BIOPHARMACEUTICAL

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.”
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 photobioreactors.
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.
Biopharmaceutical crops also represent a risk of cross-contamination with non-
engineered crops, or crops engineered for non-medical purposes.
One potential approach to this technology is the creation of a transgenic mammal
that can produce the biopharmaceutical in its milk (or blood or urine). Once an
animal is produced, typically using the pronuclear microinjection method, it
becomes efficacious to use cloning technology to create additional offspring that
carry the favorable modified genome. The first such drug manufactured from the
milk of a genetically-modified goat was ATryn, but marketing permission was
blocked by the European Medicines Agency in February 2006. This decision was
reversed in June 2006 and approval was given August 2006.
What is Biologics?
Biologics include a wide range of medicinal products such as vaccines, blood and
blood components, allergenic, somatic cells, gene therapy, tissues,
and recombinant therapeutic proteins. Biologics can be composed of sugars,
proteins, or nucleic acids or complex combinations of these substances, or may be
living entities such as cells and tissues. Biologics are isolated from a variety of
natural sources - human, animal, or microorganism - and may be produced by
biotechnology methods and other technologies. Gene-based and cellular biologics,
for example, often are at the forefront of biomedical research, and may be used to
treat a variety of medical conditions for which no other treatments are available.
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) and can therefore
be made specifically to counteract or block any given substance in the body,
or to target any specific cell type; examples of such monoclonal antibodies
for use in various diseases are given in the table below.
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.
Biologics as a class of medications in this narrower sense have had a profound
impact on many medical fields, primarily rheumatology and oncology, but also
cardiology, dermatology, gastroenterology, neurology, and others. In most of these
disciplines, biologics have added major therapeutic options for the treatment of
many diseases, including some for which no effective therapies were available, and
others where previously existing therapies were clearly inadequate. However, the
advent of biologic therapeutics has also raised complex regulatory issues (see
below), and significant pharmacoeconomic concerns, because the cost for biologic
therapies has been dramatically higher than for conventional (pharmacological)
medications. This factor has been particularly relevant since many biological
medications are used for the treatment of chronic diseases, such as rheumatoid
arthritis or inflammatory bowel disease, or for the treatment of otherwise
untreatable cancer during the remainder of life. The cost of treatment with a typical
monoclonal antibody therapy for relatively common indications is generally in the
range of € 7,000-14,000 per patient per year.
Biosimilars
Unlike the more common "small-molecule" drugs, biologics generally exhibit high
molecular complexity, and may be quite sensitive to manufacturing process
changes. 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. Notable exceptions include several
of the earliest biopharmaceuticals made via recombinant DNA technology, including
biosynthetic 'human' insulin and human growth hormone, which are grandfathered
under the U.S. Federal Food, Drug & Cosmetic Act which addresses mainly small-
molecule chemical drugs. By comparison, vaccines and most other biotech drugs
are governed under the Public Health Services Act, which would need to be
amended by U.S. Congress and signed into law by the President to allow for
generics.
In the EU a specially-adapted approval procedure has been authorized for certain
protein drugs, termed "similar biological medicinal products". This procedure is
based on a thorough demonstration of "comparability" of the "similar" product to an
existing approved product. In the US the FDA has taken the position that new
legislation will be required to address these concerns. Additional Congressional
hearings have been held, but no legislation had been approved as of June 2008. Due
to a lack of FDA manufacturing guidelines for generic versions of synthetic insulin
and human growth hormone, generics manufacturers are caught in a bind.
The FDA announced in 2001 that it was working on guidelines for pharmaceutical
companies to produce generic versions of synthetic insulin and human growth
hormone. The Agency had long had suggested the guidelines were forthcoming, but
in April 2006, the FDA suddenly announced it would not be releasing the long-
delayed guidelines for the production of generic versions of insulin and human
growth hormone as anticipated. In a March 17, 2006 letter obtained by the
Associated Press, which was written in response to a Feb. 10, 2006 letter from Sen.
Orrin Hatch (R-UT), and Rep. Henry Waxman (D-CA), the FDA associate
commissioner for legislation Patrick Ronan said that the FDA instead intended to
publish broader guidelines that applied to ALL generic versions of protein-based
drugs, also known as follow-on protein products, therefore the FDA would not be
outlining specific guidelines for insulin or human growth hormone.
