GEAPharma's Tech Blog

A comparison of Granulation methods

2011-12-29T17:05:00.001+01:00

by Dr. Harald Stahl - Senior pharmaceutical technologist, GEA Pharma Systems: CONTACT

There are a number of granulation technologies available to pharmaceutical manufacturers. Given the importance of granulation in the production of oral dosage forms, this paper offers advice on various processes.

Granulation is one of the most important unit operations in the production of pharmaceutical oral dosage forms. However, there are many different technologies each having different strengths and weaknesses. Most companies choose which one to use simply based on their own experience. This article introduces different processes, compares them objectively, offers unbiased advice on the merits of each system and then looks at the implications of selection a particular granulation process.

Granulation methods:

figure 1: A typical Single Pot set-up

Single Pot - A mixer/granulator that dries granules in the same equipment without discharging is commonly called a Single Pot Processor (or One-Pot Processor) (Figure 1). The granulation is done in a normal high shear processor; however, care must be taken to avoid the formation of lumps as they cannot be broken down before drying.

There are various options for drying in Single Pot Processors: The basic drying principle relies on the application of a vacuum in the bowl thus lowering the evaporation temperature of the used granulation liquid drastically. The traditional heat source comes from the heated dryer walls. The heat transfer is related to the surface area of the dryer walls and the volume of product treated. Therefore, this direct heating method is most effective for small scale, organic solvents or low quantities of binder fluids.

Introducing stripping gas into the pot allows lower final moisture content to be achieved. This very low moisture content is only required in some particular applications. A small quantity of gas is introduced in the bottom of the equipment, which passes through the product bed, improving the efficiency of vapour removal. However, as the heated wall is the only source of drying energy, linear scale-up is not possible. This problem is exacerbated if the material to be processed is heat sensitive (as this limits the wall temperature); if water is used as a granulation liquid (it has a relatively high boiling temperature under vacuum and a high heat of evaporation compared to organic solvents); and if used for larger-scale production (the surface/ volume ratio deteriorates as the volume increases).
Microwave energy can be used to overcome these limitations. This provides a further source of energy and has the additional advantage, with organic solvents, that only pure organic vapours must be treated on the exhaust side, and not a mixture of solvent and large volumes of process gas, as would be required in most other wet granulation technologies.

Fluid bed spray granulation - Granulation can be performed using fluid beds fitted with spray nozzles. While for many years the top spray position was preferred, now the advantages of tangential spray systems have become obvious. The main advantage is the location of the spray nozzle, in an area with significantly higher shear forces, so allowing the processing of formulations that could before be granulated only in high shear processors. Additionally the introduction of the new FlexStream™ range of fluid beds (Figure 2) also eliminates the difficulty of scale up. Over recent years fluid beds have improved dramatically in response to competition from Single Pot technology.

figure 2: FlexStream™ fluid bed processor - figure 3: Fluid bed top spray granulator

As can be seen for example in (Figure 3), it is possible to have completely closed material handling by a closed link with up and downstream equipment. Also fully automatic cleaning (CIP) in fluid beds using stainless steel filters has now reached a level that compares favourably with what is possible in a single pot.

figure 4: A typical integrated production line for
pharmaceutical granules

Integrated high shear granulation & fluid bed drying - This is the most common configuration used on an industrial scale for the production of pharmaceutical granules (Figure 4). Again, this system allows full integration with upstream and downstream equipment, and even includes a wet mill between the granulator and dryer.

With modern control systems it is easy to load, mix and granulate a second batch in the high shear granulator whilst drying the previous batch in the fluid bed prior to discharge. All equipment can be cleaned in place in a single automatic process.

Continuous granulation - As a result of various FDA initiatives to improve product quality and to reduce the risk of product failure there is a huge interest in continuous processing. A typical installation is shown in (Figure 5). The system has three modules: a wet high shear granulation module, a segmented dryer module, and a granule conditioning module.

figure 5: A Continuous Tableting Line

In the granulation module, dry ingredients are dosed individually or premixed into the continuous high shear granulator. After a small dry mix section, the granulation liquid is added, so each particle receives the same amount of liquid. The particles follow a granulation track, which mimics the granulation in a batch process. Narrow tolerances between granulation screws and the barrel minimize back-mixing. The whole wet granulation process takes place in a few seconds with only a few grams of product in process at a given time, resulting in faster start-up and no losses. The particle size can be adjusted by changing the working level in the granulator; this results in a continuous flow of wet granules with a constant quality and density that is transferred to the dryer. There are no oversized agglomerates and thus no wet milling.

The dryer module, based on the fluid bed drying principle, splits the continuous flow of granules in packages of 1,5 kg, drying them each in a separate segment of the dryer. When the content of a segment has reached the desired moisture level, it is emptied and transferred to the granule conditioning module and refilled with a new package of wet granules. The drying curve of each package is monitored. In the granule conditioning module, the dried granules can be measured for critical quality attributes such as particle size distribution, humidity and content uniformity. At any time, there are only 6 to 9 kg in process, which minimizes the amount at risk in case of an incident (e.g. a power failure). The system can handle capacities from 500 g to tons, so there is no need for scale up. The unit's small size and modular construction allows for a fast deployment and makes it easy to install with existing equipment.
GEA Pharma Systems also has developed a continuous blender, which can be used for premixing or mixing the external phase into the granules on a continuous basis; Courtoy™ tablet presses are ideally suited to complete the system to create a fully continuous tablet manufacturing line. The ability of the Courtoy™ presses to produce a consistent tablet quality independent of the press speed is key to a successful integration.

figure 6: Fluidized Spray Drying (FSD)

Fluidized spray drying (FSD) - Produces granules from a liquid in a one-step process (Figure 6). One option is to produce the active in the primary production as granules, so that it only requires blending with excipients suitable for direct compression for secondary processing. This can only be done with actives that are tacky (in a wet state) otherwise the addition of a binder is necessary. Another possible use of FSD technology is to mix all the ingredients into a solution or suspension and to produce granules in a one-step operation. During the FSD process, the liquid feed is atomized at the top of the tower in a co-current mode. After the liquid is evaporated, the particles generated leave the drying chamber together with the exhaust air. These particles are then separated in a cyclone or filter and reintroduced into the drying chamber where they come into contact with wet droplets and form agglomerates. After these agglomerates have reached a certain weight they cannot leave via the top of the tower with the exhaust air, but fall down into the integrated fluid bed at the bottom of the drying chamber. Here they are dried and cooled before being discharged. However, this type of equipment is difficult to clean, particularly the external pipe work, when changing to another product. Systems have, therefore, been developed where the external pipe work does not come into contact with the product.

Comparison of Granulation Processes
Tables I - III provide a brief overview of the implications of particular granulation methods. All information shown assumes 'normal' products. Some special products may behave differently.

Table I - Comparison of processes - general

	Option 1 Single-Pot (1)	Option 2 High Shear granulation and FBD (1)	Option 3 Fluid Bed granulation (2)	Option 4 Continuous granulation process (1)	Option 5 Spray Drying (3)
Scale Lab (LS) Tech (TS) Production (PS)	LS TS PS	LS TS PS	LS TS PS	LS (granulator) TS PS	TS PS
Definition of batch	++	++	++	material container	material container
Scalability	+	+	+	++	++
Need special building	weight	height	height	no	height
Energy/kg (4)	<0.25kW/kg	0.25kW/kg	0.37kW/kg	0.25kW/kg	7.5kW/kg
Yield	>99.5%	>99%	>99%	>99.5%	>99%
(1) Granulation with 10% granulation liquid (TS15%) (2) Granulation with 15% granulation liquid (TS15%) (3) Mix all components of formulation in liquid form (TS20%); drying step at the end of primary prod. can be saved (4) Only drying energy Key: ++ very good, + good, +-fair, - poor, -- very poor

Scales - Option 1 is available in a range of 1–1200 litres. Option 2 can handle up to 1800 litres. Batches between 30 grams and 2 tonnes can be granulated in fluid beds. For the continuous granulation technologies presented as Options 4 and 5, the situation is different. There is no upper limit (milk powder granules are produced by spray drying at a rate of up to 10 tonnes/h), these technologies are not appropriate for very small scale production, even at the laboratory trial level, as some processing time is needed to reach equilibrium conditions.

Batch definition - This is irrelevant to batch technologies presented in Options 1–3, but requires some discussion for the continuous technologies, particularly if the raw materials are fed in continuously without dispensing and pre-blending: for example, out of large tanks or silos. The most straight forward approach is to collect the dry granulates in containers and define the load of each container as one batch. This method is used when operating a tablet press. Often, the size of such a container is selected to meet the batch size of a tablet coater. Moheb Nasr of the FDA states the following on fully continuous manufacturing. "A point of confusion is the word 'batch', which can mean either the mode of manufacturing or the quantity of material being processed," says Nasr. The regulations specify: A batch is a specific quantity of a drug or material that is intended to have uniform character and quality, within specific acceptance limits, and is produced according to a single manufacturing order or during the same cycle of manufacture. [CFR, 21 Part 210.3(b)] "The definition of batch here refers to the quantity of material and does not specify the mode of manufacture," says Nasr. [Continuous Processing: Moving with or against the manufacturing flow; Alex Pellek et al; PharmTech.com, Sept. 2008].

Scalability - As developments are usually started in a laboratory, up-scaling must be considered. For Options 1–3, users will only face 'normal' up-scaling problems. Often, processes run better when scaled-up. Linear up-scaling for the Single Pot is only possible if microwaves are used, otherwise drying time will be increased. With the introduction of the FlexStream™ fluid bed, scale-up has become much easier. For continuous processes, up-scaling is easy because operation time is the only parameter to be changed. The situation becomes more complicated if it cannot be done by just running the final production plant for short periods.

Building requirements - Production-scale Singe Pots can weigh up to 10 tonnes, therefore a floor of appropriate strength must be prepared and the logistics of getting the equipment into the building considered, particularly if the equipment is not to be installed on the ground floor. For the high shear granulator/fluid bed dryer combination, both a vertical and horizontal product flow are possible. Productionscale fluid beds can be several metres high; however, it is not necessary to install the whole unit in the production room. If it is built as a 'through the wall' design, all necessary technical installations can be positioned in a technical area. The upper part of the fluid bed tower can also be in a technical area above the production room. Owing to the minimal required footprint and the built in flexibility, the continuous system (option 4) can be run in any existing GMP room. The complex material handling requirements of spray drying require this system (option 5) to be integrated into the building or, even better, the building needs to be tailored around the installation.

Energy- As energy consumption for drying is significantly higher than that generated by motors or vents, only the required drying energy amount is discussed. To evaporate 1kg of water, 0.66kWh of energy is required. The total amount of energy is both a function of the amount of liquid to be evaporated and the grade in which the equipment utilizes the energy supplied. The figures in Table I assume average cases.

Yield - The yield of a process is particularly influenced by the time the process takes and formulation. Longer processes increase yield. The wetter the granulation process, the greater the material loss (as it sticks to the walls). A third important factor is the total surface area in contact with the product. These factors are not independent from each other. They are also influenced by product characteristics. It is, therefore, not possible to provide exact figures however the data shown in Table I reflect typical scenarios.

Table II - Comparison of processes - formulation

	Option 1 Single-Pot (1)	Option 2 High Shear granulation and FBD (1)	Option 3 Fluid Bed granulation (2)	Option 4 Continuous granulation process (1)	Option 5 Spray Drying (3)
Containment	++	+	++	+	+
Organic solvents	++	+	+	+	+
Heat sensitive materials	++	+	+	+	(+)+ (-)
Limitation of different formulations	None (when exposed to microwaves)	None	PSD of raw materials	None	Fine grades of raw materials required if worked from suspensions
Amount of granulation liquid required	8-15%	8-15%	15-30%	5-12%	>100%

Containment - This is essential if processing toxic or very potent substances. In this case it is important to know if it is possible to achieve a closed material flow into and out of the equipment; if the equipment is tight; and if it can be cleaned automatically (including upstream and downstream connections), at least to a level where it can be opened without any danger. Closed material flow is possible for all processes shown. Even the very sensitive process of transferring wet granules via a wet mill from a high shear granulator into a fluid bed can be done closed. This is achieved by using modern split valve technology for contained docking to intermediate bulk containers. Whereas individual machines such as fluid beds, high shear granulators, single pots or spray dryers can be cleaned using very efficient automatic cleaning systems (WIP/CIP depending on the product), fully automatic cleaning becomes increasingly complicated as more upstream and downstream equipment are integrated. Other important factors affecting containment are how easily exhaust air filters can be changed without the risk of contamination; whether the equipment is operated continuously under negative pressure; and to what extent a sample can be contained.

Organic solvents - If processing with organic solvents, the equipment must be gas tight. To eliminate the risk of an explosion it is necessary to either ensure that the mixture of organic vapours and oxygen is outside the explosion limits (which can sometimes be achieved in a spray granulation process) or that nitrogen is used as a process gas. If such processes are to rely entirely on the elimination of all potential spark sources, they must be carefully checked, case by case. Additionally, passive measures, such as a pressure shock design, suppression or venting, are always required except when using a Single Pot. This is because the risk of explosion exists only during the drying step, which is done under vacuum conditions. If the exhaust gas contains organic vapours it must be cleaned. This can be done in a closed cycle by cooling, adsorption or catalytic burning. Again, the Single Pot, particularly if used without stripping gas, has an advantage: only the pure organic vapours must be treated.

Heat sensitive materials - To treat heat sensitive materials successfully, the temperatures and exposure time must be carefully controlled, as should the presence of moisture and oxygen. Single Pot technology provides safe drying under vacuum, particularly if the granulation is done with organic solvents because the corresponding temperature is even lower. In a spray dryer, however, relatively high temperatures are involved, but only for a very short time. A batch fluid bed granulator can operate at higher air inlet temperatures while spraying and during the beginning of drying, reducing the inlet temperature afterwards to maintain a low product temperature. The nature of the product dictates which is the most appropriate treatment.

Formulation limitations - High shear granulators are able to granulate all types of formulations. For Single Pot use, the behaviour of all components exposed to microwave energy must be considered. Although this is not critical for most materials, it should be tested for new materials because of the small risk of an unexpected thermal runaway - the (microwave) absorption behaviour relies on the moisture content or on the actual temperature. Fluid beds inherently act as a classifier: that is, the particle size distribution (PSD) of all raw materials should be similar. Processing very fine powders can also be problematic because these particles tend to stay in the filter area. Sometimes this can be solved by introducing the spray liquid. If a suspension is used to feed the spray dryer the suspended particles need to be smaller than 30 μm to allow a proper atomization.

