Impact of formulation and process design on tablet quality in continuous manufacturing

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KRISTA TAIPALE-KOVALAINEN

Impact of formulation and process design on tablet quality in continuous manufacturing

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

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IMPACT OF FORMULATION AND PROCESS DESIGN ON TABLET QUALITY IN

CONTINUOUS MANUFACTURING

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Krista Taipale-Kovalainen

IMPACT OF FORMULATION AND PROCESS DESIGN ON TABLET QUALITY IN

CONTINUOUS MANUFACTURING

To be presented by permission of the

Faculty of Health Sciences, University of Eastern Finland for public examination in CA 100 Auditorium, Kuopio

on Friday 18^thJune, at 12 o´clock noon

Publications of the University of Eastern Finland Dissertations in Health Sciences

No 630 School of Pharmacy University of Eastern Finland

Kuopio 2021

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Series Editors

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences

Professor Tarja Kvist, Ph.D.

Department of Nursing Science Faculty of Health Sciences Professor Ville Leinonen, M.D., Ph.D.

Institute of Clinical Medicine, Neurosurgery Faculty of Health Sciences

Professor Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

Lecturer Veli-Pekka Ranta, Ph.D.

School of Pharmacy Faculty of Health Sciences

Distributor:

University of Eastern Finland Kuopio Campus Library

P.O.Box 1627 FI-70211 Kuopio, Finland

www.uef.fi/kirjasto

Grano Jyväskylä, 2021

ISBN: 978-952-61-3810-7 (print/nid.) ISBN: 978-952-61-3811-4 (PDF)

ISSNL: 1798-5706 ISSN: 1798-5706 ISSN: 1798-5714 (PDF)

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Author’s address: School of Pharmacy Faculty of Health Sciences University of Eastern Finland KUOPIO

FINLAND

Doctoral programme: Doctoral programme of Drug Research Supervisors: Professor Ossi Korhonen, Ph.D.

School of Pharmacy Faculty of Health Sciences University of Eastern Finland KUOPIO

FINLAND

Professor Jarkko Ketolainen, Ph.D.

School of Pharmacy Faculty of Health Sciences University of Eastern Finland KUOPIO

FINLAND

Reviewers: Professor Frantisek Stepanek, Ph.D.

Faculty of Chemical Engineering

University of Chemistry and Technology PRAGUE

CZECH REPUBLIC

Docent Anette Larsson, Ph.D.

Department of Chemistry and Chemical Engineering Chalmers University of Technology

GOTHENBURG SWEDEN

Opponent: Docent Mia Siven, Ph.D.

School of Pharmacy University of Helsinki HELSINKI

FINLAND

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Taipale-Kovalainen, Krista

Impact of formulation and process design on tablet quality in continuous manufacturing.

Kuopio: University of Eastern Finland

Publications of the University of Eastern Finland Dissertations in Health Sciences 630. 2021, 137 p.

ISBN: 978-952-61-3810-7 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-3811-4 (PDF) ISSN: 1798-5714 (PDF)

ABSTRACT

In order to gather comprehensive information of the usability and effectiveness of a novel continuous manufacturing process line, several different set–up configurations (top-down and horizontal) were studied with direct compressible paracetamol and dry granulated ketoprofen formulations in three investigations. The impact of lubricant-based parameters on tablet quality properties was investigated in all studies. Furthermore, some effects of formulation and manufacturing process design on product quality were examined and assessed.

The first aim was to devise robust and stable continuous manufacturing process settings, by exploring the design space (DS) after an investigation of the lubrication- based parameters influencing the continuous direct compression tableting of high dose tablets. The process parameters did not affect the quality of the tablet properties;

in contrast, formulation parameters exerted a major influence on the properties of the end product. The design space created showed that this type of continuous manufacturing process line was suitable for producing high dose direct compressible paracetamol tablets, which possessed a predetermined quality.

The second aim was to determine whether intentional (e.g. overnight hold time, product concentration change) and unintentional (e.g. equipment or software failures) deviations, could affect the critical quality attributes (CQA's) of the final product, and to create a deviation document which would reveal the changes that had occurred in the product concentration during the runs. In this study, it was shown that it was possible to produce tablets with a constant quality with our set-up consisting of several unit operations. However, the set-up had to be very carefully designed and controlled to ensure process stability.

The third aim was to demonstrate the feasibility of converting of a high-shear wet granulation (HSWG) batch process to a continuous dry granulation (DG) process without any significant formulation changes, by comparing the critical quality attributes (CQA´s) of the granules and tablet products between these two processes.

The results demonstrated the possibilities to convert a batch based HSWG process to 7

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a continuous DG process by adopting a flexible and effective approach, thus representing a changing towards a more modern manufacturing process.

National Library of Medicine Classification: QV 704, QV 745, QV 778

Medical Subject Headings: Lubrication; Acetaminophen; Lubricants; Ketoprofen; Feasibility Studies; Tablets; Excipients

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Taipale-Kovalainen, Krista

Formulaation ja prosessin vaikutus tabletin laatuun jatkuvatoimisessa valmistuksessa.

Kuopio: Itä-Suomen yliopisto

Publications of the University of Eastern Finland Dissertations in Health Sciences 630. 2021, 137 s.

ISBN: 978-952-61-3810-7 (nid.) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-3811-4 (PDF) ISSN: 1798-5714 (PDF)

TIIVISTELMÄ

Väitöskirjatutkimuksen tärkein tavoite oli osoittaa uudentyyppisen jatkuvatoimisen lääkkeenvalmistusprosessin käyttökelpoisuus ja tehokkuus eri kokoonpanoilla ja asetuksilla (ylhäältä-alas sekä horisontaalinen konfiguraatio) suorapuristeisella parasetamoli -sekä kuivarakeistettavalla ketoprofeeniformulaatiolla. Liukuaineen vaikutusta tuotteen ominaisuuksiin tutkittiin kaikissa kolmessa osatutkimuksessa.

Formulaation ja valmistusprosessin vaikutusta tuotteen laatuun tutkittiin jokaisessa osa tutkimuksessa.

Ensimmäisen osatyön tavoitteena oli saada aikaan tasalaatuinen valmistusprosessi kehittämällä hyväksyttävä toiminta-alue liukuainepohjaisten parametrien pohjalta parasetamolivalmisteella. Prosessiparametreilla ei ollut merkittävää vaikutusta tuotteen laatuun, mutta formulaatiomuuttujilla vaikutusta havaittiin. Tutkimuksen aikana saavutettu hyväksyttävä toiminta-alue osoitti tutkitun prosessin kyvykkyyden saavuttaa hyväksyttävä toiminta-alue suuriannoksisella parasetamolia sisältävälle suorapuristeformulaatiolle.

