BIOPHARMACEUTICAL-AN INTRODUCTION

What is Biologics?
However, in most cases, the term "biologics" is used more restrictively for a class of
medications (either approved or in development) that are produced by means of
biological processes involving recombinant DNA technology. These medications are
usually one of three types:
1. Substances that are (nearly) identical to the body's own key signaling
proteins. Examples are the blood-production stimulating
protein erythropoietin, or the growth-stimulating hormone named (simply)
"growth hormone".
2. Monoclonal antibodies. These are similar to the antibodies that the human
immune system uses to fight off bacteria and viruses, but they are "custom-
designed" (using hybridomatechnology or other methods).
3. Receptor constructs (fusion proteins), usually based on a naturally-occurring
receptor linked to the immunoglobulin frame. In this case, the receptor
provides the construct with detailed specificity, whereas the immunoglobulin-
structure imparts stability and other useful features in terms of
pharmacology. Some examples are listed in the table below.

What is Biotechnology?
In its present form, the term “biotechnology” refers to the use of living
organisms or their products to modify human health and the human
environment.
“These are drugs produced by and harvested from living organisms.”

What is Biopharmaceutical?
Despite its definition and use being rather clear to most, there are many diverse
definitions and views of what is (and is not) a biopharmaceutical (and
biotechnology).
A pharmaceutical product manufactured by biotechnology methods
(involving live organisms; bio-processing).
A basic distinction can be made between biopharmaceuticals, manufactured by
biotechnology methods and involving complex biological molecules, and drugs,
manufactured by chemical (non-biological) means and involving small molecules
and other chemical substances.
A biopharmaceutical’s description is dependent on its identity (source), manufacture
(bio-processing) and specifications (the product-process-specifications paradigm
used in the context of discussion generic biopharmaceutical).
In US, the term is most commonly used to refer to all therapeutic, prophylactic and
in-vivo diagnostic products manufactured using live organisms or derived functional
components.
Four major views, definitions or paradigms of biopharmaceutical are
identified:
Broad Biotechnology - Biopharmaceuticals are defined as pharmaceuticals
manufactured by biotechnology methods, with the products obviously having
biological sources, usually involving live organisms or their active components
(bioprocessing; also usually very obvious; or directly involving surrogates, e.g.,
protein/gene sequences). This broad view has been adopted by Biopharmaceuticals
in the U.S. and European Markets, which includes all recombinant proteins,
(monoclonal) antibodies, vaccines, blood/plasma-derived products, nonrecombinant
culture-derived proteins, and cultured cells and tissues. This is the view/definition
most used/favored by those within the U.S. biopharmaceutical industry, and
probably best understood by the public.
New Biotechnology - This view or definition only includes those products based on
platform technologies developed in recent decades, usually only including
recombinant proteins and monoclonal antibodies as being biopharmaceuticals,
leaving out nonrecombinant cultured proteins, blood/plasma proteins, vaccines and
other classes of products. This view/definition is more predominant in Europe, e.g.,
European Union formal definitions, or is used by those whose primary/sole interest
is in recombinant and monoclonal antibody products.
Biotechnology Business - This company-centric view or definition simply includes
all/everything from biotech-like (smaller, entrepreneurial, R&D-intensive)
pharmaceutical and life science companies as being biopharmaceutical; plus
obvious biopharmaceuticals from large companies (Big Pharma). All/every non-Big
Pharma pharmaceutical or life sciences company is viewed as a biopharmaceutical
company. Many small drug R&D and service companies also describe themselves as
biopharmaceutical companies, including those designing or developing small
molecule drugs, even when their products, technologies and companies have
absolutely no use or involvement with biotechnology.
Pharma Business - This view simply includes all pharmaceuticals as
biopharmaceuticals, i.e., biopharmaceuticals is used as a synonym for
pharmaceuticals; and the pharmaceutical industry is now the biopharmaceutical
industry. Biopharmaceuticals are no longer a subset of pharmaceuticals, with
biopharmaceuticals now taking in all pharmaceutical and (Boolean OR)
biotechnology companies (with a health care orientation).