Granulation liquid - For the production of oral dosage forms, high shear granulators have almost replaced medium and low shear versions because their increased mechanical energy requires less granulation liquid to produce granules of similar properties. Also, smaller amounts of liquid added during granulation requires less evaporation during drying, resulting in a higher throughput and lower thermal stress for the active. The numbers provided in Table I largely depend on the nature of the formulation; whether the binder is added in a liquid or a solid form; and the granule characteristic required.

Table III - Comparison of granule characteristics

	Option 1 Single-Pot (1)	Option 2 High Shear granulation and FBD (1)	Option 3 Fluid Bed granulation (2)	Option 4 Continuous granulation process (1)	Option 5 Spray Drying (3)
Dust/fine particles	<12%	<8%	<5%	<3%	<1%
D₅₀:PSD	100-800 µm	120-800 µm	150-600 µm	120-400 µm	150-300 µm
Span (5):	2.5 - 3	2.5	2	2.5	1.5
Homogeneity	+	+	+	+	++
Flow properties	+	+(+)	+	++	+
Bulk density	0.7 g/cm^³	0.8 g/cm^³	0.7 g/cm^³	0.8 g/cm^³	0.6 g/cm^³
Dissolution	+	+	++	++	++
(5) Span = (D₅₀-D₁₀) / D₅₀

Fine particle amount - If the percentage of fine particles (size < 63 μm) is too large, flow problems, segregation and poor tablet formation are the most common problems to be expected. The numbers shown in table III depend heavily on the formulation and the process parameters but show a clear tendency. In option 5 the process does not allow fine particles to be discharged but ensures they are blown back into the operation zone where they are most likely to be bound into granules. The relatively high amount of fines for the Single Pot process is a typical result of all types of vacuum drying. If seen as problematic this can be reduced by adjusting the formulation.

Mean particle size - All processes allow the mean particle size to be controlled by varying some process parameters. The given limits can, in some cases, be extended for bespoke equipment.

Span - The span describes how narrow a PSD is. Not all results shown are critical for tablet compression but may be of some interest if the granules are sold as a final product.

Homogeneity - All technologies presented generally show no problems with product homogeneity. Mixing all components in a liquid stage followed by granule production in a one-step operation will give the best homogeneity level.

Flow properties - Achieving free flowing materials is a major reason for performing granulation so only processes able to fulfil this requirement are of interest. The slight differences shown in Table III result from the fact that high shear granulation in general produces more dense and mechanically more stable granules. During vacuum drying, some of these granules are destroyed and a larger amount of fines is generated.

Bulk density - The bulk density required depends on the physical densities of the materials used, from the amount and type of binder liquid, the process parameters selected and the process by which the granulation is done. The numbers shown in Table III may, therefore, vary for different materials or process conditions, but a clear pattern is shown illustrating which process will drive the bulk density in a particular direction.

Dissolution - How easily granules dissolve (instant properties) depends on their surface energy and structure. Granules produced with lower shear forces, such as in Options 3–5, show a more open porous structure, therefore, they have better instant properties, but are mechanically less stable.

Selection of Granulation Process
As mentioned at the beginning of this article in most cases the granulation process / equipment is selected based on company experience / equipment present in the company. But there are good reasons to do this selection process in a more objective way.
The following factors should be considered:

Volume of production
Multi-purpose or dedicated plant
Product mix / volumes and campaign lengths (resulting in the required number of changeovers)
Existing products / processes (process already registered for a particular product)
Need to process organic solvents
Tradition (know how/policies)
Other applications to be done in the same equipment (coating, etc.)
Potency of API (environmental / personnel)
Space / height available
Capital / operating costs

The most significant strengths and weaknesses of each technology:

1. Single Pot

+ High containment
+ One-pot operation
+ Small footprint
+ Granulation process can compensate fluctuations in raw material specification
+ Very fast changeover
+ Easy and safe handling of organic solvents
+ High Yield
+ Limited need of operators
+ Unique solution for effervescent production

- Limited throughput
- No possibility for additional unit operations
- Scale up

2. Fluid Bed Granulation

+ One-pot operation
+ Limited number of operators
+ Small footprint
+ Possibility of additional unit operations
+ Excellent compression behaviour of granules produced
+ Easy scale up (FlexStream™ range)

-   Handling of organic solvents
-   Height requirement
-   Handling of organic solvents more complex

3. Integrated High Shear Granulator & Fluid Bed Dryer

+ Established technology
+ Very high throughput
+ Granulation process can compensate fluctuations in raw material specification
+ Possibility of additional unit operations

-   Limitation in yield
-   Large footprint
-   Large height
-   Long time for change-over
-   Large number of operators
-   Handling of organic solvents requires complex set- up
-   Difficult scale up

4. Continuous granulation process

+ Small footprint and height requirement (especially if directly integrated with tablet press)
+ Minimal need operators (especially if directly integrated with tablet press)
+ Granulation process can compensate fluctuations in raw material specification
+ Fast changeover
+ No process scale-up (time is the only relevant factor)
+ High Yield
+ In line with latest FDA requirements

-   No possibility for additional unit operations
-   No possibility to work in gram scale
-   Handling of organic solvents requires complex setup

5. FSD Spray Drying

This is a totally different concept that requires the combination of primary and secondary production. This can create materials with tailor-made characteristics (enhanced bioavalability, incorporated taste masking, suitable for direct compression ...) in a one-step operation.

TCO (Total Cost of Ownership)

As the total cost of a manufacturing operation is a key decision criterion, GEA Pharma Systems offers its customers a TCO calculation on a case-by-case basis.
Required input parameters are:
Characteristics of production pattern

Average batch size	kg
Time per batch	hours
Average number of tablets per batch	tablets / batch
Average number of batches per campaign	batches / campaign
Available working hours per day	hours / day
Available working days per year	days
Total available working hours per year	hours
Time for cleaning between batches	hours
Time for campaign change-over	hours
Number of operators for production
Number of operators for cleaning
Cost per operator	€ / hour
Yield of process	%
Price of material	€ / kg

Characteristics of Investment

Price for granulation equipment	€
Depreciation time for equipment	years

Space requirement:
GMP floor	m²
GMP room	m³
Technical floor	m²
Technical room	m³
Cost for GMP space	€ / m³
Cost for technical space	€ / m³

With the above information it's possible to do TCO calculations to compare different production scenarios.

ECEC Course: Pharmaceutical Granulation and Compression

2011-12-09T06:26:00.001+01:00

Three Day Intensive Course with an Emphasis on High Speed and Fluid Bed Granulation, Layering, Pellet Manufacture, Roller Compaction, Oral Dispersion Technology, Scale-Up, Transfer Technology, Melt Extrusion, Spray Drying and Compression Machinery.

Holiday Inn Hotel, Oxford Circus, London, UK - 6th, 7th and 8th February 2011

LinkedIn Event: Pharmaceutical Granulation and Compression Course

Course Background - Granulation and compression are two very important processes that are carried out extensively by most pharmaceutical companies. However, the theory of granulation is little understood and the selection of a particular machine and granulation method, is often done on the basis of tradition, rather than by using strict scientific or cost-benefit criteria. The basic techniques have changed dramatically in recent years and granulation for controlled release, extrusion, spheronisation, fluidisation techniques, spray drying, melt extrusion, oral dispersion technology and roller compaction are new technologies that are increasingly being used in modern pharmaceutical production, which exhibit many advantages over previously available techniques. As with granulation, compression is also little understood and why some materials/formulations will compress well whilst others compact with difficulty, is slowly being elucidated. The Course will examine current granulation and compression theory and practice. Emphasis will be made as to how this theory and practice relates to current pharmaceutical development and production, with special reference to the machinery used. Scale-Up, Transfer Technology and SUPAC will also be addressed. A particular feature of the Course will be the workshop on new melt extrusion technology.

Course Objectives - The aims of the Course are to provide a comprehensive and sound understanding of the theory and practice of tablet granulation and compression and to appreciate the various processes batch or continuous, that are available. The importance of the granulation process in producing good quality tablets will be emphasised. The modern techniques of extrusion, spheronization, powder layering, roller compaction, fluid-bed processing, spray drying, melt extrusion, oral dispersion technology and tablet compression will be covered. The Course will be taught primarily by industrial scientists who have been closely involved with investigating these granulation and compression processes and thus a pragmatic approach will be adopted throughout.

GEA Pharma Systems will participate in this event with the following lecturers:
Dr. Harald Stahl Ph.D.
Harald is Senior Pharmaceutical Technologist with GEA Pharma Systems with world-wide process responsibility for the technologies supplied by GEA Pharma Systems. Previously he worked in the Pharmaceutical Development Division of Schering AG in Germany.
Jan Vogeleer B.Sc.
Jan is Manging Director of GEA Pharma Systems - Courtoy™, manufacturers of tablet presses in Belgium. He has pioneered the design of new tablet machinery to enable tablets to be produced at faster speeds with minimal clean and down time and has a huge wealth of experience in novel design of compression machinery.

Read more and download the pdf registration form.
Information about other courses from ECEC for this academic year: http://www.ecec.co.uk/courses.html

Containment in Tablet Compression

2011-11-11T08:11:00.001+01:00

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).

Fig 1 1. Tablet Press in a Isolator 2. MODUL™ tablet press with ECM

Fig 2 shows the MODUL™ S with its ECM highlighted.

Containment levels of down to 0,1μg/m³ could be achieved. The main problem of an isolator based system is the handling, with complete product change-over taking up to 16 hours in the case of the system shown in Fig 1.

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.

3. The ECM Concept

3. ECM - Exchangeable Compression Module

The key feature of the MODUL™ concept is the Exchangeable Compression Module (ECM). The ECM is a completely sealed box; it contains all product-contacting parts and is easy to remove from the machine. It is shown in more detail in Fig 3. 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. 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 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

7.1. 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 - IrelandIn 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

7.3. Ranbaxy - India

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

7.5. Teva - Hungary

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.

For further information about Contained Tablet Compression contact:
Veerle Chiau - GEA Pharma Systems - Courtoy™
courtoy@geagroup.com

VAPOVAC™ Gas Sterilization an alternative to traditional Steam Sterilization

2011-11-02T09:47:00.000+01:00

VAPOVAC™ H2O2 Gas Sterilization - Faster, Safer,
More Effective Freeze Dryer Sterilization

Why?
The production of many pharmaceuticals requires sterile conditions. Therefore freeze dryers are equipped with SIP-Systems (Sterilization-in-Place) working with steam, which means that the freeze dryers are exposed to different stresses and strains. During a freeze drying process the plants undergo pressures of 5 x 10-3 mbar up to 2,5 bar and temperatures ranging from -80°C to 121°C. Consequently the chamber, condenser and the related piping have to be built pressure proof making those freeze dryers much more expensive than the non-steam sterilisable executions.

Alternative Technology
GEA Lyophil has looked for a less expensive solution and found a way to sterilise freeze dryers at vacuum - H2O2 GAS Sterilization. The VAPOVAC™ H2O2 Gas Sterilizer, reduces the investment costs and the sterilisation cycle time. GEA Lyophil is the only manufacturer that offers this technology.

The H2O2 Sterilisation is faster, safer, more efficient and more environmentally friendly than using steam. This technology is available for new plants and as a retrofit option to existing installations.

The VAPOVAC™ steriliser uses VHP technology to sterilise equipment under vacuum. Only a very small quantity of hydrogen peroxide is used to penetrate the freeze dryer vessels and all associated piping of the equipment. This method effectively eliminates all residual contamination. The freeze dryer is then fully vented, leaving no harmful residues.
The Process
This consists of three steps:

Drying: The freeze drying chamber and condenser are dried before feeding hydrogen peroxide into the equipment.
Sterilisation: The freeze dryer is evacuated to a very low pressure. When the injection set pressure is reached, the H2O2–solution is injected into the freeze dryer.
Aeration: After sterilisation, the hydrogen peroxide is completely and safely removed from the vessels.

Benefits The VHP system have many advantages:

Very gentle treatment of freeze dryers
Pressure- and temperature-stress reduction
Minimises risk of malfunction and subsquent correction efforts (leaks, rouging)
Shorter sterilising time possible
Simpler design
lower investment costs
Less utility consumption.

Increased plant availability
The faster turn-around results in greater efficiency. The H2O2-gas sterilisation process can be performed in approximately 3 hours for an average production freeze dryer depending on the freeze dryer options, compared with approximately 8 hours for steam sterilisation. This allows the plant operators to increase productivity and make the whole system more efficient.

Low cost and kind to the environment
Very little energy is needed to operate the VAPOVAC™ steriliser, making it cost efficient. H2O2-gas-sterilization does not release harmful carcinogenic or mutagenic by-products and therefore, is kinder to the environment. The chamber, condenser and connecting pipes are used at atmospheric pressure, which makes them less expensive and easier to install. The elimination of high-pressure hoses also makes the process safer and reduces operational wear – meaning that plant system life time is extended.

Increased safety
The VAPOVAC™ system meets GAMP, cGMP, FDA, DIN, ISO and all other European and US codes. The residence time of the hydrogen peroxide can be varied as the system is monitored and can be adjusted to ensure effective sterilisation. After sterilisation, the hydrogen peroxide is completely and safely removed from the chamber – the operator having to positively confirm to the control system that H2O2 evacuation has been achieved successfully in order to complete the sterilisation process.

Retrofit maximization and application support
Retrofitting a freeze dryer with the H2O2 sterilisation system offers operators a way to increase the lifespan of existing equipment. In addition to gaining a highly efficient and cost-effective method of sterilisation, GEA Lyophil can, at the same time, enhance plant performance through a range of new systems, in addition to the H2O2 system.

GEA Lyophil’s experts can recommend various methods and equipment in increase productivity of existing plant. For example, new shelf packages and GEA Lyophil’s ALUS® (automated loading/unloading system) give plant a new lease of life and extend the operational usefulness of the entire plant.

H2O2 Gas Decontamination of Freeze Dryers - A comparison between the vacuum and atmospheric process (case study)
The use of H2O2 gas decontamination on surfaces today is leading technology throughout the pharmaceutical industry. In the early nineties H2O2 gas decontamination became a standard in isolator technology and sterile room decontamination. The reduction of bacteria and spores on surfaces and consumables using H2O2 gas is now essential in aseptic production.

The advantages of this cold sterilisation technology together with the non-toxic residual products caused the development and use of different H2O2 gas decontamination processes and generators. The following case study shows the potential and limits of those technologies and gives advice to users on choosing the appropriate process for a specified application ... Read more

PAT Technology : Lighthouse Probe™

2011-10-21T19:59:00.000+02:00

GEA Pharma Systems has created a compact and cleanable in-process optical probe for use in powder processing equipment.