Tutkimuksen toinen tavoite oli osoittaa ennalta määritellyn häiriön (yön-yli seisokki, konsentraation muutos) ja ennalta arvaamattoman häiriön (prosessilaitteen tai tietokoneen häiriöt) vaikutukset lopputuotteen laatuparametreihin ja luoda ns. häiriö- dokumentti prosessin ajalta, jonka perusteella voidaan osoittaa ko. häiriön vaikutus tuotteen konsentraatioon. Jatkuvatoiminen prosessi, johon on integroitu useampi prosessilaite, mahdollistaa laatuvaatimukset täyttävän lopputuotteen valmistamisen.

Tästä huolimatta huolellinen prosessisuunnittelu ja prosessin kontrollointi ovat tärkeitä tuotteen laadun takaamiselle.

Kolmas tavoite oli osoittaa erävalmisteisen märkärakeistettavan formulaation siirtäminen ilman merkittäviä formulaatiomuutoksia jatkuvatoimisesti valmistettavaksi kuivarakeistettavaksi formulaatioksi ja vertailla rakeiden ja tablettien laatuparametrejä näissä kahdessa valmistusprosessissa. Prosessimuutos osoitti, että tutkittu formulaatio on mahdollista muuttaa erävalmisteisesta märkärakeistettavasta tuotteesta jatkuvatoimiseen prosessiin.

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Luokitus: QV 704, QV 745, QV 778

Yleinen suomalainen ontologia: voiteluaineet; parasetamoli; ketoprofeeni; tabletit (puristeet);

täyteaineet

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ACKNOWLEDGEMENTS

I have grown in a family where the pharmacy and pharmaceutical industry was the whole life and self-evident. Thanks to my parents who really convinced me over many years to choose the field of pharmacy when I went to university.

My interests in manufacturing of medicinal products began when I started to study pharmacy in the university. The big opportunity occurred when Professor Jarkko Ketolainen Ph.D. told me that I could have a place in the research group of continuous manufacturing in the University of Eastern Finland at Kuopio during the years 2016 - 2021. Many thanks for that to Jarkko! My sincere thanks goes to the official reviewers Anette Larsson, Ph.D. and Frantisek Stepanek Ph.D., for their careful reading and valuable comments. I have the great honor of thanking Mia Sive Ph.D. who has agreed to be the opponent of my dissertation of the public examination. In addition, I wish to thank Ewen MacDonald for proofreading the language of my dissertation.

From the bottom of my heart I would like to say a big thank you to all the Promis Center research group members for their energy, understanding and help throughout my project, especially to Professor Ossi Korhonen Ph.D., who has supported me throughout this research project. It truly has been a very, very good time in this lab. I also would like to say a special thank you to my colleagues Anssi- Pekka Karttunen Ph.D. and Tuomas Ervasti Ph.D. Their great support, guidance and overall insights in this field have made this an inspiring experience for me.

And my biggest thanks to my family for all the support you have shown me while I was undertaking this research. For my daughters Milka and Mandi, this thesis is an example to you, of the kind of hard work your mother has done and to show you, if you want, then your dreams can come true! It really needs work and a great commitment. And thanks to my lovely husband Jari, for all his support, without which I would have stopped these studies many hundreds of times a long time ago.

Soon we will both have doctorial titles in our family, what an amazing and powerful family!

Kuopio, June 2021

Krista Taipale-Kovalainen

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LIST OF ORIGINAL PUBLICATIONS

This dissertation is based on the following original publications:

I Taipale-Kovalainen K, Karttunen A-P, Ketolainen J, Korhonen O. Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets. European Journal of Pharmaceutical Sciences. 2018;115: 1-10.

II Taipale-Kovalainen K, Karttunen A-P, Niinikoski H, Ketolainen J, Korhonen O.

The effects of unintentional and intentional process disturbances on tablet quality during long continuous manufacturing runs. European Journal of Pharmaceutical Sciences. 2019;129: 10-20.

III

Taipale-Kovalainen K, Karttunen A-P, Ketolainen J, Korhonen O, Ervasti T.

Converting a batch based high-shear granulation process to a continuous dry granulation process; a demonstration with ketoprofen tablets. European Journal of Pharmaceutical Sciences. 2020;151: 105381-105381.

The publications were adapted with the permission of the copyright owners.

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ABBREVIATIONS

API Active Pharmaceutical Ingredient

CDC Continuous Direct Compression cGMP Current Good

Manufacturing Practice CM Continuous Manufacturing CQA Critical Quality Attribute DG Dry Granulation

DoE Design of Experiment DS Design Space

EMA European Medicine Agency FDA United States Food and Drug

Administration HME Hot-Melt Extrusion LIW Loss-In-Weight

MA Marketing Authorisation MgSt Magnesium Stearate NIRs Near-Infrared spectroscopy HSWG High-Shear Wet Granulation ICH International Council of

Harmonisation

USP United States Pharmacopeia

PAT Process Analytical Technology

PSD Particle Size Distribution QbD Quality by Design

RTD Residence Time Distribution RTR Real Time Release

R&D Research and Development TSG Twin-Screw Granulation 3D Three-Dimensional space

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1 INTRODUCTION

Although continuous manufacturing (CM) has been used in the paper, food and petrochemical industries for over a half century (Kleinebudde et al., 2017), the pharmaceutical industry has only introduced continuous manufacturing methods very recently. The pharmaceutical industry mainly utilizes batch processing, thus the overall knowledge about continuous manufacturing is at a low level. In addition, there are huge investments involved in changing to new production lines (Kleinebudde et al., 2017).

Nonetheless, the regulatory bodies have recognized this modern way to produce medical products and substantial efforts have been made to encourage switch-overs e.g. the ICH Q13 guidelines (ICH, 2018), the article about continuous manufacturing in the US Pharmacopoiea (USP, 2018) and the United States Food and Drug Administration (FDA, 2019) providing support for the development and implementation of continuous manufacturing. In this decade, FDA and/or EMA have approved Marketing Authorisations (MA) for medicinal products which are manufactured by continuous manufacturing methods e.g. Orkambi (Vertex), Prezista (Janssen), Symdeko (Vertex), Verzenio (Eli Lilly and Company) (Nasr et al., 2017).

One of the objectives in regulatory bodies is to allow the manufacturers to employ flexible approaches to develop, implement or integrate CM processes. These offer so many interesting applications that pharmaceutical manufacturers are now beginning to investigate. Approximately 60 % of pharmaceutical manufacturing is outsourced (EPR, 2018). CM allows ´a new way of thinking´ e.g. by building a mobile CM process line. GEA has built on-demand mini-factories, which can be set up to manufacture medicines, at any production scale, almost anywhere in the world where basic utilities are available. Once production is no longer needed, they can be dismantled, transported and relocated elsewhere (GEA, 2020).

