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Scott M. Wheelwright, PhD
Strategic Manufacturing Worldwide, Inc.
iopharmaceuticals are an important part of the pharmaceutical indus-
try, constituting about one-tenth of the more than $500 billion spent
on pharmaceutical products each year worldwide. Unlike small-mol-
ecule therapeutics, which are made by a series of synthesis steps from organ-
ic molecule precursors, biopharmaceuticals are recovered from living organ-
isms, typically from single cells of microbial or animal origin.
The manufacture of biopharmaceuticals is a lengthy and difficult
process. Because the starting culture consists of living organisms that are
growing and reproducing, the culture is inherently variable, and therefore the
process for manufacture must be robust and hardy, able to handle variations
in the upstream stage while producing a product that matches all the require-
ments for parenteral injection. Most biopharmaceuticals are delivered by
injection into the patient. Biopharmaceuticals are proteins, and very few
products on the market can be delivered by routes other than direct injection.
Thus the process is doubly challenged: not only is the starting material vari-
able, but also the end product must meet the highest quality requirements.
The complexity of biopharmaceutical manufacturing leads to high
costs for production. In order to realize economies of scale and benefit from
large production operations to obtain a lower cost for each dose, manufac-
turing facilities tend to be large. The capital expense can be very high, often
exceeding $500 million and rarely below $100 million.
In addition to the high capital cost, a high level of technical expertise
is required. Biopharmaceutical manufacturing is not a garage-shop opera-
tion. Large facilities with highly trained and skilled employees are required.
As a consequence of these constraints on the industry, namely, com-
plex and variable processes, stringent quality requirements, high capital
investment and technical labor skills, the commercial production of biophar-
maceuticals has been limited to large firms in the US and Western Europe.
As the industry has grown, and as biotechnology companies that have invest-
ed in their own manufacturing facilities have suffered spectacular bankrupt-
cies, the presence of Contract Manufacturing Organizations (CMOs) has
also grown. And not only have stand alone CMOs arisen, but many compa-
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nies, both large and small, have sought to mitigate the risk of owning investors or government personnel, who can influence your CMO on
and operating their own facilities by selling their excess capacity to your behalf. This is not really any different from the way we do busi-
other firms. ness in the US and Europe.
Thus the biopharmaceutical industry has grown to include two
types of manufacturing organizations: self-sustaining firms that only Intellectual Property
contract their capacity for the production of products and product devel-
The protection of intellectual property is changing in Asia, espe-
opment firms that contract with outside companies to utilize their
cially in India and China, where laws have been enacted to provide
excess capacity. The vast majority of these firms are centered in devel-
teeth for enforcement of intellectual property controls. But the key here
oped countries, particularly in the US and in Western Europe.
again is to know who you are working with. There is no substitute for
This is beginning to change.
trust and confidence. There are however some practical measures one
Contract manufacturing of biopharmaceuticals is sprouting in
can take to reduce the risk of loss due to wayward employees (some-
Asia at a prodigious rate. New stand-alone CMOs have opened their
thing that can happen anywhere).
doors and are filling up with clients. Established Asian pharmaceutical
One action is to limit what you share. In the development of a
firms are rapidly adding capacity with the expectation it will be filled
new commercial product the developing company assembles a huge
with the products of outside clients.
body of information regarding the characterization and analysis of its
In this article we will discuss the challenges of working with bio-
product. We also assemble a detailed development report that describes
pharmaceutical CMOs in Asia and we will review some of the major
our entire process development program and how we arrived at the cur-
players in this industry.
rent process parameters. There is no need to provide such information
to a contractor. So we follow a need-to-know rule: only provide the
Key Considerations for any CMO information that is needed to perform they job they are asked to do. As
Whenever I speak with a prospective client about outsourcing or we work with them and gain trust, as we solve problems together, and
when I visit a potential manufacturing site, the first consideration is as we further expand, with the CMO, our understanding of the process,
always the same regardless of the location: is the CMO compliant. we will feel more comfortable about the information we are entrusting
Conformance to cGMP regulations is the only thing that really matters to them. We can also limit the accumulation of information to a few
in the long run; a facility that is not in compliance will not obtain trusted employees. Rather than everyone in the CMO organization hav-
approval for manufacture and products made at that facility cannot be ing access to all the documents, for example, the analytical group may
sold. It is possible to bring a non-compliant facility into conformance, only have access to test methods, the production group to manufactur-
and I have worked on projects where we have had to do so because of ing data, and so on. The cell bank should be tightly controlled and held
unique technology requirements. However, the requirement for cGMP under lock and key.