In response, Rep. Waxman said in a statement that the Agency's action was "a
misguided step that will only result in further delay" of rules for low-cost generics.
The regulatory hiatus regarding generic versions has effectively extended the
patents for the past few years at the expense of consumers and their healthcare
providers.
In August 2006, four state governors, looking to ease drug costs under state
programs, petitioned the FDA to provide guidelines for generic versions of insulin
and human growth hormone. In their petition, the governors joined other critics in
accusing the Agency of dragging its feet.
"The FDA's delay in informing manufacturers of the requirements for obtaining
approval of therapeutically equivalent versions of insulin and human growth
hormone has cost the states and other health-care providers hundreds of millions of
dollars," the petition said. Democratic Governors Kathleen Sebelius of Kansas and
Jim Doyle of Wisconsin joined Republicans Tim Pawlenty of Minnesota and James
Douglas of Vermont in signing the petition. Since then, the governors of New
Mexico, Virginia and West Virginia have also signed the petition.
"We have been informed that there are no scientific reasons for delaying the
issuance of the guidance documents FDA already has drafted," the bipartisan group
of governors wrote the FDA. "There is no legal or regulatory obstacle to the
immediate issuance of these guidance documents," they added.
The governors said that insulin and human growth hormone is a breed apart from
other biotech medicines and should therefore be considered distinct from other
biotech drugs. Insulin and human growth hormone both have relatively simple
structures and a long history of safe use, they said.
Some major points:
A basic presumption of the author and the great majority of others in the industry
(>85% in a recent survey), particularly in the U.S., is that biopharmaceutical is a
subset of pharmaceutical, i.e., that biopharmaceuticals are pharmaceuticals
inherently (usually, very obviously) biological in nature and manufactured using
biotechnology (involving use of live organisms), while drugs comprise the other
major subset of pharmaceuticals, with their source and manufacture being chemical
(non-biological) in nature.
Small molecule and other drugs are not biopharmaceuticals!
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).
Many outside the industry, including many in the financial community and
press/media, and many within the pharmaceutical and biotechnology industries,
including the major U.S. biotechnology and pharmaceutical trade associations (BIO,
PhRMA), purposely redefine and use the term much more broadly, ignoring or even
disavowing linkage to or involvement with biotechnology, and almost always with
little or no consistency. Caution! Many promulgating these abberant
views/paradigms/definitions of what is biopharmaceutical (and biotechnology) seek
to rebrand and redefine these products, the industry and themselves to promote
their own vested interests.
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. Many obvious
biopharmaceutical products are classed as as 'old' or simply ignored, including
many products developed and approved recently and incorporating more
recent/newer technology than many recombinant proteins and monoclonal
antibodies (which are based on now 'old' technologies, invented in the 1970s and
commercialized in the 1980s).
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. By this view/definition, products, technologies and companies need not
have any involvement or use of biotechnology to be called biopharmaceutical.
Those using this definition/view include many in the press, stock analysts and,
regrettably, the Biotechnology Industry Organization (BIO). 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). Much of this (mis)use
may be traceable to what this author views as the myth of convergence. Various
industry analytical reports, including those funded and issued by the
Pharmaceutical Research and Manufacturers Association (PhRMA), assert that the
pharmaceutical industry (dominated by Big Pharma) has just recently morphed or
transformed itself into the biopharmaceutical industry as a result of the
"convergence" of biotechnology and pharmaceutical industries/technologies; that
the pharmaceutical industry, through adoption of new technologies and close
relationships (primarily outsourcing, contracting and licensing) with biotech
companies, has undergone a fundamental change; and that 'new' and
'revolutionary' technologies, e.g., high-throughput screening and drug design
methodologies, are biotechnologies and have fundamentally changed the industry.
[Thus, everything in the pharmaceutical universe is now biopharmaceutical].
This author disagrees with the later three views, particularly the Biotech and
Pharma Business views/paradigms/definitions. These simply consider to
be biopharmaceutical (or biotechnology) all/anything involving small, R&D-intensive
biomedical or life sciences (biotech-like) companies or related high-tech R&D; or
all/anything pharmaceutical. Even the lay public understands that
biopharmaceuticals involve biotechnology!

What is required for safe usage of biopharmaceuticals?