Continuous manufacturing is involved in a broad area in the pharmaceutical industry when manufacturing chemicals (Diab et al., 2019; Gérardy et al., 2018; Poechlauer et al., 2012; Teoh et al., 2016), end product manufacturing (Byrn et al., 2015; Mascia et al., 2013;

Teżyk et al., 2016) and biopharmaceutical manufacturing (Rathore et al., 2015). There is growing interest on excipients and their important role in determining the possibilities to pursue continuous manufacturing. Concerning the manufacturing of oral solid dosage forms, there are four main basic methods in continuous manufacturing: continuous dry granulation (Singh et al., 2012), continuous wet granulation (Kumar et a.l, 2013; Martinez- Marcos et al., 2016; Pauli et al., 2018; Wahl et al., 2013), continuous hot-melt granulation (Maniruzzaman 2019; Monteyne et al., 2016; Weatherley et al., 2013) and continuous direct compression (Ervasti et al., 2015). These processes could be installed in different set-ups; separately or in an ´all in one´ principle (Khinast and Rantanen, 2017).

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Even though the final products have the same visual appearance from the patient’s perspective, there are differences between the methods, when the final product is made by either batch or continuous manufacturing (Karttunen et al., 2019b; Kumar et al., 2013;

Matsunami et al., 2019). The main difference between these methods is that the continuous processing is (in the ideal case) running without any pause, in contrast to batch processing, where many pauses are necessary e.g. for material loading, discharging, transferring to different process departments/rooms and for analyzing the quality of intermediates in the laboratory. Furthermore, release tests need to be performed after manufacturing which normally can take up to several weeks in batch manufacturing.

Unlike the situation with the batch process, the continuous manufacturing process is running in the same room/department and the material is automatically loaded and transferred through the integrated processes. For example, Process Analytical Technology (PAT) enables real time releasing which hastens the product release to the market (Colón et al., 2017; Fonteyne et al., 2015; Hetrick et al., 2017; Pawar et al., 2016).

There are obvious benefits associated with the continuous manufacturing as compared to batch manufacturing. Instead of step – by – step processing, continuous manufacturing enables a much shorter production time and flexible production planning and implementation. Another benefit is the good possibility of scaling-up operations (Ierapetritou et al., 2016; Lee et al., 2015). Because the whole processing development cycle can be performed with the same equipment, the batch size (output) is simply dependent on how long or how fast the process is running. Therefore, the product development life cycle is much shorter and more flexible, and product maintenance usually faster.

From the environmental and economical point of view, the cost is reduced when using continuous manufacturing (Jolliffe et al., 2016; Schaber et al., 2011). Energy consumption and the environmental burden are reduced due to the lower material wastage and consumption (De Soete et al., 2013).

By applying the advances in process knowledge about continuous manufacturing and

“Quality by Design” (QbD) conception, the quality of the final product is the same or even better as compared to batch-based manufacturing. QbD principles are intended to develop the product based on predefined parameters, process understanding and process control, based on a scientific assessment and a quality risk management (ICH Q8; ICH Q9; ICH Q10). The application of real time monitoring and analyzing systems e.g. Process Analytical Technologies (PAT) makes it possible to achieve the desired process and product performance. PAT is compatible with data collection and monitoring during the manufacturing, when there is good product knowledge combined with a basic understanding of the process and control system. Real time release (RTR) is an alternative strategy for final product testing and reducing the analytical costs.

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2 REVIEW OF THE LITERATURE

2.1 IMPLEMENTATION WORK TOWARDS CONTINUOUS MANUFACTURING IN THE PHARMACEUTICAL INDUSTRY

Process automation and process-controlled work were noticed even in the pharmaceutical industry in the 1950s as an important opportunity to achieve economical and technological benefits (Kilbridge, 1960). It is noticeable that work interruptions, outputs and standardized way of working, were highlighted even a long time ago.

Current pharmaceutical production involves mainly batch based production, which is inflexible, time-consuming and requires more employees (Plumb, 2005). Over the years, the pharmaceutical industry has tried to generate innovative solutions for new technologies and devise new ways of manufacturing products (Khanna, 2012; Lee et al., 2015; Vervaet and Remon, 2005). It took a long time before a real start took place in process improvement with the analytical tools: The Food and Drug Administration (FDA) in the USA launched a guidance for industry, the “way of work” called Process Analytical Technolgy (PAT) (FDA, 2004). Continuous manufacturing technology faces some more challenges and there were more problems encountered in applying these processes than initially believed (Pernenkil and Cooney, 2006; Plumb, 2005; Yu, 2008). However, the pharmaceutical industry is behind the times, as continuous manufacturing has been a routine way of manufacturing chemicals, pulp and paper, and metal products (Kleinebudde et al., 2017). Admittedly, it may seem initially that there are too many risks to be overcome in changing a manufacturing process, but it is now evident that the potential cost savings (Pellek and van Arnum, 2008; Schaber et al., 2011), as well as issues like environmental sustainability (Jollifee et al., 2016; De Soete et al., 2013) and better productivity (Gonnissen et al., 2008) can be achieved with continuous manufacturing. In order to reduce many of these apparent problems associated with switching to CM, much scientific work has been conducted in many universities in Europe, U.K and USA, in cooperation with the pharmaceutical industry, and equipment vendors like GEA and Siemens. The first White Paper about continuous manufacturing was published after the 1^st Symposium of Continuous Manufacturing (Badman and Trout, 2015), which involved people from scientific, regulatory and industry bodies. This kind of development has prompted large pharmaceutical companies, like Novartis and Pfizer to invest substantial financial resources for creating CM departments (Pellek and van Arnum, 2008). This is a clear indication that continuous manufacturing is gradually being absorbed into the real- world, including co-operation activities (Galbraith et al., 2019) and even to a complete end-to-end continuous manufacturing plant (Mascia et al., 2013). Subsequently, the 2^nd ISCMP was held in 2016, which promoted also harmonisation goals (Nasr et al., 2017).

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(ICH) (2018) announced the guideline ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products, with explanation concepts like startup/shutdown, state of control, process validation, etc. Due to the global nature of the pharmaceutical business, there are still regulatory and logistical barriers which prevent it from investing in the solutions intended to increase the production capacity (FDA, 2020a) and thus during drug shortages or pandemics like COVID-19 in 2020, the pharmaceutical industry has faced a real challenge of inadequate capacity (FDA 2020a; Lee et al., 2015). Furthermore, changing operations in batch-based production needs not only increased knowledge about processes and equipments, but also investments and support from regulatory bodies (Poechlauer et al., 2012). Attention has also been paid of the need for training courses (Moghtadernejed et al., 2018) to promote the know-how about continuous manufacturing principles.

Real production scale runs have been performed successfully e.g. by MSD and GEA, where a 120 h run of continuous direct compression system achieved a good product quality in a faster production time (Robinson, 2019). There is still a lack of support from regulatory bodies to promote continuous manufacturing, despite the fact that there are widely approved guidelines recommending the adoption of continuous manufacturing.

