they do not have to conduct clinical trials to prove that insulin really
works.

46
 Public always have the typical perception of about brand. They believes that branded and
expensive product is better than cheaper and less branded product and this typical way of
thinking, most of the time also applied to their selection of medications. It is the pharmacist
responsibility to educate the public about generic medicine. The most important thing is,
pharmacist must emphasize on the cost difference and efficacy difference between the original
and generic drug. In a way, pharmacist should recommend generic medicines to people
especially those who has lower income.

People understanding of generic medicine are important in increasing the sell and
marketability of generic products. Consequently, this will encourage local drug company within
Malaysia to produce generic drug and biopharmaceutical. Thus, promoting the
biopharmaceutical drug development in Malaysia.

Public understanding on generic product will convince the government to have

preference on generic medicine in list of drug expenditure. In long term run, lower government
burden on drug expenditure will encourage spending on other health purposes such as the health
preservation campaign.

47
CHAPTER 4.
ETHICAL ISSUES IN PHARMACEUTICAL
INDUSTRY
Pharmaceutical industry have been introduced a new and challenging issues caused by
competitive, commercial, and fiscal pressure. Ethics is the critical reflections about morality and
the rational analysis of it. Recently, have many ethical issues in biopharmaceutical and the
proposes mechanisms for their resolution. There have several factors that influence the
emergence of the pharmaceutical industry as a dominant commercial endeavor that is innovation,
successes in treating life-threatening disease and the increase affluence and the aging of the
population. Ethical and commercial standards are very regional as are standards of care, all of
which present potential for misuse. Pharmaceutical industry must minimize risks and
investments required for the development of new drugs [53].

4.1 BUSINESS ETHICS

The first ethical issues are business ethics. It includes commercial activities, contracts and
pricing, incentives and kickbacks, issues of good faith and fairness, liabilities and litigation.
Most large companies and internal mechanisms establish the industry and corporate standards
such as ethics ombudsman, active compliance and ethics training. To ensure the compliance,
companies need to establish and vigorously defend a corporate culture and ethical philosophy.
Many countries have regulatory and legal protections including anti-trust, competitive
surveillance and legislation to thwart efforts to exploit differences. Major factor which influence
business to perform according to ethical standards is consumer and governmental advocacy. The
power of public exposure of unethical behaviors often drives companies to reform well before
legislative actions are required [53].

Before this, the issues of insulin become the hot topics because it is produced from pigs
which cause strife among the people. However, the issue was solved after a fatwa issued that it
can be used if no choice. Many more issues of legitimate-illegal drugs produced not been
answered. That confusion is referring to the method involves the preparation of some medicines

48
through biotechnology techniques involving mixing materials doubtful. Practical method must
be carried out to convince Muslims for the lawful status of illegal drugs. We do not want drugs
used in the market now misleading the community. This misunderstanding must to be explained
through discussion between scientists and scholars that biotechnology can benefit the society.
Bioethics National Committee that suggested could be responsible for ensuring the participation
of scholars in any form of research involving biotechnology [58].

4.2 SOCIAL BEHAVIOR ETHICS

The second ethical issues are social behavior. This includes the openness of information
sharing, risk mitigation for patients and customers, and local investment. Refer to openness of
information sharing, ownership of information generated in clinical trial was assumed to be
exclusive to the company providing the financial support for the development. However the
information of patient who volunteered to participate often with little or no remuneration and
potentially subjected to life-endangering procedures or placebo treatments for their disease was
gathered by healthcare professionals [53].
Refer to risk mitigation for patients and customers, its show the improvements in
diagnoses, detection and understanding of pathology that lead to increasing in efficacy of a new
drug. Adverse drug reactions is relatively rare or infrequent and it may only become evident after
thousands or more uses of a given drug. The reasonable expectations for assessment of potential
side effects must be balance with introducing a new therapy which requires careful consideration
so as to minimize risks to patients while maximizing the utilization of important therapeutic
options. Next is local investment. There have ethical challenge since failure to return the benefits
from commercialization of a drug to the communities which lead to exploitation occur. The
formation of new therapy becomes unaffordable to the healthcare system because of standards of
care [53].
Besides, health practitioners must have ability to decide something and have the power to
act upon your decisions. They also must respect the individual autonomy of others. The decisions
you make must based on research and rational thinking but not emotional. Make sure decisions
you make not give the worst to the others in the future. The health practitioners must tell the
truth to the patients about everything such as drugs uses, treatments, and side effects. It is

49
difficult to mitigation of social behavior violations because it requires primarily a mandate from
consumer and advocacy groups for good corporate citizenship. Therefore, patients organizations
like the World Hemophilia Foundation have been effective in requiring industry to meet
minimum requirements to support and protect patients. Industry must do well to make
investments to allow the debate and balanced recommendations for standards and resolution of
complex issues [54].
Subsequently, the other way to solve this ethical social behavior is employees are
encouraged to talk to supervisors, managers or other appropriate personnel about observed illegal
or unethical behavior and, when in doubt, about the best course of action in a particular situation.
Employees, officers and directors who are concerned that violations of this Code or that other
illegal or unethical conduct by employees, officers or directors of the Company have occurred or
may occur should either contact their supervisor or superiors. If they do not believe it appropriate
or are not comfortable approaching their supervisors or superiors about their concerns or
complaints, then they may contact the company‟s legal counsel [53].

