1

2

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

3

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

4

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

5

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

6

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

7

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

8

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.

9

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

10

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

11

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

12

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

periodic syndrome (CAPS) *SIMPONI Rheumatoid Arthritis

arthritis *IXIARO Japanese Enchephalitis Vaccine

enitis *ATRYN Antithrombin deficiency

13

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

14

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

15

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

2)glass bioreactors such as spinner flasks and

plastic bioreactors such as hollow fiber

bioreactors are used as well

Suspension (or attached) cells transformed

with expression vectors genetically engineered

to contain one (or more) human genes that

produce copious amounts of their protein(s).

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

16

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

17

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

18

1.http://en.wikipedia.org/wiki/Downstream_processing

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 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.

19

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]

20

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]

21

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

22

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

encounters. [15]

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

23

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.

24

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]

25

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

26

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

27

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]

28

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]

29

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

30

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.

31

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

32

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

33

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

34

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.

Traditional Drugs Biopharmaceutical

Structure mechanism Small molecule

Moderate protein activity

Large complex molecules or

cells

Replace or supplement

naturally occurring molecule

Discovery High-throughput screening

rational drug design

Mimic or modify naturally

occurring molecules or cells

Manufacturing analysis Chemical method;

chromatographic and

spectrometric

Chemical or via host cells;

chromatographic,

spectrometric,

Structural, sequencing,

bioassay

Route of administration Oral, rectal, pulmonary,

vaginal, topical, parenteral.

Parenteral

Transport Transport across biological

barriers

Unable to cross biological

barriers

Stability Good Poor

Price Cheaper More expensive due to their

high development and

manufacturing costs

Safety, efficacy and Quality

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

More safe and has higher

efficacy due their specific

action. High quality due to

production process.

35

how elements are handled

through production

processes.[27]

Production Process

Medicines are produced

according to the national

formulary and

Good Manufacturing Practices

(GMP) standards.

Manufacturing processes for

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

products, such as interferon (IFN)a 2a, IFNb, erythropoietin, insulin and growth hormone. [29]

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

36

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

37

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

38

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]

39

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]

40

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

41

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]

42

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]

43

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

low adverse effects. [37][38][46]

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]

44

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

45

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]

46

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.

47

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.

48

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

49

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

50

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

51

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].

52

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.

53

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

54

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

55

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]

56

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

57

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

58

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].

59

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64

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