However, several regulatory agencies, e.g. the FDA, European Medicines Agency (EMA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA), strongly enhance and support these innovations and the adoption of continuous manufacturing for the pharmaceutical industry (Nasr et al., 2017). FDA´s desire to help the pharmaceutical industry change from batch processing to CM achieved a breakthrough in 2016, when a company called Continuus Pharmaceuticals, was awarded a $4.4 million contract from the FDA (Neil, 2017). The reason of the partnership was to find out how to control a line and to make sure there would be product quality maintained throughout a fully integrated end-to-end system.

2.2 A COMPARISON OF CONTINUOUS MANUFACTURING TO BATCH MANUFACTURING

Comparative investigations, also incorporating economical and green pharmaceutical points of view, have been performed extensively (De Soete et al., 2013; Karttunen et al, 2019b; Matsunami et al, 2019; Oka et al., 2017; Schaber et al., 2011). Although the conventional pharmaceutical industry and biopharmaceutical approaches are looking forward to the continuous manufacturing, they still lag far behind the automotive, aerospace and chemical industries (Cameron, 2020).

The continuous manufacturing is a flowing process which runs in the same manufacturing room, in an integrated process line without any interruptions or process hold-time on a 24/7 basis. The utilization of a real-time process automatisation technique together with PAT allows the manufacturer to achieve better process understanding in

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terms of QbD and thus offers a significant improvement in product quality. Instead, in the batch processing, every process step is performed in a different manufacturing room and the quality of the product is analysed after each process step, i.e. it is a non-flexible and time consuming approach. The scaling-up of the batch processes is known to be a challenging process (Anderson, 2001; Faure et al., 2001; Leuenberger, 2001). From the R&D operational point of view, the CM mode does not need different sizes of equipment in the R&D phase e.g. pre-formulation or clinical phases. The batch size is modified by time and/or production speed using the same equipment and thus there is no need for any traditional scaling-up (Mascia et al., 2013). Hence, with this form of manufacturing, the product launch will be faster. The understanding of the process is maintained under control in the early phase of product development; this is the basis of the use of real time release (RTR) methods which reduce significantly the analytical costs. Smaller equipment and space needs will promote a high throughput per unit volume and per unit time.

Shorter supply chains will hasten the response to market shortages and reduce storage/shipping costs for intermediates (Lee et al, 2015). Figure 1 shows the steps involved in batch and continuous mode manufacturing (Bernardes et al., 2015).

A

B

Figure 1. The manufacturing line of a) batch and b) continuous mode (Adapted from Bernardes et al., 2015).

2.2.1 Batch definition in continuous manufacturing processes

The definition of batch according to FDA´s Code of Federal Regulations Title 21 (FDA 2020b) is ´Batch means a specific quantity of a drug or other material that is intended to have

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uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture´. Additionally, a lot is defined as a batch, or a specific identified portion of a batch, that has uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity´. The batch and lot definition and the background are strongly linked in current Good Manufacturing Practice (cGMP), as for each batch and lot, there should be release specifications; the documentation during manufacturing and product control is based on batch and lot mode such that in the case of recall and unexplained discrepancies, the discrepant batch can be determined. There are different ways to determine a batch or a lot in continuous manufacturing e.g.

production time period, production variation (different lots of raw material) or equipment capacity (Chatterjee, 2012). Figure 2 shows the typical features in material traceability between batch and continuous processes (Billups and Singh, 2018).

Figure 2. Typical material traceability in a) batch and b) continuous manufacturing.

(Adapted from Billups and Singh, 2018).

2.3 QUALITY BY DESIGN PRINCIPLES

The background of the QbD concept is to build the quality of the product during planning, development and production via an understanding of the product itself and manufacturing process, (EMA, 2012) rather than checking the quality afterwards, which can take a long time. The traditional trial-and-error development for the optimization of 26

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process and formulation parameters is time consuming and demands many different types of knowledge. The basis of the QbD approach is illustrated in Figure 3.

Figure 3. The idea of the QbD approach.

In the early stage of product development, the Quality Target Product Profile for the product should be defined (FDA, 2007) in order to recognise the possible risks i.e. there should be a risk assesment strategy. The critical quality attributes (CQAs) of the drug product, material and process parameters, need to be identified (Yu, 2008). The QbD concept contains all the principles described in ICH Q8 Pharmaceutical Development;

ICH Q9 Quality Risk Management; and ICH Q10 Pharmaceutical Quality System.

The operation range is called the Design Space (DS), which makes it possible to manufacture a consistent product due to the extensive and comprehensive evaluation of process parameters that have been demonstrated to provide an assurance of quality (Chatzizacharia et al., 2014; Lionberger et al., 2008). The different operational spaces are shown in Figure 4.

QbD

Quality Target Continuous

Improvement

Control Strategy

Critical Material and Process Parameter Attributes Design

Space by DoE

Risk Assessment

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Control space Design space Knowledge space

Figure 4. Different types of operational spaces in QbD concept.

The early stage of QbD often underpins the knowledge space (Facco et al., 2015), especially when the input variables are large i.e min - max limit values. The design space is only a ´sub´ space of the knowledge space where the specification range is more narrow.

The pharmaceutical industry is mainly functioning under the control space, which is based on in-house specifications, with a narrower and more constrained region (Beg et al., 2017).

The usability of creating design space in pharmaceutical tablet formulations (Charoo et al., 2012; Chavez et al., 2015; Igne et al., 2012; Kimber et al., 2013) and unit processes have been studied (Bano et al., 2019; Kapsi et al., 2012; Nesarikar et al., 2012; Souihi et al., 2013;

Sun et al, 2019). There are still only a few studies investigating a continuous manufacturing line (Escotet-Espinoza et al., 2018; Gorringe et al., 2017; Liu et al., 2017), which is rather suprising because the design space approach is the basis of QbD and real time release (RTR) in the CM concept (Yu, 2008). RTR allows the final product to leave to the patient on the basis of the acceptable results, which are obtained by a control strategy system during the production with the help of process analytical technology (PAT) (Cameron, 2020; Ooi et al., 2013; Yu et al., 2014).

There is considerable interest in the pharmaceutical industry to change from off-line testing to real-time quality testing. For example, the industrial application, SIMATIC SIPAT, which was launched by Siemens, all the PAT tools are integrated into one platform (Siemens, 2014). However only a small portion of RTR is studied in CM processes e.g. the use of near-infrared spectroscopic (NIRS) mode, which is used for the prediction of the API concentration (Colón et al., 2017;Hetrick et al., 2017), dissolution (Pawar et al., 2016), blending, spray drying, roller compaction, twin-screw granulation and compression (Fonteyne et al., 2015).

