Title Continuous powder feeding for pharmaceutical solid dosage form

manufacture: a short review

Authors Blackshields, Caroline A.;Crean, Abina M.

Publication date 2017-06-17

Original Citation Blackshields, C. A. and Crean, A. M. (2017) 'Continuous powder

feeding for pharmaceutical solid dosage form manufacture: a
short review', Pharmaceutical Development and Technology,
23(6), pp. 554-560. doi:10.1080/10837450.2017.1339197

Type of publication Article (peer-reviewed)

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Continuous Powder Feeding for Pharmaceutical

Solid Dosage Form Manufacture: A Short Review

Caroline A Blackshields & Abina M Crean

To cite this article: Caroline A Blackshields & Abina M Crean (2017): Continuous Powder Feeding
for Pharmaceutical Solid Dosage Form Manufacture: A Short Review, Pharmaceutical Development
and Technology, DOI: 10.1080/10837450.2017.1339197

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Abstract

There has been a noticeable shift from pharmaceutical batch processing towards a more continuous

mode of manufacture for solid oral dosage forms. Continuous solid oral dose processes would not be

possible in the absence of a highly accurate feeding system. The performance of feeders defines the

content of formulations and is therefore a critical operation in continuous manufacturing of solid

dosage forms. It was the purpose of this review to review the role of the initial powder feeding step

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in a continuous manufacturing process. Different feeding mechanisms are discussed with a particular

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emphasis on screw controlled (loss in weight) LIW feeding. The importance of understanding the

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physical properties of the raw materials and its impact the feeding process is reviewed. Prior

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knowledge of materials provides an initial indication of how the powders will behave through

processing and facilitates in the selection of the most suitable (i) feeder (capacity) (ii) feeding
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mechanism and (iii) in the case of screw feeder - screw type. The studies identified in this review

focus on the impact of material on powder feeding performance.

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Keywords
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Continuous manufacturing
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Pharmaceutical powder properties

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Loss-in-weight feeding
1 Introduction

In the last decade there has been a noticeable shift to move pharmaceutical manufacturing

from a more traditional batch configuration to a continuous mode. Pharmaceutical regulatory

authorities and manufacturers acknowledge the benefits of continuous manufacturing

processing over the traditional batch configuration, in terms of cost-reduction, improved

efficiency, ease of automation, better controlled processing, reduced energy, reduced waste,

less footprint, ease of scale up, less material handling, and consistent product quality (1-3).

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Currently there are two approved commerical pharmaceutical products produced via

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continuous processes on the market. Vertex achieved FDA approval for a continuous process

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in the manufacture of the cystic fibrosis drug Orkambi, July 2015. In early 2016 the FDA

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approved, for the first time a change in production method from batch to continuous

manufacturing for the production of the protease inhibitor Prezista (Darunavir) used in the
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treatment of HIV-1 infection (4).
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The feeding of raw materials to downstream processes is a key process step in the continuous
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manufacture of any formulated product. Continuous powder processing requires a consistent,

accurate and reliable feed stream of raw materials to produce quality products. Hence the
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initial feeding stage is critical to the entire manufacturing process. This is especially true in
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the manufacture of pharmaceutical solid dosage forms such as tablets, capsules and sachets.

The ability to feed powder consistently and continuously is regarded as one of the critical
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requirements of the overall manufacturing process (5, 6). This becomes especially pertinent

when feeding active pharmaceutical ingredients (API). If the feeder is incapable of dosing

the powder feed at a desired rate it will pass any inconsistencies variability in composition

and weight to downstream unit operations such as blending or granulation (7, 8). Inconsistent
feeding can lead to quality failures such as out of specification dosage form assay and content

uniformity.