compliance is inviolate: either you are in compliance or you don’t have
a product. Communication
The second key attribute of a manufacturer is technical compe-
Bringing a commercial biopharmaceutical to market is a daunting
tence. This is of critical importance in biopharmaceutical manufactur-
task under the best of circumstances. We must be frank: outsourcing the
ing because there are always problems that arise during technology
production to Asia increases the challenge. In many Asian countries the
transfer and scaleup. The ability of the CMO to efficiently resolve these
educated staff we will be working with speak fluent English. India,
problems can save a lot of time and money. Conversely, the inability to
Singapore, and Malaysia, for example, were all British colonies and
solve issues that arise can lead to costly delays and failed batches. I am
production documents are all prepared in English and the technical staff
a firm believer that the best indicator of future performance is past
are fully competent at reading and understanding them. In other coun-
behavior. Therefore, I always ask the potential CMO for examples of
tries, the senior staff will be English fluent, but documents will be bilin-
problems they have solved and the method by which they came to the
gual or in the native language. Even in countries where English is
solution. Systematic approaches to problem solving, such as Kepner-
widely spoken and understood there will be regional variations in words
Tragoe methods, can significantly increase the probability for success.
and phrases that can throw us off and lead to confusion. We must be
There are many other points for discussion with a contract manu-
vigilant in our documentation of meetings and reports to ensure that
facturing site, but I will cover only three of them that are of particular
misunderstandings are minimized.
importance when dealing with CMOs in less developed countries: legal
Sharing of issues must happen rapidly. Most highly successful
redress, intellectual property and communication.
transfers include client personnel on site at the CMO during the entire
transfer process. There is no substitute for a person in the plant who is
Legal Redress congenial and technically astute. I have seen numerous occasions
Once when working on a contract with a lawyer, I asked him why where problems were resolved early and blowups averted by the client
the agreements he prepared were so short compared to some I had seen. representative who had developed social connections with the CMO
He replied, “Some people write contracts to cover every contingency staff.
that can arise. I consider the contract a divorce agreement: if everything A part of communication is the setting of realistic expectations,
goes well and the relationship stays positive, no matter what happens, not only between the CMO and client but also within the client compa-
things will work out. It is only when the relationship sours irretrievably ny. Most of us in this industry are optimistic; if we weren’t we would
that the conditions in the contract are invoked.” have given up long ago. But that means we often underestimate the dif-
When discussing projects in Asia, clients often express the con- ficulties (and costs) for these projects. We need to develop a culture
cern that they won’t be able to effectively sue to recover damages. My that enables open sharing of issues, that rewards honest appraisals, and
response is if you plan to sue your partner don’t sign the agreement to that ensures bad news is shared early.
start with. It is critical to understand who you are working with and to
have a strong element of trust and confidence. This may require that
you establish personal relationships with other relevant people, such as
www.americanpharmaceuticaloutsourcing.com September/October 2007
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Mitigation of Risk delivered by parenteral injection. The following list shows examples of
Given the hazards we have described, what can we due to mitigate
the risks? The first thing is to formally address the risks and map out a
strategy for dealing with them. Then we need to be very thorough in our
upfront diligence. We must take enough time, make that extra visit
when needed, and start early to complete our inquiries. We must also
put the time in, which includes face time with the CMO, to ensure we
are staying on top of the issues. This is a common source of difficulty,
On the pharmaceutical side, there are many plants in Asia that are
especially among small or over-stretched firms. Taking the time to visit
fully compliant with FDA and EMEA GMP regulations. In India there
and participate in the CMO activities is the best method to reduce the
are over 70 plants that are approved by the FDA. This means they have
potential for problems getting out of hand.
undergone FDA inspection and are permitted to export drugs to the US.
As a final note of advice, the question of whether they will be suc-
These products are typically active pharmaceutical ingredients (API)
cessful is the wrong question. The question must be, “will we be suc-
that are subject to further synthesis or formulation and product manu-
cessful.” The complexity dictates that biopharmaceutical production is
facture. Chinese pharmaceutical firms have filed over 240 drug master
a team effort. The client and the CMO must be on the same team.
files with the FDA in support of the manufacture of bulk API. Japan has
a long history of exporting compliant pharmaceuticals worldwide.
A Brief History of Bioprocessing in Asia Korea and Singapore also have substantial pharmaceutical industries.
Bioprocessing has a long history in Asia. Fermentation processes Thus, we see that firms in Asia are well poised to move into bio-
have been used for centuries to produce food and beverages. In the last pharmaceutical production. They have a historical product base in bio-
hundred years a solid industry for fine chemicals and pharmaceuticals processing. They have demonstrated the ability to comply with cGMP
has been built on bioprocess technology. requirements. They have the technical capability to manufacture high
The chemical conversion of carbohydrates into alcohols and acids quality therapeutic proteins.
is an ancient process. The conversion of juice sugars into wine by the
fermentation of yeast to produce alcohol seems to exist in all cultures.