Optical methods such as UV/Vis or NIR spectroscopy can be very powerful tools for analyzing a range of product characteristics, but in processes involving wet and sticky powders it is necessary to ensure that the system has a clear view of the product. Conventional windows used in process equipment such as fluid bed systems, high shear granulators or spray dryers have always suffered from the risk of window fouling. The new Lighthouse Probe™ has overcome this problem. In addition to in-process cleaning (CIP), to ensure a clear optical path, the Lighthouse Probe™ has been designed to enable the probe and wash system, including the critical product seal area, to be fully cleaned in place (CIP) at the end of the process. The novel design also includes a self calibration facility which can be used to positively confirm that the seven observation windows have not become contaminated and also to regularly check the calibration of the spectrometer.

The Lighthouse Probe™ uses a combination of fiber optics and mirrors to give an exceptionally compact design suitable for simple mounting on the smallest processors without disrupting the process. At the same time it offers the ability to ensure that the analyzed sample volume is consistent with the scale of scrutiny required with respect to a unit dosage.

GEA Pharma Systems will now offer the Lighthouse Probe™ Technology as part of its process equipment and will continue to use its extensive background in process engineering to develop new applications. This will enable GEA Pharma Systems to offer world-class solutions to meet the demands for pharmaceutical production in the 21st century.

Options to retrofit to existing process equipment are also available.

The Lighthouse Probe™ is a process analyzer that enables PAT

On-line and in-line analysis becomes more important today. This importance is increasing after introduction of the FDA's PAT initiative.
Some of the in-on-line analysis methods are based on optical measurements. The use of these optical methods is based on analyzing the process through a window
Window fouling is a well known phenomenon, which is often happening, leading to wrong analysis results or unwanted stops of the process.
This is a big problem for methods using optical detection
To ensure an optical detection without any problems during the process the Lighthouse Probe™ was developed

The Lighthouse Probe™ system consists of 5 elements:

Probe with optics
Spectrometer
Software (data acquisition and analysis software and programming for movement unit and CIP unit)
Movement unit and housing
CIP unit

Benefits:

No window fouling
In-line window wash
In-line calibration
Full CIP
In-product measurement with 360 degrees view
Simultaneous use of various analytical methods (NIR, FBRM etc)

Technical details:

Tubular Sapphire glass windows
Large observation area
Fibre Optic side viewing optical probe
Small probe diameter
Compact CIP skid
Customized probes
- Various lengths
- Various tips/noses
- Portable versions
- In-flow measurements
- Multi-point/-depth

Summary

The Lighthouse Probe™ provides:

In-process window cleaning at any time.
Recalibration at any time during the process
Full CIP of wash housing and seal
Always a clear view inside, even in difficult conditions

Future developments

Combining Lighthouse Probe Technology with UV/VIS-, fluorescence- and Raman spectroscopy.
Experiments with pastes and suspensions.
Tests in different vessels and tubes (flow through).
Combination of different optical methods in one probe.
Additional experiments for checking product homogeneity in vessels.

Why Containment?

2011-09-11T22:16:00.000+02:00

Containment is the area separation from Product to Personnel and Environment by barrier. Containment is used to prevent any negative impacts (contamination) from one area to the other and vice versa. Click on this link for our complete 'Containment Fundamentals' information.

"A rational approach towards containment requirements in the various production stages, can also be adopted. Indeed, the containment level required of equipment used at the dispensing stage (where the material handled is pure HPAPI in powder phase) is different from that needed in tablet coating (where the HPAPI is diluted and compressed into a tablet). The concentration of airborne API particles also varies during the different operational steps of the tablet production process. The only correct way to assess risk and determine the appropriate containment level for the various process steps/equipment is to calculate real daily intake (RDI) and compare this with the allowable daily intake (ADI)."

GEA Pharma Systems provide high containment docking systems dedicated to the pharmaceutical industry. The docking systems comprise of special split valves (Buck® Valve) or disposable & flexible Interfaces (Hicoflex®). These technologies provide high personal and product protection during all stages of the charge and discharge process of high potent APIs as they form a dust and contamination free interface. Buck®, has used its 15 years experience in the field of high containment split valve technology to begin a new era in this field: the NEW Buck® Modular Containment Valve - Buck® MC Valve (patent pending).

This new concept unifies all the current requirements in high containment equipment: full GMP design, no need for lubrication, no need for vacuum, robust centering, free orientated docking, quick release without any tools as standard. But the most innovative step is the idea of using only passive valves driven by a modular actuator unit.

Containment Experts
GEA Pharma Systems not only offers the largest variety of hardware solutions for contained materials handling, but also unrivalled experience in identifying the most appropriate solution, based on a containment risk analysis ... contact us for more details.

GEA Pharma Systems will exhibit its premier contained small scale production granulation system at Technopharm, Nürnberg in October 2011.

Totally Contained - Completely Flexible - Pharma Granulation

A complete production plant that takes the process from dispensed raw materials to finished tablet. The system on show clearly demonstrates the flexibility that can be achieved throughout the process – including high shear granulation, pelletization, drying and blending – in a totally contained environment. It illustrates how GEA Pharma Systems’ inspired technology can be selected to form a total solution tailored to suit each user’s specific requirements, whether through integration or split valve technology.

The system is aimed at producers of small quantities of highly potent compounds. The intelligent contained handling systems inherent in the GEA Pharma pilot plant allow it to be flexible, efficient, clean and safe without the need for expensive, bulky and difficult to clean isolator systems. Furthermore the level of containment avoids the need for costly and uncomfortable airsuits, allowing the users to focus on the product, creating faster and more secure results.

Process Overview
At the heart of the production plant are PharmaConnect®, and FlexStream™. PharmaConnect® is GEA’s innovative, modular granulation and blending system offering an unbeatable range of process types and capacities; FlexStream™ is the world leading process technology for spray granulation and pellet coating, delivering unbeatable benefits in terms of greater productivity, lower running costs and a robust and scaleable process.

Contained product transfer
The system includes examples of both rigid and disposable product transfer technology offering containment down to low nanogram levels. These options include: the disposable Hicoflex® system with significantly lower capital and running costs compared with rigid IBC technology and rapid product changeover for improved plant utilization; the unique, modular Buck® MC valve with its simple design that enables complete container-to-container transfer flexibility; and the Buck® TC Valve, the highest performing split valve available in the market place. By introducing a wash step prior to valve separation, the Buck® TC Valve is capable of performance to the low nanogram level.

Integrated Approach
All of these technologies are brought together for Interpack, in an integrated process system that mimics the hundreds of large-scale plants provided by GEA Pharma Systems globally. It epitomises the approach of ensuring customers receive the same technology from the laboratory through to production, using the same containment and process technologies to ensure seamless scale-up and the most flexible blend of process capabilities.

Visit GEA Pharma Systems on stand number 250, Hall 5 and see the complete production plant. Experienced GEA engineers and sales staff will be on hand to answer questions. Learn more about systems integration at TechnoPharm 2011.

For further information about Contained Granulation contact:
Mark Rowland - Product Manager Small-Scale Equipment
mark.rowland@geagroup.com

TechnoPharm 2011: Countdown for the Pharma sector’s autumn highlights

2011-09-03T14:53:00.001+02:00

Meet GEA Pharma Systems and other GEA Group companies in hall 5. | 250.
or contact us: pharma@geagroup.com

The exhibiting companies are always the heart of an informative exhibition. Over 1,000 exhibitors from all over the world are expected again in Nürnberg from 11–13 October 2011 to present products and services from the segments of mechanical processing technologies, instrumentation and life science technologies in the six halls of POWTECH and TechnoPharm.

GEA Pharma Systems will be participating at TechnoPharm 2011 next month showing a range of equipment for Pharmaceutical Processing of Solid Dosage & Liquid Steriles:

1. Contained pilot-scale Granulation system
A complete production plant that takes the process from dispensed raw materials to finished tablet. The system on show clearly demonstrates the flexibility that can be achieved throughout the process – including high shear granulation, pelletization and blending, etc. – in a totally contained environment. It illustrates how GEA Pharma Systems’ inspired technology can be selected to form a total solution tailored to suit each user’s specific requirements, whether through integration or split valve technology.

Integrated Approach
All of these technologies are brought together, in an integrated process system that mimics the hundreds of large-scale plants provided by GEA Pharma Systems globally. It epitomises the approach of ensuring customers receive the same technology from the laboratory through to production, using the same containment and process technologies to ensure seamless scale-up and the most flexible blend of process capabilities. Read more about Granulation & Drying on our website.

2. High Containment pilot-scale Tablet Compression
There is an increased demand for increased flexibility and product containment when working with potent compounds, especially with regards to small-scale tablet presses. This demand has led to the development of the Courtoy™ MODUL™ P Tablet Press.

The MODUL™ Tablet Press concept has been on the market for a few years. It is a well accepted design and concept that already feature more than 70 installations.

Key elements of the design include:

The ease of removing the Exchangeable Compression Module (ECM) from which the product cannot escape.
It eliminates the need to clean the inside and outside of the press and the room.
It results in increased operator safety and a reduction in cleaning time of up to 50%.
Read more about Contained Tablet Compression on our website.

3. Lab-scale Continuous Processing

Three years ago, GEA Pharma Systems introduced ConsiGma™, an innovative high-shear granulation and drying concept capable of producing pharmaceutical granules continuously, without start-up and shut-down waste. This concept enabled the use of the same system for development and production work without the need for scale-up, as the determining factor for batch size is running time – not the size of the equipment. Batch sizes ranging from a couple of kilogrammes up to several tonnes can be produced.

In early research and formulation development however, the availability of the active ingredient is often very limited and there is a need for process equipment that is capable of producing only a couple of hundred grams to develop new drug formulas.

In response to this need, GEA Pharma Systems developed ConsiGma™-1, the lab-scale version of the ConsiGma™ concept. This system consists of a patented continuous high shear granulator equipped with all necessary auxiliaries to allow the development of the granulation process. A small dryer equal to one drying segment of the ConsiGma™ production dryer and capable of handling 0.5 to 1.5kg of granules, can be added to the lab machine, creating a unique combination with integrated controls for the development of continuous processes.

ConsiGma™-1 is capable of running batches of a couple of hundred grams up to 5 kg (or more if necessary), with less than 10 g of product held up in the process and less than 80 g of product losses. Because of the fast processing times, minimal retention times and flexibility of the system, it is ideal for developing the formula and process parameters using Design of Experiments. The process parameters developed with ConsiGma™-1 can be directly transferred to the full ConsiGma™ system.

The system is designed for fast and easy deployment in R&D labs.

Both ConsiGma™-1 and the full continuous ConsiGma™ tabletting line can be tested in the new cleanroom at GEA Pharma Systems in Wommelgem, Belgium.

4. High performance Fermentation Systems
The pharmaceutical fermentation process requires the very highest quality of all the materials and vessels used to provide the necessary long-term sterility and ensure that all the many standards, statutory provisions and regulatory requirements are met.

As a result, pharmaceutical manufacturers demand the highest standards with regard to their fermentation systems. Every function, every component and every detail has to comply 100% with the relevant quality standards. The use of a high performance and reliable fermentation system will in itself ensure that many of these conditions, which are essential to safe and high-quality production, are fulfilled.

GEA Diessel has been developing and building fermentation systems for the cultivation of micro-organisms and human or animal cells for over 20 years. Whether for individual fermenters or multi-stage fermentation systems, manufacturers again and again put their trust in GEA Diessel’s efficient, customised plant. Read more about GEA Diessel process systems: parenterals, fermentation, feed media, blood plasma and special liquids as well as clean utilities.

5. IZMAG™ : a flow meter for when accuracy matters
IZMAG™ is a new generation of stainless steel electromagnetic flow meters that is ideal for applications throughout the pharmaceutical industry. IZMAG™ flow meters offer the unrivalled accuracy and reliability plus a host of new features including a visual display, 360° positioning, automatic calibration, automatic alarms both on the instrument and to a central monitoring station and Bluetooth® compatibility for simple data gathering. IZMAG™ has no moving parts, offers bi-directional metering for all conductive liquids, is suitable for aseptic processing and can be used at high temperatures or under vacuum conditions.

GEA Pharma Systems and sister GEA Group companies: GEA Niro, GEA Tuchenhagen, GEA Barr-Rosin, GEA Liquid Processing, GEA Delbag and GEA Deichmann are all exhibiting at TechnoPharm | Powtech 2011 on one unified GEA Group stand in hall 5, stand number 250.

TechnoPharm | Powtech 2011 - 11-13 October 2011, Nürnberg, Germany

POWTECH and TechnoPharm as app and on mobile sites
POWTECH and TechnoPharm go mobile in 2011 for the first time. Whether in the form of an iPhone app or mobile sites, anyone looking for information about the exhibition duo when underway can do this very conveniently with effect from mid July. The app offers many services: from a complete list of exhibitors – available by search terms, alphabetically or by stand position, supporting programme, site and floor plans to opening times or entrance prices. Access to the iPhone app is via the app store or the event home page. Access to the mobile sites is via: m.powtech.de (from mid July) and m.technopharm.de (from mid August).

Synthon BV : Pelletization Process Line Reducing the risk of drug development and production

2011-08-29T08:58:00.001+02:00

GEA Pharma Systems helped develop a complete process line for one of Europe’s most successful pharmaceutical companies for the manufacture of generic medicines.

The ‘Pellet Processing’ project includes the supply and integration of; granulation technology with a Collette™ UltimaGral™ and Aeromatic-Fielder™ NICA™ Pelletizing System, Coating technology with GPS’s unique PRECISION COATER™ and Fluid Bed Drying.

Synthon BV
Based at Nijmegen in the Netherlands, Synthon manufactures a range of products for worldwide distribution through its marketing partners in Europe, the USA, Canada, Australia, New Zealand, Chile, Argentina and South Africa. The development of the generic version of a drug will usually begin several years before the expiration of the patent with the aim of introducing it to the market within a few hours of the protected period ending. Synthon focuses on the more complex pharmaceuticals as fewer of its competitors have the human and technical resources to replicate them.

Development of the generic version of a drug Initially small batches of the drug are produced in the laboratory before up-scaling production to meet the demands of the market. Up-scaling production from a laboratory batch size of 200g to a typical production batch size of 500kg while maintaining the exacting standards of the formulation represents a major challenge to drug manufacturers. The choice of equipment and the expertise available from its manufacturers plays a key role in getting the product to market quickly and maintaining the required standards in production.