Regulatory authorities, such as the FDA, are supportive of the move towards pharmaceutical

continuous manufacturing (9). Successful continuous processing requires a high level of

process control via in-process testing and improved process understanding to ensure that

medicinal products are designed and produced with predictable and reproducible critical

quality attributes. These process control requirements are in line with the development of the

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following frameworks: Quality by Design (QbD) (10) and Process Analytical Technology

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(PAT) (11). The primary objectives of the QbD and PAT frameworks are to work

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retrospectively, from the end user to initial product development, in order to ensure that the

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highest level of product quality is maintained throughout the product lifecycle (12). The QbD

and PAT frameworks aim to facilitate the pharmaceutical community to attain a state
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whereby product quality and performance are accomplished and guaranteed by the design of
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effective, efficient and well understood manufacturing processes (10, 11). To fully

understand a pharmaceutical manufacturing process it is necessary to understand the

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physicochemical properties of the raw ingredients involved, which are integral to the quality

of the final product.

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Interest in the area of continuous manufacturing has increased amongst industry and

academics as is evident with the recent escalation of publications in this subject (3, 6, 8, 13,
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14). It is apparent that review publications to date refer only to the blending or granulation

steps of the continuous process train and that research articles examining the feeding process

are limited (15, 16). This review examines the feeding step of the continuous manufacturing

train with the intention to examine the criticality of raw material properties in relation to the

feeding process. The review provides a brief overview of the principles and mechanism of
continuous screw feeding, followed by a summary of studies which relate material properties

to continuous feeding behaviour.

2 Powder Feeding

2.1 Loss in Weight (Gravimetric) Feeding

Loss in weight (LIW) or gravimetric feeding is the most commonly used continuous feeding

method for pharmaceutical powders (12, 17). Despite different feeder set-ups being used for

materials with varying physical properties, the general mode of operation and mechanisms

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are essentially equivalent. All LIW feeders generally consist of three parts (i) a volumetric

feeder (ii) a weighing platform and (iii) a gravimetric controller, Figure 1.

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The volumetric feeder is mounted on the top of the weighing platform which measures the

mass of the feeder and the materials contained within. As material is dispensed via a feeding
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device, such as a screw, the controller acquires a signal from the load cell in the weighing

platform as a function of time. As shown in equation 1, using the difference in weight

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(wfeeder) measured by the platform divided by the difference in time between successive
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measurments (t), the controller can determine the instantaneous feed rate (-mfeed)
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∆𝑤𝑓𝑒𝑒𝑑𝑒𝑟
( ) = −𝑚𝑓𝑒𝑒𝑑 Equation 1
∆𝑡
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The actual weight loss (per unit time) is compared to a desired weight loss (per unit of time)
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based on a pre-programmed feed rate. Any discrepenacy between the actual and desired

weight loss per unit of time results in a correction to the speed of the feeding device to

maintain a steady feed rate, thus overcoming any variability in material bulk density (7, 18).

Gravimetric feeders can also operate in volumetric mode. In this instance bulk material is

charged from a hopper with a constant volume per unit of time by regulating the speed of the
feeding device (screws) and the volume of material dispensed is determined through

calibration (18). In general, volumetric feeding is considered to be less reliable than

gravimetric feeding due to the inherant nature of powders possessing variable densities due to

prior processing, storage, environmental or processing conditions (17, 19). Volumetric feeders

can be used in processes where the bulk density of the feed material is consistent or where

feeder accuracy is less critical. As a result, the use of volumetric feeders is generally

inappropriate for pharmaceutical continuous process applications that involve rigorous

accuracy requirements, such as consistent API feeding. During a start up or a refill procedure

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LIW feeders revert to volumetric feeders momentarily resulting in a disruption to the process.

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This will be further discussed in section 4.

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Whilst mechanically the feeder system is simple in principle, the behaviour of feed materials

can be complicated. Such complications can arise due to variability in material characteristics
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such as flow properties, particle size and bulk density and differences in target feed rates.
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Issues such as bridging, rat holding, blockages, electrostatic formation can be observed

during operation (18). LIW feeders have been developed in a wide range of sizes to
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overcome such challenges in feeding powders. In addition, replaceable tooling with various

nozzle sizes, screw sizes and types have been developed to enable ingredients with large
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variations in material properties to be fed successfully (17).

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2.2 Screw Feeders

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The use of rotating screws is commonly used to dispense raw materials using LIW feeders.