First, regarding the molecules that are called biopharmaceuticals, we should know
that they are molecules made by our cells and act upon our cells, in an extremely
powerful way. Insulin, for example, is critical for regulating the glucose metabolism
and lacking its function leads to diabetes. Interferon gamma is a protein that is
critical for the activation of the immune system to launch battles against viral
infection. These molecules act upon many cells at once and are not only potent but
also very sophisticated in every aspect of their making, modification, activation and
function. For the same cell, the molecule can do different things at different times,
at different dosages and working with different combinations of other proteins. The
responsiveness of cells to the same molecules can constantly change. Different
people's cells also can respond differently to the same dosage of the molecule,
since the responses depend upon the protein activities inside of the cells. I can go
on to list all the complications, but 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 a sources of contamination by dangerous factors
such as an undetected deadly virus.
Because of these factors, it could be a fatal mistake for policy makers to overlook
the seriousness of the issues, just because of the consideration of achieving a goal
of reducing the price of the drugs or for the sentimental pursuit of winning a
competition. Lots and lots of precious lives are involved in these decisions. While
sitting amidst a room full of people today during the hearing and listening to the
comments on trying to speed FDA approval, I had an image in my mind, quite vivid,
of the speeding Titanic, on the night of the deadly crash into the iceberg. No matter
how advanced in our intellectual pursuit, human errors due to human weaknesses,
even at one individual level, could bring the disaster to an entire nation, or even
more. This is the sadness of a scientist, who sees that the pure-hearted pursuit for
intellectual knowledge has been misused many times by irresponsible ignorance, for
an ignorant pursuit of self-gratification that disregards the fundamental laws which
the scientist honors.
Thus, I propose that the best safeguarding mechanisms we can do, in fact, is nation-
wide education. The public, who supported all the research that has led to the
current understandings of these powerful molecules, is entitled to know all aspects
of these molecules, if they are counting on the application of these molecules for
their health. The policy makers, to assure their ability to make the correct current
decision, also require an in-depth knowledge of these molecules and the art of the
management of these molecules so that wise leadership is possible. The other
critical aspect of the required education is on the science of life in general. In a
society where people's minds are dominated by competition for profit, irresponsible
actions are bound to occur. The production of biopharmaceuticals can not be
allowed to afford such irresponsibility. The real challenge we are facing is basic
human quality. Again and again, in recent years, I see the true importance of human
beings’ being able to reflect on the fundamental issues we are facing, instead of
continuously pursuing profit and immediate material benefits. This is a very big
topic which I will not extend further at present, but I recommend some of the essays
listed on our website .
Based upon these analyses, I do worry about the current state of
biopharmaceuticals in areas such as China where no safeguarding mechanisms
have been imposed. I know there are many people who are considering going to
China to start biotechnology companies for the cheap labor and loose policies. In
the past several years, we have heard bad news from China. The news was covered
up carefully and it took some very brave people to risk their safety and even their
lives to bring these issues out to the international community. These included the
HIV/AIDS crisis due to unsanitary blood collection methods, SARS of mysterious
origin, and the persecution of 100 million innocent Chinese Falun Gong practitioners
who simply believe in Truth, Compassion and Tolerance. Under such conditions, if it
is allowed for generic biopharmaceuticals to be produced and exported from China,
what will be the consequences? If American companies go into China to make
products using cheap labor, can we trust such products? Isn't it also the
responsibility of the scientific community and the government officials here to
safeguard such practices? I see an urgent need for a hearing to be called for
examining the practices in this area in China to avoid potential biotechnology
disasters.
I have also heard that FDA will hold scientific forums on this topic. Here I urge the
scientific community to take an active role in helping the government officials to
have sufficient scientific information for correct decisions to be made. It is time for
scientists to take on a new role in educating the public and all policy makers who
need health-related knowledge in order to do their job well. I also hope that the
government has new policies implemented to encourage scientists to do more dry
science, that is, to analyze and integrate the currently existing knowledge and
therefore help to reduce the amount of waste resulted from rushed or redundant
experiments, due to competition. The new non-profit organization I am working on
has the mission of delivering frontier molecular biological observations to the
general public through artistic expression and also actively enhancing the cross talk
between the ancient Eastern science and modern Western Science. My heart holds a
beautiful wish for this work to blossom for the benefit of all of us at this critical time
of history.

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