By adopting QbD, it is possible to create a control strategy in the CM line during development (Nunes de Barros and Singh, 2017; Singh et al., 2012;). In this kind of approach, a feedback system follows a parametric value in a process and reacts to any change in the parametric value being followed. The feedforward system measures important disturbance variables and enables corrective action to be initiated before they

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upset the process. This concept ensures that the product quality conforms to the predetermined CoA also in the case of variations in the process e.g. raw material variations (Singh et al., 2015)

2.4 CONTINUOUS MANUFACTURING OF TABLETS

The most common way of administration of medicine is the oral route with a solid dosage form (tablet formulation). For example, the three most widely prescribed medicines in U.S market in 2019 were tablet formulations (Statista, 2019). The importance of tablet formulation technology has increased considerably. One reason is the huge market of generic products and their cost effective production (Ierapetritou et al., 2016; Robinson, 2019). However, the manufacturers are under social and economic pressure to lower the costs of production and increase effectiveness to achieve better competitiveness in global markets (Barton and Emanuel, 2005). Thus the emphasis is moving toward to solid oral dosages, tablet formulations, from batch to continuous manufacturing and its technology by applying methods like direct compression, wet granulation and dry granulation (Vervaet and Remon, 2005). One option is hot-melt extrusion (HME), if the above- mentioned technologies are not possible (Maniruzzaman et al., 2015). The FDA defines a continuous process as ´a process consisting of at least two connected Unit Operations to which material is continuously fed and from which material (product) is continuously removed´.

According to the FDA, conventional batch processes consist of a sequence of individual process steps (FDA, 2019). The main processing steps include feeding, blending and tableting. The additional unit processes e.g. the dry granulation consists of roller compaction with milling, while the wet granulation consists of drying system with granule milling. Direct compaction does not have any granulation process prior to tableting. The main routes of a continuous manufacturing process (Rogers et al., 2013) are shown in Figure 5.

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Figure 5. The main routes of the continuous manufacturing process (Adapted from Rogers et al., 2013).

2.4.1 Continuous direct compression (CDC) process

The most simple way of producing a tablet formulation is direct compression manufacturing, where the blended materials are fed directly into the tablet press (Galbraith et al., 2019; Ervasti et al., 2015). High standards have been set for the materials used in direct compression (Jivraj et al., 2000; JRS, 2016), as the common challenges encountered are segregation of the material (Lakio et al., 2010; Lakio et al., 2017; Mateo- Ortiz et al., 2014), its cohesiveness and poor flowing properties (Allenspach et al., 2020;

Mehrotra et al., 2009). However, the studied CDC line was shown to be able to handle challenging materials and different formulations e.g. low-dose formulations, which make CDC lines a very attractive alternative to batch processing (Ervasti et al., 2020; Galbraith et al., 2019; Lakio et al., 2017; Van Snick et al., 2017), even for a formulation not normally deemed suitable for direct compression (DC) (Palmer et al., 2020). One more significant aspect is that the CDC process is more tolerant of disturbances during manufacturing.

However, Karttunen et al., 2020 showed that the production rate and the particle size of APIs have an effect on the capacity of the process to smoothen out disturbances. The larger particle size and increased production rate may be limiting parameters in achieving a product that fulfills the quality requirements. A schematic illustration of CDC line (Singh et al., 2013) is shown in Figure 6. As seen in Figure 6, the unit processes are installed in top-down configurations, which is the most common way to build the CDC

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line. The other way is a horizontal set-up with conveyers (Promis Lab, University of Eastern Finland, School of Pharmacy, Kuopio, Finland).

Figure 6. Schematic illustration of continuous direct compressible manufacturing line flow sheet (Adapted from Singh et al., 2013).

An understanding of the material throughput time and especially residence time distribution (RTD) is essential in understanding the details of the CM process, and thus has been widely studied in CM powder mixing processes (Gao et al., 2011; Gao et al., 2012; Marikh et al., 2008; Pernenkil and Cooney, 2006; Portillo et al., 2008; Ziegler and Aguilar., 2003). RTD is a typical parameter being evaluated in the CM processes; it is the probability time distribution of the material component travelling through the process, and is based on the tracebility of the materials, the batch definition and development of a control strategy (Billups and Singh, 2018; Engisch and Muzzio, 2016). RTD is described as a critical tool for quality assurance and a prerequisite for RTR of the batch (FDA, 2019).

There are many different strategies which have been adopted to determine the RTD in powder formulation in CM processes e.g. by studying different trace materials (Dülle et al., 2019; Escotet-Espinoza et al., 2019; Karttunen et al., 2019a; Kruisz et al. 2017; Mangal and Kleinebudde, 2017) or material variations utilization (Gao et al., 2011; Martinez et al., 2018). Vanarase et al., (2013) has demonstrated that certain material properties such as bulk density, and process parameters e.g. the mixer impeller speed, have an effect on RTD.

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2.4.2 Continuous wet granulation process

Granulation is the unit process, where the desired feature is an enlargement of the particles to improve their properties like powder flow, compressibility, uniformity of content and dissolution, and a reduction of dusting and segregation (Parikh, 2005). This is an alternative method if the API or excipients are not suitable for a direct compression process (Meena et al., 2017). Currently, the batch based wet granulation dominates the pharmaceutical tablet production, but efforts are underway to switch towards continuous wet granulation processes (Bandari et al., 2020; Beer et al., 2014; Li et al., 2015; Pauli et al., 2018; Schmidt et al., 2018; Singh et al., 2014; Zomer et al., 2018). The principle of high- shear continuous granulation is the same as in the batch production (Meng et al., 2019).

However, the alternative most often commonly used method in wet granulation, twin- screw granulation (TSG), is typical for CM processes, and commonly integrated with a continuous fluid-bed drying system (Pauli et al., 2018; Silva et al., 2017). The usability of the TSG process towards industrial scale processes has been widely studied (Menth et al., 2020; Osorio et al., 2017; Pawar et al., 2020; Vercruysse et al., 2015). There are commercial applications for pharmaceutical use of TSG e.g. GEA ConsiGma® GC Lines, which involve integrated continuous wet granulation, fluid bed drying and tablet compression into one efficient continuous production system.

The mechanism of granule growth in the TSG processes can be divided into four steps:

nucleation, consolidation, coalescence and breakage (Dhenge et al., 2012). These steps occur in a successive way due to the setup of the equipment; its function is based on the length of the screw, unlike in high-shear or fluid-bed granulation where the steps occur simultaneously (Iveson et.al, 2001). As stated, it is essential to have a good knowledge of all process parameters and their impact on the final product. The granule growth can be affected by varying the process parameters like the powder feed rate, L/S ratio, binder viscosity of granulation liquid and liquid type (Seem et al., 2015). Another typical feature of CM processes is the mean residence time. The effect of process parameters on the mean residence time in the wet granulation process has been studied systematically (Dhenge et al., 2010, 2011, 2012); increasing the flow rate has been shown to decrease the mean residence time. The opposite features occur with low feed rates causing so-called ´back- mixing´.

It is also worth noting that green pharmaceutical efforts have increased in the 2010s.

