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Pharmaceutical Manufacturing and Packing Sourcer

Small is Beautiful

High accuracy feeding for the milling and micronisation of powders provides the pharmaceutical industry with more formulation options than ever before.

Size reduction mills are widely used throughout the pharmaceutical industry for the reduction of active pharmaceutical ingredients (APIs), bulk pharmaceuticals (BPIs), and excipients such as lactose, hydroxypropylmethyl cellulose (HPMC) and others. Size reduction is used to increase surface area and to improve formulation dissolution properties. It is also used to maintain a consistent average particle size distribution (PSD) for the formulation, thus allowing for a better quality mixture when creating solid dosage forms such as tablets and capsules.

Conventional dry size reduction in the pharmaceutical industry is accomplished by impact. This generally falls into two categories: mechanical impact and impact via fluid energy. Examples of mechanical impact mills are hammer mills and pin mills, while spiral jet mills (see Figure 1), loop jet mills and fluidised bed jet mills are examples of micronisers or fluid energy mills.

Feeders for Milling

In most size reduction mills, the feed rate into the mill is an important factor in determining particle size distribution. Since the resulting distribution is largely dependent upon residence time in the milling device, the feeder is an important tool in controlling this residence time, and subsequently the resulting PSD.

The types of feed devices used in the industry vary from rotary valves to vibratory tray devices and screw feeders (single and twin screw types). However, as with any process, the product flow characteristics will often determine the best feed method. Since most pharmaceutical powders and formulations can have difficult flow characteristics, the twin screw feeder is often the method of choice. The ‘self-wiping’ action of the intermeshed screw flights lends itself perfectly for the feeding of difficult and cohesive powders.

Sticky powders that are particularly cohesive, or nongranular materials with high aspect ratios, can tend to pack, and will often cause clumping in a vibratory tray or packing in the vanes of a rotary valve. This agglomeration in the feeder disrupts the even metered flow required for the milling operation, thus causing a shift in the resulting particle size distribution. However, it should be noted that in some cases, the vibratory tray device might lend itself well to a low rate feed application, as shown by the feeder in Figure 2.

Typical Feed Rates

Feed rates for pharmaceutical size reduction or micronisation can range anywhere from 20g/hr (for small jet mill operation) to production mill rates of up to 840kg/hr. As with all feeders, this rate range depends on the type of screw configuration chosen, as well as the drive type and available turn down ratio; in other words, a speed controller with a DC motor and an available turndown of 100:1 versus a speed controller with a frequency inverter and an available turndown of 17:1.

Volumetric or Gravimetric?

Depending upon the accuracy of feed required, the screw feeder or vibratory feeder can be supplied in either a volumetric or a gravimetric configuration. If the material or formulation is free flowing and of constant density, the traditional range of accuracy from a volumetric twin screw feeder or vibratory tray is often acceptable.

However, it should be noted that when feeding materials with high variations in bulk density, volumetric feeders can have relatively high fluctuations in feed rate due to the resulting fluctuations in the filling of the screws. In the case of cohesive materials, it is possible in volumetric mode to have almost no material discharging while the screws are running, such as in cases of bridge building or packing in the hopper. Since the feed rate in a volumetric feeder is purely a function of screw speed, the feeder and milling process below has no way of detecting this upset condition.

Often, even the use of level sensors in the feed hopper may not alert the process of this upset in a timely fashion, and off-spec particle size distributions may occur for a significant time. This is especially relevant in high energy mills with relatively short residence times, such as jet mills or micronisers. Gravimetric feeders utilise load cells that constantly measure the weight of pharmaceutical product delivered to the process below.

Loss-in-weight feeding affords broad material handling capability, and thus excels in feeding a wide range of materials from low to high rates. In operation, the entire feeder, hopper and material are continuously weighed, and the feeder’s discharge rate (which is the rate at which the feeding system is losing weight) is precisely controlled to match the desired feed rate.

Due to their ability to provide a more accurate feed rate, and even with the difficult flow properties of the pharmaceutical material, gravimetric feeders are becoming increasingly popular for a wide variety of milling and micronising operations.