Investment in GPS equipment to manufacture and coat tiny pellets

After evaluating the systems offered by the GPS group, Synthon approached the company in 2002 when new equipment was required for a partner manufacturing plant in Greece to up-scale production of one of its products. The first requirement was for the NICA™ extrusion/spheronization equipment to manufacture tiny pellets containing the active ingredient followed by the PRECISION COATER™ with its unique airflow characteristics, giving a very exact and even coating of product both technologies supplied by Aeromatic-Fielder. Coating of the tiny pellets, which can be less than 1 mm diameter, is necessary for several reasons, for example to mask unpleasant tastes, improve appearance or, as in this case, to provide controlled release of the drug in the body. The aim is to evenly coat the pellets with just enough material to achieve the desired result and no more.

Why Synthon chose the Nica™ System

Additional NICA™ pelletizing equipment was subsequently supplied and integrated with the system to manufacture the pellets themselves. Synthon chose the NICA™ equipment, partly because of its exceptional performance and flexibility, but the co-operation of GPS as a business partner played an important role. “We looked carefully at what equipment was available commercially to do the development work,” said Synthon’s director of technology Derk Sanders. “After looking at all the possibilities we decided on the GPS Nica™ system for our development and up-scaling activities. GPS allowed us to rent the necessary equipment to produce batches under GMP requirements. The whole exercise went very well and we subsequently upgraded the systems to the largest available from GPS. We now have three NICA™ integrated extruders/Spheronizers producing a total of 2700kg a day”

Derk Sanders sited the simplicity of the GPS equipment as being a key factor in the successful development of the process. “Production has now been underway for just over a year with around 300 batches of the drug produced,” he said. “So far not a single batch has been rejected due to failure of the equipment.”

One of the main obstacles for pharmaceutical companies in the development of drugs is the cost of trials. The use of the test centre in Bubendorf significantly reduces these risks giving manufacturers confidence that critical manufacturing processes are viable without major capital expenditure.

GPS test centre facilities … an “important resource”
The GPS technology centre in Bubendorf Switzerland, which opened in 2003, has been used extensively by Synthon to develop its production processes. The technology centre provides pharmaceutical companies with a one-stop GMP environment to enable them to develop new solid dose products using the latest equipment. The centre is equipped with the full range of GPS equipment from powder mixing, through granulation and drying to tablet pressing and coating.

“The technology centre is a very important resource for Synthon. One of the main benefits is that it enables us to test our processes using small quantities of API (Active Pharmaceutical Ingredient),” continued Derk Sanders. “We need to know that the equipment we select for production will produce the formulation in large batch sizes and the facilities at the centre allow us to do that. To do the same test here in the factory would require API test batches of 500kg which would be a huge risk and prohibitively expensive. Our R&D department is using the centre more and more to help develop processes for future products.”

“We have a very good relationship with the technology centre and they’ve been very flexible in accommodating us, often at short notice. We’re a dynamic company and we have to move quickly to stay ahead, they have always given us excellent service: it is a partnership.”

GPS added, “Having the technology centre means that we can work closely with customers to conduct tests and make sure the equipment is suitable for an application before they place an order. This safeguards the customer’s interests and allows us to prove the system we are recommending. It’s a perfect tool for us.”

The vast practical experience of the machine operators is a further advantage of using the test centre. During testing, conditions are often taken to levels far beyond those experienced in normal production. The data collected often shows that conventional processing techniques can be modified with beneficial results.

Sharing valuable information for use in future projects
Development engineers from Aeromatic-Fielder’s factory in the UK make frequent visits to the test centre to see at first hand the machines working in a production environment. This provides Synthon’s R&D engineers with the opportunity to share information and give feedback to the equipment manufacturers. This regular close contact provides Synthon with valuable information for use in future projects.

A strong future for GEA Pharma Systems and Synthon
GPS’s relationship with Synthon has grown during the last 4 years and looks set to become even stronger in the future. “Our experience of working with GPS has been very favourable,” said Derk Sanders. “Business is always a two-way thing and both companies have worked together to achieve excellent results. I am very comfortable with GPS and I look forward to working with them in the future.”

For further information about Pellet Processing contact:
Mark Rowland - Product Manager NICA™ Pelletizing System
mark.rowland@geagroup.com

Pharmaceutical Spray Drying

2011-08-21T17:16:00.106+02:00

By: Dr. Harald Stahl, Senior Pharmaceutical Technologist at GEA Pharma Systems
pharma@geagroup.com

Spray drying is presently one of the most exciting technologies for the pharmaceutical industry, being an ideal process where the end-product must comply with precise quality standards regarding particle size distribution, residual moisture/solvent content, bulk density and morphology.

One advantage of spray drying is the remarkable versatility of the technology, evident when analyzing the multiple applications and the wide range of products that can be obtained. From very fine particles for pulmonary delivery to big agglomerated powders for oral dosages, from amorphous to crystalline products and the potential for one-step formulations, spray drying offers multiple opportunities!

Preparation of Granules by Spray Drying
Pharmaceutical actives are mainly produced by biotechnology or chemical methods, normally involving a drying step as one of the very last unit operations. Here the focus of interest is mainly on the residual moisture or solvent content and also in the prevention of thermal degradation. The physical appearance of the material is not of great interest at that time because this is mostly modified during secondary production.

In secondary production, the solid dosage form is manufactured by blending the active with the necessary excipients. The next step is typically to form granules from this mixture by the means of wet granulation. After this a drying step is required. The reason for this granulation/drying operation is that modern high-speed tablet presses require materials with excellent flow properties in order to produce tablets with the required homogeneity and weight consistency.

Alternative Process
A potential alternative process is to produce the active in a granular form during primary pharmaceutical production. These granules can then be blended with the excipients during secondary production. Most excipients used today can be purchased in a quality suitable for direct compression and an additional granulation/drying step then is not required. Alternatively active and excipients can be mixed together in the liquid phase and then be dried- as granules- together.

To do so it is necessary to carry out the drying at the end of primary production in a FSD™ (Fluidised Spray Dryer) spray dryer. The feed, which can be an aqueous or organic solution or a suspension of solids is pumped to the atomisation device which can be a nozzle or a rotary atomiser (spinning disk). Here the liquid droplets and the hot drying gas are brought into contact, usually in a co-current mode. Using the thermal energy of the hot air the liquid evaporates and the solids form particles. The exhaust air carrying vapour and particles leaves the drying chamber at the base. These particles are then removed from the exhaust air stream by gravity, a cyclone, a filter or a combination of these methods. Depending on the TS (Total Solids) of the feed, the atomisation and the material characteristics, the process will form single particles in a range between 2 and 250 μm. Drying single particles larger than typically 100 μm requires mostly the use of tall form dryers (an extremely high execution of a spray dryer).

To produce granules by spray drying it is necessary to use a set-up shown below.

In comparison with the conventional spray dryer described above, for the FSD the exhaust air leaves the drying chamber from the top. Fine particles are conveyed in and out of the drying chamber with the exhaust gas and these particles are removed from the gas stream external cyclone or filter unit and then re-introduced into the dryer. Depending on the material being processed and the characteristics of granules to be produced this can be done at various positions. These particles now come into contact with newly formed wet droplets to produce granules. The growing particles are re-circulated via the exhaust air and cyclone or filter unit into the process chamber until the particles grow sufficiently to form granules. On reaching a certain size the granules are too heavy to be transported with the exhaust air and fall into the lower part of the dryer. Here they are finally dried in a continuous fluid bed and cooled afterwards in a second fluid bed if required.

While spray dryers have been in existence for more than 70 years, the FSD technology was invented only 20 years ago. Since then it has been used to process a large number of products. Some important examples are:

Dyestuff
Instant Coffee
Milk Powder
Vitamins
Flavours
MCC
Sorbitol
Lactose
Antibiotics

Production capacities range from some kilograms up to 10 tons of powder per hour. The decision factors for using FSD technology is quite different for different products. Very often the excellent instant properties are the reason and for example, most food or dairy products. Today the process can be used to manufacture typical pharmaceutical excipients such as microcrystaline cellulose, vitamins or sorbitol. FSD technology is also used to produce granulated material suitable for direct compression.

The large number of variable parameters allows granules to be formed with exact pre-defined characteristics. The size of the granules is mainly determined by the materials being processed, the droplet size after atomisation and the exhaust air temperature. Adjusting these parameters will influence other characteristics such as bulk-density, porosity and granule hardness. The residual moisture content of the granules produced can be easily adjusted by variation of the fluid bed inlet temperature. For some applications it is also possible to add a binder to the feed.

Most of the FSD- plants are dedicated either to the production of one product only or if multi-production to very long production campaigns. Typically this is not the case for pharmaceutical applications, which means that a large number of change-overs and consequently frequent cleaning is necessary. An FSD plant with external powder recovery is an extremely complex system, with a large number of surfaces in contact with the product. These comprise not only the feed line, atomiser and drying chamber but also the cyclone for powder recovery, the fluid bed(s) and a considerable amount of external pipe work is in contact with the product which all needs to be cleaned when changed to another product. This has made the technology unattractive for the use in the pharmaceutical industry with its typical short production campaigns.

In order to make FSD- technology more attractive for the use in pharmaceutical production, the future plant design has to be modified so that:

The powder recovery is done internally,
The fluid beds for final drying and cooling are integrated
At least a wash-in-place (wip), but preferred a clean-in-place (cip) of the plant is possible.

A design fulfilling these demands is shown here:

The operation principle is basically the same as for a “conventional” FSD described above. In the new design the exhaust air leaves the dryer via the filters in the upper part of the drying chamber. Depending on the application these filters can be made of stainless steel, various polymers or different types of fabric. Fine particles cannot leave the dryer with the exhaust air stream but are retrained by the filters. Short pulses of compressed air from the clean side sequentially clean these filters which brings the particles back into the area of the spray were they come into contact with fresh wet droplets and form granules. After these granules have reached a certain size they fall into the lower part of the dryer. Here they are finally dried in the inner zone of the integrated fluid bed and are then cooled down in the outer zone before being discharged.

The granular product had excellent flow and compression characteristics. By the use of FSD-spray drying as one of the last unit operations in primary pharmaceutical production it is possible to simplify the process to produce granules by reducing the numbers of steps/unit operations. In order to benefit from this, there must be very close collaboration between the traditional primary and secondary pharmaceutical production operations.

Spray Drying Expertise
To meet the high requirements from the pharmaceutical industry, GEA Niro has developed a series of GMP Spray Dryers, the PHARMASD™ (PSD). GEA Niro - Worldwide leader in the supply of Spray Dryers and Spray Drying Technology - No one knows more about spray dryers and the associated spray drying technology than GEA Niro.

This experience has been gained over more than 75 years, where we have designed and supplied more than 10,000 industrial plants and numerous Small Scale and Pilot Plants. In our test centers around the globe we have 75 pilot plants where we can dry your product - be it an emulsion, a suspension or a solution – into a dry product.

Typical Application for Pharma Spray Drying
API's are typically produced by extraction or chemical syntheses. Following crystallization, the material is mechanically separated and then dried. These steps can often be replaced by spray drying which can control the humidity or residual solvent content, as well as create materials with a tailor-made particle size distribution and a dominant amount of amorphous material.

Finished drug products are produced by mixing/blending API with excipients (polymers, fine chemicals, etc.), solvents and others according to a specific formulation, after which one or several process stages follow until the final dosage form is reached.

The challenge ensuring tableting safety for high potency APIs

2011-08-14T09:33:00.002+02:00

By: Jan Vogeleer, Managing Director of GEA Pharma Systems - Courtoy™
courtoy@geagroup.com

The main challenge for tablet manufacturers processing highly potent APIs (HPAPIs) is to protect equipment operators from the inhalation of airborne particles and prevent skin contact with the product during the entire production process: dispensing, granulation, tablet compression, coating and packaging.

One of the earliest solutions was the use of air suits, but these are not at all ergonomic and protect only the operator. A tremendous amount of cleaning is also still required; all process equipment is contaminated, as are the processing rooms and corridors. Furthermore, in most Western countries, health and safety laws only allow personal protective equipment as a last resort.

To that end, isolators were introduced, which got the operator out of the air suit and reduced the amount of cleaning work. Operations, from dispensing to packaging, were integrated into large, sophisticated and highly contained isolators. However, as well as requiring large amounts of space and being impractical in terms of cleaning and product changeover, this solution quickly proved to be very expensive. WIP and CIP capabilities were integrated as much as possible, but this made installations even more complex. Moreover, in many cases, such isolator technology proved to be excessive in relation to HPAPI containment and the concentrations being processed.

One newer, more cost-effective and practical approach is to design inherently closed process equipment using 'containment at the source'. With this technique, the section of the machine in contact with the product is small and carefully isolated from both the electromechanical part of the machine and the environment. Additionally, it is easy to clean without breaching containment.

A more rational approach can also be adopted towards containment requirements in the various production stages. Indeed, the containment level required of equipment used at the dispensing stage (where the material handled is pure HPAPI in powder phase) is different from that needed in tablet coating (where the HPAPI is diluted and compressed into a tablet). The concentration of airborne API particles also varies during the different operational steps of the tablet production process. The only correct way to assess risk and determine the appropriate containment level for the various process steps/equipment is to calculate real daily intake (RDI) and compare this with the allowable daily intake (ADI).

Equipment considerations

Tablet presses for highly potent drugs need to have a compression zone that:

is as small as possible
is highly isolated from the remainder of the machine
contains the smallest possible number of mechanical components (in no case should it contain the cam tracks or compression rollers)
features automatic underpressure monitoring and control
is easily removable from the machine for fast product change-over
can be washed down off-line without breaking containment.

These requirements also apply to downstream equipment, including the tablet deduster, metal detector and the automatic tablet sampler (and tester).

The feeding of powder into the tablet press and the collection of tablets into drums or intermediate bulk containers (IBCs) also need to be conducted in a contained way. I recommend split butterfly valves as a solution to achieve this because such valves offer the requisite containment level, and allow for reliable and fast connection and disconnection, while maintaining containment. In view of this, a highly integrated solution is preferable from powder in-feed to tablet collection, with high-containment interfaces and connections between them.

With a growing number of increasingly potent new APIs often targeted at specific niche therapeutic applications, the pharma industry will need flexible medium- to small-scale, high containment tablet presses that enable swift product changeover with no risk of product cross-contamination. It follows that future design improvements for potent tablet manufacturing equipment will focus on these trends.

Extending the life of the freeze dryer – Adapting to changing requirements and regulations

2011-08-07T10:34:00.001+02:00

Freeze dryers are designed to run for decades. During this time many things can happen: Authorities tighten up regulations, you have developed a new drug and are ready to go into production, production requirements have changed - and the freeze dryer installed many years before does not meet these requirements any longer. Then time for a retrofit has come. Retrofits help you to cope with changing requirements at low investment costs.