The transition of industrial scale batch based wet granulation to continuous wet granulation has been shown to improve environmental sustainability and reduce carbon footprints significantly (De Soete et al., 2013). The schematic illustration of a continuous wet granulation process (Bandari et al., 2020) is shown in Figure 7.

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Figure 7. Schematic illustration of continuous wet granulation process (Adapted from Bandari et al., 2020).

2.4.3 Hot-melt extrusion process

The hot-melt extrusion (HME) is a process with an abundance of opportunities for pharmaceutical process applications e.g. continuous process, 3D printing, manufacturing protein products, controlled-released taste masking and solubility enhancement of poorly soluble API´s (Maniruzzaman, 2019). In fact, the use of this technology in pharmaceutical applications has significantly increased since the 1980s (Crowley et al., 2008). The process is based on a technology where the API and polymer are melted together into a solid dispersion, the molten mass is cooled and milled into granules or cut into pellets, and subsequently compressed into tablets (Maniruzzaman, 2015). Critical process parameters e.g. feed rate, screw speed, melting and cooling temperature have an impact on the final product and are easily monitored (Baronsky-Probst et al., 2016). Equally, material attributes e.g. polymer type and API-polymer solubility and miscibility may affect the properties of the final product (Lang et al., 2014). From the continuous process point of view, the scaling-up can be easily implemented by increasing either the feed rate or running the process for a longer time, increasing screw speed or its diameter (Maniruzzaman and Nochodchi, 2017). Thus, it is evident that HME represents an attractive choice for an industrial scale continuous process. The schematic illustration of a continuous HME process and its downstream processes is shown in Figure 8.

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Figure 8. An example of a continuous HME extrusion process and its downstream processes (Adapted from Markl et al., 2013).

2.4.4 Continuous dry granulation process

Dry granulation is inherently a continuous granulation method in which there is no liquid utilized; it is a suitable method for heat and moisture sensitive materials (Kleinebudde, 2004). Therefore, the possibility to implement this cost reducing method into the continuous line has been noted (Vervaet and Remon, 2005). Dry granulation is an alternative method if the materials make a poor contact with binders or if they are too cohesive to form granules. However, the selection of binder type and concentration of binders have an effect on tablet quality in the dry granulation method e.g. the dissolution profile (Inghelbrecht and Remon, 1998; Mangal et al., 2016), tensile strength of the tablets (Herting and Kleinebudde, 2008, Santl et al, 2011; Sun and Kleinebudde, 2016) and disintegration time, friability and granule size (Arndt and Kleinebudde, 2018). It has been found that the fine grades of binders exert an effect on granule size and furthermore the disintegration time is dependent on the viscosity of binders. In addition, the starting material’s properties e.g. particle size, material hardening and addition of lubricant are known to have an effect on tablet quality attributes (Grote and Kleinebudde, 2018; Mosig and Kleinebudde, 2015).

From a tableting perspective, the disadvantage of the dry granulation is the loss of tablet strength after tableting compared to direct compression of the blend (Herting and Kleinebudde, 2008; Mosig and Kleinebudde, 2015; Santl et al, 2011; Sun, 2008; Sun and Himmelspach, 2006; Sun and Kleinebudde, 2016). Sun and Himmelspach (2006) produced 34

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carefully evidence of this phenomenon, an enlargement of granules reduced the compactability. Despite the major role of lubrication noted in that investigation, there is evidence of the impact of granule size enlargement in dry granulation processes (Herting and Kleinebudde, 2008; Patel et al, 2011; Sun and Kleinebudde, 2016; Wu and Sun, 2007);

the size enlargement is highly material dependent, for example having an impact on density or brittleness (Mosig and Kleinebudde, 2014). Sun and Kleinebudde (2016) highlighted the two main features in the dry granulation process affecting the tablets:

bonding area and bonding strength. In summary, the porosity of the granules exerts an impact on the tensile strength of the tablets (Nordström and Alderborn, 2015). All these phenomena are summarised in Figure 9.

Figure 9. Factors in the dry granulation process, which have an impact on properties of the final tablets (Adapted from Sun and Kleinebudde, 2016).

The roller compaction equipment consists of three main units: feeding unit, compaction unit and granulation unit (Mangal and Kleinebudde, 2018). The blended mass is fed from the feeding unit by the ´top-down´ principle into the compaction unit, and subsequently the mass is compacted in between two high-pressure rolls producing ribbons, which are milled to desired granule size in the milling unit. Process parameters have an impact on both the properties of the granules and tablets. With in-line monitoring system, Wilms and Kleinebudde (2020) demonstrated how the compaction force could influence granule hardness. A schematic illustration of roller compaction (Saintyco, 2020) is shown in Figure 10.

mixing tableting

dry granulation

roll compaction

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Figure 10. A schematic illustration of dry granulation (Adapted from Saintyco, 2020).

2.5 THE ROLE OF THE UNIT PROCESSES IN THE CONTINUOUS LINE

The continuous manufacturing line consists of different unit operations. These may contain numerous processing equipments. The most common processing equipments are feeders and blenders. Usually the line starts with feeders, especially in dynamic weighing which is an application of a Loss-In-Weight feeding (LIW) system. The principle of the LIW operation is that the individual feed rates of each material determine the formulation of the final product, which can be from as little as grams per second up to tons per hour (Hopkins, 2006). There are different types of feeders: screw feeders, rotating cell feeders and vibratory cell feeders. The operation of feeders has been systematically studied by Engisch and Muzzio (2012; 2015). The role of LIW is important, as it measures and dispenses the material unit per time to the downstream processing (Yang and Evans, 2007).

The identification of individual feeding characteristics (flow properties) of each material is the basis on which one creates the feeding strategy (Engisch and Muzzio, 2015;

Wang et al., 2017). The feeding strategy could help to identify possible failures in the system, e.g. these could affect steady state performance and variabilities in mass flow.

Hanson (2018) demonstrated the potential of a contol loop system installed in the LIW system to enhance the accuracy and precision of material flow. Small quantity compounds (mg/s) bring their own challenge to the feeding operations, and need careful attention (Besenhard et al., 2016). A schematic illustration of a screw feeder (Hopkins, 2006) is shown in Figure 11.

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Figure 11. A schematic illustration of screw feeder (Adapted from Hopkins, 2006).

There are two modes of feeding: volumetric and gravimetric feeding. In principle, in the volumetric mode, the feeding of the material is constant in ideal cases. The screws rotate at a constant speed and there is no feedback control system, and therefore this will face accuracy limitations e.g. variations depending on the material bulk density and the fill level in the feeder hopper. The principle of the gravimetric (LIW) mode is dispensing the material at a constant rate, in spite of any variations in the material. This measures the loss of material and thus adjusts the speed of the screw. This mode has to be interrupted in cases of refill operations while the volumetric mode takes place.