Screws can be selected to provide the optimum feeding conditions based on the

characteristics of the materials being processed and the processing requirements such as pre-

determined feed rate. For instance, screws are available in a single or double configuration,

various thread depths and in spiral or auger configuration. LIW or volumetric feeders have
individualised sets of tooling such as screws and screens that are only compatible with that

feeder type (18, 20). Pre-determination of a desired feed rate based on material

concentrations in the final dosage form and downstream process capabilities, such as tablet

press or granulator throughput, is necessary in the selection of both a feeder and feeding

configuration. Screw and screen selection based on material properties will be further

discussed in section 4.

In addition to conventional LIW feeder designs discussed throughout this review, more novel

micro-feeding approaches are reviewed by Besenhard et al. (2016) (21). The authors

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demonstrate a gravimetric powder feeding system with a vibratory sieve mounted on a chute

which is capable of delivering a fair flowing powder that is sieved between 90 and 160 μm, at

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a feed rate of 0.1mg/s (RSD = 0.023) and 0.15 mg/s (RSD = 0.017).

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3 Processing and material factors to be considered

Solid oral dosage forms are multi-component containing different ingredients such as
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diluents, lubricants, disintegrants, glidants and API(s). Each component will vary in
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particulate size and shape, bulk density, compressibility, flow, cohesive strength and moisture

content, in addition to different concentrations in the final dosage form. Due to the multi-
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variate nature of raw materials, it is typically not straightforward to determine which

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properties will influence the feeding process most significantly. There is not one individual

feeder design, configuration or size that can handle all the different material characteristics
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highlighted or the different throughput requirements of the process. For feeding to be

successful, the key physical properties of the materials must be known and their behaviour

during feeding fully understood.

The optimal feeding configuration or tooling selection is based on both the desired feed rate

and powder properties. It is imperative to test and investigate each component separately to
ascertain optimal feeding conditions. This involves determining the constraints in the feeder

and feeding tooling for each individual component of the formulation, testing potentially

successful configurations and comparing the feeding performance between the different

configurations (22). Figure 2 illustrates an example of a guide to screw selection based on

material characteristics (23).

It is recommended that single screws are used for free flowing powders which can easily fill

the flights of the screws. Twin screw feeders are commonly used to transfer materials which

are particularly free flowing but require additional control to regulate the flow. Twin screw

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feeders are also useful when the formulation contains cohesive materials where additional

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force is required to feed the material or to reduce adhesion to the screw threads. Free flowing

materials tend to overfill the screw under the influence of gravity, whereas more cohesive

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materials may require increasing levels of agitation to facilitate flow into the screw (24).
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Some screw designs, such as concave screws are capable of ‘self-cleaning’ which is

particularly useful when feeding cohesive powders which are difficult to handle, such as
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colloidal silicon dioxide or magnesium sterate (22). Auger screws have the advantage of
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having a higher capacity for powders which require higher throughput but do not have the

self-cleaning function, and therefore would not be recommended for cohesive materials.
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There are a limited number of publications which directly discuss the impact of material
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properties on equipment selection and configuration. Table 1 details the continuous feeding

conditions for a range of pharmaceutical materials with varying physical properties.

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3.1.1 Influence of Powder Properties

A recent publication by Engisch and Muzzio (2015) demonstrated the influence of material

properties on feeder and tooling selection (22). A range of feeders were tested with a range of

pharmaceutical materials with varying physical charatersitics to highlight the challenges that
can be encountered with feeding. For instance, in the case of freely flowing ProSolv HD90 at

a feed rate of 13.3 kg/hr, a reduction in feeding performance was observed when tooling was

selected which allowed the material to flow too freely. This resulted in the powder

uncontrollably flushing through the flight of each screw with each rotation. The use of

concave screws, which possess smaller flights and therefore smaller pulsations, resulted in

increased control. Additional feeding control can be achieved with the inclusion of discharge

screens. However, when testing a free flowing model API at a desired feed rate of 15.6 kg/hr,

using concave screws, the presence of a discharge screen resulted in material clogging at the

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outlet, causing equipment to shut down. A more suitable feeder set-up for this powder was

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found by eliminating the discharge screen.