Changing requirements – Retrofit solution – Some Examples

Do you need to sterilise your freeze dryer and you only have a non-sterilisable one? - Enhance you freeze dryer with H2O2 – Sterilisation by our VAPOVAC® Steriliser
Do you need to proof sterility of your equipment? - Add an Integrity test
Do you want to increase the performance? - Replace old devices: New shelf package, new compressor or LN2 refrigeration unit, LN2 booster or new vacuum pump system
Do you need to use other vial sizes? - Integrate a new shelf package with other interdistances
Do you need to increase product and operator protection, increase contamination prevention?- Adjoin you freeze dryer with ALUS® Automatic Loading and Unloading System
Does the supply of spare parts for an older control system has become a problem? - Upgrade to Siemens S7 or Rockwell ControLogix
Do you need to comply to 21 CFR Part 11?- Upgrade your control software to Siemens S7 or Rockwell ControLogix Implementation of WinCC, InTouch or iFix for SCADA
Do you need Re-Validation? - Ask for IQ/OQ Documentation and execution support

by Markus Blatzheim is Team Leader, HMI/SCADA Systems, GEA Lyophil
by Olaf Plaßmann is Head of Electrical Engineering, GEA Lyophil
lyophil@geagroup.com

Old Becomes New

While lyophilizers can remain operational for many years, lyophilizer control technology has moved on – and it is this that can render a system out of date. As a way of controlling costs, one option is to retrofit the control system alone – producing a lyophilizer that will provide many more years of reliable service, without the expense of buying new equipment.

Stainless steel is everlasting – which is one reason why lyophilizers can still be still in operation after 15, 20, and sometimes over 30 years without a discernible drop in performance (vacuum, heating and cooling). In this respect, such lyophilizers are often comparable with new equipment – but to keep up with the latest technology, it is the control systems that need to be updated. Together with documentation and validation requirements, it is the lyophilizer control system that has moved on, while the basic technology has remained unchanged. The development of reliable computers – with benefits in terms of usability, security (for example, 21 CFR Part 11), visualisation and documentation – has led to a significantly different approach regarding equipment operation.

As a way of controlling costs, especially during the recent downturn, pharmaceutical companies have looked to replacement of the control system – just one part of the overall equipment – as a cost-effective option. However, retrofitting a lyophilizer control system is not without risks. There are several critical items to consider and the work must be carried out by experienced technicians. At GEA Lyophil, we have performed more than 30 control system retrofits for our own-brand lyophilizers and also for other models. A strategy and shared experience for a successful retrofit project is described below (see Figure 1).

Risk Assessment
A risk assessment is mandatory to identify, benchmark and mitigate the existing risks; this is required for the documentation, hardware (mechanical and electrical), control system and functionality. The first step of a retrofit process is a critical assessment of the current status of the equipment. The general conditions have to be verified in terms of mechanical and electrical hardware to define areas to be modified that are close to the control system retrofit itself. The control system for a lyophilizer consists of a programmable logic controller (PLC) and a human machine interface (HMI)/supervisory control and data acquisition (SCADA) system, and the related hardware. Even if in most cases the desired new functionality is limited to a new SCADA application, the entire control system must be carefully evaluated. This evaluation will determine, via a risk assessment, all the critical parts that should be replaced during a retrofit. For example, it may be difficult to get spare parts for hardware components (for example, former operating systems for the HMI), or the new PC operating system might be incompatible with the current HMI/ SCADA application. Also, legal requirements have to be evaluated and brought into the project; for example, it might be necessary for the pressure vessels to be inspected by the authorities. If this inspection is required in the near future – for example in one or two years’ time – then it should be done as part of the retrofit process to avoid further stoppages later. With respect to documentation and mechanical hardware, the risk assessment may define areas and reasons why the current status should remain unchanged – even if it does not represent the most up-to-date practice. It might be sufficient to ‘grandfather’ these aspects if the equipment has proven capable of manufacturing to the required product quality.

Limitations and Items to Consider

In order to reduce associated risks, the existing functionality must remain as validated. This applies, for example, to interfaces to the existing PLC if these do not require replacement, or if the process control is to be done in the same way as before (for example, the pressure regulation must be done with the same components). The whole refit will need to be performed in accordance with the tight schedule of a planned shutdown period. Planning must include necessary aspects such as replacement, commissioning and qualification.

Goals and Benefits
There are several advantages to installing a new control system. The main goals to aim for are:

Implementation of 21 CFR Part 11 compliance: a new SCADA system may include audit trail, userlog and user security functions that fulfil 21 CFR Part 11 requirements
State-of-the-art equipment: current hardware components are more efficient and also more reliable, and the availability of support and spare parts is guaranteed
Usability: the opportunities offered by the new control system provide better usability in terms of parameter handling, visualisation and help functionality. Networks can provide system access at various places, and the readability of results and reports can be improved
Safety: product safety may be increased due to reliability and redundancy, for example, redundant array independent disks (RAID) technology. Also, better data storage and back-up functionality can be implemented

Further Possibilities
If a decision is made in favour of an upgrade of existing equipment, then it is probably worth thinking differently. It makes sense to combine all near-future upgrades into one single change as, after implementation of a new software application, comprehensive testing will be required. Several modifications are possible without having a major impact on the mechanical hardware:

Replacement of refrigerant: for legal reasons, and in view of economic and ecological factors, consideration should be given to replacing the refrigerant from the compressors. This will probably also lead to better performance of the cooling system
Electronic expansion valves: the replacement of these valves, which control the direct expansion of refrigerant into the condenser pipes, will lead to much better performance and regulation. This also reduces energy consumption.
Silicone oil leak detection: adding a device to identify traces of silicone oil in the system (for example, a LYOPLUS® device) might be considered
Optimisation of auxiliary processes such as clean in place (CIP) or sterilise in place (SIP) to reduce lead time, and usage of steam and WFI: in recent years, the cost of supply media has increased rapidly. The reduction of operating costs and shortening of turn-around time – as well as other factors – are now a focus of the manufacturing process, whereas previously quality was the only concern. Software adaptations and process optimisation can be done to reduce process times and the use of utilities
H2O2 gas sterilisation: for an old lyophilizer that has not been designed as a pressure vessel, it may be advisable to install an H2O2 unit for gas sterilisation of the system. This can be added to any lyophilizer on the market and is accepted by the authorities
Process analytical technology (PAT): tools for analysing and controlling manufacturing during processing can, in most cases, be added to existing equipment. This not only applies to integral monitoring methods that evaluate a specific value within the entire system – such as pressure or moisture content – but also for single container based (vial or tray) monitoring devices that measure a value within a specific container (such as Lyosense™ Impedance Measuring)
Extension to customer site network: it should be possible to extend a new SCADA system to the customer site network for, for example, data export to a central archive server or connection to a higher-level system, such as manufacturing execution systems (MES)

Challenges to a Successful Project
The implementation of a new process control application will have a major impact on the system. This is independent of other modifications performed concurrently (for example, a PLC application or mechanical modifications). It has to be considered, of course, that implementation of a new control system will take some time. Generally, it should be possible to finalise the related hardware modification during regular shutdown periods, such as maintenance activities. Such modification is limited to electrical cabinets and control rooms, and so access to the clean areas is not necessary. Planning qualification activities properly also helps to keep the length of time as short as possible. Our experience has shown that these retrofits should follow the same life-cycle approach as a completely new lyophilizer project. This requires very detailed planning and project management; user requirement specifications are needed, detailed quality planning must be done and design specifications (like functional, hardware and software design specifications, FDS, HDS and SDS) must be developed and approved prior to software coding and hardware configuration. Also, the verification must be performed in terms of providing documented evidence that the new system is ready for its intended use. It is also advisable to perform software Factory Acceptance Test (FAT) at the supplier’s site. This serves as an initial testing of the new SCADA software, identifies areas to be improved and may also be used as part of the qualification activities. The installation of the computer should be verified, while the related documentation and most of the functionality can be demonstrated in simulation. To reduce the shutdown time of the lyophilizer, tests do not need to be repeated if there are no changes or it doesn’t matter where the test is performed – for example, testing the password functionality, screen layout and documentation. The number of tests required – and those that need to be repeated – has to be defined as part of the risk assessment.

Conclusion
We have recently undertaken several successful projects that have been completed according to the approach described above. It is very important to pay the same attention and put the same competence into a relatively small project as would be given to a complete lyophilizer project. An ultimately successful outcome will show that it is worth the effort. A project must be correctly prepared and accompanied by dedicated risk assessments and the prescribed GAMP approach. This reduces the time that the equipment is out of operation and helps to guarantee a successful outcome. When correctly planned and performed by experienced technicians, a retrofit project will produce a lyophilizer that will provide reliable service for 10 years or more, without the expense of buying new equipment. Isn’t it worth considering?
It has to be considered, of course, that implementation of a new control system will take some time. Generally, it should be possible to finalise the related hardware modification during regular shutdown periods, such as maintenance activities. Such modification is limited to electrical cabinets and control rooms, and so access to the clean areas is not necessary.

Genzyme : In-Line Control of High Shear Granulation with the Lighthouse Probe™

2011-07-07T20:52:00.005+02:00

by Tomas Vermeire, Lighthouse Probe™ Product Manager
tomas.vermeire@geagroup.com

Genzyme, one of the world’s leading biotechnology companies, was looking for a PAT solution to control the high shear granulation of a development product by measuring a critical product attribute, rather than relying purely on time based processing or impeller current loading. The company used an optimized Lighthouse Probe™ to get representative NIR data of a granulation process. This article explains how the data was then correlated to moisture content, bulk/tapped density and particle size of the final product.

The reason for choosing a Lighthouse Probe™ was to expose as much product to the detector as possible. This was an important consideration for a high shear granulation process where changes in the process can happen quickly. Furthermore the scanning technology used in the spectrometer was FT-NIR, which has a relatively slow scan speed when compared to diode array based spectrometers.

Also the article describes how probe fouling was overcome, by using the probe in a high shear wet granulation process. The system is capable of being upgraded to a full GMP system for installation in production.

Introduction Genzyme was in phase three of the clinical trials of a new drug. The API had a small particle size, and associated poor flow properties. This presented Genzyne with a challenge when forming the dosage for patient administration. To improve the flow characteristics the API was to be formed into granules with other excipient materials by a high shear wet granulation process.

Genzyme chose to use the Lighthouse Probe™ from GEA Pharma Systems to monitor a high shear granulation process and to measure and quantify critical granule attributes. These measurements enabled the company to monitor the formation of the granules during the process to achieve an optimal granule size distribution.

The experiment used an FT-NIR spectrometer. This technology, whilst having high resolution and low signal-to-noise ratio for spectra, has a relatively slow scanning speed, compared to monochromatic-based spectrometers, such as diode array. Therefore, for the spectrometer to receive as much information as possible on what is occurring during the granulation process, a sample interface with a large window that would not suffer from fouling was required.

The Lighthouse Probe™ The Lighthouse Probe™ solves the traditional problem in pharmaceutical processing of product sticking to observation windows of the process analyser. It can be used with a variety of spectroscopic techniques, including NIR (Near Infrared), to take reliable in-process measurements of quality-critical product characteristics during processing, for example active content identification, uniformity, moisture content, particle morphology and coat growth during coating operations.

The probe is particularly useful when working with wet or sticky products when it is essential to ensure a clear view of the product. Conventional windows can easily become fouled when processing these types of products. The Lighthouse Probe™ uses an in-line window wash to keep a clear view at all times. Further features are the in-line calibration as well as end-of-process full CIP (Clean-in-Place).

Experimental setup The experiment used a Bruker Matrix-F spectrometer, attached to GEA Pharma Lighthouse Probe™ operating in a PMA™ 1, 10 L Granulator Bowl. The Lighthouse Probe™ was inserted through customised opening in the granulator lid viewing window.

The experiment The experiment analysed 20 Batches in a manufacturing process DoE, which included five factors related to the high shear wet granulation step. NIR spectra were collected from the granulation process at a scanning speed of approximately one spectra every five seconds. The last six spectra collected from each granulation step was averaged and correlated against granule attributes, such as water content at the end of granulation, as well as particle size and den sity of the final blended product. The wet granules were subsequently tray dried, milled and blended with a lubricant.

Principle component analysis was performed on the change in spectra throughout the granulation process to provide an insight into what was occurring during the granulation process.

Results and discussion Principal component analysis of the spectra highlighted changes in the granulation process and also highlighted the effects of changes in granulation parameters. This can be seen in the Hotelling’s T2 plot (slide 2), where the first batch in the experiment had a shorter processing time due to less water added and a slower spray rate, relative to the second batch. It is thought these inflexions indicated on the plot could be related to the point where there is sufficient water added to activate the binder in the formulation of the drug product.

Good correlation was achieved for a dynamic model for correlation of the averaged spectra at the end of the granulation process to:

Water by Karl Fischer – See slide 3
Particle size D90 and D50 values for final blend
Bulk and Tapped Density - See slide 4

Conclusions Genzyme were looking for a PAT solution which would enable control of the high shear granulation step for a development product by measuring of a product attribute, rather than relying purely on time based processing or impeller current loading.

The Lighthouse Probe™ showed that it is well suited to monitoring a high shear wet granulation process when used as the sample interface with a NIR spectrometer. It minimises the potential for probe fouling based on the 360° window and allows for the maximum absorbance of light from the spectrometer, with which to provide a signal for correlation.

The Lighthouse Probe™ produced satisfactory initial models against key granule attributes such as water content, particle size and bulk tapped density.

This study proved the feasibility of Lighthouse Probe™ technology for monitoring and eventual control of a high shear wet granulation process.

Granule drying process : moving from batch to continuous processing

2011-07-03T15:55:00.004+02:00

by Griet Van Vaerenbergh, Single Pot Product Manager of GEA Pharma Systems
griet.vanvaerenbergh@geagroup.com

The requirements of a granule drying process haven’t really changed much in recent years: pharmaceutical companies still need a process/technology that is capable of drying the produced granules as fast as possible, without affecting critical quality attributes (CQAs), such as particle size and homogeneity. However, as with all other pharmaceutical processes, the pharma industry has started to focus on quality by design (QbD) for the development of granule drying processes. As such, companies are now working on controlling and analysing CQAs in‑line and during the process, as well as understanding the process better and correcting it when necessary, rather than analysing the product afterwards without a thorough understanding of what might have gone wrong during the process in case of an out‑of‑specification result.