4.3 ETHICAL DRUG DEVELOPMENT

Lastly is ethical drug development. Testing of an already licensed drug for a new
indication for which no comprehensive medical proof exists of efficacy yet, it is already in use
requires a placebo control. Health practitioners have considered the standard of care that includes
usage of the drug for the indication is unethical to subject a patient to a placebo arm. To avoid
this ethical dilemma, testing can be done in country where this standards dose not exists but
successful demonstration of efficacy may present a financial burden to the local health care
budget. Improvement over the existing standard of care is required by drug development to
justify drug licensure. The testing becomes hurdle with increased risk for the development in a
region with a high standard compared to low standard [53].
The ethical implications need to be measured against the advance of therapeutic options
for the disease if the therapy ultimately cannot be marketed in that region. Next is safety
standards and quality of care. Existing standards may not be adequate as medical research
advances into previously unconsidered areas because exploitation of regional is difference that
lead to ethical dilemma. Last but not least is post trial treatment. If marketing of the therapy is

50
not planned or uncertain it will cause a bad expectation by a sponsor. Medical society positions
are important as a local Institutional Ethical Committees, although these often do not enter into
the broader debate represented by some of the issues mentioned. Public debate of the issues is
most important to do whether in sponsored forums and scientific meetings by patient advocacy
groups or expert opinions offered by institutions like the Bayer International Bioethics Advisory
Council [53].

51
CHAPTER 5.
CONCLUSION & FUTURE DIRECTION

5.1 PERSONALIZED MEDICINE AND HEALTHCARE

The aim of personalized medicine or individualized treatment is to match the right drug
to the right patient and, in some cases, even to design the appropriate treatment for a patient
according to his/her genotype. This report describes the latest concepts of development of
personalized medicine based on pharmacogenomics, pharmacogenetics, pharmacoproteomics,
and metabolomics. Basic technologies of molecular diagnostics play an important role,
particularly those for single nucleotide polymorphism (SNP) genotyping. Diagnosis is integrated
with therapy for selection of the treatment as well for monitoring the results. Biochip/microarray
technologies are also important and finally bioinformatics is needed to analyze the immense
amount of data generated by these various technologies.[55]

Pharmacogenetics, the study of influence of genetic factors on drug action and

metabolism, is used for predicting adverse reactions of drugs. Several enzymes are involved in
drug metabolism of which the most important ones are those belonging to the family of
cytochrome P450. The knowledge of the effects of polymorphisms of genes for the enzymes is
applied in drug discovery and development as well as in clinical use of drugs. Cost-effective
methods for genotyping are being developed and it would be desirable to include this
information in the patient's record for the guidance of the physician to individualize the
treatment. Pharmacogenomics, a term that overlaps with pharmacogenetics but is distinct, deals
with the application of genomics to drug discovery and development. It involves the mechanism
of action of drugs on cells as revealed by gene expression patterns. Pharmacoproteomics is an
important contribution to personalized medicine as it is a more functional representation of
patient-to-patient variation than that provided by genotyping.A 'pharmacometabonomic'
approach to personalizing drug treatment is also described.[55]

Biological therapies such as those which use patient's own cells are considered to be
personalized medicines. Vaccines are prepared from individual patient's tumor cells.

52
Individualized therapeutic strategies using monoclonal bodies can be directed at specific genetic
and immunologic targets. Ex vivo gene therapy involves the genetic modification of the patient's
cells in vitro, prior to reimplantation of these cells in the patient's body.

Various technologies are integrated to develop personalized therapies for specific

therapeutic areas described in the report. Examples of this are genotyping for drug resistance in
HIV infection, personalized therapy of cancer, antipsychotics for schizophrenia, antidepressant
therapy, antihypertensive therapy and personalized approach to neurological disorders. Although
genotyping is not yet a part of clinically accepted routine, it is expected to have this status by the
year 2014.[55]

Several players are involved in the development of personalized therapy. Pharmaceutical

and biotechnology companies have taken a leading role in this venture in keeping with their
future role as healthcare enterprises rather than mere developers of technologies and
manufacturers of medicines.