Classification of biopharmaceuticals
Blood factors (Factor VIII and Factor IX)
Thrombolytic agents (tissue plasminogen activator)
Hormones (insulin, glucagon, growth hormone, gonadotrophins)
Haematopoietic growth factors (Erythropoietin, colony stimulating factors)
Interferons (Interferons-α, -β, -γ)
Interleukin-based products (Interleukin-2)
Vaccines (Hepatitis B surface antigen)
Monoclonal antibodies (Various)
Additional products (tumour necrosis factor, therapeutic enzymes)

Uses
Erythropoietin - Treatment of anaemia
Interferon-α - Treatment of leukaemia
Interferon-β - Treatment of multiple sclerosis
Monoclonal antibody - Treatment of rheumatoid arthritis
Colony stimulating factors - Treatment of neutropenia
Glucocerebrosidase - Treatment of Gaucher's disease

Large scale production

Biopharmaceuticals may be produced from microbial cells, mammalian cell lines
and plant cell cultures and moss plants in bioreactors of various configurations,
including photo-bioreactors.
Important issues of concern are cost of production (a low volume, high
purity product is desirable) and microbial contamination
(by bacteria, viruses, mycoplasma, etc). Alternative platforms of production
which are being tested include whole plants (plant-made pharmaceuticals).

Transgenics
A potentially controversial method of producing biopharmaceuticals
involves transgenic organisms, particularly plants and animals that have
been genetically modified to produce drugs.
The production of these organisms represents a significant risk on the part of the
investor, both in terms of the risk of failure to produce the required organism, and in
the risk of non-acceptance by government bodies due to the perceived risks and
from ethical issues.

Biosimilars
The follow-on manufacturer does not have access to the originator's
molecular clone and original cell bank, nor to the exact fermentation and
purification process. Finally, nearly undetectable differences in impurities
and/or breakdown products are known to have serious health implications.
This has created a concern that generic versions of biologics might perform
differently than the original branded version of the drug. So, unlike most drugs,
generic versions of biologics are not authorized in the US or the European Union
through the simplified procedures allowed for small molecule generics.

What is required for safe usage of biopharmaceuticals?

A simple summary is that the molecules are not mechanical entities, but living
entities. To manipulate these molecules for a single-minded purpose, we need to be
fully aware of the sophistication of these molecules. Otherwise, it is like a child who
does not understand what a bomb is, playing with a bomb. However, the current
state of our science has not yet resolved the mysteries of these molecules. In fact,
no scientist can be confident enough to say that he knows the molecule so well that
its behavior is predictable. Even for insulin, a molecule that has been used as a
biopharmaceutical for so many years, its mechanisms of action are still not fully
understood, thus its actions under new circumstances are unpredictable. Now the
production of these molecules so far has been achieved in artificial systems that in
fact are very different from human cell environment. The alterations of these
molecules in these artificial systems are major and the conditions for the making of
these molecules determine the qualities of the molecules produced. The protocols
for making these molecules involve multiple steps and the application of many
different reagents, which also include biological products from animals, such as the
serum from cattle. Thus, even if the protocol for making insulin is totally
standardized, the quality of the produced insulin is determined by so many factors
along the production line that nobody can guarantee the safety of the products until
the final product is put into clinical tests. In other words, the production of a
powerful biological molecule is an art that is still only mastered by a few. Even the
few who have mastered the art cannot guarantee the safety of these molecules
without testing in a real person, since the reagents involved are fresh and could be
sources of contamination by dangerous factors such as an undetected deadly virus.

On the occasion of the ICH6 Conference in Osaka on 15 November, it has now been
decided to develop the guidelines:
• ICH Q8 Pharmaceutical Development - Quality by Design
• ICH Q9 Risk Management
To harmonize them and to implement them establishing an ICH standard in the triad
requires the following steps:
Step 1: Consensus Building
Step 2: Start of Regulatory Actions
Step 3: Regulatory Consultation
Step 4: Adoption of Tripartite Harmonized text
Step 5: Implementation