Two major breakthroughs in granule drying technologies have taken place in recent years: the development of better and more robust and integrated PAT tools and probes, with the ability to clean and calibrate without interrupting the process, and the introduction of continuous processing for granulation and drying. The use of PAT tools for in‑line/in‑process measurement of CQAs has helped the pharma industry obtain a better understanding of processes, which makes it possible to implement QbD in the development of new products, as well as to improve current processes. This helps to improve production efficiency, product quality and safety.

However, with current batch drying technologies, it is often not possible to correct a detected out-of-specification situation during the process, which is why the introduction of continuous granulation and drying technologies is so important. A continuous system is ideally suited for the implementation of on‑line PAT measurements because it is very easy to detect a deviation from steady state and to modify the process parameters via a feedback (or even feed forward) loop to prevent the product from becoming out-of-specification. This development will lead to better process control, high production efficiency, less wasted product, and better product quality and safety.

Drawbacks of existing systems and solutions
One of the main drawbacks of current drying systems is that they are all batch systems. Even with the implementation of on-line measurement tools, batch processes are more difficult to understand and control because they are in a continuous state of change. As mentioned above, when an out‑of‑specification result is detected in batch systems, it is often not possible to correct it by changing process parameters and a complete batch is wasted.

Continuous systems can overcome this problem. As a continuous system reaches a steady state, it is much easier to understand and control. An advanced control system continuously monitors the process and when it detects a trend to deviate from steady state, it will automatically take action by changing process parameters to avoid out-of-spec results. In newly developed continuous systems, steady state is reached very fast and there is always only a small amount of product in process; in the unlikely event that out-of-spec product is produced, only a small amount needs to be discarded.

Because of the advantages, we will see a move from batch systems to continuous systems, and a widespread implementation of on‑line measurement tools and advanced control systems, such as those already seen in the chemical industry, only on a smaller scale. I also believe that continuous systems will be more flexible; not continuous systems producing only a single product for years, but systems that can produce several products in campaigns of varying length.

Additionally, given the fact that a tablet press is already a continuous process, we will see the implementation of truly continuous production systems, going from powders to tablets without products in quarantine waiting to be released after drying and before tabletting. With advanced control systems conta ining feed forward and feedback loops, the on‑line measurements of CQAs will be sufficient for real‑time release.

This week: Learn more about GEA Pharma Systems' Containment Solutions at Interphex Japan 2011

2011-06-25T14:26:00.004+02:00

GEA Pharma will be exhibiting at Interphex Japan 2011. Interphex Japan, is ASIA'S LARGEST pharmaceutical industry event with 1,850 exhibitors and 75,000 expected visitors. At the venue, business meetings are enthusiastically held between professionals of pharmaceutical manufacturers and exhibitors from all over the world. Inside concurrently held "Technical Conference," a large number of sessions/seminars also attract a large number of attendees as the best place for enhancing knowledge on the latest trends in the pharmaceutical industry. (*expected/including concurrent shows), takes place in Tokyo, 29 June - 01 July.

GEA Pharma Systems has built a reputation for matching inspiration with technology when it comes to containment in solid dose processing. But it’s the knowledge and experience to bring that technology together in a creative way to meet customers’ needs that really matters.

GEA Pharma Systems will exhibit a range of containment solutions:

GEA Pharma Systems will exhibit its premier contained pilot granulation system - It is a complete production plant that takes the process from dispensed raw materials to finished tablet. The system on show clearly demonstrates the flexibility that can be achieved throughout the process – including high shear granulation, pelletization and blending, etc. – in a totally contained environment.
The best price-performance tabletting system for high containment applications - GEA Pharma Systems - Courtoy™ will exhibit at Interphex the finest tabletting technology currently available offering the ultimate in tablet containment, a perfect example of inspiration meeting technology. The MODUL™ tablet presses from Courtoy have addressed this requirement for both fast product changeover and high containment with their Exchangeable Compression Modules (ECM).
UltimaPro™ 10 Single Pot Processor for R&D - Single pot processing allows the contained processing of highly potent active ingredients, ideal for highly potent compounds (Oncology medicines, hormones, etc.).

Also on the stand will be the NEW ConsiGma™ 1
Three years ago, GEA Pharma Systems introduced ConsiGma™, an innovative high-shear granulation and drying concept capable of producing pharmaceutical granules continuously, without start-up and shut-down waste. This concept enabled the use of the same system for development and production work without the need for scale-up, as the determining factor for batch size is running time – not the size of the equipment. Batch sizes ranging from a couple of kilogrammes up to several tonnes could be produced.

In early research and formulation development however, the availability of the active ingredient is often very limited and there is a need for process equipment that is capable of producing only a couple of hundred grams to develop new drug formulas. In response to this need, GEA Pharma Systems developed ConsiGma™-1

Visit us at Hall, stand no: East hall 1 | 21-20

Read more about containment solutions and solid dosage R&D equipment , also single pot processors and pharmaceutical continuous tableting and the GEA Pharma Systems cGMP test centre facilities.

Read more about Interphex Japan 2011.

For further business information contact:
Dilwyn Pattersom - Area Sales Manager dilwyn.patterson@geagroup.com

株式会社ユーロテクノ - GEAグループ代理店
〒105-0001 東京都港区虎ノ門3丁目8番21号　虎ノ門33森ビル5階
TEL：03-5405-1108（代）　FAX：03-5405-3336
http://www.euro-techno.com/

Tablet compression | changing trends, more demands

2011-06-19T21:46:00.003+02:00

by Jan Vogeleer, Managing Director of GEA Pharma Systems - Courtoy™
courtoy@geagroup.com

The market for tablet compression technology and the demands placed on equipment manufacturers have changed quite significantly in recent years. This has been driven by a number of factors. Firstly, the pharmaceutical industry has seen a significant shift of investments in solid dosage production equipment towards generics and contract manufacturing. As the companies in this segment of the market are, by nature, strongly focused on cost reduction, a big emphasis is placed on productivity, flexibility and process yield (i.e., minimal product loss). Equipment cost and reliability, as well as fast on-site assistance have also become key selection criteria. research and development based companies have also been forced to follow this cost reduction trend.

Secondly, the meteoric growth of new pharmaceutical markets in the Middle East and the Far East (e.g., India, China, South Korea) has led investments in solid dosage equipment in these regions to surpass the investments made in North America and Europe. This puts an increased pressure on equipment price and has resulted in several Western based companies moving the design, manufacture and assembly of their equipment to Asia.

Finally, with the increased potency of new APIs, there is a growing need for better protection of the operator against the effects of pharmaceutical product processing. Operator exposure can be reduced either through the use of Personal Protective Equipment (PPE) or by making the equipment highly contained. The latter approach is the preferred solution, primarily for ergonomic reasons and because it offers a more efficient way of protecting the environment in general, as well as the facility and other personnel.

Technology breakthroughs
Although the operating principle and fundamental design of the rotary tablet press have not changed for decades, multiple machine design improvements have been developed and implemented by various suppliers to reduce cost and lead time, and more importantly, to increase productivity, flexibility and safety performance.

The initial emphasis of innovation was on reducing the amount of time required for machine cleaning and product changeover. The first significant change was the “exchangeable turret”, introduced to the market by Fette in the early 1990s and now available from nearly all suppliers. While this machine feature offers great flexibility with regard to the tooling types that can be used on the same machine, the time saved for cleaning and format changeover is limited; after removal of the turret, the complex inside of the tablet press still needs to be cleaned. Therefore, openness of structure and accessibility were further improved (e.g., the XL range by Korsch). Taking a different approach to the challenge, IMA came up with a revolutionary design without exchangeable turret, but with centrifugal die filling and Clean-In-Place capability. Whilst in early 2000, GEA Courtoy introduced the “Exchangeable Compression Module", a concept that made extremely fast product changeover possible thanks to off-line cleaning, and also offered n increased level of dust containment compared with conventional removable turret machines.

In more recent years, various improvements in machine designs have been made to increase the instantaneous output of tablet presses. To achieve this, it was necessary to enhance the efficiency of the forced paddle feeders to guarantee uniform die filling - and consequently tablet weight stability - at these higher outputs. The next step was to increase the number of punch stations on the turret (e.g., die plate segments by Fette; exchangeable die disc with die shells by GEA Courtoy) and/or to increase the rotation speed of the turret. When increasing the rpm of the turret, the compression dwell time for each individual tablet shortens, often resulting in insufficient hardness, capping or lamination. Methods that have now been developed to maintain a longer dwell time include air compensation and, to a lesser extent, larger compression rollers and punches with special head design.

The last 10 years have also seen a significant effort to design complete tablet production lines to handle potent and toxic drugs. As the powder in‑feed, tablet handling, sampling and tablet collection all have to be performed under “high containment” conditions, it became imperative to design complete lines integrating the peripheral equipment, such as powder discharge station, tablet de-duster, metal detector, dust extractor and tablet analyser. Initially, the most common technique was to build isolators around the equipment and provide wash-in-place capability. However, the latest design trend is toward containment at the source and off-line washing, as these concepts allow equipment to be smaller, easier to install and operate, and lower priced.

Drawbacks
The main shortcoming of modern tablet presses is their lack of advanced process control. Most tablet presses are equipped with only one feedback control loop, which is based on main compression force measurement as an indirect estimation of tablet weight. Re-correction of this loop is achieved through tablet sampling: 20 tablets every 15 to 30 min are sampled while the machine runs at 200000 tablets/h. This naturally calls into question the statistical relevance and accuracy of this method. Only very few new methods of process control and new types of sensors are being offered for on-line monitoring and controlling of other tablet CQAs, such as hardness, API content and dissolution time.

Where to next?
In its continuous quest for cost reduction, the pharmaceutical industry will continue to push for a further increase in operational efficiency. This can be accomplished through higher speeds, faster cleaning and product changeover, and fully automatic unmanned operation. Flexibility will also be developed further as the complexity of tablets increases, with the emergence of special tablets, such as multiple-layer tablets and core-coated tablets.

But most of all, future developments should focus on advanced process control to guarantee improved and constant tablet quality. This is one of the basic requirements to help realise two crucially important new concepts, which will shape the future of solid dosage production: continuous processing and real-time release. The implementation of new control strategies and the implementation of new types of sensors into tablet presses are vital means to this end. With the advent of promising new devices such as NIR sensors, progress is being made, but these are just the early stages of the new developments that are required.

Advantages and applications of Single Pot Processors

2011-06-11T21:24:00.018+02:00

by Griet Van Vaerenbergh, Product Manager - Single Pot Processing
griet.vanvaerenbergh@geagroup.com

Figure 1: UltimaPro™ 75 microwave / vacuum
single-pot processor with swinging bowl

I. Introduction
Single Pot Processing was developed to provide the means for mixing, granulating, drying, and blending pharmaceutical granulations in a single apparatus. Although equipment design varies from manufacturer to manufacturer, this category of processors is comprised of a high or low shear mixer-granulator (similar to conventional granulators) fitted with a variety of drying options (Fig. 1). Initially, vacuum was combined with a heat-jacketed bowl to provide the means of drying in the single pot. Today, processors are available that provide vacuum drying with microwaves or that percolate gas under low pressure into the vacuum chamber (i.e. processing bowl). Another very interesting improvement is the use of swinging processing bowls. (1)

II. Principle of Single Pot Processing
Granulation in a one-pot system is the same as in a conventional mixer/granulator, so for the steps of dry mixing, binder addition and wet granulation, all variables considered during the manufacture of wet granulations in conventional high or low shear mixer-granulators are applicable.

For binder addition those variables include the rate of binder action, droplet size, and spray pattern (the latter two being determined by the selection of the spray nozzle and the distance between the nozzle tip and granulation bed). The speed of the main impeller and the granulating tool (e.g. high-intensity chopper bar), as well as the jacket temperature, should also be controlled during binder addition.

Following binder addition, additional energy may be applied to the granulation until the desired consistency is obtained. The speeds of the main impeller and granulating tool, wet-massing time, and jacket temperature are variables that can affect the physical attributes of the granulation. Both the bowl shape and the impeller design will affect the amount of shear applied to the granulation. Granulation endpoint may be controlled by process time, temperature of the product bed, and the energy consumption or torque of the main impeller.

Different from conventional granulation systems however, drying of the wet mass in a single pot processor is executed in the same processing chamber, without the need for a transfer process.

The following techniques are available for drying:

- Pure Vacuum drying
- Gas-assisted vacuum drying
- Microwave-vacuum drying

Pure Vacuum Drying
In pure vacuum drying, the simplest and oldest alternative, the energy needed for drying is provided by heated water jacket. Since most substances for pharmaceutical applications are sensitive to high temperatures, the maximum inside wall temperature of the vessel is limited. As the thermal conductivity of the granules is relatively low, they must be moved during drying to absorb the heat necessary for the evaporation of the solvent from the vessel wall. Since the granules are porous, thermal conductivity decreases as the vacuum pressure drops and drying progresses [2, 3]. This effect can only be accommodated by more mechanical mixing which results in a partial mechanical destruction of the granules.

Pure vacuum drying is mainly applicable for solvent-based formulations or for small batches of water-based formulations with a relatively low water content.

Gas-assisted Vacuum Drying
The vacuum drying process can be enhanced by the addition of a small amount of gas passing through the product during the drying phase: the gas-assisted vacuum drying or Transflo™ technique. This adaptation results in an increased partial pressure drop over the powder bed in the vessel, and thus an improved evaporation rate. The actual pressure in the vessel may however be higher compared to ‘pure’ vacuum drying due to the addition of the gas, which may offset the effect of the improved evaporation rate. With the correct process settings, gas-assisted vacuum drying may lead to shorter drying times and lower residual moisture content of the final product.

The applicability of this drying technique is limited to small batches of water-based formulations that require a low final moisture content.

Microwave – Vacuum Drying
High shear granulators with microwave -vacuum-drying capabilities provide the fastest drying rates in the family of single pot processors. Microwave drying is based on the absorption of electromagnetic radiation by dielectric materials, the theory of which has been extensively described [4, 5, 6].Pharmaceutical processors generally use 2450 MHz, because this frequency is most desirable when used in conjunction with vacuum.

Energy absorption of materials exposed to microwaves is described as ‘the loss factor’, which is a relative measure of how easily a material absorbs microwave energy. Various materials commonly used in pharmaceutical formulations have low loss factors and only absorb microwave energy at high field strengths. Solvents used in the granulation process (water, ethanol, isopropanol, and such), however, possess high loss factors relative to the pharmaceutical powders [5]. The dipolar component of the solvents couples with the high-frequency electromagnetic field producing high heating rates for the solvent, resulting in its evaporation and subsequent removal from the processing chamber. Table 1 lists the loss factors for various components in a typical pharmaceutical granulation [7].