Ethical issues are involved in the development of personalized medicine mainly in the
area of genetic testing. These along with social issues and consideration of race in the
development of personalized medicine are discussed. Regulatory issues are discussed mainly
with reference to the FDA guidelines on pharmacogenomics.[55]

Increase in efficacy and safety of treatment by individualizing it has benefits in financial

terms. Information is presented to show that personalized medicine will be cost-effective in
healthcare systems. For the pharmaceutical companies, segmentation of the market may not
leave room for conventional blockbusters but smaller and exclusive markets for personalized
medicines would be profitable. Marketing opportunities for such a system are described with
market estimates from2009-2019.[55]

Profiles of 222 companies involved in developing technologies for personalized medicines, along
with 414 collaborations are included in the part II of the report. Finally the bibliography contains

53
over 570 selected publications cited in the report. The report is supplemented by 59 tables and 17
figures.[55]

5.2 GENETIC TESTING

Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or
proteins. Most of the time, testing is used to find changes that are associated with inherited
disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or
help determine a person‟s chance of developing or passing on a genetic disorder. Several
hundred genetic tests are currently in use, and more are being developed.[56]

Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about
whether to be tested is a personal and complex one. A genetic counselor can help by providing
information about the pros and cons of the test and discussing the social and emotional aspects of
testing.[56]

Genetic tests are tests on blood and other tissue to find genetic disorders. About 900 such tests
are available. Doctors use genetic tests for several reasons[57]. These includes

* Finding possible genetic diseases in unborn babies

* Finding out if people carry a gene for a disease and might pass it on to their children

* Screening embryos for disease

* Testing for genetic diseases in adults before they cause symptoms

* Confirming a diagnosis in a person who has disease symptoms

54
5.3 INCREASING DEMAND OF BIOPHARMACEUTICAL

The growing population, change in disease patterns, and demand for new medicines to
combat these diseases are leading to increased demand for biotechnology drug, vaccines and
diagnostics products. The biopharmaceutical market is a strategic and highly competitive one.
There is untapped potential for companies that are properly positioned as it is a market where
high growth and rapid rise in profit is expected. Biogenerics, genomics and proteomics
expansion are likely to impact market growth. Transgenic, stem cell and cloning technologies are
a becoming a reality and will affect the biopharmaceutical manufacturing market. The future
holds many expectations for further development and implementation of transgenic technologies,
although there will doubtless be more debate on the ethical issues. [58]

Advances in bioinformatics will have a direct impact on drug discovery and target
validation. Another important aspect for the future is alternative formulation technologies, which
improve patient convenience and ease of administration. Improvements in scale and yield of
protein and antibody production are also next. This will increase availability of these and future
important biopharmaceuticals. [58]

Companies will look to differentiate and consolidate, with a move from the small
molecule blockbuster model to the biopharmaceutical model. Also, biopharmaceutical
companies will be looking to take advantage of a one-stop-shop to promote a complete portfolio
of their products under one brand, with more and more companies moving into niche areas of the
biopharmaceutical market. Additionally, greater public awareness and acceptance of
biopharmaceuticals will be evident. [58]

55
5.4 RELEVANCE OF BIOTECHNOLOGY FOR PHARMACEUTICALS AND
HEALTHCARE SERVICES
The application of biotechnology in healthcare and also in production of medicine brings
uncountable benefits for human as whole. What biotechnology can do is unimaginable. For sure,
it will transform the traditional healthcare services as we knew itbefore.

5.4.1 CONTINUOUS PROFESSIONAL EDUCATION IN BIOPHARM

Biopharmaceutical industry requires the knowledge of pharmacist and biotechnologists,

as well as other professionals. With the advancement of the biopharmaceutical industry, this field
will requires more people to join in this field. Thus, from time to time this field opens the job
opportunities for those who qualify.

As job market in biopharmaceutical industry skyrocketing, there will be a necessity for a

more carrier-focused professional education in university for students interested to work in this
area. Biopharm will be the carrier-focused education for future employees of this field.
Continuous study in this field in provides knowledgeable staffs that can work with this industry
or to do research related to this area. With this more focus professional education,
biopharmaceutical industry will grow extensively with the well-prepared staffs and it will be
very advance in bringing the drug industry forward to achieve its highest potential. Hopefully
our country will also be interested in starting our own biopharmaceutical industry within this
country.

5.4.2 GENETIC COUNSELING/GENETIC TESTING SERVICES AND

AFFILIATED SERVICE

Genetic counseling is important in this growing era of healthcare biotechnology. Through

genetic counseling, worst case scenario can be prevented. But the people who qualify to do the
counseling are not a counselor, but medical staffs themselves as they knew their biology. Genetic
testing service should be offered to the public. By doing this, the risk of error in new-born will
decreased. Chromosomal DNA abnormality can be detected earlier and with the existing
technology, genetic disorder later in one‟s life or in one‟s offspring can be prevented. Through

56
genetic tesing, early cancer risk identification also can be obtained.By this test, the risk can be
lowered by proper eating and proper exercise. Paternity testing service should be available to
public. Risk assessment test for common diseases like diabetes and etc can also be made.