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Cohesive, low density materials, such colloidal silicon dioxide and magnesium stearate are

anticipated to be particularly problematic during continuous feeding. This is primarly due to

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material adhering to equipment surfaces. Engish and Muzzio (22) studied these materials
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with various tooling configurations to determine optimum conditions. The addition of

optional tooling such as discharge screens resulted in build up of material at the outlet and
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therefore were eliminated. The use of concave screws were found to be most suitable as these

possess a ‘self cleaning’ function. In the case of colloidal silicon dioxide it was determined
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that the material should not be fed individually but as a pre-blend with the API. This was due
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to the low density of the material and intense electrostatic properties causing it to adhere to
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the downspout on the feeder outlet. A static eliminator was used with this material reducing

the RSD of the feed rate of the individual powder (at 0.4 kg/hr) from approximately 0.125%

to 0.08%. As magnesium stearate is usually present in formulations in low amounts (< 2%

w/w), microfeeders with lower throughputs, such as the KTRON MT12 or KT20 are typically

more suitable.
Cartwright et al. (2013) compared a number of LIW feeders and configurations to feed a low

density (0.14 g/ml), poor flowing API (26). Using the KTRON KT20 feeder, core and spiral

screws were selected to feed this material with an adequate degree of control. It was reported

that operator intervention was often required to prevent the formation of rat holes in the

upstream hopper. A flexible frame feeder, the Brabender FW40 was able to deliver the API

powder without manual intervention. Due to the low bulk density of the API (0.14 g/ml) a

number of technical challenges were observed with flighted auger and fine concave screws.

There was an increase in feeder motor torque over time due to the material under transport

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compacting within the screws as well as between the screws. This led to the feeder motor

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achieving maximum motor torque and shutting down as per safety controls. Fine concave

screws were successful for excipient blends which were free flowing and of consistent

density.
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4 Sources of inconsistency in feeding
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It takes a period of time following the initial start-up of a feeder for the equipment to reach a
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steady state of operation. It has been demonstrated that fluctuations in the mass flow of the

powder compared to the pre-set feed rate are observed at the start of feeding. Once the mass
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flow is equal to the set point, the feeder is said to be at steady state. The time it takes to reach
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steady state is related to the time that it takes for powder to fill the flights of the screws

before accurate feeding can begin. Simonaho et al. (2016) demonstrated this period to be 3
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minutes following start up of the KTRON K20 feeding of microcrystalline cellulose at 17.1

kg/hr and acetylsalicylic acid at 2.9 kg/hr (6). Ervasti et al. (2015) reported that a 10 minute

period was sufficient to reach equilibrium when feeding blend components at feed rates

which ranged from 0.07 kg/hr to 2.24 kg/hr using two LIW feeders (K-ML-D5-KT20 and K-

CL-SFS-KT20) (8). The study also illustrated that the relative standard deivation (RSD)
from the feeder set point was highest at the lower API feed rates due to the independence of

the absolute standard deviation of the feed rate. Data from the author’s laboratory

demonstrate that steady state (± 3) was attained at approximately 12 minutes for

microcrystalline cellulose fed at 0.25 kg/hr using a KTRON MT12 LIW feeder, Figure 3.

Once steady state is achieved, random spikes in feed rates can occur and are commonly

attributed to a range of factors; properties of the feed materials, equipment set-up (screw and

screen selection), surrounding environmental vibrations and disturbances and during refill

procedures when LIW feeders revert to volumetric feeders momentarily

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Feeding cohesive materials introduces the risk of materials adhering to the screws and

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screens, forming lumps in the feeder and causing inconsistencies in the material flow.

Accumulation of powder at the outlet of the feeder can result in the material dropping off

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causing a spike in the data read out. Some feeder models recommend the use of sieves at the
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screw outlet to prevent such accumulation of powder.

