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Roche’s Insistence on High Quality and Standards Delivers Handsome Payback

Mon, 07/09/2007 - 12:20pm
Shanghai Roche's new facility stresses environmental safety in high potency materials handling

By Bernard Tulsi


In an effort that surmounted numerous hurdles, Shanghai Roche Pharmaceuticals Limited (SRPL) not only completed its US$16.64 million Shanghai High Potent Production Project (SHiP) on schedule and under budget, but managed to win over the judges and take home an ISPE, INTERPHEX, and Pharmaceutical Processing 2007 Facility of the Year Award - for Project Execution Regional Excellence.
Initial challenges

The exterior of the completed SHiP facility
Challenges spanned financial issues - although the plant was completed for US$15.07 million, or more than US$1.5 million below budget - quality control of building processes, and the need to integrate a diverse international crew into a consolidated team that worked well together and was dedicated to the same goals, according to Paul Rosselli, Project Manager for the facility.

SPRL is a joint venture between Roche and Sunve Pharmaceuticals of Shanghai, which was initiated in 1994. The SHiP facility is located in Zhang Jiang High Tech Park in Shanghai, China and houses both the production and business operations. The plant, which went into commercial scale production around November 2006, is already shipping Cellcept, which is used for the prevention of organ rejection in transplant patients, at full capacity. It is currently gearing up for the production of cancer drug Xeloda, with first shipments expected sometime this year.

Using a modest budget, the SHiP project required the construction of a new building, with strict containment, for the production of these highly active medicines. Rosselli explained that the scope of the work included all the planning and design stages and construction. The building phase included piled foundations, reinforced concrete superstructures, construction of the building and all its fixtures and the installation of all necessary services. Sourcing, installation, commissioning and qualification of required plant and equipment were also embodied in the scope of the project.
The making of an award winner

Chillers were placed on the roof for safety and environmental reasons
Zeroing in on what might have swayed the judges, Rosselli says, "Speed was probably the most impressive factor in the execution of this project. We received building permission on April 1 rather than on January 1, 2005, as was planned, but the completion date - October 2005 - remained the same. So we had seven months to complete a project originally scheduled for ten months. I believe that was probably the most interesting aspect for the judges."

"Also of interest is the fact that the project is in China. Technology is moving fast here but it is not as simple to execute a project here as in Europe or the United States. There is, of course, the language barrier and some cultural issues. It was probably of interest to the judges that we were able to do a project with such leading edge technology here, in a relatively short period of time," says Roselli.

First construction at this site was initiated in 1995, a time when China was starting to open up to the rest of the world. Work and construction procedures were not as well developed as they are today, according to Rosselli. He explained that the SHiP facility required adding a 22,600 square feet building into the middle of the existing site, while ensuring that ongoing operations were not interrupted.
Getting the job done
The Shanghai Roche Pharmaceuticals Limited SHiP Project was constructed with equipment from suppliers around the globe. Below is a list of the major equipment suppliers, the equipment provided, and their country of origin.
Major Equipment Suppliers
Equipment TypeManufacturerLocation
Dispensing Isolator Extract Technology Limited England
Granulation Train Glatt Limited Switzerland / Germany
Blender GEA Limited England
Tablet Press Enclosure Powder Systems Limited England
Capsule Filling Machine IMA Limited Italy
Coater Manesty Limited England
Central Weighing Mettler Toledo China
Container Washing Machine Zanchetta Limited Italy
Containers Zanchetta Limited Italy
Post Hoists Zanchetta Limited Italy
Isolation Valves Zanchetta Limited Italy
Post Hoist for Blistering Servolift Limited Germany
Air Handling Units AL-KO Limited China
PUW System Christ Limited / Winatech Limited Switzerland / China
Steam System (Humidification) Apaco Limited Switzerland
BAS / BMS Sauter Limited Switzerland
Compressed Air Atlas Copco / Winatech Limited China
Dedusting Equipment CFM Limited Italy
Chillers GEA Grasso Limited Germany / China
Wastewater Neutralization Equipment Glory Engineering Limited China
Rosselli believes that the Chinese are aware that some of their approaches are different from those in other parts of the world, "so they considered the award, which represents recognition by their peers, a great honor." He notes that most members of the team were Chinese, adding, "Stephen Firmer, SHiP Start Up Manager, and myself were the only foreigners permanently involved. Other foreigners came down and completed their tasks in a week or two and left." Stephen Firmer, an 18-year Roche veteran, left China after handing over the project, and now works for a government agency in his native Australia.

The facility was constructed with mainly imported equipment with dispensing isolators, blenders and tablet presses supplied by companies in England. Italian manufacturers supplied capsule filling machines, container washing machines, containers, post hoists, isolation valves and dedusting equipment. Granulation train and other systems were imported from Switzerland and Germany. Central weighing, air handling units, compressed air and wastewater neutralization equipment were procured locally in China.

"Roche prides itself in being innovative, and the construction of the facility is very strongly in that mode," says Firmer. He says, it is a compact facility in European terms but in Chinese terms it is a very high quality facility. The facility is designed to make high potency products, and dust from the active substance are controlled to limit worker exposure to less than the occupational exposure limit.


Wastewater neutralization room
"The facility was designed for a fairly high level of automation to ensure that transfer processes in each step in the manufacturing procedure were contained. There is more automation in the plant than in the typical Chinese factory, which means that this was first time some of the equipment was used in the pharmaceutical industry in that part of the world," says Firmer.