Continuous blending is a key process (Pernenkil and Cooney, 2006), where powder blends achieve a homogenous state (Berthiaux et al., 2008), even with those materials having a tendency to segregate (Oka et al., 2017). The mixing parameters (blade configuration and impeller rotational speed) can affect the mixing performance (Osorio and Muzzio, 2016), although the predominant factor was shown to be the impeller rotational speed (Vanarase et al., 2013). The mixing behaviour and performance have been widely studied (Berthiaux et al., 2008; Marikh et al., 2005, 2008; Portillo et al., 2008, 2009; Vanarase et al., 2013; Vanarase and Muzzio, 2011). In continuous blending, radial and axial mixing of the material are co-occurring phenomena, and are highly dependent on material properties (density, particle size and cohesiveness) and operational conditions (Gao et al., 2012). Oka et al, 2016 summarized that there is less strain imposed on the material with continuous blending when compared to batch blending. There are two main differences found: the material spends a shorter time in the continuous line and there is much less total amount of material at every time point. The schematic illustration of a blending unit process is shown in Figure 12 (Oka and Muzzio, 2013).

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Figure 12. The blender unit process of the continuous manufacturing line (Adapted from Oka and Muzzio, 2013).

Tableting itself is a continuous process where mass is flowing from the hopper to the tablet press, with this being finally followed by the compression into tablets (Nakamura et al., 2011). It can be integrated into the continuous line in a top-down configuration, where the mass is flowing gravimetrically in a top-to-down mode (Figure 13a). The other integrated way utilizes a horizontal configuration with conveyers (Figure 13b).

Figure 13. The different configurations of the same continuous manufacturing plant a) top-down b) horizontal (Promis Lab, University of Eastern Finland, School of Pharmacy, Kuopio, Finland).

a b

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An equally important factor as the powder flow, is the compaction which depends on the material’s physicochemical (e.g. bulk density, particle size, cohesiveness) and mechanical properties (e.g. hardness, elasticity, plasticity, brittleness) (Zhou and Qiu, 2010). Thus, the flow-stream during the continuous process is an important factor in determining the quality of the end-product. Tye et al., 2005 demonstrated that tabletability and compressibility of some studied materials were dependent on tableting speed and thus attention should be paid to this parameter in order to select the appropriate continuous process strategy, paying special attention to the mass flow rate (Ervasti et al., 2015; Karttunen et al., 2019b).

In a CM process, tableting is a critical unit process even though the flow properties and the mechanical properties of the material are good (Hiestand, 1997; Zhou, 2010). The tableting speed needs to be related to the total flow rate in the CM process, and thus the selected formulation should be appropriate to the tableting strategy being applied with suitable materials (Sun, 2010). Tableting speed has been shown to affect to the quality of the tablets (compactibility, compressibility and tabletability) e.g. in scaling-up processes (Tye et al., 2005). This formulation aspect needs to be taken into account e.g. with paracetamol tablets, when the tableting speed was increased, this tended to increase the capping tendency, due to the elastic behavior of paracetamol during compression (Garr and Rubinstein, 1991; Wu et al., 2008). On the contrary, if there was an increasing moisture content in the paracetamol formulation, this enhanced the compactability, due to the formation of interparticle bonds (Garr and Rubinstein, 1992). However, the presence of lubricant has been shown to reduce die-wall friction, which has a decreasing effect on the capping tendency (Wu et al., 2008). A coating unit could also be integrated into the CM lines, but usually a semi-batch application is preferred (Barimani et al., 2018).

2.6 IMPACT OF LUBRICATION ON TABLET QUALITY

Successful compaction of tablet is based on the development of a suitable formulation which contains different materials i.e. drug substance, fillers, binders and lubricants (Rowe et al., 2003). Lubrication, especially with magnesium stearate, is one of the most critical stages in tableting (Li and Wu, 2014) and thus it has been widely studied (Bossert and Stains, 1980; Johansson, 1985; Paul and Sun, 2017; Wang et al., 2010). Magnesium stearate (MgSt) is the most commonly used lubricant in tablet formulation with concentrations ranging from 0.25% to 5.0% (Rowe et al., 2006), although it is preferred to use the lowest concentration due to its hydrophobic nature which can retard the dissolution of tablets. MgSt forms a layer on a surface of the particle and reduces the friction and cohesive forces between particles and the die wall, thus improving compressibility. The mechanism used in tablet formulation, is called mechanofusion (dry coating) or boundary lubrication, where MgSt has a structured contact on the host particle (Koskela et al., 2018). This phenomenon has been studied and it has been concluded that it is difficult to measure the distribution of MgSt (Lakio et al., 2013) from the surface of

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the material. It is evident that MgSt will influence powder flowability, compactability and dissolution (Llusa et al., 2010; Pingali et al., 2011). The disadvantage of MgSt is its decompactabality and increasing dissolution time mainly due to an over-lubrication phenomenon (Ketterhagen, 2015; Mosig and Kleinebudde, 2014, 2015; Narang et al., 2010;

Sun and Kleinebudde, 2016). This has been shown to be formulation (Koskela et al., 2018) and process dependent. The effect of lubrication on different integrated process units in a continuous manufacturing line has been studied to some extent in blenders (Oka et al., 2016), and in roller compaction (Akseli et al., 2011; Miguélez-Morán et al., 2008; Yu et al., 2013).

The lubrication process could be determined by measuring the coefficient of friction occurring in the ejection phenomenon during tableting. The equation of coefficient of friction is (1)

F

II

= μF

┴

(1)

where FII, μ, and F┴ are the force of friction proportional to the external load (F┴), the coefficient of friction, and the normal force applied, respectively (Li and Wu, 2014). The ejection force is needed to push the tablet out from the die in the tablet press (Wang et al, 2010). A low friction force is a desired feature, since it is desirable to keep any fragmentation and capping as low as possible (Nordström and Alderborn, 2015).

The mixing time of MgSt has been widely studied. It has been shown that the mixing parameters have a critical influence on productivity (Bolhuis et al., 1975; Ragnarsson et al., 1979; Shah and Mlodozenie, 1977). The mixing time of MgSt is a critical parameter exerting an effect on the tablets’ crushing strengths especially in scaling-up processes (Virtanen et al, 2008). A longer mixing time also increases the brittleness of the tablet and reduces tablet hardness (Bolhuis et al., 1987) which can be a quality problem in the final product. The mode of adding lubricant has a significant role e.g. in dry granulation processes (Mosig and Kleinebudde, 2014). The most typical way to add MgSt is by mixing it before tableting, but it has been shown that an external addition method could lower the amount of MgSt needed in the formulation (Yamamura et al., 2009). It has been postulated that a careful choice of the formulation ingredients e.g. the type disintegrant, could reduce the hydrophobic effect of MgSt (Bolhuis et al, 1981). The schematic illustration of MgSt’s function in flowability and compactability is shown in Figure 14 (Koskela et al., 2018).

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Figure 14. The function of MgSt in flowability and compactability (Adapted from Koskela et al., 2018).