LIW systems may be exposed to physical disturbances such as oscillations, vibrations and air
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flow in the surrounding environment which can disturb the sensitive process of gravimetric
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feeding. Many feeders have mitigation in place in their design such as dampeners,

homogenators and agitators. Feeder design can involve the use of vibration minimising
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flexible materials or stainless steel in their construction to aid the feeding (27, 28).
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Powder processing operations such as screw feeding can generate vast quantities of
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electrostatic charge via the movement of powder through the equipment. Materials such as

colloidal silcon dioxide possess intense electrostatic properties, causing the powder to

displace a strong tendacy to adhere against material tooling or the outlet tube of a feeder. In

order to reduce the effect of electrostatics, as mentioned previously, it can be necessary to

equip the feeder with a static eliminater (22). Engisch and Muzzio have investigated this
issue and were able to reduce, not eliminate, the impact of electrostatics on material build up

(22).

As mentioned in section 2, disturbances during the hopper refill procedures are attributed to a

decrease in feeding accuracy due to the changes from gravimetric to volumetric feeding..

During normal gravimetric mode of operation the feeder can respond to any changes in the

density of the material and adjust the speed to maintain an accurate feed rate. During a refill

procedure the equipment, in volumetric mode, is essentially rendered blind to any density

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changes of the incoming material. The density of the material can either (i) increase due to

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compression of the existing existing powder bed by the incoming material or (ii) decrease due

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to aeration of the powder due to the refill procedure (7). These changes in density are mainly

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due to the physical characteristics of the feed material. The level of disturbance during refill

and the frequency of refill thereforecan be minimised by tailored hopper design to match the
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feed rate and specific material properties of the raw material being fed (7, 29). Engisch and
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Muzzio (2015) recommend that the quantity of refills should be based on reducing any

deviation from the feed rate set point to a level that is acceptable to downstream unit
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operations (7). The importance of hopper fill level during a refill procedure was also clearly

demonstrated in this study. Deviations from the set point were larger when the hopper was
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refilled at lower fill levels for example 20%. While, refilling the hopper at a 60% fill level
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results in more accurate feeding it also leads to a more demanding refill regime with more
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frequent, smaller refills.

5 Application of PAT in Continuous Feeding

At certain time points during the continuous manufacturing process, it will be necessary to

examine the homogeneity of the powders streams. The in-line measurement of powder

streams is challenging due to (i) frequent fouling of the measurement probe; (ii) difficulty in
defining a ‘sample size’ and (iii) determination of the optimum probe position so it does not

interfere with the powder stream and it only measures the powder stream and not powder

adhering to the machinery (30). Additionally, the flow rate of a powder feed under a

continuous process may be much faster than what is experienced during batch blender

rotation, limiting the collection of reliable calibration data. (13).

There are limited studies discussing the application of PAT on continuous powder feeders

where individual components are being dispensed. Typically, the most significant PAT

application in this respect is identification of the feed component. However, there may be

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some applications where the feeding of blended material is required to ensure continuous

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movement of the blend through the process such as in roller compaction. When monitoring a

blend, the primary goal of any PAT application is assessing API uniformity. In continuous

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manufacturing there is movement of blend from one unit operation to another which can
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introduce challenges in the interpretation of PAT spectra. A recent publication by Shi et al.

(2015) focused on pretreatment methodologies to overcomethe impact of changing feed rate

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when assessing API potency in a blend spectroscopically (13). This work compared on-line
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NIR spectroscopic methods (Fourier Transform (FT) and dispersive spectrometers) to

investigate blend uniformity of acetaminophen mixtures dispensed from a twin screw

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volumetric feeder (13). A PLS model was applied to spectral data collected at 0 kg/hr (static),
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13.5 kg/h and 27.6 kg/hr. The pretreament of mean centering and SNV was used to reduce

the RMSE of collected spectra thus reducing the variability due to changes in feed rate
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allowing to better monitor the changes in API. Singh and co-workers (2015) recently

published a study using on-line NIR as a PAT tool to monitor bulk density of individual

materials and blends at a feeder outlet. Interestingly this study demonstrated the impact of

bulk density on the feeding mechanism and illustrated the link between variations in bulk
density of feed materials and subsequent modification in feed screw speed to compensate for

the changes (31).

