1.
Introduction
When dealing with
highly potent substances, compression is probably the most challenging stage of
the tablet manufacturing process. The main reasons are:
- The complex mechanical design and construction of the inside
of a tablet press.
- The continuous flow of materials into and out of the
press.
- The need to clean a very complex system in case of product
change-over, including upstream and downstream equipment.
- The multiple interfaces between the tablet press and its
environment (air inlet, tablet outlet, powder inlet, dust extraction), each
requiring a contained interconnection.
- The need for frequent tablet sampling for IPC – either
manually or automatically.
2. History
Various attempts have been made to address these issues.
The most
radical approach is to put the entire press into an isolator.
Courtoy built
such an isolated press as early as 1998 (shown in Fig
1).
 1. Tablet Press in a Isolator
 2. MODUL™ tablet press with ECM
In order to eliminate this drawback, a fundamentally different
machine concept was developed, whereby the powder containment is performed “at
the source”.
In 2002, Courtoy introduced the MODUL™ concept. Fig 2 shows the MODUL™ S
with its ECM highlighted.
3. The ECM
Concept
Depending on the product and production requirements, it can be
constructed in a C (normal Containment or dust-tight) or an HC (High
Containment) execution.
3. ECM - Exchangeable Compression Module For product and/or format change it can easily be removed from the press and
be replaced by a second, already prepared ECM. While the press is running
again, the contaminated ECM can be cleaned in a safe remote area: the ECM is
cleaned manually off-line, which significantly reduces the machine change-over
time.
The ECM is also available in a WOL (Wash off Line) execution,
which means that it can be connected to a special wash skid, enabling an
automatic wash-down without any need to open the ECM or to take out any part,
such as e.g. punches.
The WOL concept has significant advantages over a
WIP or CIP concept:
- Less consumption of water and detergent,
- Shorter machine downtime,
- No risk of contaminating the electromechanical parts of the
machine in case a water seal fails due to damage or wear.
4. Heat-sealing and cutting of lay-flat
tubing
As highlighted in the introduction, during operation, raw
materials constantly flow into the tablet press and finished tablets leave at
the same time. These flows must also be handled in a contained manner. The best
solution for loading is to dock the raw material container via a split
butterfly valve. The active part of the valve needs to be executed as a “quick
release” version. The tube guiding the raw material from the valve to the ECM
is connected with the ECM via LDPE lay-flat tubing. This LDPE can be
heat-sealed and cut for dismantling the powder in-feed assembly, as shown in
Fig 4.
Similar principles are applied to the other interfaces of the
ECM, such as the air inlet, the dust extraction and the tablet
outlet.
4. The Concept Applied to Check Weigher
/ Deduster / Metal Checker / Recipients
To take full advantage of the containment performance of the
MODUL™ press, the entire tablet production line can be executed in a dust-tight
or high-containment version. For this purpose, Courtoy has designed interfaces
with down-stream equipment, executed in a contained way. Peripherals available
in dust-tight or high-containment execution, in WOL and non-WOL version,
include stand-alone dedusters, metal detectors and combined systems, examples
of which are shown in Fig 5 and 6. After use they can be disconnected from the
tablet press outlet, using the heat-seal and cut principle.
5. High-Containment deduster-metal checker - 6.
Wash-off-Line deduster-metal checker
For the tablet recipient containers, various contained
solutions exist: the Buck Systems™ tablet bag (Fig 7), the continuous liner
tablet collector (Fig 8) and conventional containers connected via Hicoflex® (Fig 9). They can be
connected with the outlet of the deduster / metal checker unit either via
lay-flat tubing or using the Buck® Hicoflex® system.
7. Buck Systems™ Tablet Bag - 8. Continuous liner Tablet Collector - 9.
Hicoflex® container connection
5. Setup
As part of the setup of a high-containment MODUL™, a pressure
decay test can be carried out to check the containment prior to starting a
batch. For this purpose, a slight negative pressure of at least 2000 Pa is
applied to the press. Afterwards, the rising of the pressure inside the press
is monitored. If the time for the pressure to rise from a pre-set starting
value to a pre-set end value is within the given limits, the press is released
for production. If the pressure decay test fails, a helium leak test can be
performed in order to identify any problematic area. By performing these tests
it is assured that the press has been set up correctly and the containment
performance is as required.
6. Cleaning
At the end of a production campaign, the raw material
container can be removed in a contained manner taking advantage of its
connection via a split butterfly valve. The active valve needs to be in
quick-release execution, so the entire product inlet section can be removed
from the tablet press in a contained manner after the lay-flat tubing has been
heat-sealed and cut. The same applies to the other connections to and from the
ECM. When all connections have been secured, the completely closed ECM can be
taken out of the press and be deposited on a carrying trolley. If the WOL
execution of the ECM has been chosen, it will be washed down automatically
after connection to a wash skid. Afterwards, it can be opened in wet state
preventing any remaining traces of material from getting airborne. Such traces
can easily be removed during final manual rinsing and drying.
The dedusting and metal detection unit is also available in
wash-off-line (WOL) execution, enabling the same washing procedure.
7. Case Studies of High-Containment
Installations
The MODUL™ in itself is a closed system but it needs to be
integrated with up- and down-stream equipment to take full advantage of the
containment performance. Here some recent installations are
shown.