He notes that the quality of the facility is leading edge, especially with respect to the environmental and safety considerations in materials handling. "This ensures a safe working environment. Some of the automation concepts are leading edge too. Some of the international pharmaceutical companies have built good facilities in China but in terms of the kinds of products we are dealing with, this facility is leading edge, certainly in China - especially in dust containment and material handling," says Firmer.

"The award is validation of the effort that was put into the construction of a good quality facility, and the recognition that by maintaining high standards you can gain the recognition of your peers," says Firmer. He added that it will likely have a positive effect on future efforts like this in the country.

M+W Zander (Shanghai) Limited was commissioned to do the concept design, the basic design and the detailed design, and eventually the construction management and procurement support, under the leadership of China-based vice president Tadeusz Jaskolski.

"The way Roche works in many instances, not all, is to engage local design and construction companies but still oversee the results from Basel, Switzerland. Tadeusz worked with us on the design of the facility, and his company served as the construction manager," says Firmer. He noted that M+W Zander created an office and had some people on site but, unfortunately, not all the key people were onsite.

"There were regular meetings between the Roche representatives consisting of Paul Rosselli and his core team and the design and construction teams. I spent a lot of time liaising with M+W Zander either in the site office, in the building under construction or in their main office.


Isolation valves allow the transfer of product with a concentration in the air of less than 10 µg per cubic liter
"Shortly after I arrived on the site to oversee start up operations, we began integrating the qualification team into the design, so that when equipment arrived all the necessary preparations would be in place, and all qualification activities could be done quickly. We integrated the functions associated with start up and the players involved with those activities into the construction process at an early stage," says Firmer. That was a key decision in making sure that we achieved our overall goals, he added.

M+W Zander, a German company, is very experienced in China, especially in the building of semiconductor factories. "They know about air conditioning and clean room systems, and their experience certainly helped to ensure the success of the project," says Rosselli.

Roche's corporate directives strictly prohibited the use of ozone depleting gases in the project. "The alternative therefore was to use water cooled or air cooled chilling systems that could use either ammonia, butane or propane. We chose ammonia and decided to put the chillers on the roof, a safety measure that will result in safe dissolution into the air in the event of a leak," says Rosselli.

Ammonia and air cooled chillers have relatively good efficiency, according to Rosselli. "There was a belief that we could have reduced the power consumption by using water cooled chillers. But on the site water was literally a problem and water systems would require more maintenance, a concept that is not so well understood in China," says Rosselli.
Keeping it all contained

Close-up of the dispensing isolator for the high-potency active pharmaceutical
One of most important Roche directive on this project is that shift work staff should not be required to work in personal protection equipment. "That means that during normal working hours they had to able to work in an atmosphere with just GMP compliant overalls or clothing," says Rosselli.

That also meant that any transfer of product from one process or system to another had to be fully contained. This is not required by law in China and in most other countries but to ensure the safety of the staff and to allow them to work in a much more pleasant atmosphere, Roche decided to implement this directive, says Rosselli.

"We installed valves to allow the transfer of product with a concentration in the air of less than 10 micro grams per cubic liter. We have tested statically and dynamically the amount of active ingredient in the air at the time of transfer and the results are very positive," says Roselli.
Working together - for a common goal

The facility is currently gearing up to product Xeloda, with the first shipments expected later this year
"One of Roche's strengths is its respect for the abilities of people and of their culture. That was extended to all the people who worked on this project, who themselves displayed a sense of urgency to get the job done with the necessary speed and quality. With that in mind, we took steps at the professional, social and even the hospitality - ensuring good quality accommodations - levels to instill a sense of camaraderie among team members," says Rosselli.

"The facility was approved by Roche on the basis that the Chinese government would be pleased to see that we are extending our production facilities here in China, its economic feasibility, and the ability to protect our products against generics for a specific period of time," says Roselli.

Initially intended to produce only for the Chinese market, the factory is now capable of exporting product outside of China because it was built to European standards, according to Firmer.

Firmer notes that the genesis of the idea was to get an advantage in the Chinese market. "We then realized that with a bit more effort to ensure that the quality of the facility was high enough, we would be able to export from the facility and make better utilization of it.

"That was one the reasons why I was assigned to the project - to ensure that the facility was of a high enough standard to be able to produce for the export market. We were specifically targeting Asia-Pacific but I believe that the facility is good enough to export to EU countries. The intention in the end was to have a facility of a standard comparable to European and Australian plants," says Firmer.

On top of Roche's strict internal regulations, the facility operators needed to procure all local permissions to operate the factory. "We have to get permission from the high tech park to run the factory as well as from the Shanghai Food and Drug Administration," says Firmer.

Rosselli believes that the environmental and energy conservation initiatives incorporated in this project should be the direction of the pharmaceuticals industry in China in the future. "China imports large amounts of oil and paper. The country cannot afford to use so much energy, and efficiency is one way to address that," he says.

Firmer believes that it is essential for builders of pharmaceutical facilities in China to understand the local culture. "It is really important to be patient and not to insist that your approach is best, and everything must be done according to your plan. Systems are different and it is critical to find a way to build bridges linking the western and Chinese approaches, then select the best from both and move ahead," he says.

Bernard Tulsi is a freelance writer based in Newark, Delaware.
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