6 Conclusions

The performance of powder feeders defines the content of the final dosage form and is

therefore a critical unit operation in continuous processing of solid dosage forms. It was the

aim of this review to highlight the importance of the initial powder feeding step in the overall

manufacture of pharmaceutical solid dosage forms and focus on the impact of material

properties on feeding performance and feeding equipment selection and set-up. The literature

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related to continuous feeding of pharmaceutical powders focuses primarily on the impact of

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powder properties on feeding parameter selection. However it is also important to consider

the impact of feeding parameters on pharmaceutical powder properties during pharmaceutical

processing and more research into this area is warranted.

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Acknowledgments
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This review is funded by the Enterprise Ireland/Irish Development Authority -

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Pharmaceutical Manufacturing Technology Centre, Ireland and Science Foundation Ireland -

Synthesis and Solid State Pharmaceutical Centre (SSPC) under grant number 12/RC/2275.
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Author Information
-------------------------------------------------
Dr Caroline A Blackshields PhD (Corresponding Author)
Email: [Link]@[Link]
Affiliation 1:
University College Cork, Pharmaceutical Manufacturing Technology Centre , School of Pharmacy,

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University College Cork, Cork, Ireland

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Dr Abina M Crean

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Email: [Link]@[Link]
Affiliation 1:
University College Cork, Pharmaceutical Manufacturing Technology Centre , School of Pharmacy,
University College Cork, Cork, Ireland
Affiliation 2:
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University College Cork National University of Ireland, Synthesis and Solid State Pharmaceutical
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Centre, School of Pharmacy, University College Cork, Cork, Ireland
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Material Function Physical Feed Feeder Screw Issues Ref.
Properties Rate Model Selection
Reported (kg/h)
ProSolv Diluent Density 10.64- KTRON Coarse Powder fed too freely and filled flight of (22)
HD90 (0.49 g/ml); 16.64 KT20 concave screws and flushed out too freely.
Free KTRON Coarse auger. Screen required to retain the powder in the
Flowing KT35 screw for longer.
Colloidal Glidant Density 0.218- KTRON Coarse Feeder was instrumented with static (22)
Silicon (0.04 g/ml); 0.341 KT20 Concave eliminator to reduce material adhering to
Dioxide Cohesive; equipment. Auger screws can lead to
Electrostatic. stagnant areas within flight of screws; Fine
screws cannot deliver capacity
API (not API Density 12.48- KTRON Coarse API build up on coarse auger screw so (22)
identified) (0.61 g/ml) 19.51 KT20 concave coarse concave used due to self-cleaning
Free properties. No screen used due to build up.
flowing. KTRON Coarse auger
KT35
Magnesium Lubricant Density 0.177- KTRON Coarse Easily sheared and coats other powders and (22)

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Stearate (0.14 g/ml) 0.278 MT12 concave metal surfaces. Only tested with self-

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Fine Concave cleaning screws.
Crospovidone Disintegrant Density 0.480- KTRON Fine Concave Fed easily with no issues. Potential material (22)
(0.33 g/ml) 0.750 MT12 build up. Only tested with self-cleaning

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KTRON screws.
KT20
316 Fast Flo Diluent Density Not KTRON Coarse Material ran for all tooling conditions and (25)

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Lactose (0.58 g/ml) specified KT35 concave speed settings in volumetric and
Fine concave gravimetric mode.
Coarse auger
Fine auger
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Avicel PH Diluent Density Not KTRON Coarse Overloaded motor at highest speed setting (25)
102 (0.30 g/ml) specified KT35 concave; with coarse auger screw (highest
throughput) and fine screen.
Ceolus KG- Diluent Density Not KTRON Fine concave Both coarse auger and fine auger resulted in (25)
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802 (0.21 g/ml) specified KT35 Coarse auger motor overload with fine screen.
Fine auger
API (not API Density Not KTRON KTRON Low bulk density of API posed issues with (26)
identified) (0.14 g/ml) specified KT20; (flighted auger; flighted auger and fine concave which
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Schenk fine concave caused increase in feeder motor torque.

Accurate and core and Only core and spiral screws could feed API
AP300; spiral). which reduced machine capacity and
Brabender Brabender required much operator intervention due to
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FW40; models (Open formation of rat holes. The KTRON KT20s

Brabender spiral single rigid design posed issues. Brabender
FW18 screw) flexible frame models were more successful
in feeding particular API. .
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