Because of this large difference between the loss factors of the dry materials and the solvents used, microwave drying is very suitable for pharmaceutical processing.

Thanks to the additional energy added to the process, microwave drying is the fastest drying technique available in one-pot processing. Through careful control of product temperature and forwarded and reflected microwave power, this technique is perfectly safe for processing pharmaceutical products.

Swinging bowl
Finally, the drying process can be further enhanced by applying a tilting motion of the bowl during the drying process. This technique allows for an increase in contact between the product and the heated jacket without the negative effect of increasing the frequency of mechanical mixing. This results in an improvement of the granule characteristics and a reduction in drying time, without the risk of a negative influence on the granule properties.

III. Advantages of Single Pot Processing
In a production setting, single-pot processing may offer a number of advantages.

By integrating granulating and drying capabilities into a single unit, capital investment in equipment and good manufacturing practice (GMP) floor space may be lower than other alternatives.

The number of material-handling steps is decreased; consequently, the total processing time may be shorter while maintaining a high yield and keeping production support to a minimum.

Environmental variables, such as humidity, are eliminated from the manufacturing process, which may offer advantages for processing moisture-sensitive formulations.

The latest procedure is to fit single pot processors with clean-in-place systems, thereby enhancing operator safety by minimising exposure to the product both during manufacturing and cleaning (8).

Requirements for solvent recovery systems are lower for single-pot processors compared with fluid bed dryers. For example, contrary to fluid bed processors, no explosion ducts are required, even when working with organic solvents.

Single pot processors fitted with vacuum are ideal for evaporating solvents that are explosive or for containing drug substances with low-exposure limits. Organic solvents can be recovered relatively easily, as it is only necessary to treat the pure solvent vapour rather than a large air flow with a small organic solvent concentration as in the case of the fluidized bed process. As the granules are dried in a vacuum atmosphere containing practically no oxygen, the explosion risk is also reduced substantially.

The versatility and compactness of small-scale (3- to 25-L) single-pot processors also make the technology attractive for development and pilot laboratory facilities.

Within the last decade, equipment manufacturers began offering single-pot processors that can accommodate the batch sizes required during early development (0.3 g-10 kg).

The processors can be used as mixer-blenders for direct compression formulations, as mixer-granulators to prepare wet granulations for fluid bed drying, or utilized for their full range of capabilities as a single-processing unit for all the steps required for granulation preparation.

Some vendors offer the option of upgrading their small-scale processors. For example, a user can initially purchase a single-pot processor with vacuum-drying capabilities and add a microwave-drying system at a later time. Consequently, single-pot processors should be given strong consideration when equipping a development laboratory or pilot plant intended to offer a variety of processing options to the pharmaceutical formulator.

IV. Main Applications Fields

A. High Containment Applications
When a potent product needs to be wet granulated to allow further processing (e.g. compression, capsule or sachet filling), single pot processing is, by definition, the method of choice.

As the whole process from dry blending up to final blending and milling can be executed in 1 machine, there are only 2 transfer steps to be taken into account for exposure risk: loading of the raw materials, and discharging the finished granules for transfer to the tablet press or filling machine.

Depending on the potency of the active ingredient, different methods for charging the raw materials can be applied.

One option is to load the excipients of the formulation the ‘normal’ way by vacuum loading, while the active ingredient is charged separately using a Hicoflex® charging bag or a seed vessel equipped with split butterfly valves.

Another option is to load all the materials into an IBC, that is docked to the single pot processor using split butterfly valve technology for gravity or vacuum loading.

For the highest risk products, even a glove box can be integrated onto the single pot processor.

During processing, the machine is completely sealed, so no exposure of the product is possible. Even if an overpressure were created during the process, an overpressure valve, located behind the product filter, will ensure that the pressure always stays below the limit that would risk opening the bowl. As drying takes place under vacuum there is absolutely no risk for exposure to the product during this phase.

After drying, the external phase can be added to the finished granules in a similar way as the excipients were added.

If a milling process is required before further processing, this can also be integrated by attaching the mill directly to the discharge valve with a closed connection. Discharging will occur through the mill into an IBC, via split butterfly valves. At this stage, the containment requirements are usually less strict than for loading the product, as the active is already diluted into the whole formulation.

The manual Buck® MC Valve can be upgraded to an automatic valve, with or without UMC (extraction), depending on the potency of the active, the percentage active in the formulation and the length of the campaigns (how many batches produced before cleaning). For pharmaceutical production, it is necessary for the product to be evaluated for quality before moving to the next processing step.

For monitoring and analyzing the process in a contained way, there are also several options. One option is to install a sampling valve that allows the operator to take samples during the process without having to stop the machine, open the bowl, or even open a port in the lid, into the processing chamber and adapt it to different containment levels. The sample container is completely contained allowing the sample to be transported to the QC lab without exposure to the atmosphere. For the smaller equipment, the Hicoflex® sampling system can be used for contained sampling. Another option is to provide PAT ports for the use of on-line analytical probes. This allows real-time process monitoring, enabling real-time release and thereby avoiding the need for sampling.

Finally, cleaning of the equipment is of critical importance for containment applications as, during this operation, no exposure to the potent product may occur. Therefore Cleaning-in-Place forms an integral part of the containment strategy of GEA Pharma Systems. The UltimaPro™ can be supplied with a wide range of washing-in-place and fully automated cleaning-in-place options. CIP features include spray nozzles adapted for most adequate cleaning of product feed, product filter, bowl, lid and discharge valve (for example retractable spray nozzles for the lid). Even downstream equipment such as a mill can be incorporated in the CIP system.

B. Effervescent production
Effervescent products can be produced in many different ways, most of which include a granulation step (9).

Dry methods like slugging, direct compression or roller compaction are used quite regularly in the production of effervescent solid dosage forms as no liquid is involved, which means that no additional drying step is needed. The major argument against the use of dry methods is the need for expensive excipients which are only acceptable for small production volumes.

Where dry methods are not applicable, wet granulation needs to take place, and it is in these processes that a single pot processor can play an important role.

Wet granulation of an effervescent formulation is however a special process, because if the formulation comes into contact with water, the effervescent reaction will start, which could ruin the product if not executed under carefully controlled conditions.

Because of this, many effervescent formulations are produced using either the 2-step wet granulation process – where two separate granulation steps are run for the alkaline and the acid components with a subsequent dry blending step – or a one-step granulation method using organic solvents as the granulation liquid.

For both processes, a single pot processor is applicable to perform the granulation and drying. The specific advantages of a single pot processor when working with organic solvents is explained in the next section.

The most important application of a single pot processor for effervescent production lies however in the one step wet granulation process using water. Although this seems to be a contradiction to the statements made above, it is possible to use water as a granulation fluid. Only a very small amount of water is added which will start the pre-effervescent reaction by which some of the carbon dioxide is already released during the granulation phase, but by which water is also produced as a reaction product, which will then act as a granulation fluid producing more carbon dioxide and also more water. This avalanche needs to be stopped at a certain point by starting the drying process and removing the water. The main advantage of this production method is that it increases the stability of the effervescent formulation.

A Single Pot Processor allows excellent control of the reaction process through the fast onset of drying using vacuum (optionally assisted by microwaves for even faster drying times), leak-tight operation and a specially designed, balanced vacuum system.

C. Solvent based wet granulation processes
When using organic solvents for wet granulation, there are some special issues that need to be addressed.

First of all, there is the higher explosion risk because organic solvents have a lower MIE (minimum ignition energy) than water. For an explosion to occur, 3 elements need to be present: oxygen, a combustible product (organic solvent or dust) and an ignition source.

The strategy applied in a single pot processor to mitigate the explosion risk is to eliminate one of the elements required for an explosion: The use of vacuum drying eliminates the presence of oxygen in the bowl thereby eliminating the explosion risk. During mixing and granulation inertization, using a minimal amount of nitrogen, is used as an explosion protection strategy.

Another aspect to consider when using organic solvents for wet granulation is the exhaust of solvent vapour into the environment. In many countries, environmental legislation has become very strict, and the solvent vapour exhaust has to be controlled.

As the process takes place within a vacuum, only solvent vapours are created during the drying process, making simple condensation the ideal way of reducing and eliminating solvent emission. The vacuum system of the UltimaPro™-Eco consists of a very efficient combination of condensers (chilled to an appropriate temperature for solvent condensation) and vacuum pumps to ensure both fast and safe drying and to minimise solvent emission and waste treatment.

V. Conclusion
Single Pot Processing is a very flexible processing technique for the pharmaceutical industry. It offers many advantages for both production and R&D, mainly for production or development of highly potent product, effervescent products and solvent-based wet granulations.

VI. REFERENCES

1. G. Van Vaerenbergh. The influence of a Swinging Bowl on Granulate Properties. Pharmaceutical Technology Europe 2001, 13 (3), 36 – 43.

2. G Bellini, L Pellegrini. Non adiabaticdrying. In: Handbook of Downstream Processing, 1993.

3. P De Smet. Vacuum drying. ManufChem1989, March:37-39, p. 37.

4. AC Metaxas, RJ Meredith. Industrial Microwave Heating. London: Peter Peregrines, 1983.

5. C Doyle, MJ Cliff. Microwave drying for highly active pharmaceutical granules. ManufChem1987, Feb:23-32

6. MS Waldron. Microwave vacuum drying of pharmaceuticals: the development of a process. Pharm Eng1988, 8:9-13

7. RP Poska. Microwave processing: the development experience revisited. Pro-ceedings of International Society of Pharmaceutical Engineers Congress, September 1992.

8. G. Van Vaerenbergh.Cleaning Validation Practices Using a One-Pot Processor. Pharmaceutical Technology Europe, February 2004

9. Dr. H. Stahl. Effervescent Dosage Manufacturing. Pharmaceutical Technology Europe, April 2003

Effervescent Dosage Manufacturing

2011-06-10T19:25:00.058+02:00

by Dr. Harald Stahl, Senior pharmaceutical technologist
harald.stahl@geagroup.com

Oral dosage forms are the most popular way of taking medication even though they have some built-in principle disadvantages. One of these disadvantages is the risk of a slow absorption of the actives. One way to overcome this is to administer the drug in a liquid form, which additionally sometimes allows the use of a lower treatment dosage. The problem that a lot of actives only show a limited level of stability in a liquid form can be overcome by formulating effervescent tablets, which are dissolved in water before administration. Additional advantages of effervescent tablets are:

the chance to improve the taste (taste masking)
a more gentle treatment for the patient’s stomach
marketing aspects (fizzy tablets may have more consumer appeal than traditional dosage forms).

The downside of this is the need for quite large tablets, the more complex production process and very often the need for special packaging materials.

FUNDAMENTALS OF EFFERVESCENTS

Effervescents consist of a soluble organic acid and an alkali metal carbonate salt. Quite often the active represents one of these substances. If this combination comes into contact with water carbon dioxide gas is formed. Typical examples of substances used are:

Citric Acid
Tartaric Acid
Malic Acid
Fumaric Acid
Adipic Acid
Sodium Bicarbonate
Sodium Carbonate
Sodium Sesquicarbonate
Potassium Bicarbonate
Potassium Carbonate

For example: the reaction of Citric acid and Sodium bicarbonate

3 NaHCO3(aq) + H3C6H5O7(aq) - 3 H2O(l) + 3 CO2(g) + Na3C6H5O7(aq)

252 g (3 mol) + 192 g (1 mol) - 54 g (1 mol) + 132 g (3 mol) + 258 g (1 mol)

From this equation it can also be derived why most effervescent tablets are relatively large.

If it is assumed that a placebo tablet consisting of 192 mg H3C6H5O7 and 252 mg NaHCO3 comes into contact with 100 ml water it will react to 258 mg C3OH5(COONa)3 + 132 mg CO2 + 54 mg (of extra) H2O.

Knowing that 1 mol of CO2 is, under normal conditions, equal to 22,4 litres, which means that 132 mg of CO2 formed by the reaction of the tablet above is equal to 67,2 ml of gas. As the solubility of CO2 in water at 20 °C and 1 bar is already 90 mg of CO2 per 100 ml of water, which means that not much of the gas produced by this tablet will form bubbles, but will go directly into solution. This reaction will start even if only a very small amount of water is added, as water is also one of the reaction products. This means that during manufacturing, but also during storage, all contact with water has to be minimised as much as possible.

PRODUCTION PROCESS

Picture 1: Closed Powder Handling using IBC's, Docking Stations and Split Valve Technology by Buck Systems™

The production of effervescent tablets is first of all a conventional solid dosage form manufacturing process, which has to take into consideration, due to the special characteristics of the product, some unusual features.

Materials Handling - On the one side the material is quite hygroskopic and on the other side an intake of moisture cannot be tolerated as this will start the effervescent reaction. Principle strategies in overcoming this problem are a completely closed material handling involving IBCs, docking stations, and split valve technology as shown in picture 1(above). In addition this means that all IBCs and also all production machines must allow for proper venting with air of a sufficiently low moisture content. This method is especially attractive if, additionally, potent actives are handled which also require a high level of personal protection for the operators. The alternative is the open handling of the product which allows the use of much simpler types of equipment, but as a downside the ventilation of the production area must be down to the maximum tolerable moisture level required.

Granulation and Drying - As most tablets today are compressed by high speed rotary tablet presses, the material to feed these tablet presses has to show some special characteristics not only to avoid segregation, but also to assure a homogeneous filling of the dies to assure a weight homogeneity. The most common approach for achieving materials with these characteristics is to granulate the raw materials. As a straight forward wet granulation will ruin the product by starting the effervescent reaction, several alternatives have been established. A guide for process selection within an industrial scale for a given formulation is shown in (2).

Dry methods - Dry methods like slugging, direct compression or roller compaction are used quite regularly in the production of solid dosage forms. A detailed review of the different dry methods can be found in (1). Especially for the production of effervescents the use of these methods is attractive as no liquid is involved, which means that no additional drying step is needed. Another advantage is the reduced need for equipment due to the limited number of unit operations required. As a consequence of this, the ventilation of the machines or of the building can be simplified. Especially roller compaction as a continuous methods allows, if properly automated, the realization of a very high throughput. The major argument against the use of dry methods is the need for expensive excipients which is only acceptable for small production volumes.

Two granulates method - One possibility for making wet granulation is to run two separate granulation steps for the alkaline and the acid components with a subsequent dry blending step. This can be done in a high shear granulator, with subsequent drying, a single-pot or in a fluid bed spray granulator. Detailed reviews of all these technologies can be found in (1). Advantage of this method is that only conventional equipment is needed which can also be used for the granulation and drying of other materials. Major disadvantages are the running time required for this complex process, cleaning aspects if two parallel lines are not used for the two granulations. A critical step can be the blending process and as a consequence the homogeneity of the tablets as not all materials are bonded into one granule as in a conventional wet granulation process.