5.4.3 PATIENT EDUCATION OF BIOPHARMACEUTICALS

Publics still lack of knowledge about biopharmaceuticals. Generalization of the term

“medicine” or “drug” by the health professionals when talking to the public in daily life
conversation bring this thing to the worst. Before stepping future to enrich people‟s knowledge
about biopharmaceutical, firstly we must make sure that people aware of the differences of
traditional medicine and biopharmaceuticals. The most important thing is, to aware the existence
biopharmaceutical itself.

Knowledge of the different types of drug will give choices to public on selection of
drugs. Plus, by knowing the differences, it is easier for public to use and manage
biopharmaceutical differently from pharmaceutical product. Public should be taught on how to
use it, how to store it and also need to know about the drug expiry date and etc. Proper
explanation should be made to the public especially to those who use biopharmaceutical products
in the long term.

To educate the entire public, healthcare providers should play their role in preparing and
providing informational materials such as brochures and posters in the hospitals or in community
pharmacies on biopharmaceuticals. Explaining from one person to another is vital but not an
efficient way of transferring information to the entire public. Campaign should be done to
increase public understanding on biopharmaceutical, because it will give a great impact and big
difference in people‟s knowledge about the typesof medicine.

5.5 PROBLEM RELATED TO COST

Biopharmaceuticals and the industry undeniably improve healthcare services medicinal

wise, but the main challenge of this industry will be the cost. Research and innovation in
biopharmaceutical field really cost a lot. Starting up the industry is just impossible without big

57
financial support. Even a bottle biopharmaceutical product can cost hundreds or thousands. What
about a life time needs of biopharmaceutical? It is just unimaginable expensive.

Patients who need biotech drugs have experienced difficulty obtaining them and having
their costs covered by private health insurance. Availability always has been an issue, and
payment mechanisms have been very complicated. Many patients had their local pharmacy order
the medication, which often required immediate payment and later submission of the claim to
insurance. The high cost of these drugs presented its own dilemma, and the high rate of rejected
claims led to a precarious fiscal situation for all but the wealthiest of patients.[59]

Subsidization of biopharmaceutical product is necessary in certain situation. Every

citizen should have the right to obtain the best medicine to treat their diseases just like their right
to continue living.

5.5 CONCLUSION

Biotechnology in the field of health care promises answers for many diseases which have
remained mystery to the researchers and it increase our quality of life. Pharmacists on the other
hand should prepare themselves with biotechnology knowledge to be competitive in the future.
and should not be left out in this advancing field. In the near future, the biological correction
pencil will change. It will be easier to hold. It will erase problems more cleanly. It will be
sharper, letting us redraw the picture more precisely. Who do you think should hold that pencil?
It should be a pharmacist who can perform ensure responsible use and promote improved quality
of life for patients[59].

58
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CONTRIBUTORY
 CHAPTER 1-INTRODUCTION (REFERENCE 1 TO 3)
BY: NURUL FATIN BINTI ABDUL AZIZ

 CHAPTER 2.1-BIOPHARMACEUTICAL (REFERENCES 4 TO 26)

BY: NUR SHARIFAH KHAIRINA BINTI MASHOD

 CHAPTER 2.2-THE DIFFERENCES BETWEEN TRADITIONAL DRUGS AND

BIOPHARMACEUTICALS (REFERENCE 27 TO 28)
CHAPTER 2.3-GENERIC BIOPHARMACEUTICALS PRODUCTS /
BIOSIMILARS (REFERENCE 29 TO 34)
BY : NOR ASYKIN BINTI HAMID

 CHAPTER 2.4- CURRENT BIOPHARMACEUTICALS IN CLINICAL TRIALS

CHAPTER 2.5-GENE THERAPY (REFERENCE 35 TO 49)
BY: NUR SHAFINA AKMA ZAKARIA

 CHAPTER 2.5.5-THE ROLE OF HUMAN GENOME PROJECT IN GENE

THERAPY
CHAPTER 3-THE ROLE OF PHARMACIST IN PHARMACEUTICAL
DISPENSING
(REFERENCE 50 & 52)
BY: NURASHIKIN BINTI MAZLAN

 CHAPTER 4-ETHICAL ISSUES IN BIOPHARMACEUTICAL (REFERENCE 53)

BY: NOOR ERLIANA

 CHAPTER 5-CONCLUSION & FUTURE DIRECTIONS (REFERENCE 55 TO 59)

BY: NURASHIKIN BINTI MAZLAN

 FRONT PAGE DESIGN BY NURUL FATIN BINTI ABDUL AZIZ

 BOOKLET EDITOR: NURASHIKIN BINTI MAZLAN

64