Research paper Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets Margot Fonteyne a,⇑ , Henrika Wickström a,b , Elisabeth Peeters c , Jurgen Vercruysse c , Henrik Ehlers b , Björn-Hendrik Peters d , Jean Paul Remon c , Chris Vervaet c , Jarkko Ketolainen d , Niklas Sandler b , Jukka Rantanen e , Kaisa Naelapää e,1 , Thomas De Beer a a Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium b Pharmaceutical Sciences Laboratory, Department of Biosciences, Åbo Akademi University, Turku, Finland c Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium d School of Pharmacy, University of Eastern Finland, Kuopio, Finland e Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark article info Article history: Received 4 November 2013 Accepted in revised form 21 February 2014 Available online xxxx Keywords: Continuous pharmaceutical manufacturing Raw material variability Twin screw granulation Tableting Theophylline Particle size abstract Continuous manufacturing gains more and more interest within the pharmaceutical industry. The Inter- national Conference of Harmonisation (ICH) states in its Q8 ‘Pharmaceutical Development’ guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of raw material attributes, manufacturing process options and process parameters. This fits further into the Process Analytical Technology (PAT) and Quality by Design (QbD) framework. The present study evaluates the effect of variation in critical raw material properties on the critical quality attributes of granules and tablets, produced by a continuous from-powder-to-tablet wet granulation line. The gran- ulation process parameters were kept constant to examine the differences in the end product quality caused by the variability of the raw materials properties only. Theophylline–Lactose–PVP (30–67.5– 2.5%) was used as model formulation. Seven different grades of theophylline were granulated. Afterward, the obtained granules were tableted. Both the characteristics of granules and tablets were determined. The results show that differences in raw material properties both affect their processability and several critical quality attributes of the resulting granules and tablets. Ó 2014 Elsevier B.V. All rights reserved. 1. Introduction Currently the interest has arisen in the pharmaceutical industry to shift its manufacturing principles from traditional batch produc- tion toward continuous production [1,2]. Continuous manufactur- ing has several advantages including minimal scale-up issues, reduction in cycle time, less product variability and lower produc- tion costs, faster product release, increased flexibility and effi- ciency, and improvement of product quality. These advantages result for example in a shorter ‘‘time-to-market’’ and lower operat- ing costs. Continuous production allows ‘‘just-in-time’’ production and will minimize the stock, according to LEAN principles. Further- more, a continuous production line requires less floor space and fewer operators. Hence, once implemented, a continuous manufac- turing line will imply a significant cost reduction. Whereas contin- uous production is well implemented in chemical and food industry, it is still in its infancy when it comes to the pharmaceu- tical industry. The most common pharmaceutical solid dosage form is the tablet. Tableting often involves a granulation step. Re- cently, advances in pharmaceutical continuous granulation and tableting have been reported [3–11]. The introduction of continuous manufacturing comes with a major concern: ‘‘How to assure a persistent quality of the pharma- ceutical products?’’ The classical off-line quality control analysis http://dx.doi.org/10.1016/j.ejpb.2014.02.011 0939-6411/Ó 2014 Elsevier B.V. All rights reserved. Abbreviations: ICH, International Conference on Harmonisation; PAT, Process Analytical Technology; API, Active Pharmaceutical Ingredient; BET, Brunauer– Emmett–Teller; CQA, critical quality attributes; FDA, food and drug administration; HPMC, hydroxypropylmethylcellulose; MCC, microcrystalline cellulose; PC, Princi- pal Component; PCA, Principal Component Analysis; PLS, partial least squares; PVP, polyvinylpyrrolidone; QbD, Quality by Design; rpm, rotations per minute; SNV, standard normal variate; UV, unit variance; UV–VIS, ultraviolet–visible. ⇑ Corresponding author. Laboratory of Pharmaceutical Process Analytical Tech- nology, Ghent University, Harelbekestraat 72, Ghent, Belgium. Tel.: +32 9 264 83 55; fax: +32 9 222 82 36. E-mail addresses: Margot.Fonteyne@Ugent.be (M. Fonteyne), Thomas.Debeer@- Ugent.be (T.D. Beer). 1 Current address: Oral Protein Formulation, Novo Nordisk, Måløv, Denmark. European Journal of Pharmaceutics and Biopharmaceutics xxx (2014) xxx–xxx Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb Please cite this article in press as: M. Fonteyne et al., Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets, Eur. J. Pharm. Biopharm. (2014), http://dx.doi.org/10.1016/j.ejpb.2014.02.011