Gravimetric loss-in-weight twin screw feeders offer the processor many features and advantages, including:

  • Constant feed rate with high short-term accuracy and low set point deviation
  • Gravimetric control, which consistently checks the material weight, thus alerting users to any problems in flow to/from the feeder hopper
  • High accuracy, needed for maintaining control of pharmaceutical systems
  • A resolution of 1:4,000,000 in 80ms, as well as built in immunity to fluctuations in plant vibration and temperatures 􀁏 Simple measurement and display of feed rate, via mass flow
  • Continuous level control by analysing net weight

Handling Highly Potent Active Ingredients

Many milling and micronisation operations involve the size reduction of highly potent active pharmaceutical ingredients (APIs). As the potency of these dry compounds increases, project engineers are often faced with the requirement to place the entire feeding and milling operation in an isolator or glove box. The purpose of these isolators can be two-fold: protection of the operator from the hazards of the drug, and protection of the dry compound from the hazards of the surrounding environment. In designing such milling systems, it is imperative that the feeding device used is completely accessible and dismantled through the use of gloves in glove ports.

Integration of the pharmaceutical feeder to the wall of the isolator can be done by means of varied plate mount designs, with the motor and gearbox completely isolated from the glove box. To connect the wall of the glovebox with the wall integration plate of the feeder, a static seal (gasket or O-ring) or an inflatable seal can be used. It should be noted that this design is only possible with volumetric feeders, because there is no friction-free flexible connector available that does not affect the weight measurement. In the case of gravimetric feeders, the complete feeder is placed in the glove box, with a fully-vented enclosure around the feeder motor and the gearbox. When delivering highly potent material to the feeder hopper, split butterfly valves are often used for isolation of the container after product delivery. The feeder hopper is equipped with a docking device to connect with the corresponding active or passive device on the transfer container. This can be the case when docking from IBCs or simple small canisters.

Cleaning Requirements

Careful consideration must be given to the cleaning requirements, not only for the feeder, but also for the entire milling process. Feeders can easily be modified to include retractable spray balls for rinse-inplace cleaning. Feeder components are designed with quick easy-release clamps for ease in dismantling. All gaskets and O-rings must be compatible with the solvents or detergents used for cleaning. Flexible feeder hopper walls or liners have a tendency to wear and abrade depending upon the cleaning method, thus degrading into the product and destroying the batch.

In addition, these materials have a tendency to stain when used with tinted or coloured formulations, making them even harder to clean. For these reasons, stainless steel is recommended for hoppers and contact surfaces, with a minimum surface finish of 0.8 micron Ra. In the case of wet-in-place (WIP) designs, static or retractable spray balls can be installed in the feeder hopper to allow for a complete rinsing of the feeder device before it is dismantled for further cleaning and inspection.

Nitrogen Purging

Since the organic nature of many pharmaceutical materials results in a high potential for explosion, particularly in a milling device, the complete system is often purged with nitrogen. This nitrogen gas inerts the system to minimise the risk of explosion. Nitrogen purge fittings can be equipped in the feeder hopper as well as on all shaft seals. The use of positive pressure purges on the shaft seals thus serves a dual purpose: they aid in the inerting of the feeder as well as preventing the material from bypassing the seals and passing on to the bearing area. In the cases where high pressure gas is used for jet milling, and a closed connection is used between the feeder and the mill inlet, it is also recommended that a pressure compensation or balancing line be incorporated between the feeder outlet and the feeder hopper. The use of such a line ensures pressure balancing to avoid high vacuum, which can cause material to be sucked past the screws, as well as possible overpressure, which can prevent flow to the mill below.

Pressure Shock Resistant Milling Systems (PSR)

In some cases requiring protection from explosion, the complete mill system is designed for explosion containment. All of the system components in the containment zone are designed to withstand an internal pressure rise up to 10 bar gauge. Since designing a screw feeder for such a pressure can be extremely expensive and cost prohibitive, an oversised rotary valve, for pressure containment, is installed below the feeder outlet, prior to the mill inlet. This valve does not meter or control flow. It is oversized to simply allow flow through it and then seal or isolate the milling system in the event of a pressure rise. By installing this device after the feeder, the standard pharma design feeder can be utilised, without the requirement of a pressure containment design.

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Sharon Nowak serves as Global Business Development Manager for the Food and Pharmaceutical Industries for the K-Tron, where she works closely with the R&D and Engineering departments. Sharon has spent 26 years in the process equipment industry for food and pharmaceuticals, and holds a degree in Biochemical Engineering from Rutgers University. She has extensive experience integrating feeders into continuous and batch processes for food and pharmaceuticals including blenders/mixers, mills/micronisers, extruders, granulators and coaters, and contained processes for potent compounds.
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