Current and Projected Capabilities in Asia
The pickling of vegetables by fermentation of lactobacilli to produce
I would now like to highlight a few of the firms capable of pro-
lactic acid is widespread throughout Asia. The transformation of milk
viding contract manufacturing services in Asia. This is only a represen-
into yogurt and soybeans by aspergilla into soy sauce are also wide-
tative list and is not meant to be comprehensive. It may contain some
errors. If I have left off your favorite firm, please contact me so that I
Fermentation processes in Asia have produced fine chemicals for
can update my database.
decades. A few examples are given in the following list.
Asahi Glass Company has a division that provides drug substance
production in microbial hosts. They currently have a capacity of 400 L
and are expanding to 3000 L. AGC also has a proprietary yeast expres-
sion system for overexpression of recombinant proteins. PAC Biologics
Pharmaceutical products have also been produced by fermentation was started under Toyobo and provides cell culture production with
in many Asian countries for decades. Examples include the following. capacity up to 4000 L. Their focus is on antibodies. There are many
firms in Japan with large scale biopharmaceutical capability that is used
for their own products and potentially for client projects, including
Kyowa Hakko and Amano Seiyaku.
Celltrion is a stand-alone CMO with 50,000 L capacity for cell
Vaccines are also widely produced in Asia. The World Health
culture that is currently fully occupied under contract to BMS. Celltrion
Organization is a major provider of prophylactic vaccines for children.
is planning to expand to an eventual capacity of 150,000 L. LG Life
The WHO has their own GMP requirements that mirror standard GMPs
Sciences is a product development firm that has microbial capacity of
such as those promulgated by the FDA and EMEA. Vaccine manufac-
20,000 L, cell culture capacity of 6000 L and aseptic filling capability,
turers who become certified by the WHO are able to sell vaccines to the
including lyophilization. They have recently offered their excess capac-
WHO, which then distributes them throughout the world. Many of
ity on a contract basis.
these vaccines consist of whole cell or partially purified extracts, or
virus preparations. I have visited vaccine plants in Asia that meet FDA
requirements for GMP compliance.
Many companies located in Asia also have a history of producing A-Bio provides contract cell culture services up to 500 L scale.
therapeutics by recombinant DNA technology. The former intellectual Lonza has a commercial cell culture plant under construction and
property regimes of China and India allowed copies of proprietary prod- expected to come online in 2009 that has been fully booked in advance
ucts to be sold. While the intellectual property situation is changing, the by Genentech. Lonza plans to expand their capacity in Singapore to
technology developed by these firms has strengthened their ability to 80,000 L for commercial production.
manufacture complex biopharmaceuticals. These products are made in
bacteria, yeast and animal cell culture; they are highly purified and are
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InnoBio has a cell culture CMO facility in final startup with mul-
tiple trains up to 1000 L in capacity. Pharmaplan built the InnoBio plant
as modules in Germany that were shipped to Kuala Lumpur and
reassembled. Alpha Biologics is currently constructing an independent
cell culture CMO facility in Panang.
India has the largest number of potential biopharmaceutical
CMOs in Asia. Bharat offers both cell culture and microbial culture;
they currently produce in microbial culture a vaccine for Wyeth.
Shantha Bio has microbial capacity of 3000 L and is expanding to 9000
L. Biocon has 120,000 L microbial culture capacity and also has cell
culture capacity for monoclonal antibodies and other recombinant pro-
teins. Reliance Life Science has multiple plants in planning and under
Several companies in China have announced they are open for
business as CMOs, including Beijing Kawin Biotech, Shenzhen Watsin
Genetech, and Acon Hangzhou Biotech.
I have personally visited many biopharmaceutical plants in Asia.
Based on my more than 20 years of experience in the industry during
which I have worked in, designed, constructed and operated biopharma-
ceutical manufacturing plants in the US and in Europe, in my opinion
the plants I have seen in Asia are capable of producing biopharmaceuti-
cal drug substance in full compliance with cGMP regulations of the
FDA and EMEA. The staff members I have met with and talked to are
technically competent and able to take on sophisticated technical chal-
lenges. Further, the staff I have met with give every indication of pos-
sessing a culture of open communication, respect for client intellectual
property and a strong desire to build an operation that will be success-
ful over the long term.
In this paper I have not sought to build an argument as to why one
would consider contracting the manufacture of biopharmaceuticals to
firms in Asia. There are many reasons that we could discuss. But in the
end I can only answer, why not?
Strategic Manufacturing Worldwide, Inc., is a consultancy focused
on helping clients address the challenges of manufacturing and
process development. Founded by Scott M. Wheelwright, PhD,
SMW provides technical expertise to biotech and related industries
in the areas of manufacturing, process development, compliance,
and facilities, with particular emphasis on strategic planning and
projects in Asia. Dr. Wheelwright has over 20 years experience in
solving the challenges companies encounter when bringing biotech
and other medical products out of research and into the commer-
cial marketplace. He can be reached at email@example.com.