In the continuous manufacturing field, the effect of lubrication on the whole CM line has not been evaluated to any major extent. In a separate unit operation, Oka et al., 2016 highlighted that the risk of potential over-lubrication in continuous mixing is very low as compared to the situation in the batch mode and there is no need for a two-stage addition of MgSt. This is because the material spends a shorter time in the blender, and the amount of material in the system is lower. Furthermore, the mixing order strategy of MgSt has been shown to influence the powder flow properties, weight variability, tablet weight and dissolution in the CM line (Pingali et al., 2011).

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3 AIMS OF THE STUDY

The general aims of this study were to comprehensively demonstrate the effect of formulation and process parameters on product quality, using both short and long run continuous manufacturing process lines with different configurations (top-down and horizontal set-up). The more specific aims of the study were as follows:

I To devise a robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication- based parameters influencing the continuous direct compression tableting of high dose tablets.

II To examine how both intentional and unintentional disturbances could affect the critical quality attributes (CQA's) of the final product and to create a deviation document, which would reveal the changes during the runs.

III To demonstrate the conversion of high-shear wet granulation (HSWG) batch process to a continuous roller compaction (RC) process without any significant formulation changes.

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4 LUBRICANT BASED DETERMINATION OF DESIGN SPACE FOR CONTINUOUSLY MANUFACTURED HIGH DOSE

PARACETAMOL TABLETS

¹

ABSTRACT

The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication- based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental design was used to generate a structured study plan which involved 19 runs. The formulation variables studied were the type of lubricant (magnesium stearate or stearic acid) and its concentration (0.5, 1.0 and 1.5%). Process variables were total production feed rate (5, 10.5 and 16 kg/h), mixer speed rpm (500, 850 and 1200 rpm), and mixer inlet port for lubricant (A or B). The continuous direct compression tableting line consisted of loss-in-weight feeders, a continuous mixer and a tablet press. The Quality Target Product Profile (QTPP) was defined for the final product, as the flowability of powder blends (2.5 s), tablet strength (147 N), dissolution in 2.5 min (90%) and ejection force (425 N). A design space was identified which fulfilled all the requirements of QTPP. The type and concentration of lubricant exerted the greatest influence on the design space. For example, stearic acid increased the tablet strength.

Interestingly, the studied process parameters had only a very minor effect on the quality of the final product and the design space. It is concluded that the continuous direct compression tableting process itself is insensitive and can cope with changes in lubrication, whereas formulation parameters exert a major influence on the end product quality.

____________________________

1 Adapted with permission of Elsevier from: Taipale-Kovalainen K, Karttunen A-P, Ketolainen J, Korhonen O. Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets. European Journal of Pharmaceutical Sciences 115: 1-10,2018

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4.1 INTRODUCTION

Batch processing is widely used by the pharmaceutical industry. Most marketing authorizations (MA) for conventional pharmaceuticals are based on batch processing.

However, there is a consensus that continuous manufacturing is accepted and supported by regulatory agencies (Nasr et al., 2017). Still there is a need for harmonization of guidelines to promote the adoption of a continuous manufacturing. ICH Q8 (R2) guidance highlights an opportunity for implementation of continuous manufacturing processes into commercial applications. The need to change manufacturing from batch to continuous manufacturing has faced many challenges (Badman and Trout, 2015, Byrn et al., 2015) with problems encountered in the lack of knowledge, regulatory barriers and investments. The keypoint is to justify how the quality is built into the product and evaluated, how the material traceability is assured, and how the batch is defined (Nasr et al., 2017). Furthermore, the real-time monitoring gives the opportunity for manufacturers to use performance-based approach to justify the quality of the product and to use the real-time release testing. In addition, a greater assurance of product quality can be achieved during continuous manufacturing process by collecting product information in- line with the aid of process analytical technology (PAT) and adopting the concept of parametric release (EU GMP Annex 17, 2001).

The continuous manufacturing process emphasizes the importance of design of an effective and efficient manufacturing process based on an in-depth understanding of how formulation and process factors impact on the end product quality. Furthermore, this can help to define the design space, which is a range of process (and formulation) parameters that have been demonstrated to provide assurance of the quality of the end product. In addition, the ICH Q9 guidance recommends that product quality should be maintained throughout the product lifecycle. For example, manufacturing process parameters, which are important to the quality of the drug product should remain inside the design space.

Changing process parameters within the limits of the design space, does not require regulatory post-approval changes. The design space approach has been successfully exploited for manufacturing of a liposome based inhalable dry vaccine formulation (Ingvarsson et al., 2013), formulation optimization with different API and filler PSDs (Chavez et al., 2015) and flexibility in releasing the product in real time, i.e. various combinations of process parameters (mixer time and speed) could be selected (Charoo et al., 2012).

Paracetamol has poor compressible properties. All direct compressible grades in the market are combinations of paracetamol with binders e.g. PVP. Martino et al. (1996) has developed a pure direct compressible paracetamol grade. They also found out that different polymorphic forms of paracetamol (form I and form II) have different compression and cohesive behavior. Paracetamol DC grades are suitable for high dose formulations due to the need of small amount of excipients. Still, Li et al. (2017) has reported several problems during DC manufacturing i.e. capping, sticking and content 46

Impact of formulation and process design on tablet quality in continuous manufacturing

KRISTA TAIPALE-KOVALAINEN

Impact of formulation and process design on tablet quality in continuous manufacturing

Dissertations in Health Sciences

IMPACT OF FORMULATION AND PROCESS DESIGN ON TABLET QUALITY IN

CONTINUOUS MANUFACTURING

Krista Taipale-Kovalainen

IMPACT OF FORMULATION AND PROCESS DESIGN ON TABLET QUALITY IN

CONTINUOUS MANUFACTURING

ABSTRACT

TIIVISTELMÄ

ACKNOWLEDGEMENTS

LIST OF ORIGINAL PUBLICATIONS

III

CONTENTS

ABBREVIATIONS

1 INTRODUCTION

2 REVIEW OF THE LITERATURE

2.1 IMPLEMENTATION WORK TOWARDS CONTINUOUS MANUFACTURING IN THE PHARMACEUTICAL INDUSTRY

2.2 A COMPARISON OF CONTINUOUS MANUFACTURING TO BATCH MANUFACTURING

2.3 QUALITY BY DESIGN PRINCIPLES

QbD

2.4 CONTINUOUS MANUFACTURING OF TABLETS

2.5 THE ROLE OF THE UNIT PROCESSES IN THE CONTINUOUS LINE

2.6 IMPACT OF LUBRICATION ON TABLET QUALITY

F

= μF

(1)

3 AIMS OF THE STUDY

4 LUBRICANT BASED DETERMINATION OF DESIGN SPACE FOR CONTINUOUSLY MANUFACTURED HIGH DOSE

PARACETAMOL TABLETS

4.1 INTRODUCTION