Pictue 2: One-Pot Processor ULTIMAPro™ 75 by Collette™

One granulate method using organic solvents - As the effervescent reaction is only started if the materials come into contact with water and not if they come into contact with organic solvents, one possibility is the use of organic solvents as a granulation fluid. This can be executed in a high shear granulator and subsequent drying, a single-pot or in a fluid bed spray granulator. The only disadvantage of this method is the need for more complex equipment to handle these fluids. Especially if a fluid bed is used, then a quite complex system for the exhaust gas treatment is required as a mixture of organic vapor and a large amount of non-condensable process gas has to be treated. This system can be applied much more easily in a tray dryer or a single pot as only the organic vapor has to be handled. An example of a Single-Pot is shown in picture 2. Other than that the method offers a lot of advantages which originate from the lower heat of evaporation in comparison with water: a high throughput; the possibility for drying at lower temperatures and the freedom to use a lot of different excipients to achieve the desired product characteristics.

One granulate method using water - Although this chapter seems to be a contradiction in terms to the statements made above, it is possible to use water as a granulation fluid. Only a very small amount of water is added which will start the pre-effervescent reaction by which some of the carbondioxide is already released during the granulation phase, but by which water is also produced as a reaction product, which will then act as a granulation fluid producing more carbondioxide and also more water. This avalanche needs to be stopped at a certain point by starting the drying process and removing the water. This can be done using a high shear granulator with subsequent fluid dryer by discharging at the end of the granulation process the material into a pre heated fluid bed dryer. As the most critical step is the discharge and transfer operation this works fine for small and medium batch sizes, but might lead to problems for larger batch sizes as the long time needed for this operation is unacceptable. A second possibility is the use of a single-pot, where the granulation process can be aborted by switching to the drying mode, which can either be effected by the use of a double jacket and a vacuum system only or also gas or microwave technology assisted. While the first two possibilities work pretty well for the small and medium scale, they might be –due to the poor surface/volume ratio- too slow for the larger scale. In any case, the heat energy stored in the warm granules at the end of the granulation process will be sufficient to start the drying process the moment the vacuum exhaust system is switched on. A detailed review of drying in single-pots is given in (3).

Fluid bed spray granulation is a unique process where granulation and drying take place at the same time. This assures at all times a low moisture level limiting the pre-effervescent reaction to a minimum. In addition, when using a fluid bed for drying, it is very easy to reach the very low final moisture level required for storage. Downside is that more granulation fluid is needed than in a high shear process.

Addition Of Lubricant - It is common practice in tablet production to add a lubricant after granulation. The most commonly used substance is magnesium stearate. Its function is to improve the flow of the material, which is extremely important as the dies of a tablet press are filled by volume. A second function is to prevent the tablet sticking to the punch faces or to the walls of the dies. In effervescent production substances like magnesium stearate should not be used as they are insoluble in water and a film will consequently form on top of the water after the tablet has dissolved. Strategies to overcome this problem are the use of other lubricants which are soluble in water, for example a mixture of spray dried L-leucine and polyethylene glycol which is described in (4), (5). The other possibility is to work without any addition of a lubricant, this has the advantage of saving the blending step, but as a downside has special requirements for the tablet press which will be discussed later in that chapter.

Picture 3: Punch face and die lubrication system by Courtoy™

Tablet Compression - The compression of effervescent tablets is different from the compression of normal pharmaceutical tablets. The first aspect is that for storage over a longer time a very low moisture content such as typically less than 0,3% of water is required, while it is common for other tablets to work in the area of about 2%. In addition, effervescent tablets have a tendency to be quite large. This very often leads to the problem that the tablet hardness is not sufficient, which not only results in a significant number of broken or at least damaged tablets resulting in a poor yield, but also in a need to stop the press or the packaging line. One possibility of overcoming this problem is to increase Dwell Time by modifying the pre-compression assembly of a tablet press. The most commonly used system on the market to do this is the “Courtoy Air Compensator System” which is described in detail in (6). If one decides to work without a lubricant, the first problem is the poorer flow characteristics of the material. This can be addressed by using a constant level powder feed system, which consists of a rotary valve guaranteeing constant powder pressure on the forced filling station which in connection with two independently driven feed wheels will assure an accurate filling of the dies. Details can be found in (6). The second problem, when working without a lubricant, is that the tablets tend to stick on the die walls or on the punch faces. At the least this is a cosmetic problem, because of the scratches on the tablet surface, but it can also be real production stopper if the press has to be stopped in order to remove manually the tablets which have not properly ejected. A common practice used to overcome this is the use of a punch face and die wall lubrication system. These systems allow the addition of a very small proportion of solid or liquid lubricant to the punch faces and the die walls just before they come in contact with the granules. An excellent description of these systems can be found in (6). In picture 3 such a system is shown. Lastly, it should be mentioned that tablet presses, due to their design easily allow the processing of effervescent materials while only purging the compression zone with dry air, removing the need to vent the complete room.

Packaging - After the material has been pressed into tablets then the surface area of the material has been significantly reduced, which means that the rate moisture is absorbed from the air has also been reduced. Consequently, this means that the dehumidification of the environmental air is now less critical. Blisters and tube arrangements are used for packaging. For example, standard packaging materials are used in the packaging of food products or some nutraceuticals where shelf life is not critical. In most cases, this is not acceptable for pharmaceutical products. Aluminum, which has a lesser water permeability, is used instead of standard polymer blister materials. If ten or even more individual tablets are packed into one tube very dry air can be added, but as the user opens the tube to take out the first tablet, then ambient moist air will enter which will destroy the effervescent tablets. To overcome this silica gel or other drying agents are incorporated into most tube lids.

CONCLUSION

Effervescents are an interesting pharmaceutical dosage form offering some unique advantages when compared to simple tablets. The manufacturing process involves some critical steps which need to be addressed carefully during formulation and factory design.

Parikh, D.M., Handbook of Pharmaceutical Granulation, Marcel Dekker Inc., New York, 1997
Pearlswig, D. M., Simulation Modeling Applied To The Single Pot Processing Of Effervescent Tablets. Master's Thesis, North Carolina State University, 1995
Stahl, H., Drying of pharmaceutical granules in single pot systems. Pharm. Ind. 1999, 61 (7) ,656-661
Röscheisena, G.; Schmidt, P.C., Preparation and optimisation of – leucine as lubricant for effervescent tablet formulations. Pharmaceutica Acta Helvetiae 1995, 70 (2), 133-139
Rotthäuser, B.; Kraus, G.; Schmidt, P.C., Optimization of an effervescent tablet formulation containing spray dried L-leucine and polyethylene glycol 6000 as lubricants using a central composite design. Eur. J. Pharm. Biopharm. 1998, 46 (6), 85-94
Van der Goten, W.; Special requirements for tablet presses to be used in effervescent production. Technical Paper; Courtoy, Halle 2001

This technical article was first publish in the journal Pharmaceutical Technology Europe in April 2003, if you like to download in pdf format follow link to our library.

Inspired Contained Materials Handling

2011-06-09T22:01:00.002+02:00

Knowledge and experience of Buck Systems™

GEA Pharma Systems has built a reputation for matching inspiration with technology when it comes to containment in solid dose processing. But it’s the knowledge and experience to bring that technology together in a creative way to meet customers’ needs that really matters.

That is where Buck Systems™ comes in, to integrate materials handling, with granulation and tablet production to form efficient production lines optimised for current needs and sufficiently flexible to be updated as those needs change.

GEA Pharma Systems’ containment technology for solid dose processing falls into three distinct areas and has become trusted technology, especially for applications requiring OEB 4 and OEB 5 (Operator Exposure Band) containment levels:

The Buck® Valve range that uses the split coupling principle to transfer sensitive or highly toxic powders and granules between IBCs and the processing system; and the Hicoflex technology, a self-locking coupling that transfers them from flexible sacks into the manufacturing process or vice versa. Together these provide the means to introduce and extract product into the process line at the minimum exposure risk to operators.
The Collette™ UltimaPro™ range of Single Pot Processors that allow the contained processing of highly potent active ingredients, including mixing, granulation and drying, in a single machine. The Single Pot processors can also be fitted with the Lighthouse Probe™ (LHP) that monitors blend homogeneity, granule formulation (particle size), liquid distribution and drying that avoids the need for sampling and enables full containment to be maintained throughout the process.
The Courtoy™ MODUL™ tablet presses that provide fast product changeover and high containment using their Exchangeable Compression Modules (ECM). The ECM contains all the components that are in contact with the active ingredient to protect the operator during production. They can be switched in just 30 minutes at product changeover and washed off line (WOL).

Together these three technologies have the ability to create a complete solid dose production facility from the introduction of the active ingredients, through mixing, drying and granulation; and on to highly contained high production tablet production.

R&D flexibility and containment
In addition to the Single Pot approach, described above, GEA Pharma Systems’ range of technologies includes PharmaConnect® and the Contained MP1 Flexstream™ systems. PharmaConnect® is GEA’s innovative, modular granulation, blending and Pelletizing system that allows pharmaceutical formulation scientists to plug in to a range of processing technologies to evaluate processes and optimise product quality. Flexstream™ fluid bed processors allow easy scale up and avoid the need to have special configurations and extra product containers depending on whether the machine is to be used as a dryer, granulator or coater. Together they represent the ultimate in flexible containment technology for R&D and pilot production.

The differentiating factor But having the technology and knowing how to use it are two different things. The differentiating factor for Buck Systems™ is having the systems integration experience to get the best out of the technology. Phil Gabb, Sales Director and Product Manager for Buck Systems™ explained. “Our engineers work with this technology every day. They really understand what the customers need and how to achieve it using the GEA Pharma Systems equipment. Whatever level of containment is needed or whatever the processing requirements, we can ensure the security of outcome in both product quality and operating conditions to get products to market fast.”

Building design Intelligent use of technology can also provide savings in building construction, running costs and ergonomics. Buck Systems™ frequently adopts, for example, the sandwich method of building design with the IBCs entering the process on the top floor in a non-GMP environment, being fed via a Buck® valve to the GMP production area on the middle floor, then being discharged into a non-GMP area on the ground floor. This minimises the footprint of the building and keeps all the GMP production in a confined space to reduce the cleaning and HVAC requirements.

Future developments towards ultimate containment
In recent years the developing market for leading solid dose technology has migrated from Europe to Japan, India and South America. This has recently led to Buck Systems™ having its own manufacturing plant and service centres in these countries to provide the local contact, speed of response and on-going relationships with customers, with the support of the UK office providing system design and project management.

But it is in Japan especially where there are now moves to achieve the ultimate containment by removing the workforce completely to create a totally automated system. Buck Systems™ is currently working on a project that uses a conveyor system to move IBCs to and from the GMP area discharging raw materials and recovering finished product all within a secure environment where no operators are present. IBCs are cleaned and stored in a separate area of the plant.

Buck Systems™ is a prime example within GEA Pharma Systems of the company’s strap line ‘Where inspiration meets technology’. Using its experience of the process requirements and knowledge of the technology available Buck Systems™ is uniquely positioned to achieved the desired results, first time, every time.

Phil Gabb - Sales Director GEA Pharma Systems - Buck Systems™
257 Wharfdale Road, Tyseley, Birmingham, UK, B11 2DP
Tel: + 44 23 80 242 299
Email: phillip.gabb@geagroup.com

Where Inspiration meets Technology

2011-06-04T20:58:00.009+02:00

GEA Pharma Systems supplies advanced processing technologies for the manufacturing of oral and parenteral dosage forms.

GEA Pharma Systems’ activities include partnering with customers to develop new products and enhance clinical effectiveness; the supply of R&D-scale and stand-alone production equipment; and the installation of complete integrated production lines.

History
GEA Pharma Systems was formed early in the year 2000 after GEA Group acquired the pharmaceutical division of GEI International. The newly acquired brands Buck® - containment interfaces solutions and Buck Systems™ - contained materials handling, Collette™ - continuous granulation & single pot technology, Courtoy™ - tablet compression, were combined into GEA Pharma Systems along with the existing GEA brands, Aeromatic-Fielder™ and NICA™- granulation, drying, pelletizing and coating.

With this combination, GEA Pharma Systems became the leading international supplier of advanced processing equipment for the manufacturing of oral and parenteral dosage forms for the pharmaceutical industry.

In November 2005, followed the acquisition of the lyophilization business of Steris Gmbh by GEA Group and the renaming of the company into GEA Lyophil it joined the other pharma brands in GEA Pharma Systems. GEA Lyophil supplies specialist freeze drying technology for the pharmaceutical and biotechnology markets.

More recently, the pharma segment of GEA Diessel has joined GEA Pharma Systems. GEA Diessel supplies process systems for the production of liquid products for the pharmaceutical and biotechnological industries including: complete plant and components for the production of syrup, suspensions, parenterals, and blood plasma as well as plant for the production, storage, and distribution of clean utilities. Systems for the preparation of media, fermentation, and purification for the production of vaccines, therapeutic and biotechnologically manufactured agents are also part of the scope of supply.

Where Inspiration meets Technology

For GEA Pharma Systems, innovation is the key to our success and to continued prosperity for our customers. In fact it’s more than that. We know that by continually stretching the boundaries of what is possible in pharmaceutical processing we have the ability to support our Customers in enhancing the opportunities available to millions of people all over the world. This is what drives our business.

Our inspired innovation takes many forms and affects all parts of the process. We innovate to increase production and reduce costs, to improve containment and safeguard the workforce, to achieve better clinical effectiveness and to enhance quality control. At GEA Pharma Systems the innovation never stops – it’s just part of what we do.

For example we have pioneered Pharma spray drying to provide unprecedented control of particle form and release profile for drug development, meeting the most demanding clinical needs. FlexStream™ (patent pending): our new fluid bed processor offers multiple processing from a single bowl providing both flexibility and cost benefits. MODUL™ and PERFORMA™ tablet presses combine unrivalled containment with fast product change-over and high productivity. The Buck® MC Valve makes the contained handling of active pharmaceutical ingredients much easier and less expensive than has been possible in the past. ConsiGma™: a unique continuous granulation, drying and tableting process that drastically reduces time to market of new medicines and enables the move to a 6-Sigma process; and PharmaConnect™ which enables diverse GEA development equipment to be docked into a single ‘plug and play’ module with full cGMP compliance.

Under the following links you can discover a more indepth corporate history of the individual brands and companies that make up GEA Pharma Systems:

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