Headquartered in Basel,
Switzerland,
Roche is widely recognized as a leader in research-focused healthcare and
biotechnology, with proven in-vitro products, tissue-based cancer diagnostics
and diabetes management offerings. A key element of the company’s continued
position atop the pharmaceuticals marketplace has been in the development of
new and more efficient ways to bring their products to market.
This would be vital for one of Roche’s newest offerings –
the MyDose Vartridge. MyDose being the trade name for a single use infusion
device that enables the subcutaneous administration of large quantities of
liquid medication. The medicine contained in this particular product allows for
the delivery of a new formulation of drugs containing various monoclonal anti-bodies,
such as Herceptin, MabThera and Actemra. MyDose’s main functional component is
the Vartridge – a hybrid container combining the features of glass vials and
cartridges.
The patient puts the Vartridge on their stomach where an
adhesive patch keeps it in place. A button is pressed and a sterile needle
penetrates the abdominal wall and the necessary medication is injected. The
Vartridge uses a fluid path container set in motion by a battery-powered,
motorized drive that depresses a conic-shaped piston. This ensures the
Vartridge is completely empty when the piston is compressed.
Over 40 steps are needed to assemble the 83-component
device, which is produced at Roche’s Kaiseraugst site along the Rhine valley, approximately 10 miles east of the company’s
global headquarters. Annually, this facility produces 120 million packages of
medication used in 130 countries.
In getting the Vartridge to market as quickly as possible,
Roche needed to upgrade the Kaiseraugst facility with state-of-the-art process
modules that would be tailored specifically to the production of the MyDose
device, including a high degree of flexibility to allow for producing various
device sizes and active substances.
In addition to customizing processing equipment and
investing in new technologies, a key element of this project was Roche’s
establishment of a Cross Functional Team (CFT), their traditional approach to
these fast-tracked projects. The company feels these teams ensure direct
communication and faster decisions.
The uniqueness of this CFT was that people from product
development and project management worked together to achieve a common goal.
This would be vital, as the development of the device had not been finished
when the project was initiated, so the team needed their plans to stay on
schedule.
A New Bonding Experience
The production process for the MyDose device is unique to
Roche, as no other product in their galenical manufacturing approach (also
known as formulation, or the manufacturing process by which all active
pharmaceutical ingredients produced chemically or by biotechnology are
transformed into application forms suitable to treat patients) demands many
state-of-the-art production steps.
The challenges associated with developing/designing the
device were vastly outweighed by the challenges of producing the correct,
optimized manufacturing process layout in a relatively small space, and still
meet all timelines. Vartridge required the modification of standard machines
for production steps such as washing, siliconization and filling, yet strict
temperature control requirements had to be maintained during the whole
production process, due to temperature sensitivities.
Uwe Bank, Head of Process Technologies, explains. “The
familiar processes of washing and siliconization turned out to be challenging
since the new primary container is open on both sides. So we had to develop a
new spraying needle and a new spraying sequence for this kind of shape.
“The difference between the bigger and smaller vial
diameters also forced us to develop new washing cycles,” he continues. “An ordinary
vial has a bottom and generates a back pressure and therefore a mechanical
force which helps to clean a vial more efficiently.
“Another challenge was the machine noise. Only with the
special design of some parts and changes in the construction could we achieve
the required 78 dBA.”
The Zoning Concepts were also extremely strict. The product
requires Zone Grade C (ISO 8) with Grade A (ISO 5) air supply for the filled
Vartridge from the inspection step until welding. The unique integration of a laser
welding process under clean room conditions also represented a potential
bottleneck in production that had to be adjusted.
Production of the device involves many more steps and
components than a “normal” auto injector device, which Roche grouped in to four
major segments.
1. Vartridges are delivered to the production line in trays,
followed by careful washing, siliconizing, depyrogenization, sterile filling
and closing of the Vartridge to provide for the core characteristic of the
product.
2. Manual quality inspection.
3. Assembly and welding of the fluid path components
(Vartridge, cartridge holder and transfer unit) to produce the finished fluid
path. This would prove to be the most complex step, as it called for
implementing assembly and welding processes under clean room conditions.
4. Further assembly, including base plate, housing, fluid
path and plaster before country-specific labeling and packaging.
During step three, trays and tubs are delivered manually to
the assembly and welding machine. A clean room validated robot picks the three
components (transfer unit, filled Vartridge, and cartridge holder) one after
another and assembles them. The laser welding process, under controlled
conditions, follows to seal the transfer unit with the cartridge holder. Once
in this state, this new component is called a fluid path, and must be air tight
to guarantee sterility.
The welding process posed a big challenge for Roche’s
validation team. Sophisticated measurements were developed to prove the
stability and reliability of the process, with several testing methods, such as
a helium leakage test, developed to validate the quality of the laser welding
seam.
Roche worked with two companies, Leister and Insys, for the
laser technology. “Introducing this kind of technology into the pharmaceutical
industry in a clean room environment was a very challenging task because of
three factors; the compound of the plastic parts, the guarantee of sterility,
and the development of welding parameters,” offers Bank.
“The compound of the plastic parts is crucial for the
welding success,” he continues. “A slight variation of carbon black particles
would fail the laser welding process.
"That means that the supplier of the plastic components
to be welded together had to implement validated processes to guarantee the
right percentage of carbon black particles. Proof of tightness, to guarantee
sterility in the inner room of the cartridge holder, had to be demonstrated and
there is no procedure at all to execute such a test.
“So, Roche developed a test method, based on the proofed
concept of a helium leakage test. The final challenge was developing
welding parameters during project execution. The welding actually happens
trough the transparent cartridge holder, introducing heat at the ‘black part’
(transfer unit). Since the product is temperature sensitive, we had to make
sure that the welding temperature would not harm the product, and demonstrate
this to the authorities and our internal quality department. Therefore, we had
to record continuously the welding temperature and define a boundary with upper
and lower limits.”
Additionally, process equipment for this project was
designed and built as packaged units, including all instrumentation. They were
brought into finished, empty halls and connected to their corresponding media,
energy supply and IT. Roche felt one of the main advantages with such an
approach was a higher quality installation due to assembly under factory clean
conditions.
The production process underwent several major changes, as
the design of the devices developed and the full implications of the production
process were understood (i.e. laser welding of the fluid path components under
clean room conditions).
However, regardless of all these potential obstacles, by July
1, 2010 the design, construction, installation and qualification of equipment
in an environment Zone Grade A (ISO 5) of an existing clinical supply unit was
complete.
Roche had handed the design and production of the Vartridge
to their Global Engineering Department, and they responded with a project
completed in 13 months (four months ahead of schedule) and at a total project
cost that was 1.3 percent under budget.