10. Setup at J&J PRD, Belgium
J&J PRD Belgium, which in 1998 purchased the isolator
solution shown above, decided in 2005 to install a MODUL™ S tablet press with
WOL-ECM and WOL-peripherals. The actual setup is shown in
Fig 10. It consists of a MODUL™ S with WOL-ECM, a Buck Systems™ post hoist and
powder IBCs, a Buck® Valve HC DN100 split-butterfly valve in quick-release
execution and a Krämer HC WOL deduster + Lock metal-check. An LDPE transparent
continuous liner is used to collect good tablets as well as rejected tablets.
Samples are taken manually from the same LDPE liner, with the heat-seal and cut
technique.
The containment performance of this system has been measured extensively,
using air sample and swab test methodology. The results of the tests are
discussed in chapter 8.
11. Servier - Ireland
MODUL™ S with
WOL-ECM
7.2. Servier - Ireland
In 2008, Servier Ireland invested in three high-containment MODUL™ S
tablet presses with WOL-ECM, as shown in Fig 11. The raw material comes in
IBCs, which are lifted above the press with a post hoist. The material is fed
to the press via a split butterfly valve.
A custom-designed high-containment PharmaTechnology
system is installed for dedusting and checking for metal particles, while also
enabling visual inspection in a buffer before the tablets are released into an
IBC.
Accepted tablets are collected in an IBC, which is
connected via a SBV, while rejected tablets are taken to a closed bin with
spigot.
A separate Kraemer-Elektronik washable high-containment Combi-Test
performs automatic tablet sampling and measuring for batch reporting and
process control.
12. Ranbaxy - India MODUL™ P
with
WOL-ECM
Also in 2008, Ranbaxy India invested in a high-containment
MODUL™ P with WOL-ECM, shown in Fig 12. For raw material loading the same
principle as in the previous examples is used. At the outlet of the press a
PharmaTechnology HC WOL deduster / metal-checker is installed. Tablets are
collected in a Hicoflex® SL tablet bag for good tablets (up to 50 litres),
while bad tablets are collected in a closed bin with spigot. Samples are taken
manually using a continuous liner at the sampling outlet of the
press.
13. Haupt Pharma - Germany
MODUL™ S with
WOL-ECM 7.4. Haupt Pharma -
Germany
In 2008, Haupt Pharma purchased two
high-containment MODUL™ S tablet presses with WOL-ECM. The principal setup is
shown in Fig 13.
Raw material is loaded into the tablet press through a
Buck® MC-200 valve. During production, sample tablets are taken by means of the
integrated sample gate on the tablet chute. The tablets are channelled to a
Sotax four-parameter tester and the results are downloaded to the Courtoy
Multi-Control 4 software for evaluation.
Prior to collection in containers, the tablets are
conducted through a Pharma-Flex deduster for dedusting and
deburring.
14. Teva - Hungary MODUL™ S
with
WOL-ECM
In 2008, Teva Hungary invested in 2 MODUL™ S presses with
WOL-ECM. The set-up is shown in Fig 14.
Granules are loaded into the tablet press through a Buck®
MC-200 valve.
The production line also includes a PharmaTechnology
dust-tight combined deduster / metal-checker, as well as a Kraemer-Elektronik
AWS (Automatic Weighing System).
An ILC Dover continuous liner for good tablets is installed, as well as for
the collection of bad tablets, at the outlet of the metal-checker.
8. Containment
Performance
The containment performance of a MODUL™ has been assessed by
the customer whose setup is described in example 7.1.
The tests were carried out according to the ISPE SMEPAK
guidelines. For reasons of compressibility of the material, a different
formulation was used instead of the standard lactose grade suggested by the
guidelines. This formulation consisted of
- 10% micronized Paracetamol,
- 87,5% Prosolv,
- 0,5% Aerosil
- 2% Magnesium Stearate.
For an entire shift, the airborne concentration of
Paracetamol was measured. All phases of operating and running the press were
tested:
- the docking of the raw material container,
- the setup of the compression parameters,
- the routine production,
- the removal of individual bags of tablets produced,
- the preparations for cleaning,
- the removal of the ECM,
- the automatic washing of the ECM,
- the manual cleaning of last remaining traces.
Test results:
a) Based
on measurement of instantaneous airborne concentration levels, a safe and
conservative estimation is that the C-ECM can handle a formulation with up to
10% API concentration, whereby the API OEL is lower than or equal to 10 µg/m³.
The WOL-ECM can handle a formulation of up to 10% API, whereby the OEL is lower
than or equal to 1 µg/m³.
b)
Based on the method of ADI (Acceptable Daily Intake)
calculation for a typical MODUL™ installation with WOL-ECM, with peripherals as
shown in 7.1. and a typical production sequence, the equivalent LT TWA (Long
Term Time Weighted Average) airborne concentration was 88 ng/m³ (or 0,088
µg/m³) for the above formulation with 10% API. This indicates a containment
level that is more than adequate for the majority of potent pharmaceutical
compounds.
9. Conclusion
Customers are advised to consult with the containment experts
from GEA Pharma Systems in the early stages of their tableting project, as a
large number of input parameters - such as the potency of the API, the dilution
ratio with excipients, the number of operations, the duration of production
runs, the presence of operators and the cleaning philosophy - influence the
containment requirements of a tablet compression suite.
Contact details:
GEA Courtoy nv
Bergensesteenweg 186
B-1500 Halle Belgium
Tel: +32 2 363 8300, Fax:
+32 2 356 0516
E-mail: courtoy@geagroup.com
© GEA Pharma Systems – GEA Courtoy nv
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