Installing a new granulation suite is littered with technological
and legislative obstacles and often has to be undertaken in existing production
facilities. This article looks at how SB overcame the problems associated with
this task. This is particularly difficult when there is a tight project
deadline. Hence a specific window of opportunity in the planned production
programme for a shutdown of the manufacturing area based on the desired stock
build of products to cover the sales volumes to satisfy the markets during the
installation of the system. The shutdown was limited to the time required to
move every item of equipment into the area.
A survey of literature on modern pharmaceutical processing will advise that
it is essential to prepare a User Requirements Specification to ensure that the
design of the equipment/ system is procured and installed according to the
needs of the end user. The design and fabrication of a production system with
optimal process flow is then based on this document. The system can then,
finally, be installed into a building.
Unfortunately, it is rarely possible to locate the system in a new building
and it is usually necessary to utilise existing buildings to increase the
production capacity - while still meeting stringent regulatory requirements -
within a previously used production area. Needless to say, the project has to
be cost-effective with as little impact on existing and continuing production
processes as possible. This article describes how such a scenario was achieved
at SmithKline Beecham in Crawley. ^
Background
SKB has manufactured solid dosage
forms on its Crawley site since 1980. Within Granulation Suite 1, the original
equipment was nearly 20 years old and no longer fulfilled the GMP demands or
health & safety requirements. The weakest points of the existing
installation were:
- poor separation of production and technical areas
- open product handling
- no automated batch recording
- minimal equipment qualification and process validation.
After an internal audit in 1996 it was decided that Crawley would remain a
production facility within the worldwide SKB organisation, but existing
equipment would need to be replaced.
SKB decided to carry out a design study with Aeromatic-Fielder as the
company was already contracted to carry out onsite calibration and maintenance
and its ability to provide a ‘turnkey’ supply for a whole new suite. The main
requirements for the new production facility were that it must:
- allow contained product handling
- have a full separation of production and technical area
- be equipped only with qualified machines to allow a full process validation
- allow automated batch recording.
As well as these requirements the whole project had to be carried out within
an existing manufacturing building without interference to continuing
production. As a result of the design phase a flowsheet, installation strategy
and a detailed layout was created with proposals for machine specifications and
necessary ancillaries. This was presented in December 1997.
Planning
The plans were given the go-ahead in
January 1998 and included the design and building of the equipment as well as
- a full factory acceptance trial duplicating the final layout (all
interconnections preassembled to reduce installation time)
- decommissioning and Removal of the existing equipment
- planning of the necessary services and ancillaries
- co-ordination of the building works with SB
- co-ordination of services tie ins with SB projects
- control of the area as a site within a site for Health and Safety CDM
Regulations.
The project was to be totally completed by 13th of November of the same
year.
Process
The equipment was designed to perform
a vacuum loading of the raw material into the mixer/granulator, prepare a dry
mix there, add binder liquid and form granulates. These granulates are then
discharged and transferred via an integrated wet mill into a fluid bed. There
the product is dried, discharged afterwards via an integrated dry mill and
transferred via vacuum conveying into an IBC for adding a lubricant, final
blending and transport to the tablet press. The installation is equipped for
waterbased products only. As well as the process described above it is also
possible to use the fluid bed as a spray granulator.
Layout
A fundamental requirement was the
ability to use the existing production building; therefore the installation was
realised in a one level concept. The maximum height was 4,50 meters. The
complete equipment was executed in a ‘through-the-wall’ design. This means that
material and personnel can access the process room out of the production area
while all technical installations can be accessed from the technical area.
Leading of raw materials
The raw material is
delivered in drums from the dispensing room. It is then loaded into the Mixer/
Granulator by the use of a kill-vacuum so that the bowl is evacuated to a
certain vacuum level before the vacuum line is closed. The product infeed line
is then opened and the raw material is sucked in. This is repeated until the
complete batch is in. The whole action is automatically controlled by the PLC.
To load a batch of 300 kg takes typically less than 10 minutes. Advantage of
the use of kill vacuum for loading is that the risk for a filter blinding is
minimised.
Granulator
The Mixer/Granulator is an
Aeromatic-Fielder PMA 800. This is a bottom drive machine with a chopper on the
side. In this installation the granulator is equipped with vacuum loading,
sight glass and a spray lance for the introduction of the granulation liquid. A
fixed location peristaltic pump from a solution container wheeled into the
production room delivers this liquid.
Transfer of wet granules screening
After the
granulation the wet granules are discharged via an integrated wet mill (Comill
U20) directly into the fluid bed. Due to a special conveying airflow creating a
vortex effect, this is possible without blocking the mill or the transfer line.
Because of the optimised airflow the granules are immediately fluidised after
entering the fluid bed and do not start to build up on the wall opposite the
inlet valve, which is equipped with a DC motor variable speed drive to allow
accurate control of the discharge rate.
Fluid bed drying
The fluid bed can also be
used as a dryer. Upgrading to a spray granulator is simply a matter of
introducing a spray arm. The process filter system is executed as a double
shaker with cloth filters. The bottom of the hinged product container does not
contain the traditional mounted sandwich of hole plate and mesh but a Niro
overlap non-sifting gillplate. The advantage of the gillplate is that it can be
cleaned without disassembling. Additionally it creates - alongside the
tangential air infeed in the lower plenum - a homogeneous air distribution,
which results in an even temperature distribution and a reduction of lump
formation. It is also possible to realise a side discharge without any moving
parts in contact with the product because of the tangential air inlet.
Discharge/screening
After drying the granules
are discharged via a mobile dry mill and then by vacuum transfer dumped into an
IBC where the lubricant is added.
Cleaning
The complete installation is equipped
for washing-in-place (wip). This means that in the technical area a Water
Preparation Unit is installed wh ere all fluids (cold water, hot water,
DI-water, surfactant solution) are prepared, brought to the correct
temperature, pressure and concentration and then delivered to the nozzles and
spray heads inside the installation. All this is controlled and monitored by
the PLC from a production recipe. Cleaning liquid is introduced into the
granulator through the same openings used for the air purge at the seals of
main impeller and chopper. Operating the impeller and chopper assists the
cleaning. The fluid bed is equipped with fabric filters, which can be made wet
before removal to bind dust. After removal of the filters, the fluid bed can be
cleaned completely by the nozzles installed in the tower and in the lower
plenum in a top down process. The complete equipment can be dried afterwards by
the use of the process air of the fluid bed.
Current status
Full installation, operation
and process qualification has been performed on the integrated granulation
equipment. Following full process validation of an anti-viral formulation, the
granulation suite is in full time operation. It is intended that a further two
products will be validated for manufacture within this equipment shortly.
Article published in the February 2001 addition of Life Science Today.
©
Niro Pharma System 2001 / © GEA Pharma System
Authors: Mick Heywood of SKB
Crawley, Dr Dilwyn Patterson of Aeromatic-Fielder, and Dr Harald Stahl of GEA
Pharma Systems (formerly known as Niro Pharma Systems).
Contact: Dr Harald Stahl
Tel: +49 7631 7016 14
E-mail:
harald.stalh@geapharmasy
stems.com