(303c) A QbD Approach to Continuous Tablet Manufacture

Freeman, T., Freeman Technology Inc.
Delancy, M., Freeman Technology Inc.
Birkmire, A., GEA Pharma Systems
Yin, J., Freeman Technology Inc
Armstrong, B., Freeman Technology Ltd

Wet granulation is a common unit operation in the pharmaceutical, food, FMCG and chemical industries [1].  It converts fine powders into granules with a much larger particle size and is usually carried out batch wise in either a fluidized bed or a high shear mixer.  This yields benefits that include, improved flow properties, reduced segregation (especially of active ingredients) and hence better content uniformity.  Additional advantages are reduced dusting, increased density and lower packed volume (since larger particles can pack more closely than smaller cohesive ones that tend to trap air) which lead to improved compression properties.  It is for these reasons that wet granulation is employed in a significant number of pharmaceutical tablet formulations.

However, there are a number of issues relating to the quality control of any batch operation – not least the control of the consistency of the final product in terms of content uniformity, particle size distribution and granule strength – which, in turn, impact the quality of the final tablet.  Historically many batches have required re-work or have even been scrapped due to them failing to meet the required standard.

The pharmaceutical industry is looking to continuous processing to enhance production efficiency and product quality, in line with guidance from regulatory agencies [2-4].  Whilst process control in continuous manufacture is arguably more straightforward, it becomes necessary to define, measure and link material quality parameters, at all stages during processing, to those of the final product so that the processing regime can be optimized.  This has proved challenging when applied to particulate systems due to the immense complexity of the relationships between the particulate properties (size, size distribution, shape, texture, granule friability/strength etc.), the properties of the final product (tablet content uniformity, strength, weight) and the unit operations (mixing, granulation, milling tableting). 

Recent developments in both continuous granulation combined with advanced powder/granule characterisation mean that the necessary powder/granulate quality parameters can now be precisely defined and linked to manufacturing procedures and ultimately to tablet quality. 

A preliminary study was conducted on granules manufactured using the ConsiGma-1™ continuous granulation/drying system (GEA Pharma Systems) from two formulations (dibasic calcium phosphate [DCP] based and N-acetyl-p-aminophenol [APAP] based).  The flow properties of the granulate were measured at all manufacturing stages, including granulated wet mass, using an FT4 Powder Rheometer® (Freeman Technology).

The results from this initial evaluation show the change in flow behaviour (basic flowability energy – BFE) with respect to the operational parameters of the granulation system (screw speed, water addition and feedrate).  Earlier studies [6, 7] have demonstrated how the properties of the granules are affected by the processing conditions in batch granulation systems and indeed how these properties relate to the properties of the resultant tablet [6]. 

From these results it could be seen that granules with extremely repeatable flow properties could also be generated from a continuous granulation system and it becomes a simple exercise to target a specific BFE defined granule quality by means of adjusting the various processing parameters – water content; granulator speed; manufacturing (feed) rate.

The initial study was then extended to include the manufacture and evaluation of tablets based on experimental batches of granules of the APAP based formulation. 

Specific quality/flow characteristics were targeted and were achieved using four sets of contrasting variable process conditions (combinations of water addition rate, input powder feed rates and granulator screw speed) – Conditions 1 to 4, shown in Table 1. 

Table 1. Combinations of process conditions chosen to target specific granule properties

Screw Speed (RPM)

Powder Feed (kg/hr)

Liquid Feed (g/min)

Moisture (%)

Condition 1





Condition 2





Condition 3





Condition 4





The resultant granules were dried, milled and lubricated in an identical manner prior to tableting in a GEA Modul™ S rotary tablet press. 

The results from the flow property testing and evaluation of the resultant tablet hardness are shown in Table 2.  The tablet hardness is presented as an average of 10 measurements; the BFE was measured three times for each set of process conditions.

Table 2. Wet mass, granule and tablet properties.

BFE – Wet Mass (mJ)

BFE – Dry Granules (mJ)

BFE – Milled Granules (mJ)

BFE – Lubricated Granules (mJ)

Tablet Hardness (kPa)

Condition 1






Condition 2






Condition 3






Condition 4






The BFE of Conditions 1 & 2 generated values around 2200mJ when testing the wet mass, whereas Conditions 3 & 4 had BFE values around 3200mJ.  As the granules progress through the manufacturing process, the relative BFE values at each discrete stage remain consistently grouped – the BFE’s of Conditions 3 & 4 always higher than those of 1 & 2.  This observation suggests that granule properties are dependent on manufacturing conditions, but importantly it is possible to produce the required granule quality using more than one manufacturing route.

If the relationship between the flow properties of the granules at each stage of manufacture and the hardness of the tablets is plotted, the correlation is extremely strong between tablet hardness and the BFE for the dried and milled granules with an R2 value of greater than 0.99.  The slightly poorer (but still significant) correlation for the wet mass and lubricated granules can be attributed to the presence of the additional components – water or lubricant (MgSt) – which are known to have an exaggerated influence on the bulk flow properties considering their low concentrations.

It is therefore possible to conclude that there is a direct relationship between the bulk flow properties of the granules at all stages of manufacture, as quantified by the BFE, and a critical quality attribute (CQA) of the final tablet – tablet hardness.

In summary, this study shows it is possible to target specific tablet properties using different combinations of process conditions, and that a defined granule property can be used to predict a characteristic of the tablet – a significant step towards a full Design Space specification.  These results also provide the opportunity to develop scaling criteria for batch granulation processes.  Once a specific flow property – the Basic Flowability Energy (BFE) – has been linked to the optimal Critical Quality Attributes for the final product, the manufacturing requirement is no longer focused on particular equipment types or operational settings.  As long as the wet granule attains the target BFE, the tablet quality can be assured. 

Future work will assess the correlation between granule properties and other CQAs of the tablet, such as content uniformity, weight variation and dissolution.


[1] Ennis, B. J., Witt, W., Weinekoter, R., Sphar, D., Gommeran, E., Snow, R. H., Allen, T., Raymus, G. J., & Litster, J. D., "Solid-Solid Operations and Processing," in D. W. Green & R. H. Perry, (Eds.), Perry's Chemical Engineers' Handbook, 8 edn, McGraw-Hill Professional. 2007. 

[2] International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use 2005, Quality Risk Management, Q9.

[3] International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use 2008, Pharmaceutical Quality System, Q10.

[4] International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, 2009, Pharmaceutical Development Q8(R1)

[5] Freeman R., 2007. Measuring the flow properties of consolidated, conditioned and aerated powders - A comparative study using a powder rheometer and a rotational shear cell. Powder Technology, 174, pp. 25-33.

[6] Cassidy O.E. & Thomas W.I., 2002. Characterisation of wet masses using a powder rheometer, Poster Session 1 - Pharmaceutics. Journal of Pharmacy and Pharmacology, 54, pp. 25-46.

[7] Freeman, T.C. and Armstrong, B, The characterisation of granulation wet masses using powder rheometry, 5th International Granulation Workshop, Lausanne, Switzerland, 20-21 June 2011.


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